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One-Minute Telegram Archive

Last updated: September 13, 2021

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This article contains a collection of content written during 2021 for the One-Minute Telegram, a biweekly newsletter that presents the newest medical research condensed into just one minute of reading. This newsletter is designed for all of our colleagues who want to stay current on the latest medical literature without having to comb through and dissect medical studies themselves. It is peer-reviewed by our team of physician editors and integrated into the Amboss library. Even after a long night shift or a busy day on the wards, it should go down easy. Subscribe by clicking on the image or via the link in “Tips and Links” below.

For the One-Minute Telegram, AMBOSS has partnered with QxMD to bring you seamless access to the medical literature that we review. Read by QxMD can serve as your own personalized medical and scientific journal, allowing you to keep up with the latest new research that impacts your practice in minutes per day. Read is integrated with full-text holdings at thousands of institutions around the globe, including Harvard, Yale, and the Massachusetts General Hospital. Read by QxMD is available for all mobile devices (iOS and Android) and accessible via all web browsers. See “Tips and links” below to try it out.

See also our One-Minute Telegram Archive 2020

COVID-19: Does therapeutic anticoagulation improve outcomes in non-critically ill patients?

One-Minute Telegram 34-2021-1/3 - COVID-19 can trigger a potentially fatal hypercoagulable state, the treatment of which has been the subject of research throughout the pandemic. [1]

In this open-label international trial, 2219 patients hospitalized with non-critical COVID-19 were randomized to receive either therapeutic anticoagulation (TA) with heparin for up to 14 days or until recovery (n = 1171) or thromboprophylaxis (TP) according to the local standards of practice (n = 1048).

The primary outcome was the number of days patients were without cardiovascular or respiratory organ support at 21 days.

The trial was stopped early after an initial analysis revealed that patients in the TA group had a 98.6% probability of more organ support-free days than those in the TP group (median adjusted OR, 1.27; 95% credible interval, 1.03–1.58).

Survival until hospital discharge was high in both the TA and the TP group at 92.7% and 91.8%, respectively (median adjusted OR, 1.21; 0.87–1.68).

Major bleeding occurred more frequently in the TA group (1.9%) than in the TP group (0.9%).

Limitations include the open-label design, heterogeneous anticoagulation protocols across study centers, the significantly lower adherence in the therapeutic-dose anticoagulation group (88.3% vs. 98.3%), and the omission of full criteria for exclusion from the trial.

The take‑home message?

This study on non-critically ill patients hospitalized with COVID-19 showed that those who received empiric therapeutic anticoagulation with heparin had a higher probability of survival and reduced need for organ support when compared to those receiving pharmacologic thromboprophylaxis. However, because this study has several limitations and treatment effects were small, the superiority of therapeutic anticoagulation should be taken with a grain of salt.

  • Title of study: Therapeutic anticoagulation with heparin in noncritically ill patients with COVID-19 [2]
  • Authors: The ATTACC, ACTIV-4a, and REMAP-CAP Investigators
  • Journal: NEJM
  • AMBOSS Links: COVID-19

Can a monoclonal antibody prevent malaria?

One-Minute Telegram 34-2021-2/3 - Despite international efforts to limit the spread of malaria, incidences are rising, with the number of deaths approaching half a million per year. Recent developments in vaccine research have shown some promise but efficacy is still too low to sufficiently reduce infection rates. [3][4]

This open-label phase 1 clinical trial assessed the safety, pharmacokinetics, and efficacy of CIS43LS, a monoclonal antibody directed against a circumsporozoite protein of P. falciparum.

In Part A of the study, 21 healthy adults between 18 and 50 years of age without previous malaria infection or vaccination received a subcutaneous or intravenous dose of CIS43LS (5–40 mg/kg of body weight).

No infusion-related reactions, dose-limiting toxic effects, or serious adverse events were observed. CIS43LS was shown to have a half-life of 56 days.

In Part B, 9 participants who had received CIS43LS and 6 controls were exposed to controlled human malaria infection and monitored for 21 days with PCR-testing.

No participants who received CIS43LS developed parasitemia through day 21. Five of the six control participants did develop parasitemia.

Limitations of this study include the small sample size and that subcutaneous CIS43LS could not be assessed in the efficacy analysis due to COVID-19-related delays.

The take‑home message?

In this phase 1 study, administration of a monoclonal antibody (CIS43LS) against P. falciparum did not raise any safety concerns. Furthermore, no patients who received the drug intravenously showed parasitemia after controlled exposure to P. falciparum. Additional studies are necessary to establish the protective serum concentration and evaluate the efficacy of subcutaneous administration. Nonetheless, monoclonal antibodies appear to be a promising alternative to conventional chemoprophylaxis for malaria.

How reliably can microRNAs detect early-stage gastric cancer?

One-Minute Telegram 34-2021-3/3 - MicroRNAs (miRNAs) are non-coding RNAs involved in gene regulation and tumorigenesis. While their use as biomarkers of cancer has been discussed in the past, the diversity of tumors has limited the diagnostic utility of single miRNAs. To overcome these limitations, this study combined multiple miRNAs to identify a novel signature of gastric cancer (GC). [6][7]

GC tissues were analyzed to identify candidates for the novel signature, which were subsequently tested on tumoral and normal tissue for validation and determination of a 3-miRNA signature. The utility of the miRNA signature was tested retrospectively on the serum of patients with known GC or with a negative endoscopy.

The last phase of the study consisted of a prospective performance evaluation in serum specimens collected from 176 patients with GC and 173 healthy matched control participants.

Results showed that the 3-miRNA signature had a sensitivity of 71.6% and specificity of 87.9% in discriminating between healthy participants and those with GC (area under the curve [AUC] 0.86; 95% CI, 0.83–0.90). The results furthermore showed a sensitivity of 72% and specificity of 88% (AUC 0.85) in discriminating between healthy participants and those with stage 1 GC, outperforming the established biomarkers CEA (AUC 0.65) and CA-19-9 (AUC 0.67).

Limitations include the relatively small study sample and that all samples came from a Japanese population, potentially limiting the generalizability of the results to other populations.

The take‑home message?

In this study, a newly developed serum signature of three miRNAs had high sensitivity and specificity in discriminating between healthy participants and those with stage 1 GC, outperforming the established biomarkers CEA and CA-19-9. While these results look promising, larger real-world screening studies are necessary to assess the effectiveness and efficiency of combined miRNAs in cancer screening.

  • Title of study: Assessment of the diagnostic efficiency of a liquid biopsy assay for early detection of gastric cancer [8]
  • Authors: Izumi D et al.
  • Journal: JAMA Network Open

Does ketamine provide faster sedation in severely agitated patients than haloperidol/diazepam?

One-Minute Telegram 33-2021-1/3 - Severely agitated patients in the emergency department (ED) can pose a risk to themselves and staff, often requiring sedation to permit diagnosis and treatment. However, evidence is lacking as to which medication is most effective in securing rapid and safe sedation. [9]

Ketamine use is well established in preclinical and ED settings, e.g. during rapid sequence induction and procedural sedation, as it provides analgesia and sedation without significant impact on hemodynamics or respiration. Several small studies have suggested a role for ketamine in managing acute agitation in the emergency department. [10][11][12]

In this single-center blinded randomized controlled trial, 81 patients aged 19 to 60 years who showed severe psychomotor agitation (Richmond Agitation Score (RASS) ≥ +3) in the ED were randomized to receive an intramuscular (IM) injection of either 5 mg/kg ketamine or 5 mg midazolam plus 5 mg haloperidol.

Compared to the patients in the midazolam plus haloperidol group, patients who received ketamine showed a shorter median time to sedation (i.e., RASS ≤ -1 in 5.8 minutes vs. 14.7 minutes; 95% CI, 3.0–14.5). Serious adverse effects within 72 hours and the need for rescue medication did not differ significantly between the groups.

Limitations include the exclusion of patients > 60 years of age and the relatively small study sample-size, which limited the study’s power to detect differences in adverse effects.

The take‑home message?

This relatively small randomized trial demonstrated that IM ketamine in the ED leads to faster sedation in patients with severe agitation than the combination of midazolam plus haloperidol. However, ketamine’s comparative safety profile requires more extensive studies with participants of all age groups.

How sensitive is point-of-care ultrasound in the diagnosis of pneumothorax?

One-Minute Telegram 33-2021-2/3 - Pneumothorax (PTx) is a potentially life-threatening condition frequently seen in the emergency department (ED). While CT of the chest is the gold standard for diagnosis, point-of-care ultrasound (POCUS) is more readily available and may enable faster diagnosis and therapy, with the added benefit of not having to transport the patient to radiology. [14]

This trial included 200 patients who had been admitted to an ED with blunt or penetrating chest trauma, mostly due to motor vehicle accidents. All patients first received POCUS and then a CT of the chest.

CT established PTx in 47 of the total 400 hemithoraces examined. Ultrasound diagnosis identified 45 of these, thus showing a sensitivity of 95.74%. The two pneumothoraces missed by ultrasound were both small. There were no false-positive results in ultrasound.

Limitations include that ultrasound was performed by senior emergency physicians with more than four years of experience in eFAST Scan. Accordingly, sensitivity and specificity are likely to be lower in physicians with less expertise. Also, approximately 80% of the patients were male, limiting the study’s generalizability. [15]

The take-home message?

Compared to CT chest, POCUS showed a sensitivity of 95.74% and specificity of 100% in the ED for the diagnosis of traumatic pneumothorax after blunt or penetrating chest trauma, contributing to growing evidence that ultrasound (in the hands of an experienced examiner) can be a fast and reliable screening tool for pneumothorax. [16]

Overcoming vaccine hesitancy: Does offering the J&J COVID-19 vaccine in the ED lower the threshold to take the shot?

One-Minute Telegram 33-2021-3/3 - The COVID-19 pandemic has dramatically illustrated how distribution and socioeconomic factors can affect the immunization of entire populations and lead to discrepancies in vaccination rates within those populations.

Johnson & Johnson's single-dose vector-based COVID-19 vaccine, Janssen, may help increase the number of fully immunized individuals by eliminating the need for a second dose.

In this trial, patients attending an emergency department (ED) in Middlesex County, NJ, were offered the Janssen vaccine. The sociodemographic data of the first 365 persons to accept the offer was then compared to that of the general vaccinated population in the county and in the state.

Demographic data collected on persons vaccinated in the ED showed the following characteristics in comparison to the data on the general vaccinated population in the county and in the state:

  • Higher percentage of Hispanic persons (28.5%; 95% CI, 23.9–33.1% vs. 8.0% in the state and 6.0% in the county).
  • Higher percentage of African American persons (23.6%; 19.2–27.9% vs. 5.0% and 4.0%)
  • Higher percentage of men (54.0%; 48.8–59.1% vs 43.0% and 44.0%)
  • Higher percentage of persons without health insurance (18.4% vs. 9.2% and 7.7%)
  • In addition, patients vaccinated in the ED were more likely to be < 65 years of age and less likely to be > 65 years of age compared to individuals vaccinated in other locations.

Limitations include the relatively small number of participants and that the ED was located in an urban area. Accordingly, some of the observed effects were likely due to a sampling bias. Also, the trial was conducted from March 4 to March 23, 2021, when vaccine eligibility was restricted to at-risk groups, limiting the study’s generalizability to today.

The take-home message?

A vaccination campaign offering the single-dose COVID-19 vaccine Janssen in an ED led to significantly higher proportions of vaccinated individuals from populations who otherwise showed low vaccination rates. This trial emphasizes the importance of diversifying vaccination efforts to reach those who might otherwise be unlikely to achieve full immunization.

  • Title of study: Reaching the hard to reach: Characteristics of patients who received a COVID-19 vaccine in the emergency department [18]
  • Authors: Heinhart SW et al
  • Journal: Academic Emergency Medicine
  • AMBOSS Links: COVID-19

Allergic reaction after first dose of mRNA COVID-19 vaccine: is the second dose safe?

One-Minute Telegram 32-2021-1/3 - Allergic reactions to the mRNA COVID-19 vaccines are estimated to occur in about 2% of recipients. [19] The CDC recommends that if an immediate allergic reaction of any kind occurs after the first dose, a non-mRNA vaccine should be chosen for the second one. [20] So far, however, the risk of patients who experienced an allergic reaction with the first dose of an mRNA vaccine experiencing a more severe allergic reaction with the second dose has not been investigated.

In this retrospective study, 189 participants who had an immediate allergic reaction to the first dose of an mRNA vaccine were enrolled. A total of 159 (84%) participants, including 19 with anaphylactic first-dose reaction, received a second dose. Of those 159 participants, 20% reported immediate allergic symptoms, all of which were self-limited, mild, and/or resolved with antihistamines alone.

Limitations include that some patients who showed an allergic reaction to the first dose did not receive a second dose, possibly leading to a selection bias. Also, the study was not controlled and one third of participants received premedication (mostly antihistamines) before the second dose, likely masking some allergic symptoms.

The take‑home message?

In this small retrospective study, a second dose of mRNA COVID-19 vaccine was found to be safe among recipients who had shown an immediate allergic reaction (including anaphylaxis) to the first dose, with only 20% experiencing mild allergic symptoms. However, controlled studies with a larger size sample are needed to provide more robust evidence.

  • Title of study: Safety evaluation of the second dose of messenger RNA COVID-19 vaccines in patients with immediate reactions to the first dose [21]
  • Authors: Krantz MS et al.
  • Journal: JAMA Internal Medicine
  • AMBOSS Links: COVID-19

What is the influence of continued smoking on survival and disease progression in lung cancer?

One-Minute Telegram 32-2021-2/3 - Lung cancer has a high incidence and a low survival rate compared to other types of cancer, making it the leading cause of cancer deaths worldwide. [22][23] While the association between lung cancer and smoking is well established, evidence about the effects of quitting smoking on disease progression and survival is largely lacking.

This prospective trial included 517 smokers diagnosed with early-stage (I, II, or IIIA) non-small cell lung cancer (NSCLC). The patients were interviewed at the time of diagnosis and, subsequently, annually for an average of 7 years.

57.4% of participants continued smoking, whereas 42.5% reported that they had quit, mostly within the first year of follow-up (86.3%). Of all participants, 52.8% died due to lung cancer and 33.7% showed tumor progression during the study period.

Patients who quit smoking showed the following results compared to those who continued:

  • 21.6 months higher median overall survival time (6.6 vs. 4.8 years; P = 0.001)
  • Higher 5-year survival (60.6% vs. 48.6%; P = 0.001)
  • Higher progression-free survival (54.4% vs. 43.8%; P = 0.004)

These effects were similar regardless of whether the participants were light, moderate, or heavy smokers; had earlier- or later-stage cancer; or received chemotherapy and/or radiotherapy.

Limitations include that information was based on self-reported questionnaires.

The take‑home message?

In this prospective observational study, smoking cessation following a diagnosis of early-stage NSCLC was associated with significantly higher rates of progression-free and overall survival when compared with ongoing smoking. These findings emphasize the importance of quitting smoking after a lung cancer diagnosis.

  • Title of study: Postdiagnosis smoking cessation and reduced risk for lung cancer progression and mortality: A Prospective Cohort Study [24]
  • Authors: Sheikh M et al.
  • Journal: Annals of Internal Medicine

Are seven days of antibiotics sufficient to treat UTI in men?

One-Minute Telegram 32-2021-3/3 - The duration of antibiotic courses for common infections has been a focus of recent research, as shorter courses, if equally effective when compared to standard treatment, may help reduce adverse effects and antibiotic resistance. The optimal duration of antibiotics for the treatment of afebrile UTI in men is not known.

This double-blinded noninferiority trial included 272 men with symptoms of UTI (e.g., dysuria) but no fever who were prescribed either ciprofloxacin or trimethoprim/sulfamethoxazole. Participants continued the antibiotics initially prescribed by their clinician for 7 days and were randomized to receive either continued antibiotic therapy (with the same antibiotic) or placebo for an additional 7 days.

In the primary as-treated analysis, symptom resolution by day 14 in the 7-day group (93.1%) was similar to that in the 14-day group (90.2%): a difference of 2.9% (1-sided 97.5% CI, -5.2% to ∞), meeting the prespecified noninferiority criterion of 10%.

In addition, as-treated analysis of secondary outcomes showed the following results in the 7-day group (n = 131) compared to the 14-day group (n = 123):

  • Similar rates of recurrent UTI within 28 days of stopping treatment (9.9% vs. 12.9%, P = 0.70)
  • Slightly lower rates of adverse events (19.8% vs. 23.6%)

Limitations include that confirmation with urine culture was not required for diagnosis. Thus, if a significant proportion of patients did not actually have a UTI, the results would be biased towards not finding a difference between the groups.

The take‑home message?

This trial provides evidence to support the use of a 7-day-course of either ciprofloxacin or trimethoprim/sulfamethoxazole as an alternative to a 14-day-course in the treatment of afebrile UTI in men. Further studies are needed to determine whether shorter and equally effective regimens are possible with other antibiotics.

Bariatric surgery associated with very high risk of long-term anemia

One-Minute Telegram 31-2021-1/3 - Bariatric surgery involves anatomical changes to the gastrointestinal tract that may lead to iron and vitamin B12 deficiency, which in turn can cause anemia. [26] Despite this potential consequence, there remains a paucity of large trials examining the long-term outcomes for patients undergoing bariatric surgery. Between 1987 and 2001, this prospective multicenter trial recruited 2007 patients with obesity who had undergone bariatric surgery and compared them to 2040 matched controls who had received standard obesity care.

Compared to standard care, bariatric surgery was associated with a significantly higher cumulative incidence of anemia during a median follow-up of 10 years (IQR 3–20):

  • 69% after gastric bypass (HR 5.05; 95% CI, 3.94–6.48)
  • 37% after vertical-banded gastroplasty (HR 2.67; 2.25–3.18)
  • 36% after gastric banding (HR 2.76; 2.15–3.52)
  • 24% with standard care

Limitations include the absence of randomization and significant residual differences between the groups despite matching (e.g., younger age and higher BMI in the surgery subgroups). Also, surgical advancements of the past 20 years (e.g., sleeve gastrectomy) since recruitment ended in 2001 are not accounted for.

The take‑home message?

Patients who underwent gastric bypass, vertical-banded gastroplasty, or gastric banding had around twice to five times the risk of developing anemia compared to matched controls treated conservatively over the course of 20 years. These results highlight the need for long-term nutritional monitoring and supplementation for nutritional deficiencies and anemia following bariatric interventions.

SARS-CoV-2 mRNA-based vaccines prevent COVID-19 complications in patients with cirrhosis

One-Minute Telegram 31-2021-2/3 - It has previously been shown that individuals with cirrhosis are hyporesponsive to certain vaccines, highlighting the importance of testing the efficacy of mRNA-based vaccines against SARS-CoV-2 in this patient population. [28]

This retrospective study of data from the Veterans Health Administration (VHA) in the US compared adult patients with cirrhosis who received an mRNA-based vaccination (n = 20,037) to propensity-matched controls (n = 20,037) who did not receive a vaccination and had a similar baseline risk of infection and severe disease.

The following results were seen in vaccinated patients as compared to the control group:

  • 0–28 days after the first dose: similar infection rates
  • At 28 days after the first dose: 64.8% reduction in SARS-CoV-2 infection and 100% protection against hospitalization or death due to SARS-CoV-2 infection
  • At 7 days after the second dose: 78.6% reduction in SARS-CoV-2 infection and 100% protection against hospitalization or death due to SARS-CoV-2 infection

There was a lower vaccine efficacy for protection against infection after the first dose in patients with decompensated cirrhosis (50.3%) than in patients with compensated cirrhosis (66.8%).
Limitations include retrospective design, a low percentage of female participants (2.8%), and the possibility for residual confounding, such as potential differences in COVID-19 exposure and testing between the groups.

The take‑home message?

This retrospective study from the VHA provides evidence that mRNA-based vaccines against SARS-CoV-2 are efficacious in patients with cirrhosis, but with a somewhat delayed and reduced protection from infection in comparison to randomized-controlled trials conducted in the general population. Importantly, none of the vaccinated patients in this study were hospitalized or died due to COVID-19, suggesting a strong protective effect against complications in this patient group.

Benefits to rehabilitation programs for older patients with heart failure?

One-Minute Telegram 31-2021-3/3 - Acute decompensated heart failure is associated with impaired physical function and high rates of rehospitalization among older patients. [30] Improved rehabilitation programs may reduce readmission rates and have a positive impact on long-term physical fitness.

In this trial, 349 patients over 60 years of age who were currently or recently hospitalized due to acute heart failure were randomized to receive either standard care (n = 174) or an individualized, progressive rehabilitation program (including three 60-minute sessions per week for a total of 12 weeks) that focused on four physical function domains (strength, balance, mobility, and endurance; n = 175).

In comparison to the standard care group, patients receiving the intervention achieved a significantly higher score in the short physical performance battery at 3 months (mean between-group difference, 1.5; 95% CI, 0.9–2.0; with 0.5 considered to be the minimal clinically important difference). However, at 6 months, there were no significant differences between groups in mortality rates and rates of rehospitalization for any cause. [31]

Limitations include relatively low (67%) adherence to the intervention sessions.

The take‑home message?

Among older patients hospitalized for acute heart failure, an early tailored rehabilitation program focusing on multiple physical-function domains led to significant clinical improvement of physical function at 3 months but had no impact on mortality or rehospitalization rates.

The COVID-19 pandemic has widened the gap in life expectancy between the US and other high-income countries

One-Minute Telegram 30-2021-1/3 - For over 30 years, the US has been lagging behind other high-income countries with regard to increases in life expectancy. [33] This gap was expected to grow during the COVID-19 pandemic, which became the third leading cause of death in the US in 2020. [34]

In this study, the authors drew on existing life tables and official databases to collect and compare life expectancy data for the US and 16 other high-income countries between 2010 and 2018. Life expectancy for 2020 was derived from computer modeling.

Results showed that life expectancy in the US had decreased by 1.87 years between 2018 and 2020, the greatest decrease since 1943. This decrease was 8.5 times greater than the average decrease seen in the peer countries. Hispanic and non-Hispanic black populations were disproportionately affected compared to non-Hispanic white populations, experiencing reductions in life expectancy of 3.88, 3.25, and 1.36 years, respectively.

Limitations of the study include that life tables for 2019 were incomplete, life expectancies for 2020 were simulated with preliminary mortality data, and data on race and ethnicity was not available for peer countries.

The take‑home message?

The decrease in life expectancy between 2018 and 2020 was 8.5 times greater in the US than in other high-income nations, illustrating the amplification of a preexisting divide in life expectancy by the COVID-19 pandemic. The disproportionately greater increase in mortality among Hispanic and black Americans likely reflects racial inequality in health and health care policy.

  • Title of study: Effect of the covid-19 pandemic in 2020 on life expectancy across populations in the USA and other high income countries: simulations of provisional mortality data [35]
  • Authors: Woolf SH et al.
  • Journal: BMJ
  • AMBOSS links: COVID-19

Is a single dose of azithromycin as effective as a longer course of doxycycline in the treatment of rectal chlamydia?

One-Minute Telegram 30-2021-2/3 - Rectal chlamydia is a relatively common, yet often asymptomatic sexually transmissible infection (STI) among men who have sex with men. A single-dose treatment with azithromycin is practical, but may not be as effective as a longer course of doxycycline. [36]

This double-blind trial included 625 men with asymptomatic rectal chlamydia infection detected during screening in Australian sexual health clinics. Participants were randomized to receive either doxycycline (100 mg twice daily for 7 days) or azithromycin (a single 1 g dose).

After 4 weeks of treatment, participants underwent nucleic acid amplification testing (NAAT) for chlamydia, yielding the following results:

Doxycycline group: chlamydia not detectable in 96.9% (95% CI, 94.4–98.9)
Azithromycin group: chlamydia not detectable in 76.4% (95% CI, 73.8–79.1)
These results translate into an adjusted risk difference of 19.9% (95% CI, 14.6–25.3) in favor of doxycycline.

Adverse events were reported more frequently in the azithromycin group than in the doxycycline group (risk difference -11.3%, 95% CI, -19.5 to -3.2).

Limitations include that only men participated in the study and that symptomatic chlamydia infections were not considered.

The take‑home message?

This trial showed that, despite being the simplest choice, a single dose of azithromycin may result in more adverse events and may be less effective than a seven days course of doxycycline in the treatment of asymptomatic rectal chlamydia in men.

Does imatinib slow the destruction of β-cells in type 1 diabetes?

One-Minute Telegram 30-2021-3/3 - Type 1 diabetes is an autoimmune disorder that leads to the destruction of insulin-producing β-cells. Novel therapies may be able to protect the β-cells in early stages of the disease, reducing the dependence on exogenous insulin. For example, the tyrosine kinase inhibitor imatinib has shown promising results in preclinical studies. [38] In this double-blinded phase 2 trial, adults aged 18–45 years who had been diagnosed with type 1 diabetes within the past 100 days were randomized 2:1 to receive either 400 mg imatinib daily (n = 43) or a placebo (n = 21) for 26 weeks. The primary endpoint was the C-peptide response after a mixed meal tolerance test (MMTT), assessed by calculating the area under the curve (AUC) of C-peptide levels in the first 2 hours after the MMTT:

  • At 12 months:
    • Adjusted mean difference: 0.095 in favor of imatinib (90% CI, -0.003 to 0.191)
    • Treatment effect of 19.4%
  • At 24 months: no significant difference

The need for exogenous insulin was significantly lower at 3 and 6 months in the imatinib group, but this was not observed in the subsequent follow-ups.

71% (n = 32) of participants who received imatinib had a grade 2 or worse severity adverse event, compared to 59% (n = 13) of participants who received placebo. Six patients in the imatinib group discontinued the treatment due to adverse events.

Limitations include the small sample size, the relatively short treatment period, and the lack of racial diversity in the study population.

The take‑home message?

A 26-week course of imatinib resulted in preserved β-cell function at 12 months in adults with recent-onset type 1 diabetes. This effect was not sustained at 24 months. Confirming the benefits of imatinib will require future research involving longer treatment periods, higher doses, and, ideally, larger study populations.

Deployment of bacteria-infected mosquitoes lowers incidence of symptomatic dengue

One-Minute Telegram 29-2021-1/3 - Dengue is a potentially lethal, mosquito-borne disease with 50–100 million symptomatic cases each year. Specific treatment is lacking, but measures against its primary vector, Aedes aegypti, can aid in disease control. [40]

In this study, populations of Aedes aegypti were infected with Wolbachia pipientis (an insect bacterium that can confer resistance to dengue infection). These mosquitoes were released in 12 randomly selected geographic clusters (intervention clusters) in Indonesia. The same number of geographic clusters was randomly selected as control clusters and received no deployment. [41]

Researchers followed the network of primary care clinics in the region to identify individuals presenting with fever possibly caused by dengue acquired in the investigation clusters. A total of 6306 participants were recruited: 2905 from the intervention clusters and 3401 from the control clusters.

PCR or ELISA for dengue were obtained in all participants and showed that the incidence of dengue in the intervention clusters was significantly lower compared to that in the control clusters (OR 0.23; 95% CI, 0.15–0.35), suggesting a protective efficacy of 77.1% (95% CI, 65.3–84.9%).

Limitations include that only infections in individuals who presented to the clinics were registered (possibly missing out on a proportion of infected patients with milder disease courses or lack of access to health care).

The take‑home message?

Results from this trial in Indonesia show that the release of Wolbachia-infected mosquitoes significantly decreased the incidence of symptomatic dengue in geographic clusters. Further studies could investigate whether the release of modified mosquitoes could also control transmission of other mosquito-borne diseases (e.g., Zika, chikungunya, yellow fever, and Mayaro viruses).

  • Title of study: Efficacy of Wolbachia-infected mosquito deployments for the control of dengue [42]
  • Authors: Utarini A et al.
  • Journal: NEJM

Effects of IVIG in vaccine-induced immune thrombotic thrombocytopenia – a case series

One-Minute Telegram 29-2021-2/3 - Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare side effect of adenoviral vector vaccines against COVID-19 that is characterized by platelet consumption, thrombocytopenia, and platelet factor 4 (PF4) reactive antibodies. Intravenous immunoglobulin (IVIG) is recommended for this condition as it may inhibit VITT-antibodies, but data on real-world efficacy is limited. [43][44]

This case series included 3 patients who developed VITT after receiving the AstraZeneca ChAdOx1 vaccine and were subsequently treated with IVIG.

Patients showed initial high reactivity in ELISA against PF4, with no reduction after treatment with IVIG.

Limitations include that the changes in platelet count cannot be definitively linked to IVIGs, because many other factors influenced the outcomes.

The take‑home message?

This case series reports data of 3 older patients who received IVIG as therapy for VITT after vaccination with ChAdOx1. All patients showed a significant rise in the number of platelets after IVIG administration, but there was no proof of IVIG inhibiting PF4 reactive antibodies. Further research is necessary to understand the role of IVIG in the treatment of VITT.

Eptinezumab shows promise in the treatment of migraine attacks

One-Minute Telegram 29-2021-3/3 - Eptinezumab is a humanized monoclonal antibody that targets calcitonin gene-related peptides (CGRP). The FDA approved the drug for the preventive treatment of migraine, as it showed efficacy on day 1 after infusion. [46]

This double-blind, randomized, placebo-controlled trial examined the effects of eptinezumab during a migraine attack. Participants had a history of migraine and reported migraine attacks on 4 to 15 days per month.

A 100-mg dose of eptinezumab (n = 238) or a placebo (n = 242) were administered within 1 to 6 hours of migraine onset. In comparison to placebo, the eptinezumab group showed the following statistically significant results:

  • Faster headache relief: median 4 vs. 9 hours (HR 1.54, P < 0.001)
  • Faster amelioration of most bothersome symptom (i.e., nausea, photophobia, or phonophobia): median 2 vs. 3 hours (HR 1.75, P < 0.001)
  • Significantly fewer patients used rescue medication within the next 24 hours (31.5% vs. 59.9%; OR 0.31, 95% CI, 0.21–0.45).

No serious adverse events were reported.

Limitations include the lack of comparison to a guideline-recommended therapy.

The take‑home message?

Among patients eligible for preventive migraine therapy, the administration of eptinezumab during a migraine attack led to faster and more frequent headache relief and decreased use of rescue medication within 24 hours of infusion start compared to placebo. Future studies are needed to compare this drug to other guideline-recommended medications for migraine attacks.

  • Title of study: Effects of intravenous eptinezumab vs placebo on headache pain and most bothersome symptom when initiated during a migraine attack: A randomized clinical trial [47]
  • Authors: Winner PK et al
  • Journal: JAMA
  • AMBOSS links: Migraine

COVID-19: Does bamlanivimab prevent infection and disease?

One-Minute Telegram 28-2021-1/3 - Bamlanivimab is a neutralizing monoclonal antibody against SARS-CoV-2 that was granted Emergency Use Authorization by the FDA in combination with etesevimab for mild to moderate COVID-19. However, data regarding its potential prophylactic benefits is limited. [48]

This industry-sponsored randomized phase 3 clinical trial evaluated the preventive effects of bamlanivimab against COVID-19. Between August and November 2020, residents and workers from 74 skilled nursing and assisted living facilities in which at least 1 SARS-CoV-2 index case had been confirmed were enrolled. A total of 966 participants with no known history of COVID-19 and who tested negative for SARS-CoV-2 using PCR and serology tests received either a single infusion of bamlanivimab (n =550) or placebo (n =548). The participants were followed for 24 weeks.

The bamlanivimab group showed the following results in comparison to the placebo group:

  • By day 29: lower incidence of infection (OR, 0.66; 95% CI, 0.46–0.94)
  • By day 57:

Of the participants who contracted COVID-19, those who had received bamlanivimab had lower viral loads on their first positive tests and a greater decrease in viral load after one week of infection.

The rate of adverse events was similar in both groups.

Limitations include that the participants could have had different levels of exposure to the index cases. Furthermore, since the study was conducted before vaccine rollout and prior to the spread of SARS-CoV-2 variants, benefits in vaccinated persons and action against variants that have since emerged could not be assessed. In addition, participants were predominantly white and female, restricting generalizability to other populations.

The take‑home message?

In this study, bamlanivimab reduced the incidence and severity of COVID-19 among at-risk residents and workers in skilled nursing and assisted living facilities. Future studies are needed to examine the drug's effectiveness against SARS-CoV-2 variants and its benefits in the vaccinated as well as male and nonwhite population.

How long should be the treatment of prosthetic joint infections?

One-Minute Telegram 28-2021-2/3 - Prosthetic joint infections are rarely treated with surgery alone and can require 12 to 24 weeks of antibiotic therapy. However, whether a shorter course of antibiotic treatment might be equally effective remains unclear. [50]

In this open-label noninferiority trial, 410 patients with microbiologically confirmed prosthetic joint infection (hip or knee) were randomized 1:1 to receive antibiotic therapy for either 6 or 12 weeks after surgery.

Persistent infection within 2 years of completion of antibiotic therapy occurred in 18.1% of patients in the 6-week group and 9.4% of patients in the 12-week group. Functional outcomes, rates of serious adverse events, rates of C. difficile infection, and duration of hospital stay did not differ significantly between groups.

Limitations include the open-label design and the incorporation of different surgical procedures in a single trial (i.e., implant retention and prosthetic joint replacement). In addition, 20 patients who died during follow-up were excluded from the analysis.

The take‑home message?

In this trial, persistent infection within 2 years of postoperative antibiotic therapy for prosthetic joint infection was higher among patients who received 6 weeks of antibiotic therapy compared to those who received 12 weeks of antibiotic therapy.

Aspirin for cardiovascular disease: How much is enough?

One-Minute Telegram 28-2021-3/3 - Aspirin is one of the most commonly used drugs worldwide, not least because it can improve outcomes in atherosclerotic cardiovascular disease. However, due to inconsistent findings from a broad range of studies, the dose of aspirin used for secondary prevention of adverse cardiovascular events can be highly variable. [52]

In this open-label trial, 15,076 patients with established atherosclerotic cardiovascular disease were randomized 1:1 to receive either 81 mg or 325 mg of aspirin per day and were followed for a median of 26.2 months. The primary outcome was the time to first hospitalization for myocardial infarction or stroke, or death by any cause. The primary safety outcome was hospitalization for major bleeding.

Neither the primary outcome (HR, 1.02; 95% CI, 0.91–1.14) nor the safety outcome (HR 1.18; 0.79–1.77) differed between groups.

Limitations include the open-label design and the fact that the initial randomly assigned aspirin dose could be switched. Dose switching occurred more often in patients assigned to the higher-dose (41.6% vs. 7.1%), leading to fewer median days of exposure to 325 mg compared to 81 mg (434 days IQR 139–737 vs. 650 days IQR 415–922). In addition, minor bleeding events or other side effects (e.g., dyspepsia) were not included in the safety analysis.

The take‑home message?

This randomized, open-label trial did not reveal significant differences in the time to occurrence of cardiovascular events or death in patients taking 81 mg or 325 mg of aspirin daily, with similar rates of major bleeding events for both groups. However, due to the open-label design, a significant portion of patients switched their dose during the study. Accordingly, blinded studies are needed to verify these results.

Are SARS-CoV-2 specific antibodies secreted in breast milk after vaccination with an mRNA-based vaccine?

One-Minute Telegram 27-2021-1/3 - Since pregnant and breastfeeding women were not included in most of the initial studies on COVID-19 vaccines, data on their efficacy in and effects on mothers and their infants remains lacking.

This cohort study included 84 breastfeeding women, who received two doses of the Pfizer-BioNTech vaccine 21 days apart. Samples of breast milk were collected before vaccine administration and then once weekly for 6 weeks. IgG and IgA levels were measured via quantitative ELISA, and specific cut-offs were defined for being antibody-positive for IgA and IgG.

Mean levels of anti-SARS-CoV-2-specific IgA antibodies in the breast milk were significantly elevated (2.05 ratio; P < 0.001) at week 2 after the first dose, at which point 61.8% of all samples were considered to be antibody-positive. Positivity rose to 86.1% at week 4 (1 week after the second dose) and decreased to 65.7% at week 6.

91.7% of samples tested positive for anti-SARS-CoV-2-specific IgG antibodies at week 4, increasing to 97% at weeks 5 and 6.

No serious adverse events were observed in the mothers or their infants during the study period.

Limitations include that no functional assays were used, meaning that the neutralizing capacity of these antibodies could not be demonstrated. Also, rates of COVID-19 infection were not assessed.

The take‑home message?

This small cohort study showed that SARS-CoV-2 specific IgA and IgG antibodies are secreted in breast milk after vaccination with an mRNA-based vaccine as early as 2 and 4 weeks, respectively. Further studies are required to clarify the clinical significance of these findings.

CA-125 and ultrasound for ovarian cancer screening: Can mortality be reduced?

One-Minute Telegram 27-2021-2/3 - Ovarian cancer rarely causes symptoms early in the course of the disease, which means that it typically goes undiagnosed until later stages, which are associated with poor survival. This study aimed to determine whether screening for early ovarian cancer can reduce mortality. [55]

Between 2001 and 2005, 202,638 postmenopausal women aged 50–74 years were randomized to annual multimodal screening (MMS; with longitudinal CA125 measurements PLUS transvaginal ultrasound), annual transvaginal ultrasound screening (USS), or no screening in a 1:1:2 ratio for a median follow-up of 16.3 years.

In each group, 1% of women were diagnosed with tubal or ovarian cancer.

Compared to the no screening group, the MMS group had the following results with respect to ovarian cancer diagnosis:

  • Stage I disease incidence was 47.2% higher (95% CI 19.7 to 81.1%)
  • Stage IV disease incidence was 24.5% lower (-41.8 to -2.0%)

There was no difference in the rates of diagnosis for any stage between the USS group and the no-screening group.

Despite the reduction in stage IV disease in the MMS group, mortality due to tubal or ovarian cancer did not differ across the groups (0.6% in each group).

Limitations include that this trial was started in the early 2000s, which means that more recent advances in clinical management were not taken into account.

The take‑home message?

In this large randomized, controlled trial, multimodal screening with imaging and tumor markers helped to identify ovarian cancer at earlier stages of the disease, but this did not translate to a reduction of mortality. There is still no evidence to support population screening for ovarian cancer with the methods currently available.

  • Title: Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial [56]
  • Authors: Menon U et al.
  • Journal: The Lancet

Final report of the SPRINT-trial supports lower BP targets to reduce the risk of cardiovascular disease and mortality

One-Minute Telegram 27-2021-3/3 - The initial report of the SPRINT trial published in 2015 suggested that patients with elevated systolic blood pressure benefit from a more intensive systolic blood pressure treatment target of < 120 mm Hg compared to a standard treatment target of < 140 mm Hg. The final report has now fully assessed the previously collected data on outcome events and the posttrial follow-up data collected through July 29, 2016. [57]

This final report of the SPRINT trial included 9361 participants, who were 50 years of age or older, had a systolic blood pressure of 130 to 180 mm Hg with or without antihypertensive drug treatment, and were at increased risk of cardiovascular disease. Patients were evaluated during the intervention period (median follow-up: 3.33 years) and for an additional observational postintervention period (median total follow-up: 3.88 years).

Events occurring throughout the intervention and postintervention periods showed that the composite primary outcome (myocardial infarction, other acute coronary syndromes, stroke, acute decompensated heart failure, or death from cardiovascular causes) and overall death rates were significantly lower in the intensive treatment group compared to the standard-treatment group (HR for the primary outcome, 0.76; 95% CI, 0.65–0.88; HR for death, 0.79; 95% CI, 0.66–0.94). Patients in the intensive treatment target group had a higher rate of treatment-related adverse events (i.e., hypotension, electrolyte abnormalities, acute kidney injury, and syncope).

Limitations include the exclusion of patients with diabetes, previous stroke, or dementia reducing this study’s generalizability.

The take‑home message?

The final report of the SPRINT trial confirmed the association between a blood pressure treatment target of < 120 mm Hg and lower rates of cardiovascular events as well as all-cause mortality compared to the standard < 140 mm Hg target. Benefits persisted throughout the observational follow-up period. Further studies are needed to assess whether intensive blood pressure control might also benefit other patient groups, especially those younger than 50 years and those with diabetes.

  • Title: Final report of a trial of intensive versus standard blood-pressure control [58]
  • Authors: The SPRINT Research Group
  • Journal: NEJM
  • AMBOSS links: ASCVD

Antibiotics for respiratory infections: Better late than early (or never)

One-Minute Telegram 26-2021-1/3 - Strategies to reduce unnecessary antibiotic use are urgently needed to curb antibiotic resistance rates and improve patient outcomes. [59]

This systematic review set out to determine whether delayed antibiotic prescription, defined as an antibiotic prescription with the advice not to start taking the medication unless symptoms worsen or fail to improve within a set period of time, was as effective as no antibiotics or immediate antibiotic prescription in the outpatient management of respiratory tract infections. Nine RCTs and 4 observational cohort studies were included, with a total of 55,682 patients of all age groups. Comparisons were adjusted to baseline severity, age, infection type, and study type.

  • Symptom severity 2–4 days after initial consultation, ranging from 0 (normal) to 7 (severe symptoms) did not differ between the groups.
  • Complications leading to hospital admission or death were similar for delayed antibiotics compared to no antibiotics (OR, 0.62; 95% CI, 0.30–1.27) and immediate antibiotics (OR, 0.78; 0.53–1.13)
  • The following findings suggested that delayed antibiotic prescriptions were acceptable to patients:
    • Reconsultation rates were similar to immediate antibiotics and lower than no antibiotics (OR, 0.72; 0.60 to 0.87)
    • Patient satisfaction was similar to immediate antibiotics but increased compared to no antibiotics (adjusted mean difference 0.09; 95% CI, 0.06 to 0.11)

Limitations include heterogeneity of included studies, that not all studies reported on all outcomes, and that the great majority of patients included in the analyses were from high-income countries, limiting the generalizability of results to low- and middle-income countries.

The take‑home message?

This study suggests that delayed antibiotic prescription for respiratory infections in an outpatient setting is as effective as immediate antibiotics or no antibiotics independently of baseline disease severity, patient age, or infection type. Delayed antibiotic prescription may also help reduce reconsultation rates and increase patient satisfaction compared to no antibiotics.

  • Title of study: Delayed antibiotic prescribing for respiratory tract infections: individual patient data meta-analysis [60]
  • Authors: Stuart B et al.
  • Journal: BMJ

No one-size-fits-all vaccination strategy for SARS-CoV-2

One-Minute Telegram 26-2021-2/3 - Immunosuppressed patients are at higher risk of COVID-19 complications and have generally been prioritized to get their vaccination. However, immunosuppression may potentially affect the degree of protection in this patient group. [61][62][63]

Researchers measured the antibody response 21 days after the first dose and 29 days after the second dose of mRNA vaccines in 658 solid organ transplant recipients between December 2020 and March 2021.

  • The following responses were found:
    • 15% of participants showed a response after dose 1.
    • 39% showed a response after dose 2 but not after dose 1.
    • 46% showed no response at all.
  • Factors associated with a lower probability of postvaccination antibody responses after 2 doses included older age (P = 0.002), fewer years since transplant (P < 0.001), and taking antimetabolites as part of the immunosuppression regimen (P < 0.001).
  • Patients receiving the mRNA-1273 (Moderna) vaccine were more likely to develop antibodies after dose 1 or 2 compared to patients receiving the BNT162b2 (Pfizer-BioNTech) vaccine (60 vs. 48%; P < 0.001).

Limitations of this study include the lack of an immunocompetent group for comparison, that only antibodies and not cellular responses were measured, and that postvaccination SARS-CoV-2 infection rates were not assessed.

The take‑home message?

Almost half of organ transplant recipients in this study mounted no antibody response after 2 mRNA vaccines. However, responses did increase from 15% after one dose to 54% after the second dose. Of note, antibody level thresholds for protective immunity against SARS-CoV-2 have not been established. Further research is needed into methods of boosting the immune response to vaccination in this patient population (e.g., using booster doses) and to assess the effect of existing vaccination regimens on infection rates.

Better, faster, stronger: 4-month vs. 6-month antibiotic regimen for pulmonary TB

One-Minute Telegram 26-2021-3/3 - The Directly Observed Treatment Short-Course (DOTS) strategy for tuberculosis (TB) using isoniazid, rifampin, pyrazinamide, and ethambutol remains one of the pillars of the global “End TB strategy”. However, contrary to what its name suggests, this 6-month course is often experienced as very long by patients, thus reducing treatment adherence and, consequently, increasing the prevalence of drug-resistant TB strains and negatively affecting patient outcomes. [65][66][67]

In this open-label, phase 3 noninferiority randomized controlled trial, 2,343 patients ≥ 12 years of age from 13 countries with newly diagnosed pulmonary TB and a positive culture for drug-sensitive M. tuberculosis were randomized 1:1:1 to either:

Unfavorable outcome events were measured (i.e., microbiological evidence of tuberculosis at week 12, death, withdrawal from study, lost to follow-up, or required additional TB treatment), and a prespecified cutoff point for noninferiority was set at 6.6% difference.

Limitations include the lack of blinding of patients and trial clinicians to treatment group assignments and a lack of power to compare regimens in HIV-positive individuals, as this group comprised only 8% of participants.

The take‑home message?

For drug-sensitive pulmonary TB, a 4-month rifapentine-moxifloxacin-based regimen was noninferior to the standard 6-month DOTS regimen. However, a 4-month rifapentine-based regimen without moxifloxacin did not meet noninferiority criteria. This trial provides further evidence that fluoroquinolone-based anti-TB regimens can shorten treatment duration for pulmonary TB.

Male sex, wellness, and work culture associated with less burnout among clinicians

One-Minute Telegram 25-2021-1/3 - Burnout is an underrecognized and growing problem among health care workers that has, furthermore, been shown to negatively affect the quality of patient care. [70][71]
This cross-sectional study set out to identify the factors at the workplace that contribute to burnout among clinicians. Participants (n = 1310) completed a survey on burnout, wellness, and work satisfaction. Burnout was defined as a score of ≥ 50 points on a modified Maslach Burnout Inventory. Results were then correlated with their usage of electronic health record (EHR) metadata.
Results from a regression model showed that female sex increased the likelihood of burnout independently of other demographics, EHR metrics, and work culture (OR, 1.3; 95% CI, 1.0–1.7).

Factors that independently decreased the likelihood of burnout included:

  • Work culture domains
    • Self-reported high levels of commitment (OR, 0.54; 0.42–0.68)
    • Work-life balance (OR, 0.64; 0.55–0.73)
    • Teamwork (OR, 0.52; 0.40–0.67)
    • Diversity (OR, 0.83; 0.71–0.98)
  • EHR use
    • Surprisingly, burnout rates did not rise with EHR usage but, on the contrary, fell with the number of days spent using the EHR per month (OR, 0.96; 0.93–0.99). The authors theorized that this could have been due to efficiency in using the EHR increasing with the amount of its use.

Clinical volume metrics (e.g., total patient encounters per month) were not associated with burnout.

Limitations include the single-center design, which limits generalizability, and that the study did not measure patient outcomes.

The take‑home message?

This study showed that female clinicians were more likely to experience burnout than their male colleagues. Work culture domains (i.e., high levels of commitment, work-life balance, teamwork, and diversity at the workplace) were associated with fewer reports of burnout, while EHR usage and patient volumes did not have a strong influence.

Interleukin-6 receptor antagonists show promise in critically ill patients with COVID-19

One-Minute Telegram 25-2021-2/3 - While an excessive host inflammatory response (e.g., cytokine storm) has been identified as a significant exacerbating factor for the course of COVID-19, studies have shown that steroids can reduce mortality. [73] This has led to further investigations of interleukin-6 receptor antagonists and their cytokine-blocking action in patients with COVID-19.

In this industry-sponsored international adaptive platform trial [74], patients critically ill with COVID-19, who had been put on organ support (i.e., high-flow oxygen or mechanical ventilation and/or vasopressors or inotropes) within the preceding 24 hours were randomized to receive either tocilizumab (n = 353), sarilumab (n = 48), or standard care (n = 402). Compared to the standard care group:

  • There was an increase in the median number of organ support-free days:
    • Tocilizumab 10 days (median adjusted cumulative OR, 1.64; 95% credible interval, 1.25–2.14)
    • Sarilumab 11 days (1.76; 1.17–2.91)
  • In-hospital mortality was lower in the pooled interleukin-6 receptor antagonist groups (27 vs. 36%).
  • 90-day survival analysis also showed better outcomes in the pooled interleukin-6 receptor antagonist groups (HR 1.61; 1.25 to 2.08).

Limitations include the study’s open-label design and a lack of information on longer-term outcomes.

The take‑home message?

This trial provides evidence that interleukin-6 receptor antagonists can improve survival in critically ill patients with COVID-19 when started within 24 hours after being placed on organ support therapy.

Can in-home medical care improve outcomes in the geriatric population?

One-Minute Telegram 25-2021-3/3 - Hospitalization of elderly individuals frequently leads to complications such as nosocomial infection and delirium, which, in turn, increase health care costs and reduce patient well-being.

In this multicenter randomized trial, 1055 physiologically stable geriatric patients (mean age 83.3 years), who had been referred to the hospital for care, were randomized 2:1 to either hospital-at-home (HAH) care or hospital admission. HAH involved a multidisciplinary rapid-response service that performed a comprehensive geriatric assessment and provided transport for radiologic investigations as needed, home oxygen, and the administration of intravenous medication. The primary study outcome was the proportion of participants living at home 6-months after discharge, which did not differ between the groups (78.6% vs. 75.3%, P = 0.36).

Secondary outcomes included:

  • Death rate at 6 months was similar between the groups (16.9 vs. 17.7%, P = 0.92).
  • Participants in the HAH group were less likely to be newly admitted to long-term residential care at 6 months (RR, 0.58; 95% CI, 0.45–0.76) and 12 months (RR, 0.61; 0.46–0.82).
  • HAH participants had an increased risk for readmission and transfer to hospital at 1 month (RR, 1.32; 1.06–1.64), though not at 6 months.
  • Presence of delirium at days 3 and 5 was similar between the groups, but was lower at 1 month in the HAH group (1.7 vs. 4.4%, adjusted RR, 0.38; 0.19–0.76).
  • Patient satisfaction (measured using the EQ-5D-5L tool) [76] was higher in the HAH at 1 month.

Limitations include that about a third of eligible participants chose not to take part in the study, potentially leading to a nonparticipation bias, thus compromising the external validity of the study.

The take‑home message?

Hospital-at-home care for stable geriatric patients with acute illness did not change the likelihood of being able to live at home 6-months after discharge when compared to hospitalization. However, avoiding hospital admission resulted in reduced delirium rates, increased patient satisfaction, and a decreased likelihood of living in residential care a year later.

  • Title of study: Is comprehensive geriatric assessment admission avoidance hospital at home an alternative to hospital admission for older persons? [77]
  • Authors: Shepherd S et al.
  • Journal: Annals of Internal Medicine

Budesonide shows promise in reducing symptoms and preventing progression of mild COVID-19

One-Minute Telegram 24-2021-1/3 - It is known already that oral and IV dexamethasone can improve the outcomes of patients with COVID-19 who require respiratory support. [78] However, this is not applicable to patients with mild COVID-19, and effective treatment options for this group are still lacking. [79] Researchers set out to determine if the use of inhaled glucocorticoids could be beneficial in mild COVID-19.

This phase II open label randomized control trial included 146 patients ≥ 18 years who had been diagnosed with mild symptomatic COVID-19 within the preceding 7 days. Patients were randomly assigned in a 1:1 ratio to a usual care group (i.e., antipyretics and honey for cough) or a usual care plus inhaled budesonide group (800 mcg twice daily). Both groups were monitored at home for 14 days. Participants already on budesonide were excluded. Patients’ age, baseline symptoms, and comorbidities were similar between the groups.

  • Compared to the usual care group, the budesonide group had the following outcomes:
    • Main composite outcome: reduced number of COVID-19 related visits to the ER and/or admissions (3 vs 15%; P =0.009); number needed to treat of 8
    • Secondary outcomes:
      • Earlier recovery (median 7 vs. 8 days, P = 0.007)
      • Fewer patients with persistent symptoms at day 14 (10 vs. 30% P = 0.003)
      • Lower proportion of days with fever (2 vs. 8%, P = 0.051) and use of antipyretics (27 vs. 50%, P = 0.025)
      • No significant difference in oxygen saturation and SARS-CoV-2 viral load
  • Safety profile: Five participants reported mild adverse events.

Limitations of this study include the lack of placebo group and a relatively small sample size.

The take‑home message?

Results from this study suggest that the addition of inhaled budesonide to the usual outpatient treatment can reduce the likelihood of clinical deterioration and need for hospitalization in adults with mild COVID-19. Since budesonide is an easily accessible medication, this could become a widely applicable measure to treat mild COVID-19 worldwide and ease the burden on hospitals.

  • Title of study: Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial [80]
  • Authors: Ramakrishnan S et al.
  • Journal: Lancet Respiratory Medicine
  • AMBOSS links: COVID-19

Hard work pays off: High vs. low intensity walking interventions in patients with peripheral artery disease

One-Minute Telegram 24-2021-2/3 - Interventions to curb the progression of peripheral artery disease (PAD) are limited and often require challenging lifestyle changes, which may be difficult to adhere to (e.g., supervised exercise). [81]

This multicenter randomized clinical trial aimed to determine the effect of two different home-based exercise interventions on walking capacity (defined as maximal distance walked in 6 minutes) and self-reported limitations (measured by the Walking Impairment Questionnaire) in individuals with PAD. [82] Participants were randomized to a low-intensity walking group (not inducing ischemic symptoms; n = 116), a high-intensity walking group (inducing ischemic symptoms; n =124), and a non-exercise control group (n= 65). Patients in the intervention groups were instructed to complete five 50-minute sessions per week for 1 year.

Changes in 6-minute walking distance after 12 months:

  • Non-exercise control group: 15-meter mean reduction
  • Low-intensity walking group: 6.4-meter mean reduction (mean difference compared to no exercise, + 8.7 meters; P =0.44)
  • High-intensity walking group: 34.5-meter mean increase (mean difference compared to low-intensity + 40.9 meters; P < 0.001)
  • While low-intensity walking was not found to significantly improve objective walking capacity compared with no exercise, patients in the low-intensity walking group did show significant improvement in self-reported limitations of both walking distance and speed.

Limitations of this study include a lack of data on 18% of participants who did not return for testing after 12 months. Some follow-ups could not be completed due to the onset of the COVID-19 pandemic.

The take‑home message?

A home-based high-intensity walking exercise intervention was effective in significantly improving the 6-minute walk distance of patients with PAD, while low-intensity walking improved self-reported limitations but did not improve the 6-minute walk distance compared to no exercise.

  • Title of study: Effect of low-intensity vs high-intensity home-based walking exercise on walk distance in patients with peripheral artery disease: The LITE randomized clinical trial [83]
  • Authors: McDermott MM et al.
  • Journal: JAMA

Long COVID after mild COVID?

One-Minute Telegram 24-2021-3/3 - Patients hospitalized with COVID-19 report symptoms like dyspnea and fatigue many months after overcoming the disease. [84] However, information regarding the persistence of symptoms after mild COVID-19 is scarce.

Participants in this study were 1395 health care professionals recruited between April and May 2020, who were followed for a period of 8 months. Blood samples were collected at baseline and every four months thereafter. Seropositive participants with severe symptoms and seronegative participants who subsequently seroconverted were excluded. Information regarding the presence, duration, and severity of long-term symptoms (e.g., anosmia, fatigue, dyspnea) was collected via a smartphone questionnaire.

Participants who were SARS-CoV-2 seropositive at baseline (n = 323) were compared to those who were SARS-CoV-2 seronegative at baseline (n = 1072) with the following results:

  • 26% of seropositives vs. 9% of seronegatives reported ≥ 1 moderate or severe symptom, lasting ≥ 2 months (RR, 2.9; 95% CI, 2.2-3.8)
  • 15% of seropositives vs. 3% of seronegatives reported ≥ 1 moderate or severe symptom lasting ≥ 8 months (RR, 4.4; 2.9-6.7)
  • The most commonly reported symptom persisting ≥ 2 months was anosmia.

Using the Sheehan disability scale it was determined that symptoms lasting ≥ 2 months caused long-term functional impairment. [85] Compared to seronegative participants, seropositive participants reported higher rates of disruption in their work, social, and home life.

Limitations of this study include case-definition by serology rather than PCR and the potential for recall bias.

The take‑home message?

Results from this study suggest that long-term symptoms potentially disruptive to work, social, and home life are frequent even after mild COVID-19.

  • Title of study: Symptoms and functional impairment assessed 8 months after mild COVID-19 among health care workers [86]
  • Authors: Havervall S et al.
  • Journal: JAMA
  • AMBOSS links: COVID-19

Prevention of HIV infection using neutralizing antibodies?

One-Minute Telegram 23-2021-1/3 - It is estimated that there are about 30 million people worldwide currently living with HIV/AIDS. Even though global efforts since 2010 have led to a decline in new HIV infections by almost a quarter, there were still over 1.5 million new infections in 2019. [87][88]

Two parallel phase 2 randomized controlled trials aimed to determine the efficacy of the novel HIV-1 neutralizing antibody VRC01 in preventing infection among persons at risk (e.g., high-incidence populations). Trial one was conducted in North America, South America, and Europe (n = 2699), trial two in sub-Saharan Africa (n = 1924). Participants were randomly assigned 1:1:1 to receive intravenous low-dose VRC01, intravenous high-dose VRC01, or placebo every 8 weeks for 20 months. Median age was 28 years in trial one and 26 years in trial two. 98 and 76 infections were registered during follow-up in trial one and trial two, respectively.

Both high- and low-dose VRC01 were highly effective compared to placebo in preventing infection with HIV-1 strains susceptible to VRC01 in vitro (75.4%; 95 CI 45.5 to 88.9). However, such strains represented only a third of the strains identified in the trial regions, so that efficacy as a whole turned out to be low compared to placebo (P values for efficacy 0.15 and 0.70).

Limitations include that the use of the antibody may have applied selective pressure at early stages of the study, consequently inducing infections by HIV-1 strains resistant to VRC01.

The take‑home message?

In these two trials conducted in 4 different continents, the neutralizing antibody VRC01 was generally not effective in preventing new HIV-1 infection. However, for HIV-1 strains with in vitro susceptibility to the antibody, prevention efficacy was high. These results suggest a potential benefit of neutralizing antibodies in preventing HIV infection, possibly using combination regimens in order to cover HIV-1 strains with different susceptibilities, but further trials are needed to confirm these hypotheses.

  • Title of study: Two randomized trials of neutralizing antibodies to prevent HIV-1 acquisition [89]
  • Authors: Corey L et al.
  • Journal: NEJM

The age of innocence: Younger patients less likely to develop symptoms after SARS-CoV-2 infection

One-Minute Telegram 23-2021-2/3 - Since the beginning of the pandemic, there have been numerous questions regarding the proportion of infected patients that remain asymptomatic and the role these individuals play in the transmission of the virus. Especially, whether certain groups are more prone to being asymptomatic than others remains a matter of debate. [90]

Researchers conducted a cohort study to determine if the development of COVID-19 symptoms is associated with age.

5,484 participants who had had close contact with patients with confirmed COVID-19 were included and monitored for 2 weeks for the development of infection and symptoms. Median age was 50 years (IQR 30–61), 56.3% were female. 51.5% tested positive for SARS-CoV-2 infection (n = 2824), either via RT-PCR or serological assay; 69% of the infected contacts did not develop respiratory symptoms or fever (n = 1948), and 2.7% developed severe disease (n = 75). The development of symptoms was associated with increasing age, with the highest rates of symptomatic disease and critical illness seen in patients ≥ 80 years (64.56% and 18.35%, respectively) and the lowest rates occurring in patients ≤ 19 years (18.1% and 0%, respectively).

Limitations of this study include that the infection rate seen was not representative of the general population, as only close contacts were included, and that different laboratory methods were used to define infection.

The take‑home message?

In this study, younger age was associated with a lower rate of symptomatic SARS-CoV-2 infection, while higher age was associated with both symptomatic infection and a higher risk of progression to critical illness, with the group of patients ≥ 80 years being the most severely affected. The high rate of asymptomatic infection among young patients warrants further discussion regarding the best prevention strategy to stop viral transmission in these age groups.

  • Title of study: Association of age with likelihood of developing symptoms and critical disease among close contacts exposed to patients with confirmed SARS-CoV-2 infection in Italy [91]
  • Authors: Poletti P et al.
  • Journal: JAMA Network Open
  • AMBOSS links: COVID-19

COVID-19: Helmet noninvasive ventilation associated with lower rates of endotracheal intubation compared to high-flow oxygen

One-Minute Telegram 23-2021-3/3 - The best strategy for ventilation in patients with hypoxemic respiratory failure due to SARS-CoV-2 infection remains a pressing area of research. Helmet-based ventilation, a noninvasive form of ventilation that delivers oxygen to the patient via a helmet secured to the shoulders, is one option. [92]

This multicenter randomized clinical trial conducted between October and December 2020 in 4 ICUs evaluated the effect of at least 48 hours of continuous treatment with helmet ventilation (initial PEEP 10–12 cm H2O; initial pressure support 10–12 cm H2O), followed by continuous Venturi mask or high-flow nasal oxygen (intervention group; n = 54), compared to high-flow nasal oxygen 60 L/min alone (control group; n =55).

Patients had a PCR-confirmed COVID-19 infection and moderate to severe hypoxemic respiratory failure (PaO2/FIO2 < 200).

Results in the intervention group compared to the control group:

  • Primary outcome: no difference in median days free of respiratory support [20 (IQR 0–25) vs. 18 days (0–22), P = 0.26]
  • Secondary outcomes:
    • Lower rate of endotracheal intubation within 28 days of hospitalization in intervention group of 30% vs. 51% (OR, 0.41; 95% CI, 0.18 to 0.89)
    • No difference in mortality rates at 28 and 60 days and mean duration of stay
  • Safety endpoints: no difference in the median hours to intubation and no need for emergency intubation in either group.

Limitations include that, due to the relatively small sample size, the study may have been underpowered to detect differences in the primary outcome. These results cannot be generalized to patients with respiratory failure from causes other than COVID-19.

The take‑home message?

Results from this study show that in patients with moderate/severe hypoxemia, helmet ventilation compared to high flow nasal oxygen alone was not associated with a reduced number of respiratory support days. However, results suggest that helmet ventilation may prevent the necessity of endotracheal intubation within 28 days of hospitalization, but this result requires confirmation by future trials.

  • Title of study: Effect of helmet noninvasive ventilation vs high-flow nasal oxygen on days free of respiratory support in patients with COVID-19 and moderate to severe hypoxemic respiratory failure [93]
  • Authors: Grieco DL et al.
  • Journal: JAMA
  • AMBOSS links: COVID-19

Your Easter edition: Rabbit fever, baskets and eggs!

One-Minute Telegram 22-2021-1/3

Rabbit fever – If the Killer Rabbit of Caerbannog has taught us anything [94], it’s that a cottontail’s adorable appearance can be deceptive, but it isn’t just its bite that’s potentially deadly. Rabbit fever, or tularemia, is a vector-borne disease predominantly transmitted by ticks and caused by the bacteria Francisella tularensis, for whom rabbits are a common reservoir host. A recent case report by Lukas Antonitsch and colleagues narrates the case of a 53-year-old man who presented with a 3-week history of fever, diarrhea, vomiting, cough, and significant weight loss unresponsive to supportive measures. [95] While the patient did not report attacks by ferocious rabbits or ravenous ticks, a more detailed investigation of his history revealed that he had been working in the woods over the past 6 weeks. Accordingly, a diagnosis was suspected and serological testing with ELISA confirmed the presence of IgG and IgM antibodies against F. tularensis. This case report highlights the importance of proper history taking when it comes to patients with fever of unknown origin – and of keeping rabbit fever in mind as a differential diagnosis, considering its very variable manifestations (e.g., ulceroglandular, glandular, oculoglandular, pharyngeal, pulmonary, typhoid).

Are your baskets ready? – Word around town is the Easter Bunny is already busy decorating eggs and we’re all itching to go hunt them! But what if the Easter Bunny gets COVID-19?! There is plenty of evidence that animals (e.g., minks) are susceptible to SARS-CoV-2 infection and that some may even develop symptoms. [96][97] But what about bunnies? Anna Z. Mykytyn and colleagues recently conducted an experimental study to determine the response of rabbits to inoculation with SARS-CoV-2 and found that, while no rabbits developed symptoms, they were indeed susceptible to infection. [98] However, transmission between themselves and to other species is yet to be determined. In conclusion, we probably shouldn’t be all too concerned about the Easter Bunny developing COVID-19, nor do we believe the Easter Bunny poses much of a risk to humans, considering his shy and sneaky nature. However, we would greatly appreciate Dr. Fauci’s opinion just to be sure!

The take‑home message?

If you are getting ready to hunt for eggs this Easter, try not to get bitten by ticks (or killer rabbits) and, as always, take a look at the CDC holiday tips to protect yourself and your loved ones against SARS-CoV-2 infection. [99]

Combination of remdesivir and baricitinib in fighting COVID-19

One-Minute Telegram 22-2021-2/3: So far, dexamethasone is the only drug that has clearly been shown to reduce mortality in severe COVID-19, most likely due to its antiinflammatory effects. [78][100] This has inspired research into the effects of other immunosuppressants as well. One such candidate is baricitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2 that inhibits the intracellular signaling pathway of cytokines, which are known to be elevated in patients with severe COVID-19.

In this multicenter study, 1033 hospitalized patients with moderate or severe COVID-19 were randomized to receive either a combination treatment with remdesivir and baricitinib (n = 515) or remdesivir and placebo (n = 518). The primary outcome measure was the time to recovery.

Patients who received the combination treatment with remdesivir and baricitinib showed the following results in comparison to those receiving remdesivir alone:

  • Shorter median time to recovery: 7 days versus 8 days (rate ratio, 1.16; 95% CI, 1.01 to 1.32) and 10 days versus 18 days in patients who were receiving high-flow oxygen or noninvasive ventilation at enrollment (rate ratio, 1.51; 1.10 to 2.08). This beneficial effect was not seen in patients receiving low-flow oxygen or no oxygen at baseline.
  • Higher odds of improved clinical status at day 15 (OR, 1.3; 1.0 to 1.6)
  • Lower frequency of serious adverse events (16.0% vs. 21.0%; P = 0.03)
  • Lower incidence of new use of oxygen (difference, -17.4%; -31.6 to -2.1) and new use of mechanical ventilation or ECMO (difference, -5.2%; -9.5 to -0.9)
  • Lower 28-day mortality 5.1% vs. 7.8%, though this did not reach statistical significance (HR for death, 0.65; 0.39 to 1.09)

Limitations of this study include the fact that it was not powered to detect differences in mortality between the two groups and the lack of follow-up on potential longer-term drug effects beyond 28 days.

The take‑home message?

This study showed that a combination of remdesivir and baricitinib compared to remdesivir monotherapy reduced the median time to recovery in hospitalized patients with COVID-19, with the highest efficacy seen in patients receiving high-flow oxygen or noninvasive ventilation at baseline. Combination therapy was also associated with a reduced need for respiratory support and lower incidence of serious short-term adverse events. Further studies are needed to assess the effect of baricitinib PLUS remdesivir on mortality and to compare the efficacy, safety, and cost-effectiveness of baricitinib with that of dexamethasone.

Recolonizing the colon: New treatment for recurrent Clostridioides difficile infection

One-Minute Telegram 22-2021-3/3: Fecal microbiota transplantation (FMT) is a highly effective therapy for recurrent C. difficile infection, but carries a certain risk of infection transmission (e.g., pathogenic E. coli), besides being potentially unpleasant. [102] Now, a safer and possibly more appealing way to reconstitute the gut microbiome has been developed. The Microbial Ecosystem Therapeutic 2 (MET-2) is an encapsulated formulation of 40 bacterial species that were extracted from the stool of a healthy donor and subsequently highly purified and cultured independently of donor stool.

In this phase 1, open-label, single-group study, 19 patients with mild or moderate recurrent C. difficile infection received an oral course of treatment with MET-2 after completing initial treatment with oral vancomycin. Of these, 15 participants (79%) showed absence of recurrent C. difficile infection at day 40. The four patients who did not respond to initial treatment were retreated with a higher dose of MET-2. Three of these did not experience recurrence of C. difficile at 30 days following retreatment. By day 130 of the initial treatment 16 of 19 patients (84%) did not experience C. difficile recurrence.

No serious adverse events, MET-2-associated infections, or deaths were observed.

Limitations include the absence of a control group, the small sample size, and lack of longer-term follow-up.

The take‑home message?

In this small, industry sponsored phase-1 trial, MET-2, a highly purified orally administered mix of gut bacteria was shown to be well-tolerated and effective in treating recurrent C. difficile infection. Randomized-controlled studies are required to confirm these results and to compare the efficacy of MET-2 against that of FMT.

  • Title of study: The effect of a microbial ecosystem therapeutic (MET-2) on recurrent Clostridioides difficile infection: a phase 1, open-label, single-group trial [103]
  • Authors: Kao D et al.
  • Journal: Lancet Gastroenteroly & Hepatology

Do antibodies against SARS-CoV-2 protect against reinfection?

One-Minute Telegram 21-2021-1/3 - Case reports on COVID-19 reinfection raise the question of whether or not SARS-CoV-2 antibodies from a previous infection provide long-term immunity. [104]

Using laboratory data from 3,257,478 US patients, this retrospective cohort study attempted to determine if previous exposure to SARS-CoV-2 (defined as an initial positive antibody test) resulted in protection against future infection as confirmed by nucleic acid amplification test (NAAT). At baseline, 88.3% of patients had negative and 11.6% had positive antibody test results. From day 0 to 30, initially seropositive patients were more likely to have positive NAAT results, probably due to continued viral shedding (ratio 2.85; 95% CI, 2.73–2.97). After 30 days of follow-up, however, patients who were initially seropositive became much less likely than initially seronegative patients to have positive NAAT for SARS-CoV-2:

  • Day 31–60: ratio 0.67; 95% CI, 0.6–0.74
  • Day 61–90: ratio 0.29; 95% CI, 0.24–0.35
  • After day 90: ratio 0.10; 95% CI, 0.05–0.19

Limitations include a lack of data regarding possible differences in viral exposure between the groups. In addition, patients’ awareness of their initial serological test result may have influenced their behavior, including their engagement in social activities and motivation to seek further tests. Furthermore, the study did not provide information on whether positive NAAT results in either group were associated with the development of symptoms.

The take‑home message?

Results from this large study with over 3 million participants suggest that patients who are seropositive for SARS-CoV-2 have a decreased risk of future SARS-CoV-2 infection. However, the duration of immunity from infection remains to be determined.

  • Title of study: Association of SARS-CoV-2 seropositive antibody test with risk of future infection [105]
  • Authors: Harvey RA et al.
  • Journal: JAMA Internal Medicine
  • AMBOSS links: COVID-19

Amoxicillin-clavulanate: An alternative to fluoroquinolones in treating diverticulitis?

One-Minute Telegram 21-2021-2/3 - Concerns over the adverse effects of fluoroquinolones have led the FDA to advise restricting their use to conditions for which there is no equivalent treatment. However, data regarding the comparative effectiveness of fluoroquinolones and other antibiotics in various infections is scarce. [106]

This retrospective study compared the outpatient treatment of diverticulitis with a combination of metronidazole and fluoroquinolone (n = 124,000) vs. amoxicillin-clavulanate (n = 15,869) in immunocompetent patients, measuring the risks for admission, urgent surgery, and Clostridium difficile infection over the following year and the need for elective surgery over the following 3 years.

There was no difference between the groups in 1-year admission risk, 1-year urgent surgery risk, or 3-year elective surgery risk. In the subgroup of patients aged over 65 years, the 1-year risk of infection with C. difficile was slightly higher for patients treated with metronidazole and fluoroquinolone (risk difference 0.6%; 95% CI, 0.2–1.0).

Limitations include the retrospective study design based on insurance claims, which may have led to residual confounding as a result of missing data on potentially relevant patient characteristics. In addition, the study did not report on adverse effects associated with these antibiotics (e.g., drug-induced liver injury from amoxicillin-clavulanate).

The take‑home message?

This retrospective study showed that outpatient treatment of diverticulitis with amoxicillin-clavulanate was as effective as treatment with metronidazole and fluoroquinolone, providing a safe alternative to fluoroquinolones. However, randomized-controlled studies are needed to verify these results.

Effects of a diet with a high glycemic index and glycemic load on cardiovascular events and death

One-Minute Telegram 21-2021-3/3 - The glycemic index (GI) reflects the glucose-raising effect of any carbohydrate relative to the glucose-raising effect of glucose, while the glycemic load (GL) accounts for both the GI and the quantity of carbohydrates consumed. High-GI and high-GL diets have been linked to diabetes and cardiovascular disease (CVD) in high-income countries; however, this association has not been studied as extensively in other regions of the world. [108]

The present study included 137,851 individuals living in high-, middle-, and low-income countries across five continents. The GI and GL of their diets were estimated using questionnaires, and participants were followed for a median of 9.5 years. During this period, the investigators recorded 8,780 deaths and 8,252 major cardiovascular events.

A high-GI diet was associated with an increased risk of a major cardiovascular event or death. This association was seen in participants with preexisting CVD (HR 1.51; 95% CI, 1.25–1.82) as well as in those without preexisting CVD (HR 1.21; 1.11–1.34). In participants with preexisiting CVD, a high-GL diet was likewise associated with major cardiovascular events and death (HR 1.34; 1.08-1.67).

Limitations of this study include the reliance on self-reported dietary intake data and the questionnaire’s limited scope. In addition, the number of participants per country was too low to permit regional analyses.

The take‑home message?

This international study shows that a high-GI and high-GL diet is associated with an increased risk of major cardiovascular events and death. It furthermore provides evidence that this association is not limited to high-income countries.

  • Title of study: Glycemic index, glycemic load, and cardiovascular disease and mortality [109]
  • Authors: Jenkins DJA et al.
  • Journal: NEJM

Better outcomes after implementation of critical care management protocols?

One-Minute Telegram 20-2021-1/3 - An effective pharmacological therapy for COVID-19 remains elusive, but clinical experience in the critical care of other respiratory conditions may lead the way in establishing management protocols for SARS-CoV-2 infection.

This multi-center retrospective cohort US study determined the 28-day outcomes of 147 critically ill patients with COVID-19 to evaluate the impact of an evidence-based management protocol for respiratory failure and ARDS (n=54) compared to standard ICU care (n=93). The primary outcome was ventilator-free days. [110]

The study found the following benefits in patients treated according to the evidence-based management protocol:

Limitations include potential differences not accounted for between the groups, given that patients came from hospitals serving different populations and with different standards for ICU care. In addition, the retrospective design of this study makes it susceptible to bias and residual confounding and limits the ability to attribute superior outcomes to protocol implementation.

The take‑home message?

In this study, ICU patients with COVID-19 who were treated with an evidence-based respiratory management protocol had lower mortality, more ventilator-free days, and less need for renal replacement therapy compared to those treated with standard ICU care during a 28-day observation. While it remains to be seen which parts of the protocol benefited the patients most, it is good news that the experience of intensive care medicine translates into measurable benefits in the treatment of COVID-19.

Hepatitis C vaccine: The search continues

One-Minute Telegram 20-2021-2/3 - Chronic hepatitis C virus (HCV) infection is a leading cause of death worldwide, and incidence has sharply increased in the United States, in part due to the opioid crisis. Although there are drugs that can cure HCV infection, treatment regimens last for 8–12 weeks and require strict adherence, which is frequently lacking in high-risk groups. The advent of a vaccine would be a game-changer in the fight against HCV, especially in at-risk patient groups. [112][113][114]

This double-blinded study used a heterologous prime-boost immunization strategy, based on a recombinant chimpanzee adenovirus and an attenuated poxvirus vaccine. 548 HCV-uninfected adults who had injected drugs within 90 days before study participation were randomly assigned in a 1:1 ratio to the vaccine or placebo group. Both groups received an intramuscular injection on days 0 and 56 of the study, containing either the vaccine or placebo.

At 9 months follow-up, 14 participants in each group had developed chronic HCV infection defined as persistent viremia for 6 months (HR [vaccine vs. placebo] 1.53; 95% CI, 0.66-3.55). However, T-cell responses to HCV were present in 78% of participants in the vaccine group but only in 3% of participants in the placebo group. There were no reports of vaccine-related serious adverse events.

Limitations of this study include the fact that, while groups were stratified by sex, men were significantly overrepresented (78%).

The take‑home message?

The HCV vaccine candidate evaluated in this study elicited HCV-specific T-cell responses but failed to prevent chronic HCV infection. The search for an HCV-vaccine, therefore, remains ongoing.

Semaglutide helps reduce weight – in patients without diabetes

One-Minute Telegram 20-2021-3/3 - Semaglutide is a modified human glucagon-like peptide-1 (GLP-1) analogue that has been approved and successfully used to reduce weight, improve glycemic control, and reduce adverse cardiovascular events in patients with type 2 diabetes. Whether the positive effects of the drug extend to patients without type 2 diabetes has been a matter of ongoing research. [116][117]

In this double-blinded international trial, 1961 adults without diabetes and a body-mass index of 30 or greater (or ≥ 27 in persons with ≥ 1 weight-related coexisting condition) were randomized in a 2:1 ratio for 68 weeks of treatment with a once-weekly dose of 2.4 mg subcutaneous semaglutide or placebo. All participants additionally received counseling sessions targeting lifestyle interventions.

At week 68, patients in the semaglutide group had lost 14.9% of their body weight compared to 2.4% in the placebo group (treatment difference of -12.4% [95% CI, -13.4 to -11.5; P < 0.001]). Compared to patients in the placebo group, patients in the semaglutide group were more likely to achieve body weight reductions of ≥ 5% (86.4% vs. 31.5%), ≥ 10% (69.1% vs. 12.0%), and ≥ 15% (50.5% vs. 4.9%) during the study period (P < 0.001 for all three comparisons of odds). In addition, physical functioning scores (SF-36) improved significantly in the semaglutide group (P < 0.001).

Adverse events were mild to moderate, with gastrointestinal side-effects (i.e., nausea, diarrhea) sometimes leading to termination of participation in the semaglutide group.

Limitations include the lack of long-term follow-up and the high percentage of female (74.1%) and white participants (75.1%) included in the study.

The take‑home message?

In this randomized double-blinded trial the use of once weekly semaglutide in obese and overweight patients without diabetes led to clinically significant weight loss. However, longer-term follow-up is necessary to determine whether the treatment effect lasts and whether semaglutide also improves cardiovascular outcomes in this population.

  • Title of study: Once-weekly semaglutide in adults with overweight or obesity [118]
  • Authors: Wilding JPH et al.
  • Journal: NEJM

Anticoagulation in COVID-19 – does it affect mortality?

One-Minute Telegram 19-2021-1/3 - Early in the pandemic, reports of high rates of venous and arterial thromboembolism gave rise to recommendations for empiric therapeutic anticoagulation in critically ill patients with COVID-19. However, comprehensive data regarding the effects of therapeutic anticoagulation on mortality has remained scarce. [119][120]

This multicenter US cohort study analyzed the incidence of venous thromboembolism (VTE) and major bleeding in patients with COVID-19 within 14 days of admission to an intensive care unit (ICU). Of 3239 critically ill patients with COVID-19 who were included, 43.6% received therapeutic anticoagulation, 6.3% developed VTE, and 2.8% developed major bleeding.

In addition, the investigators performed a target trial emulation that compared survival in patients who had received therapeutic anticoagulation within 2 days of ICU admission to survival in those who had not. [121] Of the 2809 patients included in the analysis, 11.9% received early therapeutic anticoagulation. During follow-up (median of 27 days), the risk of death did not differ significantly between patients who received early therapeutic anticoagulation and those who did not (HR 1.12; 95% CI, 0.92–1.35).

Limitations of this study include observational design, heterogeneous anticoagulation dosing across study centers, and lack of data regarding reasons for the timing of anticoagulation in individual patients. Moreover, lack of specific screening may have led to underestimation of VTE rates.

The take‑home message?

This observational multicenter study reported 6.3% VTE and 2.8% major bleeding incidence among ICU-admitted COVID-19 patients of whom 43.6% had received therapeutic anticoagulation. A target trial emulation showed that early therapeutic anticoagulation did not reduce the risk of death compared to late or no therapeutic anticoagulation. Although the results aid our understanding of the role and timing of therapeutic anticoagulation in COVID-19 patients, they still require confirmation by randomized clinical trials.

  • Title of study: Thrombosis, bleeding, and the observational effect of early therapeutic anticoagulation on survival in critically ill patients with COVID-19 [122]
  • Authors: Al-Samkari H, et al.
  • Journal: Annals of Internal Medicine
  • AMBOSS links: COVID-19

The long shadow of COVID-19: Respiratory and functional sequelae in survivors

One-Minute Telegram 19-2021-2/3 - Evidence is mounting that COVID-19 has long-term sequelae ranging from neurological symptoms to persistent fatigue and lung damage. [123] However, large case series on this new entity termed “long COVID” remain scarce. [124]

This Italian case series included 238 hospitalized patients with severe COVID-19 and assessed pulmonary function, functional impairment, and psychological sequelae 4 months after discharge.

After 4 months, diffusing lung capacity for carbon monoxide (DLCO) was measured in 219 patients. Results showed a DLCO < 80% of normal capacity in 51.6% of patients and a DLCO < 60% of normal capacity in 15.5% of patients.

53.8% of patients showed some degree of functional impairment as measured by a Short Physical Performance Battery (SPPB) and, in some cases, a 2-minute walk test. Moderate or severe posttraumatic stress symptoms were reported in 17.2% of patients. Ageusia was present in 5.0%, anosmia in 4.6%, and arthralgia and myalgia in 5.9% of patients.

Limitations of this study include a high risk of selection bias, as 64.4% of eligible patients wished not to participate. Also, since only hospitalized patients with severe COVID-19 were included, the results cannot be generalized to other populations. Lastly, neurological symptoms were not specifically tested even though they are common and may have contributed to functional impairment. [125]

The take‑home message?

In this case series of patients who had been hospitalized for COVID-19, more than half showed reduced lung function (tested with DLCO) and functional impairments at 4 months after discharge. Posttraumatic stress symptoms were reported in almost one-fifth of patients, while ageusia, anosmia, arthralgias, and myalgias were less frequent. This report contributes to specifying the emerging entity termed “long COVID,” but comprehensive analyses and definitions are still lacking.

  • Title of study: Respiratory and psychophysical sequelae among patients with COVID-19 four months after hospital discharge [84]
  • Authors: Bellan M, et al.
  • Journal: JAMA Network Open
  • AMBOSS links: COVID-19

Your Valentine’s Day edition: Of broken hearts, happy hearts, and STIs

One-Minute Telegram 19-2021-3/3

Don’t go breaking my heart – Severe physical and emotional stress can literally break your heart or, as a physician might say, cause Takutsubo syndrome (TTS) – a ballooning of the ventricles that eventually leads to acute systolic heart failure. [126] TTS is typically thought to occur secondary to stressors such as negative life events; and – as if evidence of an association between COVID-19 and increased risk of cardiomyopathy weren’t enough – it now appears that the burden of the pandemic may be another such stressor. A recent case series by Devika Kir and colleagues discussed two women who presented with TTS. Upon questioning the first patient reported extreme emotional distress caused by social isolation, while the second was distressed by her inability to access routine healthcare. [127] The association of pandemic stress and TTS was confirmed by a recent retrospective cohort study by Ahmad Jabri and colleagues, which found that the incidence of TTS among patients presenting with acute coronary syndrome increased from 1.5–1.8% pre-pandemic to 7.8% during the pandemic (rate ratio = 4.58; 95% CI, 4.11–5.11). This increase was not attributable to SARS-CoV-2 infection, since all patients in the study were PCR negative. [128] Turns out the owner of a lonely heart is also at risk of owning a broken heart.

Happy heart syndrome – Can a heart also break from happiness? The short answer is: yes. Jelena R. Ghadri and colleagues studied data from the International Takotsubo Registry to determine whether there was an association between positive emotional stress and TTS. Of the 1750 patients with TTS included in the study, 485 reported a definite emotional trigger prior to the diagnosis, with 20 (4.1%) reporting a positive emotional trigger such as winning a jackpot, attending celebrations like birthday parties and weddings, or reveling in one's favorite driver winning a race. [129] Sure, we’re all eager for the COVID-19 restrictions to end, but maybe we shouldn’t get too excited when they actually do?

Love bites – The consequences of love are many and, unfortunately, include sexually transmitted infections (STIs). But what effect has the advice to stay home, keep your distance, and cover up infectious orifices had on the incidence of STIs? A study by Matthew A. Crane and colleagues looked at CDC data from 2020 and found that the mean number of reported cases of chlamydia and gonorrhea declined after week 11, near the date when the COVID-19 outbreak was declared a national emergency. [130] You might think this was a cause for celebration, heightened only by the fact that almost every other notifiable disease showed a decrease in reported cases during this period as well. But – and we do hope this emotional roller coaster ride won't give anyone TTS – it turns out the news is not so good after all. Rather than reduced transmission, the authors concluded that reduced testing and reporting were more likely responsible for the decrease in numbers.

The take‑home message?

This Valentine's Day don't go breaking any hearts, try to fall madly in love (just don’t get too emotional about it), and barrier-protect the ones you fall in love with!

Online harassment – how are physicians affected?

One-Minute Telegram 18-2021-1/3 - With social media today spanning all walks of life, online harassment has become a problem that affects all of society. As a professional group faced with moral decisions on a daily basis, physicians have always been exposed to their fair share of controversy, but how has social media changed the discourse, and what are the issues stirring the most controversy today?

This report discusses an online survey of 464 participants who self-identified as physicians, 57.8% of which were women and 76.9% of which were white. Nearly one-quarter of participants (23.3%) reported personal harassment on social media over the topics of vaccines (n=10), race (n=4), religion (n=3), gun control (n=3), abortion (n=2), and smoking (n=2), with no significant difference between men and women. However, women were significantly more likely than men to report online sexual harassment (16.4% vs 1.5%, P < 0.001), i.e., explicit messages (n=12) and threats of assault (n=2).

Limitations of the study include the high risk of a reporting and selection bias, as participants were recruited from the study authors’ Twitter followers; the self-report design of the study, which makes it impossible to confirm the accounts of harassment; and the fact that the majority of participants was white, limiting the generalizability of the results.

The take‑home message?

This report strongly suggests that physicians are no exception with regard to the harassment people face in social media. While anti-vaccination stances are a common trigger, harassment over non-medical issues such as race, religion, and gun control are also prevalent. Moreover, female physicians experience sexual harassment more frequently than their male colleagues, reflecting a similar situation in other areas of social and professional life. A more representative examination is needed to assess the extent of the problem in detail and to determine what actions should be taken to address it.

  • Title of study: Prevalence of personal attacks and sexual harassment of physicians on social media [131]
  • Authors: Pendergrast TR et al.
  • Journal: JAMA Internal Medicine

Transfusion of plasma with high antibody levels could reduce mortality in COVID-19 – if the timing is right

One-Minute Telegram 18-2021-2/3 - The evidence on whether the transfusion of plasma with anti-SARS-CoV-2 IgG antibodies reduces mortality in COVID-19 has so far been inconclusive, and there are no established protocols regarding the timing of the transfusion and the levels of antibodies required. [132]

This retrospective cohort study assessed the 30-day mortality of 3082 patients with COVID-19 who had received one unit of convalescent plasma with either low, medium, or high anti-SARS-CoV-2 IgG antibody levels. Demographic characteristics, risk factors associated with severe COVID-19, and concomitant use of therapeutic agents were similar in all three groups.

Among patients who were not on mechanical ventilation, those who received plasma with high levels of antibodies had a significantly lower 30-day mortality than those who received plasma with low levels of antibodies (RR 0.66; 95% CI, 0.48 to 0.91). Unadjusted mortality rates were lower for patients who received the transfusion within the first three days of COVID-19 diagnosis, compared to patients who received the transfusion ≥ 4 days after diagnosis (22.2% vs. 29.5%, respectively).

No effect on mortality was observed in patients who were on mechanical ventilation at the time of plasma transfusion.

Limitations include the retrospective design and the lack of a control group for comparison.

The take‑home message?

Hospitalized patients with COVID-19 who are not on mechanical ventilation may benefit from receiving plasma transfusions with high levels of anti-SARS-CoV-2 IgG antibodies, especially if the treatment is provided within 3 days of diagnosis. However, further studies are needed to confirm this benefit.

New monoclonal antibody helps to reduce body fat in patients with type 2 diabetes

One-Minute Telegram 18-2021-3/3 - Acknowledging the association between obesity and increased insulin resistance, the FDA has approved a number of weight-loss drugs in recent years. [134][135]

The novel antibody bimagrumab was originally developed to treat pathological muscle loss and weakness in sporadic inclusion body myositis but failed to meet its primary endpoint in a phase IIb/III study. The present double-blinded, randomized phase II clinical trial has investigated the drug’s weight-loss effects in patients with type 2 diabetes who were not taking any weight-reducing drugs and who had HbA1c levels between 6.5% and 10% and a BMI between 28 and 40 kg/m2. [136]

75 patients were randomized 1:1 and received either bimagrumab (n = 37, 62.2% women) or a placebo (n = 38, 31.6% women) every 4 weeks for 48 weeks. Furthermore, patients in both groups were advised to follow a calorie-restricted diet and met with a registered dietitian in person at each monthly study visit.

At week 48, patients treated with bimagrumab showed a significant reduction in total body fat mass of -7.31 kg (80% CI: -8.48 to -6.14; P < 0 .001) more than the placebo group. In addition, body weight and HbA1c level were significantly reduced in the bimagrumab group compared to the placebo group (P < 0.001 and P = 0.005, respectively).

More patients experienced transient elevations of pancreatic and liver enzymes in the bimagrumab group, but the frequency of adverse and serious adverse events did not differ between groups.

Limitations of this study include the small sample size and a slight gender imbalance between the groups.

The take‑home message?

In this phase II trial, 48 weeks of treatment with the novel antibody bimagrumab combined with lifestyle interventions helped to significantly reduce total body fat mass, body weight, and HbA1c levels in overweight and obese patients with type 2 diabetes. If a phase III trial can replicate these positive results, bimagrumab could become a valuable addition to the arsenal of treatment for type 2 diabetes.

A CRISPR-Cas miracle? Report on two successful attempts at treatment

One-Minute Telegram 17-2021-1/3 - Hopes are high that selective gene-editing therapy with CRISPR-Cas9 can provide a curative and safe alternative to bone marrow transplant for patients with sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT). These reports discuss the use of CRISPR-Cas9 on autologous hematopoietic stem and progenitor cells (HSPCs) to reduce the expression of BCL11A, a transcription factor that suppresses the production of fetal hemoglobin. Two patients, one with SCD and the other with TDT, received the autologous CRISPR-Cas9–edited CD34 + HSPCs in a single transfusion following myeloablation with busulfan.

Serious adverse events were mostly related to severe neutropenia following myeloablation.

The take‑home message?

These two case reports demonstrate that CRISPR-Cas9 has evolved from the laboratory to become a real-world alternative in the treatment of monogenic hematological diseases. While large-cohort trials with long-term follow-up are needed to confirm the effects of treatment and assess adverse events, these reports already bear positive news for patients living with genetic diseases such as sickle cell disease and thalassemias.

COVID-19: The Moderna vaccine

One-Minute Telegram 17-2021-2/3 - The mRNA-1273 vaccine, developed by Moderna, relies on mRNA technology and is the second COVID-19 vaccine to receive emergency use approval by the FDA. [139][140]

A total of 30,420 participants aged 18 years or older were randomized 1:1 to receive either 2 doses of the vaccine or a placebo, 28 days apart. The mean age of the participants was 51.4 years; enrollment was adjusted for equal representation of racial and ethnic minorities.

  • Vaccine efficacy to prevent symptomatic COVID-19 with onset ≥ 14 days after the second injection was 94.1% (95% CI, 89.3% to 96.8%; 11 cases vs. 185 cases, respectively).
    • Efficacy was similar across age, sex, race, and ethnicity as well as in patients with and without risk factors for severe disease (e.g., chronic lung disease, cardiac disease, severe obesity).
    • There were no severe courses of COVID-19 (e.g., ARDS or shock) in the vaccine group, in contrast to the placebo group, in which 30 patients developed a severe course.
  • The safety profile was favorable.
    • The most common local reaction was mild to moderate pain at the injection site (reported in ∼ 75%). The most common systemic symptoms were fatigue, myalgia, arthralgia, and headache (reported in ∼ 50%).
    • The overall incidence of serious adverse events did not differ significantly between groups. No deaths occurred in relation to the vaccine.
    • Limitations include that the study was not powered to detect rare adverse events and that the long-term effects remain unknown. The exclusion of children, pregnant women, and immunocompromised patients limits the generalizability of the results.

The take‑home message?

This industry-sponsored study showed that the mRNA-1273 vaccine has a high efficacy and favorable safety profile (with the added benefit that it can be stored at 2–8°C). While this vaccine is already being administered, further investigations are necessary to establish safety and efficacy profiles for populations not included in this study as well as to assess its long term effects. [141]

COVID-19: Variation in hospital mortality rates across the US

One-Minute Telegram 17-2021-3/3 - Mortality from COVID-19 can be influenced by many factors, but does in-hospital mortality vary between hospitals, and has in-hospital mortality changed since the start of the pandemic? [143]

This cohort study used data from 38,517 adult patients with COVID-19 admitted to different hospitals in the US to analyze the differences in the hospital’s risk-standardized event rate (RSER), a composite of inpatient mortality or referral to hospice within 30 days of initial admission.

The overall mean RSER was 11.8% (SD 2.5%) but varied considerably across hospitals (ranging from 5.70% to 24.65%). There was no association between a hospital’s RSER and the number of intensive care unit beds, academic status, profit status, or urban/nonurban setting.

Changes in the RSER over time were assessed for a subset of 27,801 patients in 398 hospitals (n = 27,801; 72.2%). The mean RSERs improved from 16.56% (SD 3.99%) to 9.29% (SD 2.08%) between two study periods from January 1 to April 30, 2020, and May 1 to June 30, 2020. Worsening RSER was associated with an increase in the prevalence of COVID-19 in the hospital’s surrounding communities.

Limitations include that the data was based on a single insurer’s claims. Also, out-of-hospital mortality was not considered. Furthermore, the reasons for the decrease in mortality remain unclear.

The take‑home message?

Overall mortality or referral to hospice in COVID-19 patients decreased in US hospitals over the early course of the pandemic. Hospitals with higher mortality rates had a higher prevalence of COVID-19 in their area compared to hospitals with lower rates. However, further studies are needed to identify other underlying mechanisms for the improvement in mortality, as they may help to guide future hospital policies and treatment strategies.

COVID-19: The BioNTech-Pfizer vaccine is here. How safe and effective is it?

One-Minute Telegram 16-2021-1/2 - After much research and effort, a highly effective and specific treatment for COVID-19 has not been found, but in less than one year after starting development, vaccines are here and have been granted emergency use approval by the FDA. [145][146]

This blinded study presents the results of the mRNA-vaccine (BNT162b2) developed by BioNTech and Pfizer. A total of 43,548 participants were randomized to receive either 2 doses of the vaccine (n = 21,720) or a placebo (n =21,728) 21 days apart. Participant ages ranged from 16 to 91 years and 35.1% of participants were classified as having obesity. Comorbidities included HIV, malignancy, diabetes, and vascular diseases.

  • Vaccine efficacy was 95.0% (95% CI, 90.3–97.6), ≥ 7 days after the second vaccine dose (8 cases vs. 162 cases, respectively).
    • Efficacy was similar among different groups of age, sex, race, ethnicity, BMI, and comorbidities.
    • Severe COVID-19 occurred in one patient in the vaccine group, and nine patients in the placebo group.
  • The safety profile was favorable.
    • The most common local reaction was mild to moderate pain at the injection site. The most common systemic symptoms were fatigue and headache (reported in ≥ 50%).
    • The incidence of serious adverse events did not differ significantly between the vaccine and the placebo groups (0.6% and 0.5%, respectively) and no deaths occurred related to the vaccine.

Limitations include that the study was not powered to detect rare adverse events (like anaphylaxis) and that long-term effects are unknown. [147] Exclusion of children, pregnant women, and immunocompromised patients limits the generalizability of the results.

The take‑home message?

This industry-sponsored study showed that the mRNA-vaccine BNT162b2 is safe and effective in protecting against COVID-19. However, further investigations are needed to confirm if protection is similar between different groups within the studied population, if the vaccine could limit severe disease in people who do get infected, and to establish safety and efficacy for populations not included in this study.

Impact of race and ethnicity on COVID-19 outcomes: what is driving the death rate?

One-Minute Telegram 16-2021-2/2 - Black and Hispanic populations are more affected by COVID-19, but are race and ethnicity independently driving these disproportionately high death rates? [149]

The aim of this retrospective cohort study was to compare the outcome of patients with COVID-19 based on race and ethnicity. Data from 9,722 patients in an integrated health-care system in New York City was used to explore the effect of race and ethnicity on the likelihood of having PCR positive COVID-19 and subsequently worse health outcomes, after adjusting for age, sex, insurance, and comorbidity.

  • Race or ethnicity were independent risk factors for testing positive for COVID-19 for black (adjusted OR 1.3; 95% CI, 1.2-1.6) and Hispanic patients (adjusted OR 1.5; 1.3–1.7), compared to white patients.
  • Among positive patients, Asian patients had the highest likelihood of hospitalization (adjusted OR 1.6; 1.1–2.3). Hispanic, black, and white patients had a similar likelihood of being hospitalized.
  • Black patients were less likely to have critical illness (adjusted OR 0.6; 0.4–0.8) and also had a lower risk of death compared with white patients (HR, 0.7; 0.6–0.9); the likelihood among Hispanic, Asian, and white patients was similar.

Limitations include that data on the final outcome was not available for 4.5% of the patients at the end of the study period.


The take‑home message?

Black and Hispanic patients had a higher likelihood than white patients of testing positive for COVID-19. However, once hospitalized, their health outcomes were similar to or better than white patient outcomes. So why then is their non-adjusted, general risk of death due to COVID-19 higher? The authors' hypothesis: social determinants of health increase the probability of contracting the disease and barriers to seeking healthcare increase the number of deaths occurring at home. [150]

  • Title of study: Assessment of racial/ethnic disparities in hospitalization and mortality in patients with COVID-19 in New York City [151]
  • Authors: Ogedegbe et al.
  • Journal: JAMA Network Open
  • AMBOSS links: COVID-19
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