Interleukin-1 Receptor Antagonist Gene (IL1RN) Variants Modulate the Cytokine Release Syndrome and Mortality of COVID-19.

BACKGROUND: We examined effects of single-nucleotide variants (SNVs) of IL1RN, the gene encoding the anti-inflammatory interleukin 1 receptor antagonist (IL-1Ra), on the cytokine release syndrome (CRS) and mortality in patients with acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: IL1RN CTA haplotypes formed from 3 SNVs (rs419598, rs315952, rs9005) and the individual SNVs were assessed for association with laboratory markers of inflammation and mortality. We studied 2589 patients hospitalized with SARS-CoV-2 between March 2020 and March 2021. RESULTS: Mortality was 15.3% and lower in women than men (13.1% vs 17.3%, P = .0003). Carriers of the CTA-1/2 IL1RN haplotypes exhibited decreased inflammatory markers and increased plasma IL-1Ra. Evaluation of the individual SNVs of the IL1RN, carriers of the rs419598 C/C SNV exhibited significantly reduced inflammatory biomarker levels and numerically lower mortality compared to the C/T-T/T genotype (10.0% vs 17.8%, P = .052) in men, with the most pronounced association observed in male patients ≤74 years old, whose mortality was reduced by 80% (3.1% vs 14.0%, P = .030). CONCLUSIONS: The IL1RN haplotype CTA and C/C variant of rs419598 are associated with attenuation of the CRS and decreased mortality in men with acute SARS-CoV-2 infection. The data suggest that the IL1RN pathway modulates the severity of coronavirus disease 2019 (COVID-19) via endogenous anti-inflammatory mechanisms.

Emergence and dissemination of SARS-CoV-2 XBB.1.5 in New York.

The recombinant SARS-CoV-2 Omicron XBB.1.5 variant was first detected in New York City (NYC) and rapidly became the predominant variant in the area by early 2023. The increased occurrence of circulating variants within the SARS-CoV-2 XBB-sublineage prompted the modification of COVID-19 mRNA vaccines by Moderna and Pfizer-BioNTech. This update, implemented in mid-September 2023, involved the incorporation of a monovalent XBB.1.5 component. Considering that NYC probably played a central role in the emergence of the XBB.1.5 variant, we conducted phylogeographic analysis to investigate the emergence and spread of this variant in the metropolitan area. Our analysis confirms that XBB.1.5 emerged within or near the NYC area and indicates that XBB.1.5 had a diffusion velocity similar to that of the variant Alpha in the same study area. Additionally, the analysis of 2,392 genomes collected in the context of the genomic surveillance program at NYU Langone Health system showed that there was no increased proportion of XBB.1.5, relative to all cocirculating variants, in the boosted compared to unvaccinated individuals. This study provides a comprehensive description of the emergence and dissemination of XBB.1.5.

Contemporary Prevalence of Oral Clefts in the US: Geographic and Socioeconomic Considerations.

Background: Socio-economic status, living environments, and race have been implicated in the development of different congenital abnormalities. As orofacial clefting is the most common anomaly affecting the face, an understanding of its prevalence in the United States and its relationship with different determinants of health is paramount. Therefore, the purpose of this study is to determine the modern prevalence of oral-facial clefting in the United States and its association with different social determinants of health. Methods: Utilizing Epic Cosmos, data from approximately 180 US institutions were queried. Patients born between November 2012 and November 2022 were included. Eight orofacial clefting (OC) cohorts were identified. The Social Vulnerability Index (SVI) was used to assess social determinants of health. Results: Of the 15,697,366 patients identified, 31,216 were diagnosed with OC, resulting in a prevalence of 19.9 (95% CI: 19.7-20.1) per 10,000 live births. OC prevalence was highest among Asian (27.5 CI: 26.2-28.8) and Native American (32.8 CI: 30.4-35.2) patients and lowest among Black patients (12.96 CI: 12.5-13.4). Male and Hispanic patients exhibited higher OC prevalence than female and non-Hispanic patients. No significant differences were found among metropolitan (20.23/10,000), micropolitan (20.18/10,000), and rural populations (20.02/10,000). SVI data demonstrated that OC prevalence was positively associated with the percentage of the population below the poverty line and negatively associated with the proportion of minority language speakers. Conclusions: This study examined the largest US cohort of OC patients to date to define contemporary US prevalence, reporting a marginally higher rate than previous estimates. Multiple social determinants of health were found to be associated with OC prevalence, underscoring the importance of holistic prenatal care. These data may inform clinicians about screening and counseling of expectant families based on socio-economic factors and direct future research as it identifies potential risk factors and provides prevalence data, both of which are useful in addressing common questions related to screening and counseling.

Quantifying the impact of telemedicine and patient medical advice request messages on physicians' work-outside-work.

The COVID-19 pandemic has boosted digital health utilization, raising concerns about increased physicians' after-hours clinical work ("work-outside-work"). The surge in patients' digital messages and additional time spent on work-outside-work by telemedicine providers underscores the need to evaluate the connection between digital health utilization and physicians' after-hours commitments. We examined the impact on physicians' workload from two types of digital demands - patients' messages requesting medical advice (PMARs) sent to physicians' inbox (inbasket), and telemedicine. Our study included 1716 ambulatory-care physicians in New York City regularly practicing between November 2022 and March 2023. Regression analyses assessed primary and interaction effects of (PMARs) and telemedicine on work-outside-work. The study revealed a significant effect of PMARs on physicians' work-outside-work and that this relationship is moderated by physicians' specialties. Non-primary care physicians or specialists experienced a more pronounced effect than their primary care peers. Analysis of their telemedicine load revealed that primary care physicians received fewer PMARs and spent less time in work-outside-work with more telemedicine. Specialists faced increased PMARs and did more work-outside-work as telemedicine visits increased which could be due to the difference in patient panels. Reducing PMAR volumes and efficient inbasket management strategies needed to reduce physicians' work-outside-work. Policymakers need to be cognizant of potential disruptions in physicians carefully balanced workload caused by the digital health services.

Electronic Health Record Messaging Patterns of Health Care Professionals in Inpatient Medicine.

This cross-sectional study examines secure messaging patterns among health care professionals in the internal medicine inpatient setting.

Selective adaptation of SARS-CoV-2 Omicron under booster vaccine pressure: a multicentre observational study.

BACKGROUND: High rates of vaccination and natural infection drive immunity and redirect selective viral adaptation. Updated boosters are installed to cope with drifted viruses, yet data on adaptive evolution under increasing immune pressure in a real-world situation are lacking. METHODS: Cross-sectional study to characterise SARS-CoV-2 mutational dynamics and selective adaptation over >1 year in relation to vaccine status, viral phylogenetics, and associated clinical and demographic variables. FINDINGS: The study of >5400 SARS-CoV-2 infections between July 2021 and August 2022 in metropolitan New York portrayed the evolutionary transition from Delta to Omicron BA.1-BA.5 variants. Booster vaccinations were implemented during the Delta wave, yet booster breakthrough infections and SARS-CoV-2 re-infections were almost exclusive to Omicron. In adjusted logistic regression analyses, BA.1, BA.2, and BA.5 had a significant growth advantage over co-occurring lineages in the boosted population, unlike BA.2.12.1 or BA.4. Selection pressure by booster shots translated into diffuse adaptive evolution in Delta spike, contrasting with strong, receptor-binding motif-focused adaptive evolution in BA.2-BA.5 spike (Fisher Exact tests; non-synonymous/synonymous mutation rates per site). Convergent evolution has become common in Omicron, engaging spike positions crucial for immune escape, receptor binding, or cleavage. INTERPRETATION: Booster shots are required to cope with gaps in immunity. Their discriminative immune pressure contributes to their effectiveness but also requires monitoring of selective viral adaptation processes. Omicron BA.2 and BA.5 had a selective advantage under booster vaccination pressure, contributing to the evolution of BA.2 and BA.5 sublineages and recombinant forms that predominate in 2023. FUNDING: The study was supported by NYU institutional funds and partly by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center.

TRainee Attributable & Automatable Care Evaluations in Real-time (TRACERs): A Scalable Approach for Linking Education to Patient Care.

Competency-based medical education (CBME) is an outcomes-based approach to education and assessment that focuses on what competencies trainees need to learn in order to provide effective patient care. Despite this goal of providing quality patient care, trainees rarely receive measures of their clinical performance. This is problematic because defining a trainee's learning progression requires measuring their clinical performance. Traditional clinical performance measures (CPMs) are often met with skepticism from trainees given their poor individual-level attribution. Resident-sensitive quality measures (RSQMs) are attributable to individuals, but lack the expeditiousness needed to deliver timely feedback and can be difficult to automate at scale across programs. In this eye opener, the authors present a conceptual framework for a new type of measure - TRainee Attributable & Automatable Care Evaluations in Real-time (TRACERs) - attuned to both automation and trainee attribution as the next evolutionary step in linking education to patient care. TRACERs have five defining characteristics: meaningful (for patient care and trainees), attributable (sufficiently to the trainee of interest), automatable (minimal human input once fully implemented), scalable (across electronic health records [EHRs] and training environments), and real-time (amenable to formative educational feedback loops). Ideally, TRACERs optimize all five characteristics to the greatest degree possible. TRACERs are uniquely focused on measures of clinical performance that are captured in the EHR, whether routinely collected or generated using sophisticated analytics, and are intended to complement (not replace) other sources of assessment data. TRACERs have the potential to contribute to a national system of high-density, trainee-attributable, patient-centered outcome measures.

Novel Note Templates to Enhance Signal and Reduce Noise in Medical Documentation: Prospective Improvement Study.

BACKGROUND: The introduction of electronic workflows has allowed for the flow of raw uncontextualized clinical data into medical documentation. As a result, many electronic notes have become replete of "noise" and deplete clinically significant "signals." There is an urgent need to develop and implement innovative approaches in electronic clinical documentation that improve note quality and reduce unnecessary bloating. OBJECTIVE: This study aims to describe the development and impact of a novel set of templates designed to change the flow of information in medical documentation. METHODS: This is a multihospital nonrandomized prospective improvement study conducted on the inpatient general internal medicine service across 3 hospital campuses at the New York University Langone Health System. A group of physician leaders representing each campus met biweekly for 6 months. The output of these meetings included (1) a conceptualization of the note bloat problem as a dysfunction in information flow, (2) a set of guiding principles for organizational documentation improvement, (3) the design and build of novel electronic templates that reduced the flow of extraneous information into provider notes by providing link outs to best practice data visualizations, and (4) a documentation improvement curriculum for inpatient medicine providers. Prior to go-live, pragmatic usability testing was performed with the new progress note template, and the overall user experience was measured using the System Usability Scale (SUS). Primary outcome measures after go-live include template utilization rate and note length in characters. RESULTS: In usability testing among 22 medicine providers, the new progress note template averaged a usability score of 90.6 out of 100 on the SUS. A total of 77% (17/22) of providers strongly agreed that the new template was easy to use, and 64% (14/22) strongly agreed that they would like to use the template frequently. In the 3 months after template implementation, general internal medicine providers wrote 67% (51,431/76,647) of all inpatient notes with the new templates. During this period, the organization saw a 46% (2768/6191), 47% (3505/7819), and 32% (3427/11,226) reduction in note length for general medicine progress notes, consults, and history and physical notes, respectively, when compared to a baseline measurement period prior to interventions. CONCLUSIONS: A bundled intervention that included the deployment of novel templates for inpatient general medicine providers significantly reduced average note length on the clinical service. Templates designed to reduce the flow of extraneous information into provider notes performed well during usability testing, and these templates were rapidly adopted across all hospital campuses. Further research is needed to assess the impact of novel templates on note quality, provider efficiency, and patient outcomes.

Interleukin-1 receptor antagonist gene ( IL1RN ) variants modulate the cytokine release syndrome and mortality of SARS-CoV-2.

Objective: To explore the regulation of the inflammatory response in acute SARS-CoV-2 infection, we examined effects of single nucleotide variants (SNVs) of IL1RN , the gene encoding the anti-inflammatory IL-1 receptor antagonist (IL-1Ra), on the cytokine release syndrome and mortality. Methods: We studied 2589 patients hospitalized with SARS-CoV-2 between March 2020 and March 2021 at NYU Langone's Tisch Hospital. CTA and TTG haplotypes formed from three SNVs (rs419598, rs315952, rs9005) and the individual SNVs of the IL1RN gene were assessed for association with laboratory markers of the cytokine release syndrome (CRS) and mortality. Results: Mortality in the population was 15.3%, and was lower in women than men (13.1% vs.17.3%, p<0.0003). Carriers of the CTA-1/2 IL1RN haplotypes exhibited decreased inflammatory markers and increased plasma IL-1Ra relative to TTG carriers. Decreased mortality among CTA-1/2 carriers was observed in male patients between the ages of 55-74 [9.2% vs. 17.9%, p=0.001]. Evaluation of individual SNVs of the IL1RN gene (rs419598, rs315952, rs9005) indicated that carriers of the IL1RN rs419598 CC SNV exhibited lower inflammatory biomarker levels, and was associated with reduced mortality compared to the CT/TT genotype in men (OR 0.49 (0.23 - 1.00); 0.052), with the most pronounced effect observed between the ages of 55-74 [5.5% vs. 18.4%, p<0.001]. Conclusion: The IL1RN haplotype CTA, and sequence variant of rs419598 are associated with attenuation of the cytokine release syndrome and decreased mortality in males with acute SARS-CoV2 infection. The data suggest that IL1RN modulates the COVID-19 cytokine release syndrome via endogenous " anti-inflammatory" mechanisms. Significance statement: We provide evidence that variants of IL1RN modulate the severity of SARS-CoV-2 infection. The IL1RN CTA haplotype and rs419598 CC single nucleotide variant are associated with decreased plasma levels of inflammatory markers, interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), interleukin-2 (IL-2), C-reactive protein (CRP), D-dimer, ferritin, and procalcitonin, in association with higher levels of IL-1Ra and IL-10, anti-inflammatory proteins. Both haplotype CTA and rs419598 CC genotype are associated with a significant reduction in the mortality of men. These data provide genetic evidence that inflammasome activation and the IL-1 pathway plays an important role in the mortality and morbidity associated with severe SARS-CoV-2 infection, and that genetic regulation of inflammatory pathways by variants of IL1RN merits further evaluation in severe SARS-CoV-2 infection.

The Use of High-Dose Corticosteroids Versus Low-Dose Corticosteroids With and Without Tocilizumab in COVID-19 Acute Respiratory Distress Syndrome.

BACKGROUND: Corticosteroids and tocilizumab have been shown to improve survival in patients who require supplemental oxygen from coronavirus disease 2019 (COVID-19) pneumonia. The optimal dose of immunosuppression for the treatment of COVID-19 acute respiratory distress syndrome (ARDS) is still unknown. OBJECTIVE: The objective of this study was to evaluate the effectiveness and safety of high- versus low-dose corticosteroids with or without tocilizumab for the treatment of COVID-19 ARDS. METHODS: This was a retrospective study of patients admitted to the intensive care unit (ICU) requiring mechanical ventilation who received high- versus low-dose corticosteroids with or without tocilizumab. The primary outcome was survival to discharge. Safety outcomes included infections and incidence of hyperglycemia. RESULTS: In this cohort, 110 (54%) and 95 (46%) patients received high-dose (≥10 mg dexamethasone equivalent) and low-dose (<10 mg dexamethasone equivalent) corticosteroids for more than 3 consecutive days, respectively. Thirty-five patients (32%) in the high-dose group and 33 patients (35%) in the low-dose group survived to hospital discharge (P = 0.85). There was no difference in 28-day mortality in patients who received high-dose corticosteroids without tocilizumab compared with those who received low-dose corticosteroids with tocilizumab (n = 38/82, 46% vs n = 19/40, 48% P = 0.99); however, there was a higher mortality if patients received low-dose corticosteroids without tocilizumab (n = 39/55, 71%, P = 0.01). The highest rate of a bacterial pneumonia was in patients who received high-dose corticosteroids with tocilizumab. CONCLUSIONS: In critically ill patients with COVID-19 ARDS requiring mechanical ventilation, we found no difference in high- versus low-dose corticosteroids with regard to survival to hospital discharge. However, patients receiving only low-dose corticosteroids without tocilizumab did worse than the other groups. Larger prospective studies are needed to determine the optimal immunosuppression dosing strategy in this patient population.

Smoking Status, Nicotine Medication, Vaccination, and COVID-19 Hospital Outcomes: Findings from the COVID EHR Cohort at the University of Wisconsin (CEC-UW) Study.

INTRODUCTION: Available evidence is mixed concerning associations between smoking status and COVID-19 clinical outcomes. Effects of nicotine replacement therapy (NRT) and vaccination status on COVID-19 outcomes in smokers are unknown. METHODS: Electronic health record data from 104 590 COVID-19 patients hospitalized February 1, 2020 to September 30, 2021 in 21 U.S. health systems were analyzed to assess associations of smoking status, in-hospital NRT prescription, and vaccination status with in-hospital death and ICU admission. RESULTS: Current (n = 7764) and never smokers (n = 57 454) did not differ on outcomes after adjustment for age, sex, race, ethnicity, insurance, body mass index, and comorbidities. Former (vs never) smokers (n = 33 101) had higher adjusted odds of death (aOR, 1.11; 95% CI, 1.06-1.17) and ICU admission (aOR, 1.07; 95% CI, 1.04-1.11). Among current smokers, NRT prescription was associated with reduced mortality (aOR, 0.64; 95% CI, 0.50-0.82). Vaccination effects were significantly moderated by smoking status; vaccination was more strongly associated with reduced mortality among current (aOR, 0.29; 95% CI, 0.16-0.66) and former smokers (aOR, 0.47; 95% CI, 0.39-0.57) than for never smokers (aOR, 0.67; 95% CI, 0.57, 0.79). Vaccination was associated with reduced ICU admission more strongly among former (aOR, 0.74; 95% CI, 0.66-0.83) than never smokers (aOR, 0.87; 95% CI, 0.79-0.97). CONCLUSIONS: Former but not current smokers hospitalized with COVID-19 are at higher risk for severe outcomes. SARS-CoV-2 vaccination is associated with better hospital outcomes in COVID-19 patients, especially current and former smokers. NRT during COVID-19 hospitalization may reduce mortality for current smokers. IMPLICATIONS: Prior findings regarding associations between smoking and severe COVID-19 disease outcomes have been inconsistent. This large cohort study suggests potential beneficial effects of nicotine replacement therapy on COVID-19 outcomes in current smokers and outsized benefits of SARS-CoV-2 vaccination in current and former smokers. Such findings may influence clinical practice and prevention efforts and motivate additional research that explores mechanisms for these effects.

Sex differences in the prognostic value of troponin and D-dimer in COVID-19 illness.

BACKGROUND: Male sex, elevated troponin levels, and elevated D-dimer levels are associated with more complicated COVID-19 illness and greater mortality; however, while there are known sex differences in the prognostic value of troponin and D-dimer in other disease states, it is unknown whether they exist in the setting of COVID-19. OBJECTIVE: We assessed whether sex modified the relationship between troponin, D-dimer, and severe COVID-19 illness (defined as mechanical ventilation, ICU admission or transfer, discharge to hospice, or death). METHODS: We conducted a retrospective cohort study of patients hospitalized with COVID-19 at a large, academic health system. We used multivariable regression to assess associations between sex, troponin, D-dimer, and severe COVID-19 illness, adjusting for demographic, clinical, and laboratory covariates. To test whether sex modified the relationship between severe COVID-19 illness and troponin or D-dimer, models with interaction terms were utilized. RESULTS: Among 4,574 patients hospitalized with COVID-19, male sex was associated with higher levels of troponin and greater odds of severe COVID-19 illness, but lower levels of initial D-dimer when compared with female sex. While sex did not modify the relationship between troponin level and severe COVID-19 illness, peak D-dimer level was more strongly associated with severe COVID-19 illness in male patients compared to female patients (males: OR=2.91, 95%CI=2.63-2.34, p<0.001; females: OR=2.31, 95%CI=2.04-2.63, p<0.001; p-interaction=0.005). CONCLUSION: Sex did not modify the association between troponin level and severe COVID-19 illness, but did modify the association between peak D-dimer and severe COVID-19 illness, suggesting greater prognostic value for D-dimer in males with COVID-19.

Relations of Current and Past Cancer with Severe Outcomes among 104,590 Hospitalized COVID-19 Patients: The COVID EHR Cohort at the University of Wisconsin.

BACKGROUND: There is mixed evidence about the relations of current versus past cancer with severe COVID-19 outcomes and how they vary by patient and cancer characteristics. METHODS: Electronic health record data of 104,590 adult hospitalized patients with COVID-19 were obtained from 21 United States health systems from February 2020 through September 2021. In-hospital mortality and ICU admission were predicted from current and past cancer diagnoses. Moderation by patient characteristics, vaccination status, cancer type, and year of the pandemic was examined. RESULTS: 6.8% of the patients had current (n = 7,141) and 6.5% had past (n = 6,749) cancer diagnoses. Current cancer predicted both severe outcomes but past cancer did not; adjusted odds ratios (aOR) for mortality were 1.58 [95% confidence interval (CI), 1.46-1.70] and 1.04 (95% CI, 0.96-1.13), respectively. Mortality rates decreased over the pandemic but the incremental risk of current cancer persisted, with the increment being larger among younger vs. older patients. Prior COVID-19 vaccination reduced mortality generally and among those with current cancer (aOR, 0.69; 95% CI, 0.53-0.90). CONCLUSIONS: Current cancer, especially among younger patients, posed a substantially increased risk for death and ICU admission among patients with COVID-19; prior COVID-19 vaccination mitigated the risk associated with current cancer. Past history of cancer was not associated with higher risks for severe COVID-19 outcomes for most cancer types. IMPACT: This study clarifies the characteristics that modify the risk associated with cancer on severe COVID-19 outcomes across the first 20 months of the COVID-19 pandemic. See related commentary by Egan et al., p. 3.

Coinfections and antimicrobial use in patients hospitalized with coronavirus disease 2019 (COVID-19) across a single healthcare system in New York City: A retrospective cohort study.

Background and objective: With the coronavirus disease 2019 (COVID-19) pandemic, rates of in-hospital antimicrobial use increased due to perceived bacterial and fungal coinfections along with COVID-19. We describe the incidence of these coinfections and antimicrobial use in patients hospitalized with COVID-19 to help guide effective antimicrobial use in this population. Setting: This study was conducted in 3 tertiary-care referral university teaching hospitals in New York City. Methods: This multicenter retrospective observational cohort study involved all patients admitted with COVID-19 from January 1, 2020, to February 1, 2021. Variables of interest were extracted from a de-identified data set of all COVID-19 infections across the health system. Population statistics are presented as median with interquartile range (IQR) or proportions with 95% confidence intervals (CIs) as indicated. Results: Among 7,209 of patients admitted with COVID-19, 663 (9.2%) had a positive culture from the respiratory tract or blood sometime during their initial hospital admission. Positive respiratory cultures occurred found in 449 (6.2%) patients, and 20% were collected within 48 hours of admission. Blood culture positivity occurred in 334 patients (4.6%), with 33.5% identified within 48 hours of admission. A higher proportion of patients received antimicrobials in the first wave than in the later pandemic period (82.4% vs 52.0%). Antimicrobials were prescribed to 70.1% of inpatients, with a median of 6 antimicrobial days per patient. Infection-free survival decreased over the course of hospitalization. Conclusions: We detected a very low incidence of coinfection with COVID-19 at admission. A longer duration of hospitalization was associated with an increased risk of coinfection. Antimicrobial use far exceeded the true incidence and detection of coinfections in these patients.

The impact of COVID-19 monoclonal antibodies on clinical outcomes: A retrospective cohort study.

PURPOSE: Despite progress in the treatment of coronavirus disease 2019 (COVID-19), including the development of monoclonal antibodies (mAbs), more clinical data to support the use of mAbs in outpatients with COVID-19 is needed. This study is designed to determine the impact of bamlanivimab, bamlanivimab/etesevimab, or casirivimab/imdevimab on clinical outcomes within 30 days of COVID-19 diagnosis. METHODS: A retrospective cohort study was conducted at a single academic medical center with 3 campuses in Manhattan, Brooklyn, and Long Island, NY. Patients 12 years of age or older who tested positive for COVID-19 or were treated with a COVID-19-specific therapy, including COVID-19 mAb therapies, at the study site between November 24, 2020, and May 15, 2021, were included. The primary outcomes included rates of emergency department (ED) visit, inpatient admission, intensive care unit (ICU) admission, or death within 30 days from the date of COVID-19 diagnosis. RESULTS: A total of 1,344 mAb-treated patients were propensity matched to 1,344 patients with COVID-19 patients who were not treated with mAb therapy. Within 30 days of diagnosis, among the patients who received mAb therapy, 101 (7.5%) presented to the ED and 79 (5.9%) were admitted. Among the patients who did not receive mAb therapy, 165 (12.3%) presented to the ED and 156 (11.6%) were admitted (relative risk [RR], 0.61 [95% CI, 0.50-0.75] and 0.51 [95% CI, 0.40-0.64], respectively). Four mAb patients (0.3%) and 2.64 control patients (0.2%) were admitted to the ICU (RR, 01.51; 95% CI, 0.45-5.09). Six mAb-treated patients (0.4%) and 3.37 controls (0.3%) died and/or were admitted to hospice (RR, 1.61; 95% CI, 0.54-4.83). mAb therapy in ambulatory patients with COVID-19 decreases the risk of ED presentation and hospital admission within 30 days of diagnosis.

The first 20 months of the COVID-19 pandemic: Mortality, intubation and ICU rates among 104,590 patients hospitalized at 21 United States health systems.

MAIN OBJECTIVE: There is limited information on how patient outcomes have changed during the COVID-19 pandemic. This study characterizes changes in mortality, intubation, and ICU admission rates during the first 20 months of the pandemic. STUDY DESIGN AND METHODS: University of Wisconsin researchers collected and harmonized electronic health record data from 1.1 million COVID-19 patients across 21 United States health systems from February 2020 through September 2021. The analysis comprised data from 104,590 adult hospitalized COVID-19 patients. Inclusion criteria for the analysis were: (1) age 18 years or older; (2) COVID-19 ICD-10 diagnosis during hospitalization and/or a positive COVID-19 PCR test in a 14-day window (+/- 7 days of hospital admission); and (3) health system contact prior to COVID-19 hospitalization. Outcomes assessed were: (1) mortality (primary), (2) endotracheal intubation, and (3) ICU admission. RESULTS AND SIGNIFICANCE: The 104,590 hospitalized participants had a mean age of 61.7 years and were 50.4% female, 24% Black, and 56.8% White. Overall risk-standardized mortality (adjusted for age, sex, race, ethnicity, body mass index, insurance status and medical comorbidities) declined from 16% of hospitalized COVID-19 patients (95% CI: 16% to 17%) early in the pandemic (February-April 2020) to 9% (CI: 9% to 10%) later (July-September 2021). Among subpopulations, males (vs. females), those on Medicare (vs. those on commercial insurance), the severely obese (vs. normal weight), and those aged 60 and older (vs. younger individuals) had especially high mortality rates both early and late in the pandemic. ICU admission and intubation rates also declined across these 20 months. CONCLUSIONS: Mortality, intubation, and ICU admission rates improved markedly over the first 20 months of the pandemic among adult hospitalized COVID-19 patients although gains varied by subpopulation. These data provide important information on the course of COVID-19 and identify hospitalized patient groups at heightened risk for negative outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04506528 (https://clinicaltrials.gov/ct2/show/NCT04506528).

Clinical and genomic signatures of SARS-CoV-2 Delta breakthrough infections in New York.

BACKGROUND: In 2021, Delta became the predominant SARS-CoV-2 variant worldwide. While vaccines have effectively prevented COVID-19 hospitalization and death, vaccine breakthrough infections increasingly occurred. The precise role of clinical and genomic determinants in Delta infections is not known, and whether they contributed to increased rates of breakthrough infections compared to unvaccinated controls. METHODS: We studied SARS-CoV-2 variant distribution, dynamics, and adaptive selection over time in relation to vaccine status, phylogenetic relatedness of viruses, full genome mutation profiles, and associated clinical and demographic parameters. FINDINGS: We show a steep and near-complete replacement of circulating variants with Delta between May and August 2021 in metropolitan New York. We observed an increase of the Delta sublineage AY.25 (14% in vaccinated, 7% in unvaccinated), its spike mutation S112L, and AY.44 (8% in vaccinated, 2% in unvaccinated) with its nsp12 mutation F192V in breakthroughs. Delta infections were associated with younger age and lower hospitalization rates than Alpha. Delta breakthrough infections increased significantly with time since vaccination, and, after adjusting for confounders, they rose at similar rates as in unvaccinated individuals. INTERPRETATION: We observed a modest adaptation of Delta genomes in breakthrough infections in New York, suggesting an improved genomic framework to support Delta's epidemic growth in times of waning vaccine protection despite limited impact on vaccine escape. FUNDING: The study was supported by NYU institutional funds. The NYULH Genome Technology Center is partially supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center.

The Impact of Telemedicine on Physicians' After-hours Electronic Health Record "Work Outside Work" During the COVID-19 Pandemic: Retrospective Cohort Study.

BACKGROUND: Telemedicine as a mode of health care work has grown dramatically during the COVID-19 pandemic; the impact of this transition on clinicians' after-hours electronic health record (EHR)-based clinical and administrative work is unclear. OBJECTIVE: This study assesses the impact of the transition to telemedicine during the COVID-19 pandemic on physicians' EHR-based after-hours workload (ie, "work outside work") at a large academic medical center in New York City. METHODS: We conducted an EHR-based retrospective cohort study of ambulatory care physicians providing telemedicine services before the pandemic, during the acute pandemic, and after the acute pandemic, relating EHR-based after-hours work to telemedicine intensity (ie, percentage of care provided via telemedicine) and clinical load (ie, patient load per provider). RESULTS: A total of 2129 physicians were included in this study. During the acute pandemic, the volume of care provided via telemedicine significantly increased for all physicians, whereas patient volume decreased. When normalized by clinical load (ie, average appointments per day by average clinical days per week), telemedicine intensity was positively associated with work outside work across time periods. This association was strongest after the acute pandemic. CONCLUSIONS: Taking physicians' clinical load into account, physicians who devoted a higher proportion of their clinical time to telemedicine throughout various stages of the pandemic engaged in higher levels of EHR-based after-hours work compared to those who used telemedicine less intensively. This suggests that telemedicine, as currently delivered, may be less efficient than in-person-based care and may increase the after-hours work burden of physicians.

Pathogen Species Is Associated With Mortality in Nosocomial Bloodstream Infection in Patients With COVID-19.

Background: The epidemiology of nosocomial bloodstream infections (NBSIs) in patients with coronavirus disease 2019 (COVID-19) is poorly understood, due in part to substantial disease heterogeneity resulting from multiple potential pathogens. Methods: We identified risk factors for NBSIs and examined the association between NBSIs and mortality in a retrospective cohort of patients hospitalized with COVID-19 in 2 New York City hospitals during the height of the pandemic. We adjusted for the potential effects of factors likely to confound that association, including age, race, illness severity upon admission, and underlying health status. Results: Between January 1 and October 1, 2020, 1403 patients had a positive blood culture, and 79 and 101 met the stringent criteria for NBSI among non-COVID-19 and COVID-19 patients, respectively. NBSIs occurred almost exclusively among patients who were severely ill with COVID-19 at hospital admission. NBSIs were associated with elevated mortality, even after adjusting for baseline differences in COVID-19 illness (55% cases vs 45% controls; P = .13). Mortality was concentrated in patients with early-onset pneumonia caused by S. aureus and gram-negative bacteria. Less virulent Candida (49%) and Enterococcus (12%) species were the predominant cause of NBSI in the latter stages of hospitalization, after antibiotic treatment and COVID-19 treatments that attenuate immune response. Most Enterococcus and Candida infections did not have an identifiable source and were not associated with common risk factors for infection by these organisms. Conclusions: Pathogen species and mortality exhibited temporal differences. Early recognition of risk factors among COVID-19 patients could potentially decrease NBSI-associated mortality through early COVID-19 and antimicrobial treatment.

Interferon pathway lupus risk alleles modulate risk of death from acute COVID-19.

Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR = 29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in antiviral immunity.