Safety and Virologic Impact of Haploidentical NK Cells Plus Interleukin 2 or N-803 in HIV Infection.

BACKGROUND: Natural killer (NK) cells are dysfunctional in chronic human immunodeficiency virus (HIV) infection as they are not able to clear virus. We hypothesized that an infusion of NK cells, supported by interleukin 2 (IL-2) or IL-15, could decrease virus-producing cells in the lymphatic tissues. METHODS: We conducted a phase 1 pilot study in 6 persons with HIV (PWH), where a single infusion of haploidentical related donor NK cells was given plus either IL-2 or N-803 (an IL-15 superagonist). RESULTS: The approach was well tolerated with no unexpected adverse events. We did not pretreat recipients with cyclophosphamide or fludarabine to "make immunologic space," reasoning that PWH on stable antiretroviral treatment remain T-cell depleted in lymphatic tissues. We found donor cells remained detectable in blood for up to 8 days (similar to what is seen in cancer pretreatment with lymphodepleting chemotherapy) and in the lymph nodes and rectum up to 28 days. There was a moderate decrease in the frequency of viral RNA-positive cells in lymph nodes. CONCLUSIONS: There was a moderate decrease in HIV-producing cells in lymph nodes. Further studies are warranted to determine the impact of healthy NK cells on HIV reservoirs and if restoring NK-cell function could be part of an HIV cure strategy. Clinical Trials Registration. NCT03346499 and NCT03899480.

Acute Appendicitis Treatment Strategies and Mortality Based on Critical Illness on Admission: An Observational Study.

Background: Trials have shown non-inferiority of non-operative management (NOM) for appendicitis, although critically ill patients have been often excluded. The purpose of this study is to evaluate surgical versus NOM outcomes in critically ill patients with appendicitis by measuring mortality and hospital length of stay (LOS). Patients and Methods: The Healthcare Cost and Utilization Project's (HCUP) Database was utilized to analyze data from 10 states between 2008 and 2015. All patients with acute appendicitis by International Classification of Diseases, Ninth Revision (ICD-9) codes over the age of 18 were included. Negative binomial and logistic regression were used to determine the association of acute renal failure (ARF), cardiovascular failure (CVF), pulmonary failure (PF), and sepsis by treatment strategy (laparoscopic, open, both, or no surgery) on mortality and hospital LOS. Results: Among 464,123 patients, 67.5%, 23.3%, 8.2%, and 0.8% underwent laparoscopic, open, NOM, or both laparoscopic and open surgery, respectively. Patients who underwent surgery had 58% lower odds of mortality and 34% shorter hospital LOS compared with NOM patients. Patients with ARF, CVF, PF, and sepsis had 102%, 383%, 475%, and 666% higher odds of mortality and a 47%, 46%, 71%, and 163% longer hospital LOS, respectively, compared with patients without these diagnoses on admission. Conclusions: Critical illness on admission increases mortality and hospital LOS. Patients who underwent laparoscopic, and to a lesser extent, open appendectomy had improved mortality compared with those who did not undergo surgery regardless of critical illness status.

Factors Associated with Mortality in Patients with COVID-19 Receiving Prolonged Ventilatory Support.

Background: Since its emergence in early 2020, coronavirus disease 2019 (COVID-19)-associated pneumonia has caused a global strain on intensive care unit (ICU) resources with many intubated patients requiring prolonged ventilatory support. Outcomes for patients with COVID-19 who receive prolonged intubation (>21 days) and possible predictors of mortality in this group are not well established. Patients and Methods: Data were prospectively collected from adult patients with COVID-19 requiring mechanical ventilation from March 2020 through December 2021 across a system of 11 hospitals. The primary end point was in-hospital mortality. Factors associated with mortality were evaluated using univariable and multivariable logistic regression analyses. Results: Six hundred six patients were placed on mechanical ventilation for COVID-19 pneumonia during the study period, with in-hospital mortality of 40.3% (n = 244). Increased age (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.03-1.09), increased creatinine (OR, 1.40; 95% CI, 1.08-1.82), and receiving corticosteroids (OR, 2.68; 95% CI, 1.20-5.98) were associated with mortality. Intubations lasting longer than 21 days (n = 140) had a lower in-hospital mortality of 25.7% (n = 36; p < 0.001). Increasing Elixhauser comorbidity index (OR, 1.12; 95% CI, 1.04-1.19) and receiving corticosteroids (OR, 1.92; 95% CI, 1.06-3.47) were associated with need for prolonged ventilation. In this group, increased age (OR, 1.06; 95% CI, 1.01-1.08) and non-English speaking (OR, 3.74; 95% CI, 1.13-12.3) were associated with mortality. Conclusions: In-hospital mortality in mechanically ventilated patients with COVID-19 pneumonia occurs primarily in the first 21 days after intubation, possibly related to the early active inflammatory process. In patients on prolonged mechanical ventilation, increased age and being non-English speaking were associated with mortality.

Efficacy of Losartan in Hospitalized Patients With COVID-19-Induced Lung Injury: A Randomized Clinical Trial.

Importance: SARS-CoV-2 viral entry may disrupt angiotensin II (AII) homeostasis, contributing to COVID-19 induced lung injury. AII type 1 receptor blockade mitigates lung injury in preclinical models, although data in humans with COVID-19 remain mixed. Objective: To test the efficacy of losartan to reduce lung injury in hospitalized patients with COVID-19. Design, Setting, and Participants: This blinded, placebo-controlled randomized clinical trial was conducted in 13 hospitals in the United States from April 2020 to February 2021. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already using a renin-angiotensin-aldosterone system (RAAS) inhibitor were eligible for participation. Data were analyzed from April 19 to August 24, 2021. Interventions: Losartan 50 mg orally twice daily vs equivalent placebo for 10 days or until hospital discharge. Main Outcomes and Measures: The primary outcome was the imputed arterial partial pressure of oxygen to fraction of inspired oxygen (Pao2:Fio2) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity; days without supplemental o2, ventilation, or vasopressors; and mortality. Losartan pharmacokinetics and RAAS components (AII, angiotensin-[1-7] and angiotensin-converting enzymes 1 and 2)] were measured in a subgroup of participants. Results: A total of 205 participants (mean [SD] age, 55.2 [15.7] years; 123 [60.0%] men) were randomized, with 101 participants assigned to losartan and 104 participants assigned to placebo. Compared with placebo, losartan did not significantly affect Pao2:Fio2 ratio at 7 days (difference, -24.8 [95%, -55.6 to 6.1]; P = .12). Compared with placebo, losartan did not improve any secondary clinical outcomes and led to fewer vasopressor-free days than placebo (median [IQR], 9.4 [9.1-9.8] vasopressor-free days vs 8.7 [8.2-9.3] vasopressor-free days). Conclusions and Relevance: This randomized clinical trial found that initiation of orally administered losartan to hospitalized patients with COVID-19 and acute lung injury did not improve Pao2:Fio2 ratio at 7 days. These data may have implications for ongoing clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT04312009.

Comparison of Outcomes and Process of Care for Patients Treated at Hospitals Dedicated for COVID-19 Care vs Other Hospitals.

Importance: Early in the SARS-CoV-2 pandemic, the M Health Fairview Hospital System established dedicated hospitals for establishing cohorts and caring for patients with COVID-19, yet the association between treatment at COVID-19-dedicated hospitals and mortality and complications is not known. Objective: To analyze the mortality rate and complications associated with treatment at the COVID-19-dedicated hospitals. Design, Setting, and Participants: This retrospective cohort study evaluated data prospectively collected from March 1, 2020, through June 30, 2021, from 11 hospitals in Minnesota, including 2 hospitals created solely to care for patients with COVID-19. Data obtained included demographic characteristics, treatments, and outcomes of interest for all patients with a confirmed COVID-19 infection admitted to this hospital system during the study period. Exposures: Patients were grouped based on whether they received treatment from 1 of the 2 COVID-19-dedicated hospitals compared with the remainder of the hospitals within the hospital system. Main Outcomes and Measures: Multivariate analyses, including risk-adjusted logistic regression and propensity score matching, were performed to evaluate the primary outcome of in-hospital mortality and secondary outcomes, including complications and use of COVID-specific therapeutics. Results: There were 5504 patients with COVID-19 admitted during the study period (median age, 62.5 [IQR, 45.0-75.6] years; 2854 women [51.9%]). Of these, 2077 patients (37.7%) (median age, 63.4 [IQR, 50.7-76.1] years; 1080 men [52.0%]) were treated at 1 of the 2 COVID-19-dedicated hospitals compared with 3427 (62.3%; median age, 62.0 [40.0-75.1] years; 1857 women (54.2%) treated at other hospitals. The mortality rate was 11.6% (n = 241) at the dedicated hospitals compared with 8.0% (n = 274) at the other hospitals (P < .001). However, risk-adjusted in-hospital mortality was significantly lower for patients in the COVID-19-dedicated hospitals in both the unmatched group (n = 2077; odds ratio [OR], 0.75; 95% CI, 0.59-0.95) and the propensity score-matched group (n = 1317; OR, 0.78; 95% CI, 0.58-0.99). The rate of overall complications in the propensity score-matched group was significantly lower (OR, 0.81; 95% CI, 0.66-0.99) and the use of COVID-19-specific therapeutics including deep vein thrombosis prophylaxis (83.9% vs 56.9%; P < .001), high-dose corticosteroids (56.1% vs 22.2%; P < .001), remdesivir (61.5% vs 44.5%; P < .001), and tocilizumab (7.9% vs 2.0; P < .001) was significantly higher. Conclusions and Relevance: In this cohort study, COVID-19-dedicated hospitals had multiple benefits, including providing high-volume repetitive treatment and isolating patients with the infection. This experience suggests improved in-hospital mortality for patients treated at dedicated hospitals owing to improved processes of care and supports the use of establishing cohorts for future pandemics.

A multi-center phase II randomized clinical trial of losartan on symptomatic outpatients with COVID-19.

BACKGROUND: The SARS-CoV-2 virus enters cells via Angiotensin-converting enzyme 2 (ACE2), disrupting the renin-angiotensin-aldosterone axis, potentially contributing to lung injury. Treatment with angiotensin receptor blockers (ARBs), such as losartan, may mitigate these effects, though induction of ACE2 could increase viral entry, replication, and worsen disease. METHODS: This study represents a placebo-controlled blinded randomized clinical trial (RCT) to test the efficacy of losartan on outpatients with COVID-19 across three hospital systems with numerous community sites in Minnesota, U.S. Participants included symptomatic outpatients with COVID-19 not already taking ACE-inhibitors or ARBs, enrolled within 7 days of symptom onset. Patients were randomized to 1:1 losartan (25 mg orally twice daily unless estimated glomerular filtration rate, eGFR, was reduced, when dosing was reduced to once daily) versus placebo for 10 days, and all patients and outcome assesors were blinded. The primary outcome was all-cause hospitalization within 15 days. Secondary outcomes included functional status, dyspnea, temperature, and viral load. (clinicatrials.gov, NCT04311177, closed to new participants). FINDINGS: From April to November 2020, 117 participants were randomized 58 to losartan and 59 to placebo, and all were analyzed under intent to treat principles. The primary outcome did not differ significantly between the two arms based on Barnard's test [losartan arm: 3 events (5.2% 95% CI 1.1, 14.4%) versus placebo arm: 1 event (1.7%; 95% CI 0.0, 9.1%)]; proportion difference -3.5% (95% CI -13.2, 4.8%); p = 0.32]. Viral loads were not statistically different between treatment groups at any time point. Adverse events per 10 patient days did not differ signifcantly [0.33 (95% CI 0.22-0.49) for losartan vs. 0.37 (95% CI 0.25-0.55) for placebo]. Due to a lower than expected hospitalization rate and low likelihood of a clinically important treatment effect, the trial was terminated early. INTERPRETATION: In this multicenter blinded RCT for outpatients with mild symptomatic COVID-19 disease, losartan did not reduce hospitalizations, though assessment was limited by low event rate. Importantly, viral load was not statistically affected by treatment. This study does not support initiation of losartan for low-risk outpatients.

Translocated microbiome composition determines immunological outcome in treated HIV infection.

The impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways driven by changes in the abundance ratio of Serratia to other bacterial genera. Increased CD4 T cell numbers over the first year were associated with high Serratia abundance, pro-inflammatory innate cytokines, and metabolites that drive Th17 gene expression signatures and restoration of mucosal integrity. Subsequently, decreased Serratia abundance and downregulation of innate cytokines allowed re-establishment of systemic T cell homeostasis promoting restoration of Th1 and Th2 gene expression signatures. Analyses of three other geographically distinct cohorts of treated HIV infection established a more generalized principle that changes in diversity and composition of translocated microbial species influence systemic inflammation and consequently CD4 T cell recovery.

Morbidity and Mortality Trends of Pancreatitis: An Observational Study.

Background: Pancreatitis accounts for more than $2.5 billion of healthcare costs and remains the most common gastrointestinal (GI) admission. Few contemporary studies have assessed temporal trends of incidence, complications, management, and outcomes for acute pancreatitis in hospitalized patients at the national level. Methods: We used data from one of the largest hospital-based databases available in the United States, the Healthcare Cost and Utilization Project's (HCUP) State Inpatient Database, from 10 states between 2008 and 2015. We included patients with a diagnosis of acute pancreatitis (ICD-9 CM 577.0). Patient- and hospital-level data were used to estimate incidence and inpatient mortality rates. Results: From 80,736,256 hospitalizations, 929,914 (1.15%) cases of acute pancreatitis were identified, 186,226 (20.2%) of which were caused by gallbladder disease). The median age was 53 years (interquartile range [IQR], 41-67) and 50.8% were men. In-hospital mortality was 2.5% and crude mortality rates declined from 2.9% to 2.0% over the study period. Admission year remained significant after adjusting for patient demographics and comorbidities (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.89-0.90; p < 0.001). Gallbladder disease was associated with decreased odds of mortality (OR, 0.60; 95% CI, 0.57-0.62). Median length of stay was four days (IQR, 2-7) and decreased over time. The rates of surgical and endoscopic interventions were highest in 2011 (peak incidence of 16.1% and 9.5%, respectively) and have been decreasing since. Surgical providers were, on average, more likely than medical providers to perform surgery in both those with and without gallbladder disease etiology (gallbladder disease OR, 7.11; 95% CI, 5.46-9.25; non-gallbladder disease OR, 20.50; 95% CI, 16.81-25.01), endoscopy (gallbladder disease OR, 1.22; 95% CI, 0.87-1.72; non-gallbladder disease OR, 1.60; 95% CI, 1.18-2.16), or both (gallbladder disease OR, 7.00; 95% CI, 5.22-9.37; non-gallbladder disease OR, 8.85; 95% CI, 5.61-13.96). Conclusions: The incidence of pancreatitis, from 2008 to 2015, has increased whereas inpatient mortality (i.e., case fatality) has decreased. Understanding temporal trends in outcomes and management along with provider, hospital, and regional variation can better identify areas for future research and collaboration in managing these patients.

Characterizing COVID-19 clinical phenotypes and associated comorbidities and complication profiles.

PURPOSE: Heterogeneity has been observed in outcomes of hospitalized patients with coronavirus disease 2019 (COVID-19). Identification of clinical phenotypes may facilitate tailored therapy and improve outcomes. The purpose of this study is to identify specific clinical phenotypes across COVID-19 patients and compare admission characteristics and outcomes. METHODS: This is a retrospective analysis of COVID-19 patients from March 7, 2020 to August 25, 2020 at 14 U.S. hospitals. Ensemble clustering was performed on 33 variables collected within 72 hours of admission. Principal component analysis was performed to visualize variable contributions to clustering. Multinomial regression models were fit to compare patient comorbidities across phenotypes. Multivariable models were fit to estimate associations between phenotype and in-hospital complications and clinical outcomes. RESULTS: The database included 1,022 hospitalized patients with COVID-19. Three clinical phenotypes were identified (I, II, III), with 236 [23.1%] patients in phenotype I, 613 [60%] patients in phenotype II, and 173 [16.9%] patients in phenotype III. Patients with respiratory comorbidities were most commonly phenotype III (p = 0.002), while patients with hematologic, renal, and cardiac (all p<0.001) comorbidities were most commonly phenotype I. Adjusted odds of respiratory, renal, hepatic, metabolic (all p<0.001), and hematological (p = 0.02) complications were highest for phenotype I. Phenotypes I and II were associated with 7.30-fold (HR:7.30, 95% CI:(3.11-17.17), p<0.001) and 2.57-fold (HR:2.57, 95% CI:(1.10-6.00), p = 0.03) increases in hazard of death relative to phenotype III. CONCLUSION: We identified three clinical COVID-19 phenotypes, reflecting patient populations with different comorbidities, complications, and clinical outcomes. Future research is needed to determine the utility of these phenotypes in clinical practice and trial design.

Discordant Cardiopulmonary Resuscitation and Code Status at Death.

CONTEXT: One fundamental way to honor patient autonomy is to establish and enact their wishes for end-of-life care. Limited research exists regarding adherence with code status. OBJECTIVES: This study aimed to characterize cardiopulmonary resuscitation (CPR) attempts discordant with documented code status at the time of death in the U.S. and to elucidate potential contributing factors. METHODS: The Cerner Acute Physiology and Chronic Health Evaluation (APACHE) outcomes database, which includes 237 U.S. hospitals that collect manually abstracted data from all critical care patients, was queried for adults admitted to intensive care units with a documented code status at the time of death from January 2008 to December 2016. The primary outcome was discordant CPR at death. Multivariable logistic regression models were used to identify patient-level and hospital-level associated factors after adjustment for age, hospital, and illness severity (APACHE III score). RESULTS: A total of 21,537 patients from 56 hospitals were included. Of patients with a do-not-resuscitate code status, 149 (0.8%) received CPR at death, and associated factors included black race, higher APACHE III score, or treatment in small or nonteaching hospitals. Of patients with a full code status, 203 (9.0%) did not receive CPR at death, and associated factors included higher APACHE III score, primary neurologic or trauma diagnosis, or admission in a more recent year. CONCLUSION: At the time of death, 1.6% of patients received or did not undergo CPR in a manner discordant with their documented code statuses. Race and institutional factors were associated with discordant resuscitation, and addressing these disparities may promote concordant end-of-life care in all patients.

"Who wants me to do what?" varied expectations from key stakeholder groups in the surgical intensive care unit creates a challenging learning environment.

BACKGROUND: Surgical intensive care units (SICU) require complex care from a multi-disciplinary team. Frequent changes in team members can lead to shifting expectations for junior general surgical trainees, which creates a challenging working and learning environment. We aim to identify expectations of junior surgery trainee's medical knowledge and technical/non-technical skills at the start of their SICU rotation. We hypothesize that expectations will not be consistent across SICU stakeholder groups. METHODS: Twenty-eight individual semi-structured interviews were conducted with six SICU stakeholder groups at a medium-sized academic hospital. Expectations were identified from interview transcripts. Frequency counts were analyzed. RESULTS: Forty-one expectations were identified. 4 expectations were identified by a majority of interviewees. Most expectations were identified by 7 or fewer interviewees. 23 (53%) expectations were shared by at least one stakeholder group. 2 (8%) expectations were shared by all groups. CONCLUSIONS: SICU stakeholder groups identified ten medical knowledge, ten technical skill, and three non-technical skill expectations. Yet, few expectations were shared among the groups. Thus, SICU stakeholder groups have disparate expectations for surgery trainees in our SICU.

National Trends and Variation of Functional Status Deterioration in the Medically Critically Ill.

OBJECTIVES: Physical and psychologic deficits after an ICU admission are associated with lower quality of life, higher mortality, and resource utilization. This study aimed to examine the prevalence and secular changes of functional status deterioration during hospitalization among nonsurgical critical illness survivors over the past decade. DESIGN: We performed a retrospective longitudinal cohort analysis. SETTING: Analysis performed using the Cerner Acute Physiology and Chronic Health Evaluation outcomes database which included manually abstracted data from 236 U.S. hospitals from 2008 to 2016. PATIENTS: We included nonsurgical adult ICU patients who survived their hospitalization and had a functional status documented at ICU admission and hospital discharge. Physical functional status was categorized as fully independent, partially dependent, or fully dependent. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Functional status deterioration occurred in 38,116 patients (29.3%). During the past decade, functional status deterioration increased in each disease category, as well as overall (prevalence rate ratio, 1.15; 95% CI, 1.13-1.17; p < 0.001). Magnitude of functional status deterioration also increased over time (odds ratio, 1.03; 95% CI, 1.03-1.03; p < 0.001) with hematological, sepsis, neurologic, and pulmonary disease categories having the highest odds of severe functional status deterioration. CONCLUSIONS: Following nonsurgical critical illness, the prevalence of functional status deterioration and magnitude increased in a nationally representative cohort, despite efforts to reduce ICU dysfunction over the past decade. Identifying the prevalence of functional status deterioration and primary etiologies associated with functional status deterioration will elucidate vital areas for further research and targeted interventions. Reducing ICU debilitation for key disease processes may improve ICU survivor mortality, enhance quality of life, and decrease healthcare utilization.

Epidemiological trends of surgical admissions to the intensive care unit in the United States.

BACKGROUND: Epidemiologic assessment of surgical admissions into intensive care units (ICUs) provides a framework to evaluate health care system efficiency and project future health care needs. METHODS: We performed a 9-year (2008-2016), retrospective, cohort analysis of all adult admissions to 88 surgical ICUs using the prospectively and manually abstracted Cerner Acute Physiology and Chronic Health Evaluation Outcomes database. We stratified patients into 13 surgical cohorts and modeled temporal trends in admission, mortality, surgical ICU length of stay (LOS), and change in functional status (FS) using generalized mixed-effects and Quasi-Poisson models to obtain risk-adjusted outcomes. RESULTS: We evaluated 78,053 ICU admissions and observed a significant decrease in admissions after transplant and thoracic surgery, with a concomitant increase in admissions after otolaryngological and facial reconstructive procedures (all p < 0.05). While overall risk-adjusted mortality remained stable over the study period; mortality significantly declined in orthopedic, cardiac, urologic, and neurosurgical patients (all p < 0.05). Cardiac, urologic, gastrointestinal, neurosurgical, and orthopedic admissions showed significant reductions in LOS (all p < 0.05). The overall rate of FS deterioration increased per year, suggesting ICU-related disability increased over the study period. CONCLUSION: Temporal analysis demonstrates a significant change in the type of surgical patients admitted to the ICU over the last decade, with decreasing mortality and LOS in selected cohorts, but an increasing rate of FS deterioration. Improvement in ICU outcomes may highlight the success of health care advancements within certain surgical cohorts, while simultaneously identifying cohorts that may benefit from future intervention. Our findings have significant implications in health care systems planning, including resource and personnel allocation, education, and surgical training. LEVEL OF EVIDENCE: Economic/decision, level IV.Epidemiologic, level IV.

Understanding the renin-angiotensin-aldosterone-SARS-CoV axis: a comprehensive review.

IMPORTANCE: Coronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a global pandemic with significant morbidity and mortality since first appearing in Wuhan, China, in late 2019. As many countries are grappling with the onset of their epidemics, pharmacotherapeutics remain lacking. The window of opportunity to mitigate downstream morbidity and mortality is narrow but remains open. The renin-angiotensin-aldosterone system (RAAS) is crucial to the homeostasis of both the cardiovascular and respiratory systems. Importantly, SARS-CoV-2 utilises and interrupts this pathway directly, which could be described as the renin-angiotensin-aldosterone-SARS-CoV (RAAS-SCoV) axis. There exists significant controversy and confusion surrounding how anti-hypertensive agents might function along this pathway. This review explores the current state of knowledge regarding the RAAS-SCoV axis (informed by prior studies of SARS-CoV), how this relates to our currently evolving pandemic, and how these insights might guide our next steps in an evidence-based manner. OBSERVATIONS: This review discusses the role of the RAAS-SCoV axis in acute lung injury and the effects, risks and benefits of pharmacological modification of this axis. There may be an opportunity to leverage the different aspects of RAAS inhibitors to mitigate indirect viral-induced lung injury. Concerns have been raised that such modulation might exacerbate the disease. While relevant preclinical, experimental models to date favour a protective effect of RAAS-SCoV axis inhibition on both lung injury and survival, clinical data related to the role of RAAS modulation in the setting of SARS-CoV-2 remain limited. CONCLUSION: Proposed interventions for SARS-CoV-2 predominantly focus on viral microbiology and aim to inhibit viral cellular injury. While these therapies are promising, immediate use may not be feasible, and the time window of their efficacy remains a major unanswered question. An alternative approach is the modulation of the specific downstream pathophysiological effects caused by the virus that lead to morbidity and mortality. We propose a preponderance of evidence that supports clinical equipoise regarding the efficacy of RAAS-based interventions, and the imminent need for a multisite randomised controlled clinical trial to evaluate the inhibition of the RAAS-SCoV axis on acute lung injury in COVID-19.

Concordance Between Expert and Nonexpert Ratings of Condensed Video-Based Trainee Operative Performance Assessment.

OBJECTIVE: We examined the impact of video editing and rater expertise in surgical resident evaluation on operative performance ratings of surgical trainees. DESIGN: Randomized independent review of intraoperative video. SETTING: Operative video was captured at a single, tertiary hospital in Boston, MA. PARTICIPANTS: Six common general surgery procedures were video recorded of 6 attending-trainee dyads. Full-length and condensed versions (n = 12 videos) were then reviewed by 13 independent surgeon raters (5 evaluation experts, 8 nonexperts) using a crossed design. Trainee performance was rated using the Operative Performance Rating Scale, System for Improving and Measuring Procedural Learning (SIMPL) Performance scale, the Zwisch scale, and ten Cate scale. These ratings were then standardized before being compared using Bayesian mixed models with raters and videos treated as random effects. RESULTS: Editing had no effect on the Operative Performance Rating Scale Overall Performance (-0.10, p = 0.30), SIMPL Performance (0.13, p = 0.71), Zwisch (-0.12, p = 0.27), and ten Cate scale (-0.13, p = 0.29). Additionally, rater expertise (evaluation expert vs. nonexpert) had no effect on the same scales (-0.16 (p = 0.32), 0.18 (p = 0.74), 0.25 (p = 0.81), and 0.25 (p = 0.17). CONCLUSIONS: There is little difference in operative performance assessment scores when raters use condensed videos or when raters who are not experts in surgical resident evaluation are used. Future validation studies of operative performance assessment scales may be facilitated by using nonexpert surgeon raters viewing videos condensed using a standardized protocol.

Outcomes and influences of rural-focused integrated clerkship programs in general surgery.

BACKGROUND: A shortage of general surgeons is predicted in the future, with particular impact on rural surgery. This is an exploratory analysis on a rural-focused longitudinal integrated clerkship to determine if such clerkships can be used to increase interest and recruitment in rural general surgery. METHODS: An institutional database was reviewed to identify students who became general surgeons after completing a rural-focused longitudinal integrated clerkship. Telephone interviews were conducted on a portion of these surgeons. RESULTS: Fifty-seven students (3.6%) completing the rural-focused longitudinal integrated clerkship became general surgeons. Of those participating in phone interviews, most (90%) decided to become surgeons during their experience while all stated that preclinical years did not influence their specialty decision. CONCLUSIONS: A substantial portion of these surgeons went on to practice in rural communities. Pre-existing rural and primary care-focused education could help to address the future projected shortage of rural general surgeons.

Undergraduate, Nonmedical Students can Pass the FLS Manual Skills Exam With Minimal Practice.

OBJECTIVES: The primary objective of this study is to investigate whether undergraduate, nonmedical students could pass the FLS Manual Skills Exam with minimal practice. The secondary objective is to examine ACGME case log data from graduating chief residents over the past 18 years to examine how laparoscopic experience has evolved over that time period. DESIGN: Undergraduate, nonmedical students received training and unlimited practice time before being tested on each task of the FLS Manual Skills Exam. Each task was timed and scored using the MISTELS system. ACGME case log data from graduating chief residents over the past 18 years was obtained. SETTING: The setting is SimPortal, the simulation center associated with the University of Minnesota Medical School. PARTICIPANTS: The participants are 25 undergraduate, nonmedical students from the University of Minnesota. Participants were recruited on campus. RESULTS: Twenty-three out of 25 (92%) undergraduate, nonmedical students successfully completed one attempt for each task of the FLS Manual Skills Exam and 21 out of 25 (84%) completed both attempts. The average total practice time was 39 minutes. Over the past 18 years, the average number of laparoscopic cases completed by a graduating chief increased from 142 to 275 cases (93% increase). Additionally, the average number of cases of the top 5 most common laparoscopic operations increased from 25% to over 400%. CONCLUSIONS: Undergraduate, nonmedical students can pass the FLS Manual Skills Exam with minimal practice. Additionally, general surgery residents and medical students continue to gain more laparoscopic experience throughout medical training as laparoscopic surgery is utilized for more operations. The FLS Manual Skills Exam should be re-examined to determine its utility as a high-stakes exam.