Examining the approach to medical remediation programmes-an observational study.

BACKGROUND: Remediation of underperforming students is recognised as an important tool in medical education; however, there is no universally agreed approach. AIMS: This study aimed to evaluate the effectiveness of a remediation program for final year medical students who failed their first long case assessment (LCA1) and to compare their academic performance with their peers who passed their first long case assessment. METHODS: The study consisted of two phases. Phase 1 analysed the demographics and academic performance data for the 9% of the class in the remediation group. Phase 2 focused on collecting similar data for the remaining 91% of students in the non-remediation group. Statistical analyses including the Wilcoxon rank sum test and Pearson correlation coefficients were used to compare the groups. RESULTS: Phase 1 showed 88% of students who participated in remediation successfully passed the second long case assessment (LCA2); however, 25% of this cohort ultimately failed the academic year due to poor results in other assessments. Phase 2 results revealed that non-remediation group students scored significantly higher in LCA2 (59.71% vs 52.07%, p < 0.001) compared to their remediation counterparts, despite 19% of them failing this assessment. Non-remediation group students consistently outperformed their remediation group counterparts in formative and summative assessments. Overall, 6.25% of the entire class failed the academic year. CONCLUSION: This study demonstrates the need to focus on overall academic performance to identify struggling students rather than one high stakes exam. Most of the students in the remediation programme ultimately passed LCA2.

Predicting neurobehavioral performance of resident physicians in a Randomized Order Safety Trial Evaluating Resident-Physician Schedules (ROSTERS).

OBJECTIVES: Mathematical models of human neurobehavioral performance that include the effects of acute and chronic sleep restriction can be key tools in assessment and comparison of work schedules, allowing quantitative predictions of performance when empirical assessment is impractical. METHODS: Using such a model, we tested the hypothesis that resident physicians working an extended duration work roster, including 24-28 hours of continuous duty and up to 88 hours per week averaged over 4weeks, would have worse predicted performance than resident physicians working a rapidly cycling work roster intervention designed to reduce the duration of extended shifts. The performance metric used was attentional failures (ie, Psychomotor Vigilance Task lapses). Model input was 169 actual work and sleep schedules. Outcomes were predicted hours per week during work hours spent at moderate (equivalent to 16-20 hours of continuous wakefulness) or high (equivalent to ≥20 hours of continuous wakefulness) performance impairment. RESULTS: The model predicted that resident physicians working an extended duration work roster would spend significantly more time at moderate impairment (p = .02, effect size=0.2) than those working a rapidly cycling work roster; this difference was most pronounced during the circadian night (p < .001). On both schedules, performance was predicted to decline from weeks 1 + 2 to weeks 3 + 4 (p < .001), but the rate of decline was significantly greater on extended duration work roster (p < .01). Predicted performance impairment was inversely related to prior sleep duration (p < .001). CONCLUSIONS: These findings demonstrate the utility of a mathematical model to evaluate the predicted performance profile of schedules for resident physicians and others who experience chronic sleep restriction and circadian misalignment.

Impact of vaccination and variants of concern on long COVID clinical phenotypes.

BACKGROUND: Defining patterns of symptoms in long COVID is necessary to advance therapies for this heterogeneous condition. Here we aimed to describe clusters of symptoms in individuals with long COVID and explore the impact of the emergence of variants of concern (VOCs) and vaccination on these clusters. METHODS: In a prospective, multi centre cohort study, individuals with symptoms persisting > 4 weeks from acute COVID-19 were divided into two groups based on timing of acute infection; pre-Alpha VOC, denoted wild type (WT) group and post-Alpha VOC (incorporating alpha and delta dominant periods) denoted VOC group. We used multiple correspondence analysis (MCA) and hierarchical clustering in the WT and VOC groups to identify symptom clusters. We then used logistic regression to explore factors associated with individual symptoms. RESULTS: A total of 417 individuals were included in the analysis, 268 in WT and 149 in VOC groups respectively. In both groups MCA identified three similar clusters; a musculoskeletal (MSK) cluster characterised by joint pain and myalgia, a cardiorespiratory cluster and a less symptomatic cluster. Differences in characteristic symptoms were only seen in the cardiorespiratory cluster where a decrease in the frequency of palpitations (10% vs 34% p = 0.008) and an increase in cough (63% vs 17% p < 0.001) in the VOC compared to WT groups was observed. Analysis of the frequency of individual symptoms showed significantly lower frequency of both chest pain (25% vs 39% p = 0.004) and palpitations (12% vs 32% p < 0.001) in the VOC group compared to the WT group. In adjusted analysis being in the VOC group was significantly associated with a lower odds of both chest pain and palpitations, but vaccination was not associated with these symptoms. CONCLUSION: This study suggests changes in long COVID phenotype in individuals infected later in the pandemic, with less palpitations and chest pain reported. Adjusted analyses suggest that these effects are mediated through introduction of variants rather than an effect from vaccination.

Feeling sleepy? stop driving-awareness of fall asleep crashes.

STUDY OBJECTIVES: To examine whether drivers are aware of sleepiness and associated symptoms, and how subjective reports predict driving impairment and physiological drowsiness. METHODS: Sixteen shift workers (19-65 years; 9 women) drove an instrumented vehicle for 2 hours on a closed-loop track after a night of sleep and a night of work. Subjective sleepiness/symptoms were rated every 15 minutes. Severe and moderate driving impairment was defined by emergency brake maneuvers and lane deviations, respectively. Physiological drowsiness was defined by eye closures (Johns drowsiness scores) and EEG-based microsleep events. RESULTS: All subjective ratings increased post night-shift (p < 0.001). No severe drive events occurred without noticeable symptoms beforehand. All subjective sleepiness ratings, and specific symptoms, predicted a severe (emergency brake) driving event occurring in the next 15 minutes (OR: 1.76-2.4, AUC > 0.81, p < 0.009), except "head dropping down". Karolinska Sleepiness Scale (KSS), ocular symptoms, difficulty keeping to center of the road, and nodding off to sleep, were associated with a lane deviation in the next 15 minutes (OR: 1.17-1.24, p<0.029), although accuracy was only "fair" (AUC 0.59-0.65). All sleepiness ratings predicted severe ocular-based drowsiness (OR: 1.30-2.81, p < 0.001), with very good-to-excellent accuracy (AUC > 0.8), while moderate ocular-based drowsiness was predicted with fair-to-good accuracy (AUC > 0.62). KSS, likelihood of falling asleep, ocular symptoms, and "nodding off" predicted microsleep events, with fair-to-good accuracy (AUC 0.65-0.73). CONCLUSIONS: Drivers are aware of sleepiness, and many self-reported sleepiness symptoms predicted subsequent driving impairment/physiological drowsiness. Drivers should self-assess a wide range of sleepiness symptoms and stop driving when these occur to reduce the escalating risk of road crashes due to drowsiness.

National improvements in resident physician-reported patient safety after limiting first-year resident physicians' extended duration work shifts: a pooled analysis of prospective cohort studies.

BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) enacted a policy in 2011 that restricted first-year resident physicians in the USA to work no more than 16 consecutive hours. This was rescinded in 2017. METHODS: We conducted a nationwide prospective cohort study of resident physicians for 5 academic years (2002-2007) before and for 3 academic years (2014-2017) after implementation of the 16 hours 2011 ACGME work-hour limit. Our analyses compare trends in resident physician-reported medical errors between the two cohorts to evaluate the impact of this policy change. RESULTS: 14 796 residents provided data describing 78 101 months of direct patient care. After adjustment for potential confounders, the work-hour policy was associated with a 32% reduced risk of resident physician-reported significant medical errors (rate ratio (RR) 0.68; 95% CI 0.64 to 0.72), a 34% reduced risk of reported preventable adverse events (RR 0.66; 95% CI 0.59 to 0.74) and a 63% reduced risk of reported medical errors resulting in patient death (RR 0.37; 95% CI 0.28 to 0.49). CONCLUSIONS: These findings have broad relevance for those who work in and receive care from academic hospitals in the USA. The decision to lift this work hour policy in 2017 may expose patients to preventable harm.

Identification of Distinct Long COVID Clinical Phenotypes Through Cluster Analysis of Self-Reported Symptoms.

Background: We aimed to describe the clinical presentation of individuals presenting with prolonged recovery from coronavirus disease 2019 (COVID-19), known as long COVID. Methods: This was an analysis within a multicenter, prospective cohort study of individuals with a confirmed diagnosis of COVID-19 and persistent symptoms >4 weeks from onset of acute symptoms. We performed a multiple correspondence analysis (MCA) on the most common self-reported symptoms and hierarchical clustering on the results of the MCA to identify symptom clusters. Results: Two hundred thirty-three individuals were included in the analysis; the median age of the cohort was 43 (interquartile range [IQR], 36-54) years, 74% were women, and 77.3% reported a mild initial illness. MCA and hierarchical clustering revealed 3 clusters. Cluster 1 had predominantly pain symptoms with a higher proportion of joint pain, myalgia, and headache; cluster 2 had a preponderance of cardiovascular symptoms with prominent chest pain, shortness of breath, and palpitations; and cluster 3 had significantly fewer symptoms than the other clusters (2 [IQR, 2-3] symptoms per individual in cluster 3 vs 6 [IQR, 5-7] and 4 [IQR, 3-5] in clusters 1 and 2, respectively; P < .001). Clusters 1 and 2 had greater functional impairment, demonstrated by significantly longer work absence, higher dyspnea scores, and lower scores in SF-36 domains of general health, physical functioning, and role limitation due to physical functioning and social functioning. Conclusions: Clusters of symptoms are evident in long COVID patients that are associated with functional impairments and may point to distinct underlying pathophysiologic mechanisms of disease.

Assessing the impact of FFP3 masks to oxygen saturation and pulse rate in the Oral Surgery department at the Glasgow Dental Hospital during the COVID-19 pandemic: an observational study.

Aim: The impact on physiological parameters and well-being from potential respiratory distress caused by FFP3 masks, particularly during extensive clinical sessions, has been widely speculated during the COVID-19 pandemic. This study aims to investigate the effect of FFP3 mask wear on clinicians' pulse rate and oxygen saturation. Material & Methods: Clinical staff within the Oral Surgery department recorded their oxygen saturation (SpO2) and pulse rate prior to donning an FFP3 mask, prior to doffing FFP3 mask and after doffing FFP3 mask using a finger pulse oximeter for a two-week period in May-June 2020. The duration of wear, the session (AM/PM), the brand of mask and the presence of previous COVID-19 symptoms were also recorded. Results: Twenty-eight data sets were collected from twelve participants (1M:11F). Of the FFP3 masks worn, nineteen (67.86%) were ARCOTM, eight (28.57%) were 3MTM masks and one (3.57%) was 3M+TM. At baseline, the mean SpO2 was 98.39% and the mean pulse rate was 72.11. Prior to mask removal, the mean SpO2 was 97.82% and the mean pulse rate was 70.04. At the end of the session, the mean SpO2 was 98.14% and the mean pulse rate was 69.54. The mean duration of wear was 150.34 min. Data sets were collected evenly across AM (14) and PM (14) sessions. Five participants (17.86%) reported previous COVID-19 symptoms. Conclusion: The data demonstrated a mean reduction of 0.25% in oxygen saturation and 3.56% in pulse rate, following the use of an FFP3 mask. These changes in physiological parameters are not clinically significant and sessional use appears to be safe.

The Implementation and Acceptability of a Combined Mobile Application with a COVID-19 at-Home Test Kit.

Introduction: Testing facilities for COVID-19 were stood up around the country during the pandemic, but could not handle the demand. This study aimed to combine a mobile application (App) with an at-home test kit to facilitate home-based testing. Methods: After integrating an App with an at-home testing service, we measured the time between sample collection and notification of results. We recruited 92 volunteers to utilize the platform. Results: Sixty-one percent (55/92) responded to the survey. Median sample collection-to-result time was 2.2 days (IQR = 1.3-3.2). Eighty-two percent (45/55) found the self-test kit and App easy to use. Eighty-four percent agreed that the combined solution is an acceptable way to receive health care services. Discussion: Decreasing testing time and providing timely test results improve care access and decrease the risk of infection. Combining a tailored App with an at-home testing service is a feasible solution to reaching that goal.

Algorithmic amplification of politics on Twitter.

Content on Twitter's home timeline is selected and ordered by personalization algorithms. By consistently ranking certain content higher, these algorithms may amplify some messages while reducing the visibility of others. There's been intense public and scholarly debate about the possibility that some political groups benefit more from algorithmic amplification than others. We provide quantitative evidence from a long-running, massive-scale randomized experiment on the Twitter platform that committed a randomized control group including nearly 2 million daily active accounts to a reverse-chronological content feed free of algorithmic personalization. We present two sets of findings. First, we studied tweets by elected legislators from major political parties in seven countries. Our results reveal a remarkably consistent trend: In six out of seven countries studied, the mainstream political right enjoys higher algorithmic amplification than the mainstream political left. Consistent with this overall trend, our second set of findings studying the US media landscape revealed that algorithmic amplification favors right-leaning news sources. We further looked at whether algorithms amplify far-left and far-right political groups more than moderate ones; contrary to prevailing public belief, we did not find evidence to support this hypothesis. We hope our findings will contribute to an evidence-based debate on the role personalization algorithms play in shaping political content consumption.

Multicomponent Plasmid Protects Mice From Spontaneous Autoimmune Diabetes.

Type 1 diabetes is an autoimmune disease in which insulin-secreting ß-cells are destroyed, leading to a life-long dependency on exogenous insulin. There are no approved disease-modifying therapies available, and future immunotherapies would need to avoid generalized immune suppression. We developed a novel plasmid expressing preproinsulin2 and a combination of immune-modulatory cytokines (transforming growth factor-beta-1, interleukin [IL] 10 and IL-2) capable of near-complete prevention of autoimmune diabetes in non-obese diabetic mice. Efficacy depended on preproinsulin2, suggesting antigen-specific tolerization, and on the cytokine combination encoded. Diabetes suppression was achieved following either intramuscular or subcutaneous injections. Intramuscular plasmid treatment promoted increased peripheral levels of endogenous IL-10 and modulated myeloid cell types without inducing global immunosuppression. To prepare for first-in-human studies, the plasmid was modified to allow for selection without the use of antibiotic resistance; this modification had no impact on efficacy. This pre-clinical study demonstrates that this multi-component, plasmid-based antigen-specific immunotherapy holds potential for inducing self-tolerance in persons at risk of developing type 1 diabetes. Importantly, the study also informs on relevant cytokine and immune cell biomarkers that may facilitate clinical trials. This therapy is currently being tested for safety and tolerability in a phase 1 trial (ClinicalTrials.gov Identifier: NCT04279613).

Multicomponent Plasmid Protects Mice From Spontaneous Autoimmune Diabetes.

Type 1 diabetes is an autoimmune disease in which insulin-secreting ß-cells are destroyed, leading to a life-long dependency on exogenous insulin. There are no approved disease-modifying therapies available, and future immunotherapies would need to avoid generalized immune suppression. We developed a novel plasmid expressing preproinsulin2 and a combination of immune-modulatory cytokines (transforming growth factor-beta-1, interleukin [IL] 10 and IL-2) capable of near-complete prevention of autoimmune diabetes in non-obese diabetic mice. Efficacy depended on preproinsulin2, suggesting antigen-specific tolerization, and on the cytokine combination encoded. Diabetes suppression was achieved following either intramuscular or subcutaneous injections. Intramuscular plasmid treatment promoted increased peripheral levels of endogenous IL-10 and modulated myeloid cell types without inducing global immunosuppression. To prepare for first-in-human studies, the plasmid was modified to allow for selection without the use of antibiotic resistance; this modification had no impact on efficacy. This pre-clinical study demonstrates that this multi-component, plasmid-based antigen-specific immunotherapy holds potential for inducing self-tolerance in persons at risk of developing type 1 diabetes. Importantly, the study also informs on relevant cytokine and immune cell biomarkers that may facilitate clinical trials. This therapy is currently being tested for safety and tolerability in a phase 1 trial (ClinicalTrials.gov Identifier: NCT04279613).

A hybrid mechanistic-empirical model for in silico mammalian cell bioprocess simulation.

In cell culture processes cell growth and metabolism drive changes in the chemical environment of the culture. These environmental changes elicit reactor control actions, cell growth response, and are sensed by cell signaling pathways that influence metabolism. The interplay of these forces shapes the culture dynamics through different stages of cell cultivation and the outcome greatly affects process productivity, product quality, and robustness. Developing a systems model that describes the interactions of those major players in the cell culture system can lead to better process understanding and enhance process robustness. Here we report the construction of a hybrid mechanistic-empirical bioprocess model which integrates a mechanistic metabolic model with subcomponent models for cell growth, signaling regulation, and the bioreactor environment for in silico exploration of process scenarios. Model parameters were optimized by fitting to a dataset of cell culture manufacturing process which exhibits variability in metabolism and productivity. The model fitting process was broken into multiple steps to mitigate the substantial numerical challenges related to the first-principles model components. The optimized model captured the dynamics of metabolism and the variability of the process runs with different kinetic profiles and productivity. The variability of the process was attributed in part to the metabolic state of cell inoculum. The model was then used to identify potential mitigation strategies to reduce process variability by altering the initial process conditions as well as to explore the effect of changing CO2 removal capacity in different bioreactor scales on process performance. By incorporating a mechanistic model of cell metabolism and appropriately fitting it to a large dataset, the hybrid model can describe the different metabolic phases in culture and the variability in manufacturing runs. This approach of employing a hybrid model has the potential to greatly facilitate process development and reactor scaling.

Extended Work Shifts and Neurobehavioral Performance in Resident-Physicians.

OBJECTIVES: Extended-duration work rosters (EDWRs) with shifts of 24+ hours impair performance compared with rapid cycling work rosters (RCWRs) that limit shifts to 16 hours in postgraduate year (PGY) 1 resident-physicians. We examined the impact of a RCWR on PGY 2 and PGY 3 resident-physicians. METHODS: Data from 294 resident-physicians were analyzed from a multicenter clinical trial of 6 US PICUs. Resident-physicians worked 4-week EDWRs with shifts of 24+ hours every third or fourth shift, or an RCWR in which most shifts were ≤16 consecutive hours. Participants completed a daily sleep and work log and the 10-minute Psychomotor Vigilance Task and Karolinska Sleepiness Scale 2 to 5 times per shift approximately once per week as operational demands allowed. RESULTS: Overall, the mean (± SE) number of attentional failures was significantly higher (P =.01) on the EDWR (6.8 ± 1.0) compared with RCWR (2.9 ± 0.7). Reaction time and subjective alertness were also significantly higher, by ∼18% and ∼9%, respectively (both P <.0001). These differences were sustained across the 4-week rotation. Moreover, attentional failures were associated with resident-physician-related serious medical errors (SMEs) (P =.04). Although a higher rate of SMEs was observed under the RCWR, after adjusting for workload, RCWR had a protective effect on the rate of SMEs (rate ratio 0.48 [95% confidence interval: 0.30-0.77]). CONCLUSIONS: Performance impairment due to EDWR is improved by limiting shift duration. These data and their correlation with SME rates highlight the impairment of neurobehavioral performance due to extended-duration shifts and have important implications for patient safety.

Regulation of Metabolic Homeostasis in Cell Culture Bioprocesses.

Mammalian cells are the main tool for the production of therapeutic proteins, viruses for gene therapy, and cells for cell therapy. In production processes cell metabolism is the main driver that causes changes in the growth environment and affects productivity and product quality. Of all nutrients, glucose has the most prominent impact on bioprocesses. We summarize recent findings on the regulation of glucose and energy metabolism in cultured cells. Local allosteric regulations and post-translational modifications of enzymes in metabolic networks interplay with global signaling and transcriptional regulation. These regulatory networks sustain homeostasis across the cytosolic and mitochondrial compartments. Understanding the regulation of glucose metabolism and metabolic state is crucial for enhancing process productivity and product quality.

Effect on Patient Safety of a Resident Physician Schedule without 24-Hour Shifts.

BACKGROUND: The effects on patient safety of eliminating extended-duration work shifts for resident physicians remain controversial. METHODS: We conducted a multicenter, cluster-randomized, crossover trial comparing two schedules for pediatric resident physicians during their intensive care unit (ICU) rotations: extended-duration work schedules that included shifts of 24 hours or more (control schedules) and schedules that eliminated extended shifts and cycled resident physicians through day and night shifts of 16 hours or less (intervention schedules). The primary outcome was serious medical errors made by resident physicians, assessed by intensive surveillance, including direct observation and chart review. RESULTS: The characteristics of ICU patients during the two work schedules were similar, but resident physician workload, described as the mean (±SD) number of ICU patients per resident physician, was higher during the intervention schedules than during the control schedules (8.8±2.8 vs. 6.7±2.2). Resident physicians made more serious errors during the intervention schedules than during the control schedules (97.1 vs. 79.0 per 1000 patient-days; relative risk, 1.53; 95% confidence interval [CI], 1.37 to 1.72; P<0.001). The number of serious errors unitwide were likewise higher during the intervention schedules (181.3 vs. 131.5 per 1000 patient-days; relative risk, 1.56; 95% CI, 1.43 to 1.71). There was wide variability among sites, however; errors were lower during intervention schedules than during control schedules at one site, rates were similar during the two schedules at two sites, and rates were higher during intervention schedules than during control schedules at three sites. In a secondary analysis that was adjusted for the number of patients per resident physician as a potential confounder, intervention schedules were no longer associated with an increase in errors. CONCLUSIONS: Contrary to our hypothesis, resident physicians who were randomly assigned to schedules that eliminated extended shifts made more serious errors than resident physicians assigned to schedules with extended shifts, although the effect varied by site. The number of ICU patients cared for by each resident physician was higher during schedules that eliminated extended shifts. (Funded by the National Heart, Lung, and Blood Institute; ROSTERS ClinicalTrials.gov number, NCT02134847.).

Tbx2a Modulates Switching of RH2 and LWS Opsin Gene Expression.

Sensory systems are tuned by selection to maximize organismal fitness in particular environments. This tuning has implications for intraspecies communication, the maintenance of species boundaries, and speciation. Tuning of color vision largely depends on the sequence of the expressed opsin proteins. To improve tuning of visual sensitivities to shifts in habitat or foraging ecology over the course of development, many organisms change which opsins are expressed. Changes in this developmental sequence (heterochronic shifts) can create differences in visual sensitivity among closely related species. The genetic mechanisms by which these developmental shifts occur are poorly understood. Here, we use quantitative trait locus analyses, genome sequencing, and gene expression studies in African cichlid fishes to identify a role for the transcription factor Tbx2a in driving a switch between long wavelength sensitive (LWS) and Rhodopsin-like (RH2) opsin expression. We identify binding sites for Tbx2a in the LWS promoter and the highly conserved locus control region of RH2 which concurrently promote LWS expression while repressing RH2 expression. We also present evidence that a single change in Tbx2a regulatory sequence has led to a species difference in visual tuning, providing the first mechanistic model for the evolution of rapid switches in sensory tuning. This difference in visual tuning likely has important roles in evolution as it corresponds to differences in diet, microhabitat choice, and male nuptial coloration.

The Association Between Resident Physician Work-Hour Regulations and Physician Safety and Health.

BACKGROUND: In 2011, the Accreditation Council for Graduate Medical Education (ACGME) instituted a 16-h limit on consecutive hours for first-year resident physicians. We sought to examine the effect of these work-hour regulations on physician safety. METHODS: All medical students matched to a US residency program from 2002 to 2007 and 2014 to 2017 were invited to participate in prospective cohort studies. Each month participants reported hours of work, extended duration shifts, and adverse safety outcomes, including motor vehicle crashes, percutaneous injuries, and attentional failures. The incidence of each outcome was compared before and after the 2011 ACGME work-hour limit. Hypotheses were tested using generalized linear models adjusted for potential confounders. RESULTS: Of all first-year resident physicians nationwide, 13% participated in the study, with 80,266 monthly reports completed by 15,276 first-year resident physicians. Following implementation of the 16-h 2011 ACGME work-hour limit, the mean number of extended duration (≥24-h) shifts per month decreased from 3.9 to 0.2. The risk of motor vehicle crash decreased 24% (relative risk [RR] 0.76; 0.67-0.85), percutaneous injury risk decreased more than 40% (relative risk 0.54; 0.48-0.61), and the rate of attentional failures was reduced 18% (incidence rate ratio [IRR] 0.82; 0.78-0.86). Extended duration shifts and prolonged weekly work hours were associated with an increased risk of adverse safety outcomes independent of cohort. CONCLUSIONS: The 2011 ACGME work-hour limit was associated with meaningful improvements in physician safety and health. Surveillance is needed to monitor the ongoing impact of work hours on physician safety, health, and well-being.