Quantitative Measurement of the Direct Public Health Impact of Medicines Withdrawals in Europe: Development of a Modelling Method and Proof-of-Concept Study to Estimate the Morbidity and Mortality Prevented by Regulatory Action.

PURPOSE: Removing medicines from market may benefit public health by preventing adverse drug reactions (ADRs), which should be quantified. This study's aim was to identify a model to quantify the impact of medicines' marketing authorisation (MA) withdrawal and revocation in terms of preventing morbidity and mortality. METHODS: MA withdrawals and revocations for safety reasons in France, Germany and/or the United Kingdom between July 2012 and December 2016 were identified for prescription medicines. Annual exposure was estimated for each medicine, using IQVIA Medical Research Data (IMRD)-France, IMRD-Germany and IMRD-UK primary care electronic health record databases. European Medicines Agency records provided reasons for regulatory action for each medicine. Absolute risks of ADRs which led to MA withdrawal were estimated for patients exposed to each medicine by systematic review of quantitative research. Public health impact, expressed as annual number of ADRs avoided, was estimated by modelling exposure and ADR risk. RESULTS: Four MA withdrawals and two revocations met study inclusion criteria. Each product's usage decreased following MA withdrawal or revocation. Absolute risk for ADRs was 0.1%-41.25%. To estimate impact of each withdrawal or revocation, its average annual exposure within each IMRD population was multiplied by the absolute risk to give the crude number of ADRs prevented annually due to regulatory action. CONCLUSIONS: This model quantifies the public health impact of MA withdrawal and revocation in terms of serious morbidity, resulting from eliminated or reduced usage of medicines. This method can be applied to products in other settings to quantify the impact of other pharmacovigilance actions.

General Surgery Residency Application Evaluation in a USMLE Step 1 Pass/Fail World: A Retrospective Comparison.

Introduction The United States Medical Licensure Exam (USMLE) Step 1 has been used as both a licensing exam and a way for residency programs to evaluate applicants. It has had significant impact upon the match process over time. With the 2020 decision to make the exam pass/fail due to its unclear validity as an evaluation for future physician performance, programs will go through the match without the Step 1 score. We set out to better understand the effects of the exam score on our selection process, with the hypothesis that without the step 1 score, the ranking of our applicants would be significantly altered. Methods We performed a retrospective analysis of applications to a single General Surgery residency program with 4 categorial residents per year at a physician led, academic, tertiary care medical center from 2017-2020. Important applicant factors including USMLE Step 1 and 2, AOA status, science grades, clerkship scores, audition rotations, volunteer activities, research activities, letters of recommendation, and personal statements were given points and evaluated through our equation, the sum of which was used to create a rank list and offer interviews. The standard deviation of scores was calculated with and without Step 1, and the distribution of scores compared. The range and average of applicants' change in point scores were examined. Results The applications of 653 students were reviewed. After removal of USMLE step 1 points, 40% of all applicants decreased in rank, 35% remained the same, and 24% increased. Specifically, 18.8% of the top third dropped to the middle third, and 11.7% of the bottom third jumped to the middle third, while the middle third changed little (0.2% dropped and 0.9% jumped out of middle third). The points given for USMLE step 1 created a wider distribution of scores with a negative skewness, suggesting there were more applicants below the mean than above. After removing those points, applicants' scores had a narrower distribution and skewness closer to 0, showing fewer upper outliers and more applicants near the mean. Conclusions The USMLE Step 1 score significantly affected the evaluation of applicants, and the removal of it from the recruitment criteria tightened applicant rankings. The elimination of the USMLE Step 1 score in the assessment of applicants will allow for its replacement with variables that better reflect the core values of residency programs.

Application Factors May Not Be Predictors of Success Among General Surgery Residents as Measured by ACGME Milestones.

BACKGROUND: Can factors within the Electronic Residency Application Service application be used to predict the success of general surgery residents as measured by the Accreditation Council for Graduate Medical Education (ACGME) general surgery milestones? METHODS: This is a retrospective study of 21 residents who completed training at a single general surgery residency program. Electronic Residency Application Service applications were reviewed for objective data, such as age, US Medical Licensing Examination scores, and authorship of academic publications as well as for letters of recommendation, which were scored using a standardized grading system. These factors were correlated to resident success as measured by ACGME general surgery milestone outcomes using univariate and multivariate analyses. This study was conducted at a single academic tertiary care and level 1 trauma facility. Residents who completed general surgery residency training from the years of 2012-2018 were included in the study. RESULTS: There were few correlations between application factors and resident success determined by the ACGME milestones. CONCLUSIONS: Application factors alone do not account for ongoing growth and development throughout residency. Unlike the results presented in the literature for other surgical subspecialties, predicting general surgery resident success based on application factors is not straightforward.

The Hepatitis C Virus-induced NLRP3 Inflammasome Activates the Sterol Regulatory Element-binding Protein (SREBP) and Regulates Lipid Metabolism.

Hepatitis C virus (HCV) relies on host lipids and lipid droplets for replication and morphogenesis. The accumulation of lipid droplets in infected hepatocytes manifests as hepatosteatosis, a common pathology observed in chronic hepatitis C patients. One way by which HCV promotes the accumulation of intracellular lipids is through enhancing de novo lipogenesis by activating the sterol regulatory element-binding proteins (SREBPs). In general, activation of SREBPs occurs during cholesterol depletion. Interestingly, during HCV infection, the activation of SREBPs occurs under normal cholesterol levels, but the underlying mechanisms are still elusive. Our previous study has demonstrated the activation of the inflammasome complex in HCV-infected human hepatoma cells. In this study, we elucidate the potential link between chronic hepatitis C-associated inflammation and alteration of lipid homeostasis in infected cells. Our results reveal that the HCV-activated NLRP3 inflammasome is required for the up-regulation of lipogenic genes such as 3-hydroxy-3-methylglutaryl-coenzyme A synthase, fatty acid synthase, and stearoyl-CoA desaturase. Using pharmacological inhibitors and siRNA against the inflammasome components (NLRP3, apoptosis-associated speck-like protein containing a CARD, and caspase-1), we further show that the activation of the NLRP3 inflammasome plays a critical role in lipid droplet formation. NLRP3 inflammasome activation in HCV-infected cells enables caspase-1-mediated degradation of insulin-induced gene proteins. This subsequently leads to the transport of the SREBP cleavage-activating protein·SREBP complex from the endoplasmic reticulum to the Golgi, followed by proteolytic activation of SREBPs by S1P and S2P in the Golgi. Typically, inflammasome activation leads to viral clearance. Paradoxically, here we demonstrate how HCV exploits the NLRP3 inflammasome to activate SREBPs and host lipid metabolism, leading to liver disease pathogenesis associated with chronic HCV.

The International Working Group on New Developments in Pharmacovigilance: Advancing Methods and Communication in Pharmacovigilance.

PURPOSE: In 2019, the International Working Group (IWG), focusing on New Developments in Pharmacovigilance, was established. This group is coordinated by the Drug Safety Research Unit in the United Kingdom, and the mission of the IWG is to progress pharmacovigilance methodologies and promote the safe and effective use of medicines and vaccines, thereby further protecting patients. Novel therapeutics are continuously being developed to alleviate medical conditions, but with advancing technologies, innovative pharmacovigilance methodologies need to be developed to effectively monitor the use and safety of these products. With reduced timelines proposed for premarketing clinical trials and increased application of real-world evidence supporting regulatory approvals, products may be used in real-world clinical practice in shorter timeframes than before. Therefore, the need for effective methods of monitoring medicines and collecting safety data in real-time is of paramount importance to public health. METHODS: The IWG aims to advance existing methodologies used in the detection, monitoring, and analysis of safety data in pharmacovigilance and to communicate best practice proposals to support decision making in health care. The IWG will identify areas requiring review of current processes or methodologic research and will communicate the output of the IWG through peer-reviewed publications, reports, and presentation of findings at relevant conferences and scientific meetings. FINDINGS: The IWG is currently reviewing two areas in pharmacovigilance; case-level causality assessment and the strengths and limitations of data sources. The IWG is advancing these areas by producing two scoping reviews which will be easily accessible to regulatory agencies, industry, academia, and interested persons or organizations. IMPLICATIONS: The scoping reviews comply with the IWGs mission to progress pharmacovigilance methodologies and promote the safe and effective use of medicines and vaccines. The present article shares details of the objectives of the IWG and provides an overview on the status of IWG activities.

A systematic review of flurbiprofen 8.75 mg dose and risk of adverse events (excluding haemorrhagic) resulting from drug-drug interactions.

Background: Flurbiprofen 8.75 mg lozenges and oromucosal sprays are used for symptomatic relief of sore throat in patients aged 12 years and over. The documented adverse events of flurbiprofen use include those related to its pharmacological actions, namely, increased risk of haemorrhagic events, however other adverse events (such as nephrotoxicity and cardiac failure) have been known to occur. The likelihood of occurrence of adverse events increases when flurbiprofen is used concomitantly with some other medications. Therefore, the objective of this systematic review was to collate the current evidence on adverse events which occur with flurbiprofen 8.75 mg dose (any formulation), in particular as a result of interaction with other medicinal products, with a focus on non-haemorrhagic events. Methods: Systematic searches of the literature were conducted to identify literature on any formulation of flurbiprofen 8.75 mg up to the date of the electronic database search (data lock: 28 April 2020). Publications were screened to identify studies reporting non-haemorrhagic adverse events with flurbiprofen 8.75 mg and/or non-haemorrhagic adverse events in the comparator arm. Data extraction was performed for eligible studies according to pre-defined criteria and summarised in narratives, tables and figures. Risk of bias and certainty of evidence assessments were planned for each included study where results relating to the primary objective of the systematic review were available. Results: Of 1,528 publications identified by systematic literature searches, 26 met the inclusion criteria and were included in this review. None of these 26 studies contained information on non-haemorrhagic adverse events occurring as a result of a drug-drug interaction (interaction with concomitant medication used with flurbiprofen 8.75 mg), as per the primary objective and secondary objectives of the systematic review. Conclusion: Results from this systematic review on the risk of non-haemorrhagic events did not provide evidence for these events occurring as a result of interaction with other medicinal products. Additional appropriately designed studies would be required to confirm whether these findings suggest a true absence of risk or limitations in reporting.

Hemophagocytic lymphohistiocytosis (HLH) in a 25-year-old presenting with multisystem organ failure.

Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome of extreme inflammation caused by pathologic activation of the immune system. Diagnosis of HLH is challenging as the clinical presentation is similar to common medical entities such as sepsis. When a source of the extreme inflammation is not found, HLH should be considered in the differential diagnosis. In HLH, inflammatory markers such as soluble CD25 and ferritin levels are elevated. Ferritin assay is widely available at most institutions; a level greater than 10,000 is highly suggestive of HLH.2 Delayed diagnosis and failure to initiate cytotoxic chemotherapy will result in a fatal outcome.

Assessing Case Fatality on Cases of Thrombosis with Concurrent Thrombocytopenia Following COVID-19 Vaccine AstraZeneca (Vaxzevria) in the United Kingdom: A Review of Spontaneously Reported Data.

INTRODUCTION: Thrombotic thrombocytopenia syndrome (TTS) events were reported very rarely following the coronavirus disease 2019 (COVID-19) vaccine AstraZeneca (Vaxzevria). Clinical and demographic characteristics of the affected people, including the outcomes of TTS events, need to be examined using available information to better understand aspects of this association. OBJECTIVE: To analyse clinical and demographic information of TTS events, including calculating the case fatality of reported cases of TTS by age and sex, using spontaneously reported data from the UK's Yellow Card spontaneous reporting system of suspected adverse drug reactions. METHODS: TTS events reported to the Yellow Card scheme were extracted at weekly time points between 12 May 2021 and 25 May 2022. Cumulative numbers of TTS cases and deaths were recorded for each weekly interval, overall and stratified by age, sex, and vaccine dose. RESULTS: To 25 May 2022, 443 cases (81 fatal, 18.28%) had been reported in the UK. Events more frequently occurred following the first vaccine dose. No trends were observed for case fatality overall, or by age or sex. CONCLUSION: In the UK, case fatality of TTS events reported to the Medicines and Health products Regulatory Agency (MHRA) following Vaxzevria has been approximately 17-18% since May 2021. There were no statistical differences in fatality based on age or sex. Most reports followed the first vaccine dose; none have been reported following a third dose to date, although Vaxzervia was not recommended for a third dose of COVID-19 vaccine in the UK. TTS remains very rare, and benefits of vaccination outweigh the risks.

Reports of myocarditis and pericarditis following mRNA COVID-19 vaccination: a systematic review of spontaneously reported data from the UK, Europe and the USA and of the scientific literature.

OBJECTIVES: To combine spontaneously reported data from multiple countries to estimate reporting rate, and better understand risk factors for myocarditis and pericarditis following COVID-19 messenger RNA (mRNA) vaccines. DESIGN: Systematic review of spontaneously reported data from UK, USA and European Union/European Economic Area (EU/EEA) and of the scientific literature. DATA SOURCES: UK Yellow Card scheme, Vaccine Adverse Event Reporting System (VAERS), EudraVigilance were searched from date of vaccine launch to 14 March 2022-16 March 2022. PubMed/MEDLINE and Embase were searched to 15 March 2022. ELIGIBILITY CRITERIA: We included publicly available spontaneous reporting data for 'Myocarditis' and 'Pericarditis' from UK, USA and EU/EEA following COVID-19 mRNA vaccines. Pharmacoepidemiological observational studies investigating myocarditis/pericarditis following mRNA COVID-19 vaccines were included (no restrictions on language or date). Critical Appraisal Skills Programme tools assessed study quality. DATA EXTRACTION AND SYNTHESIS: Two researchers extracted data. Events of myocarditis and pericarditis were presented for each data source, stratified by vaccine, age, sex and dose (where available). Reporting rates were calculated for myocarditis and pericarditis for each population. For published pharmacoepidemiological studies, design, participant characteristics, and study results were tabulated. RESULTS: Overall, 18 204 myocarditis and pericarditis events were submitted to the UK, USA and EU/EEA regulators during the study period. Males represented 62.24% (n=11 331) of myocarditis and pericarditis reports. In the UK and USA, most reports concerned vaccinees aged <40 years (59.7% and 47.3% of reported events, respectively); trends in age were less clear for EU/EEA. Reports were more frequent following a second dose (47.1% of reports, where data available). Reporting rates were consistent between the data sources. Thirty-two pharmacoepidemiological studies were included; results were consistent with our spontaneous report analyses. CONCLUSIONS: Younger vaccinees more frequently report myocarditis and pericarditis following mRNA COVID-19 vaccines than older vaccinees. Results from published literature supported the results of our analyses.

Systematic review of spontaneous reports of myocarditis and pericarditis in transplant recipients and immunocompromised patients following COVID-19 mRNA vaccination.

OBJECTIVES: To determine whether spontaneous reporting rates of myocarditis and pericarditis differed in immunocompromised patients compared with the whole population overall, and in terms of demographics, vaccine dose and time-to-onset. DESIGN: Systematic review of spontaneously reported data from the European Union/European Economic Area (EU/EEA), the USA and the UK. DATA SOURCES: EudraVigilance (EU/EEA), Vaccine Adverse Event Reporting System (VAERS; USA) and the Medicines and Healthcare products Regulatory Agency (UK) spontaneous reporting databases were searched from date of vaccine launch to 1 December 2021. ELIGIBILITY CRITERIA: Publicly available spontaneous reporting data for 'myocarditis' and 'pericarditis' from EU/EEA and USA following COVID-19 messenger RNA vaccines. Reports with comorbidities or concurrent medication indicative of transplantation, HIV infection or cancer ('immunocompromised' population) were compared with each overall database population. DATA EXTRACTION AND SYNTHESIS: Two researchers extracted data. Spontaneously reported events of myocarditis and pericarditis were presented for immunocompromised populations for each data source, stratified by age, sex, dose and time-to-onset (where available). Seriousness of each event was determined according to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guideline E2A definition. Proportional reporting ratio (PRR) was calculated. RESULTS: There were 178 reports of myocarditis and pericarditis among immunocompromised individuals overall. Seriousness was comparable between the immunocompromised and overall populations in both databases. No trends in age or sex were observed among immunocompromised individuals. Most reports followed a second vaccine dose and occurred within 14 days. The frequency of reporting was similar to the wider population (PRR=1.36 (95% CI=0.89 to 1.82) for VAERS population). CONCLUSIONS: Myocarditis and pericarditis following COVID-19 vaccination are very rare, and benefits of COVID-19 vaccination continue to outweigh any perceived risks. Reporting rates of myocarditis and pericarditis were similar in immunocompromised individuals, however defining characteristics differed compared with the whole population; therefore, continued monitoring of adverse events following vaccination remains vital to understand differences between population subgroups.

The Role of the Contextual Cohort to Resolve Some Challenges and Limitations of Comparisons in Pharmacoepidemiology.

In pharmacoepidemiology, comparison studies can provide a useful estimate of the level of increased or decreased risk of specific events with a medication (through a measure of effect). A key focus of pharmacoepidemiological studies is the safety and effectiveness of medicines in their real-world use, and adequate comparisons of effect estimates are critical. However, consideration of guidelines, pharmacoeconomic assessments, and policies for reimbursement have made comparisons in pharmacoepidemiological studies far more difficult to conduct in recent years. Where certain subject characteristics influence the probability of being exposed to a treatment, this can introduce issues of selection bias and confounding. Methodologies are available to minimise selection bias (through case-only and randomised study designs) and deal with confounding (such as regression modelling or propensity score matching methods), however these each have their own limitations. Where prescribing guidelines are present, conducting comparisons in pharmacoepidemiology produces many challenges and not all of these can be easily overcome. Patient channelling can be more frequent with adherence to clinical guidelines compared with when prescribing decisions by doctors are based predominantly on their clinical judgement. Use of a contextual cohort could be considered as an option to characterise the adoption of new medications into clinical practice and describe the prevalence of clinical characteristics and risk factors in the two cohorts, rather than compare event rates and produce an estimate of effect.

Activation and repression of prion protein expression by key regions of intron 1.

Expression of the prion protein is necessary for infection with prion diseases. Altered expression levels may play an important role in susceptibility to infection. Therefore, understanding the mechanisms that regulate prion protein expression is of great importance. It was previously shown that expression of the prion protein is to some degree regulated by an alternative promoter within intron 1. Studies using GFP and luciferase reporter systems were undertaken to determine key sites for the repression and activation of expression of the prion protein driven by intron 1. We identified a region within intron 1 sufficient to drive prion protein expression. Our findings highlight two potential repressor regions. Both regions have binding sites for the known repressor Hes-1. Hes-1 overexpression caused a dramatic decrease in PrP protein expression. Additionally, we have identified Atox-1 as a transcription factor that upregulates prion protein expression. These findings clearly indicate that intron 1 plays a key role in regulation of prion protein expression levels.

How Applicants to General Surgery Residency Define Resilience.

OBJECTIVE: Resilience is a vital quality for the successful completion of any residency training program. Resilience is a commonly used but poorly understood term and is defined in multiple ways by people during different times of their lives. The transition from medical student to general surgical resident (GSR) is one of the most formative times in a young surgeon's professional career. The purpose of this study is to determine how a cohort of aspiring surgical residents define resilience. DESIGN: This is a qualitative study where interviews were conducted prospective GSRs over 2 application seasons. During the institution's standard interview process, applicants were asked to provide a definition of resilience. Responses were documented. Qualitative content analysis was conducted by the research team. Initial codes were developed and defined. Research team members independently coded the responses, and then an iterative group consensus process was used to develop the final themes. SETTING: This study was conducted at Geisinger Medical Center, an academic tertiary care hospital in Danville, PA with 5 categorical GSR positions per year. PARTICIPANTS: All applicants who underwent an in-person interview were included in this study. RESULTS: A total of 261 comments about resilience were available from 117 interviews. These responses were categorized into 5 themes: support, learning from failure, adaptability, self-reflection, and perseverance. CONCLUSION: Resilience as defined by applicants to a general surgery residency program is a multifaceted term. The thematic categories suggest that resilience can be viewed through the framework of the 5 components of emotional intelligence: self-aware, self-regulation, motivation, empathy, and social skills.

Remdesivir in Treatment of COVID-19: A Systematic Benefit-Risk Assessment.

INTRODUCTION: There is a need to identify effective, safe treatments for COVID-19 (coronavirus disease) rapidly, given the current, ongoing pandemic. A systematic benefit-risk assessment was designed and conducted to examine the benefit-risk profile of remdesivir in COVID-19 patients compared with standard of care, placebo or other treatments. A key objective of this study was to provide a platform for a dynamic systematic benefit-risk evaluation, which starts with inevitably limited information (to meet the urgent unmet public health need worldwide), then update the benefit-risk evaluation as more data become available. METHODS: The Benefit-Risk Action Team (BRAT) framework was used to assess the overall benefit-risk of the use of remdesivir as a treatment for COVID-19 compared with standard of care, placebo or other treatments. We searched PubMed, Google Scholar and government agency websites to identify literature reporting clinical outcomes in patients taking remdesivir for COVID-19. A value tree was constructed and key benefits and risks were ranked by two clinicians in order of considered importance. RESULTS: Using the BRAT method, several key benefits and risks for use of remdesivir in COVID-19 compared with placebo have been identified. In one trial, the benefit of time to clinical improvement was not statistically significant (21 vs 23 days, HR 1.23, 95% CI 0.87-1.75), although the study was underpowered. In another trial, a shorter time to recovery in patients treated with remdesivir was observed (11 vs 15 days), with non-significant reduced mortality risk (8% vs 12%). Risk data were only available from one trial. This trial reported fewer serious adverse events in patients taking remdesivir (18%) compared with the placebo group (26%); however, more patients in the remdesivir group discontinued treatment as a result of an adverse event compared with those patients receiving placebo (12% vs 5%). CONCLUSIONS: Preliminary clinical trial results suggest that there may be a favourable benefit-risk profile for remdesivir compared with placebo in severe COVID-19 infection and further data on benefits would strengthen this evaluation. There is limited safety data for remdesivir, which should be obtained in further studies. The current framework summarises the key anticipated benefits and risks for which further data are needed. Ongoing clinical trial data can be incorporated into the framework when available to provide an updated benefit-risk assessment.

Lopinavir-Ritonavir in the Treatment of COVID-19: A Dynamic Systematic Benefit-Risk Assessment.

INTRODUCTION AND OBJECTIVE: COVID-19 is an ongoing, global public health crisis for which safe and effective treatments need to be identified. The benefit-risk balance for the use of lopinavir-ritonavir in COVID-19 needs to be monitored on an ongoing basis, therefore a systematic benefit-risk assessment was designed and conducted. A key objective of this study was to provide a platform for a dynamic systematic benefit-risk evaluation; although initially this evaluation is likely to contain limited information, it is required because of the urgent unmet public need. Importantly, it allows additional data to be incorporated as they become available, and re-evaluation of the benefit-risk profile. METHODS: A systematic benefit-risk assessment was conducted using the Benefit-Risk Action Team (BRAT) framework. The exposure of interest was lopinavir-ritonavir treatment in severe COVID-19 compared to standard of care, placebo or other treatments. A literature search was conducted in PubMed and Embase to identify peer-reviewed papers reporting clinical outcomes. Two clinicians constructed a value tree and ranked key benefits and risks in order of considered clinical importance. RESULTS: We screened 143 papers from PubMed and 264 papers from Embase for lopinavir-ritonavir; seven papers were included in the final benefit-risk assessment. In comparison to standard of care, data for several key benefits and risks were identified for lopinavir-ritonavir. Time to clinical improvement was not significantly different for lopinavir-ritonavir in comparison to standard of care (hazard ratio 1.31, 95% confidence interval 0.95-1.80). From one study, there were fewer cases of acute respiratory distress syndrome with lopinavir-ritonavir compared with standard of care (13% vs 27%). There also appeared to be fewer serious adverse events with lopinavir-ritonavir (20%) vs standard of care (32%). Limited data were available for comparison of lopinavir-ritonavir to other treatments. CONCLUSIONS: Based on currently available data, there was no clear benefit for the use of lopinavir-ritonavir compared to standard of care in severe COVID-19. Risk data suggested a possible decrease in serious adverse events. There was a reduction in acute respiratory distress syndrome with lopinavir-ritonavir in one study. Overall, the benefit-risk profile for lopinavir-ritonavir in severe COVID-19 cannot be considered positive until further efficacy and effectiveness data become available.

Meaningful autonomy in general surgery training: Exploring for gender bias.

BACKGROUND: Resident autonomy is essential to the development of a surgical resident. This study aims to analyze gender differences in meaningful autonomy (MA) given to general surgery trainees intraoperatively. METHODS: This is a retrospective study of general surgery residents at an academic-affiliated tertiary care facility. Attending surgeons completed post-operative evaluations based on the Zwisch model (4-point scale, ≥3 indicating MA). RESULTS: Attending faculty members (37 males, 15 females) completed evaluations of 35 residents (18 males, 17 females). A total of 3574 evaluations were analyzed (1380 female, 2194 male residents) over 28 months. Multivariate analysis revealed case complexity, post graduate year level and rater gender were significantly associated with MA. Resident gender and faculty experience did not impact MA. CONCLUSIONS: In contrast to published literature, resident gender did not influence MA. This may be encouraging to surgical programs seeking strategies to address gender bias.

The Value of Surgical Graduate Medical Education (GME) Programs Within An Integrated Health Care System.

OBJECTIVE: Surgical graduate medical education (GME) programs add both significant cost and complexity to the mission of teaching hospitals. While expenses tied directly to surgical training programs are well tracked, overall cost-benefit accounting has not been performed. In this study, we attempt to better define the costs and benefits of maintaining surgical GME programs within a large integrated health system. DESIGN: We examined the costs, in 2018 US dollars, associated with the surgical training programs within a single health system. Total health system expenses were calculated using actual and estimated direct GME expenses (salary, benefits, supplies, overhead, and teaching expenses) as well as indirect medical education (IME) expenses. IME expenses for each training program were estimated by using both Medicare percentages and the Medicare Payment Advisor Commission study. The projected cost to replace surgical trainees with advanced practitioners or hospitalists was obtained through interviews with program directors and administrators and was validated by our system's business office. SETTING: A physician lead, integrated, rural health system consisting of 8 hospitals, a medical school and a health insurance company. PARTICIPANTS: GME surgical training programs within a single health system's department of surgery. RESULTS: Our health system's department of surgery supports 8 surgical GME programs (2 general surgery residencies along with residencies in otolaryngology, ophthalmology, oral-maxillofacial surgery, urology, pediatric dentistry, and vascular surgery), encompassing 89 trainees. Trainees work an average of 64.4 hours per week. Total health system cost per resident ranged from $249,657 to $516,783 based on specialty as well as method of calculating IME expenses. After averaging program costs and excluding IME and overhead expenses, we estimated the average annual cost per trainee to be $84,171. We projected that replacing our surgical trainees would require hiring 145 additional advanced practitioners at a cost of $166,500 each per year, or 97 hospitalists at a cost of $346,500 each per year. Excluding overhead, teaching and IME expenses, these replacements would cost the health system an estimated additional $16,651,281 or $26,119,281 per year, respectively. CONCLUSIONS: Surgical education is an integral part of our health system and ending surgical GME programs would require large expansion of human resources and significant additional fiscal capital.

Low skeletal muscle capillarization limits muscle adaptation to resistance exercise training in older adults.

OBJECTIVES: Adequate muscle perfusion supports the transport of nutrients, oxygen and hormones into muscle fibers. Aging is associated with a substantial decrease in skeletal muscle capillarization, fiber size and oxidative capacity, which may be improved with regular physical activity. The aim of this study was to investigate the relationship between muscle capillarization and indices of muscle hypertrophy (i.e. lean mass; fiber cross sectional area (CSA)) in older adults before and after 12 weeks of progressive resistance exercise training (RET). DESIGN: Interventional study SETTING AND PARTICIPANTS: 19 subjects (10 male and 9 female; 71.1 ±â€¯4.3 years; 27.6 ±â€¯3.2 BMI) were enrolled in the study and performed a whole body RET program for 12 weeks. Subjects where then retrospectively divided into a LOW or HIGH group, based on their pre-RET capillary-to-fiber perimeter exchange index (CFPE). Physical activity level, indices of capillarization (capillaries-to-fiber ratio, C:Fi; CFPE index and capillary-to-fiber interface, LC-PF index), muscle hypertrophy, muscle protein turnover and mitochondrial function were assessed before and after RET. RESULTS: Basal capillarization (C:Fi; CFPE and LP-CF index) correlates with daily physical activity level (C:Fi, r = 0.57, p = 0.019; CFPE index, r = 0.55, p = 0.024; LC-PF index, r = 0.56, p = 0.022) and CFPE and LC-PF indices were also positively associated with oxidative capacity (respectively r = 0.45, p = 0.06; r = 0.67, p = 0.004). Following RET, subjects in the HIGH group underwent hypertrophy with significant improvements in muscle protein synthesis and muscle fiber CSA (p < 0.05). However, RET did not promote muscle hypertrophy in the LOW group, but RET significantly increased muscle capillary density (p < 0.05). CONCLUSION/IMPLICATIONS: Muscle fiber capillarization before starting an exercise training program may be predictive of the muscle hypertrophic response to RET in older adults. Increases in muscle fiber size following RET appear to be blunted when muscle capillarization is low, suggesting that an adequate initial capillarization is critical to achieve a meaningful degree of muscle adaptation to RET.