Faculty Bibliography

INTRODUCTION/BACKGROUND:Approximately 50 % of resected stage II-IV melanoma patients develop recurrent disease by 5 years despite adjuvant anti-PD-1 therapy. Data to define best management of recurrences is lacking. METHODS:This was a multicentre, international, retrospective cohort study. Patients with resected stage II-IV melanoma who commenced adjuvant anti-PD-1-based therapy before January 2022 and later recurred were identified. Data on demographics, disease characteristics, recurrence patterns, management and outcomes were collected. RESULTS:711 patients from 17 sites were included. Median age was 60 [range 16-92], 64 % were male, 2 % stage II, 91 % were stage III, 7 % stage IV. Median time to recurrence was 6.2 months (0-68.5) and median follow up time from recurrence was 19.8 months (range 0.2-73.1). 63 % recurred on anti-PD-1 therapy, 36 % off therapy [3 % < 6 months, 33 % > 6 months]. Initial recurrences were locoregional (LR) alone in 44 %, distant alone (DR) in 43 %, and 11 % in both sites. LR recurrences were managed with local therapy, alone (62 %) or with "second adjuvant" anti-PD-1 (14 %) or BRAF/MEK therapy (23 %); 12 m RFS2 was 25 %, 29 % and 69 % respectively (p = 0.0045). Definitive systemic therapy at first recurrence was given in 16 % LR and 86 % DR, with best outcomes for anti-CTLA4 + anti-PD-1 and trial combinations (24 m PFS 63 % and 69 %, respectively). The 24 m OS for the entire cohort was 65 %. CONCLUSION/CONCLUSIONS:Most recurrences following adjuvant anti-PD-1 based therapy occur early and while still on drug. Outcomes are poor, regardless of site, timing of recurrence, and subsequent treatment.

Conscientious objection is a legally protected right of medical professionals to recuse themselves from patient care activities that conflict with their personal values. Anesthesiology is different from most specialties with respect to conscientious objection in that the focus is to facilitate safe, efficient, and successful performance of procedures by others, rather than to perform the treatment in question. This could give rise to a unique, somewhat indirect ethical tension between the application of conscientious objection and potential infringement upon patient autonomy and well-being. While some situations have clear grounds and precedent for conscientious objection (e.g., abortion, or futile procedures), newer procedures, such as gender-affirming surgery and xenotransplantation, may trigger conscientious objection for complex reasons. This review discusses ethical, legal, and practical aspects of conscientious objection; challenges to anesthesia groups, departments, and healthcare organizations when conscientious objection is invoked by anesthesiologists; and strategies to help mitigate the ethical dilemmas.

Treatment with the hypomethylating agent 5-azacytidine (AZA) increases survival in high-risk (HR) myelodysplastic syndrome (MDS) patients, but predicting patient response and overall survival remains challenging. To address these issues, we analyzed mutational and transcriptional profiles in CD34+ hematopoietic stem/progenitor cells (HSPCs) before and following AZA therapy in MDS patients. AZA treatment led to a greater reduction in the mutational burden in both blast and hematological responders than non-responders. Blast and hematological responders showed transcriptional evidence of pre-treatment enrichment for pathways such as oxidative phosphorylation, MYC targets, and mTORC1 signaling. While blast non-response was associated with TNFa signaling and leukemia stem cell signature, hematological non-response was associated with cell-cycle related pathways. AZA induced similar transcriptional responses in MDS patients regardless of response type. Comparison of blast responders and non-responders to normal controls, allowed us to generate a transcriptional classifier that could predict AZA response and survival. This classifier outperformed a previously developed gene signature in a second MDS patient cohort, but signatures of hematological responses were unable to predict survival. Overall, these studies characterize the molecular consequences of AZA treatment in MDS HSPCs and identify a potential tool for predicting AZA therapy responses and overall survival prior to initiation of therapy.

BACKGROUND:rVSVΔG-ZEBOV-GP is the first approved vaccine with clinical efficacy against Ebola virus disease. Although a seroprotective threshold has not been defined for those at occupational risk of exposure, the current vaccine strategy is to attain a sustained high level of antibody titres. The aim of this trial was to explore the effects of delayed boosting upon both the height and duration of antibody titres following primary immunisation. METHODS:plaque-forming unit per mL of VSVΔG-ZEBOV-GP. 18 months later, individuals who consented and were still eligible were randomly assigned 1:1 to receive either a homologous booster dose or no booster. Study visits for safety and serial blood collections for antibody titres were done on enrolled participants at months 0, 1, 3, 6, 12, 18, 19, 24, 30, and 36. Through July, 2021, a web-based application was used for randomisation, including assignments with schedules for each of the five sites using mixed permuted blocks. The trial was not masked to participants or site staff. The primary endpoint was a comparison of geometric mean titres (GMTs) of anti-Ebola virus glycoprotein IgG antibody at month 36 (ie, 18 months after randomisation) for all randomly assigned participants who completed the 36 months of follow-up (primary analysis cohort). Investigators were aware of antibody titres from baseline (enrolment) through month 18 but were masked to summary data by randomisation group after month 18. This study is registered with ClinicalTrials.gov (NCT02788227). FINDINGS/RESULTS:Of the 248 participants who enrolled and received their primary immunisation, 114 proceeded to the randomisation step at month 18. The two randomisation groups were balanced: 57 participants (24 [42%] of whom were female; median age was 42 years [IQR 35-50]) were randomly assigned to the booster group and 57 (24 [42%] of whom were female; median age was 42 years [IQR 36-51]) to the no-booster group. Of those randomly assigned, 92 participants (45 in the booster group and 47 in the no-booster group) completed 36 months of follow-up. At 18 months after primary immunisation, GMTs in the no-booster group increased from a baseline of 10 ELISA units (EU)/mL (95% CI 7-14) to 1451 EU/mL (1118-1882); GMTs in the booster group increased from 9 EU/mL (6-16) to 1769 EU/mL (1348-2321). At month 19, GMTs were 31 408 EU/mL (23 181-42 554) for the booster group and 1406 EU/mL (1078-1833) for the no-booster group; at month 36, GMTs were 10 146 EU/mL (7960-12 933) for the booster group and 1240 EU/mL (984-1563) for the no-booster group. Accordingly, the geometric mean ratio (GMR) of antibody titres had increased almost 21-fold more in the booster versus no-booster group at 1 month after booster administration (GMR 20·6; 95% CI 18·2-23·0; p<0·0001) and was still over 7-fold higher at month 36 (GMR 7·8; 95% CI 5·5-10·2; p<0·0001). Consistent with previous reports of this vaccine's side-effects, transient mono-articular or oligo-articular arthritis was diagnosed in 18 (9%) of 207 primary vaccination recipients; after randomisation, arthritis was diagnosed in one (2%) of 57 participants in the no-booster group. No new cases of arthritis developed after booster administration. Four serious adverse events occurred following randomisation: one (epistaxis) in the booster group and three (gastrointestinal haemorrhage, prostate cancer, and tachyarrhythmia) in the no-booster group. None of the serious adverse events was judged attributable to the booster vaccination assignment. INTERPRETATION/CONCLUSIONS:In addition to no new safety concerns and in marked contrast to earlier trials evaluating short-term boosting, delaying a rVSVΔG-ZEBOV-GP booster until month 18 resulted in an increase in GMT that remained several-fold above the no-booster group GMT for at least 18 months. These findings could have implications for defining the optimal timing of booster doses as pre-exposure prophylaxis in populations at ongoing risk for Ebola virus exposure. FUNDING/BACKGROUND:The Division of Intramural Research and the Division of Clinical Research of the National Institute of Allergy and Infectious Diseases at the US National Institutes of Health, Canadian Immunization Research Network through the Public Health Agency of Canada, Canadian Institutes of Health Research, and the US Defense Threat Reduction Agency.

BACKGROUND:Benzodiazepines are frequently prescribed drugs; however, their prolonged use can lead to tolerance, dependence, and other adverse effects. Despite these risks, long-term use remains common, presenting a public health concern. This study aims to explore the beliefs and opinions held by the public regarding benzodiazepines, as understanding these perspectives may provide insights into their usage patterns. METHODS:We collected public tweets published in English between January 1, 2019, and October 31, 2020, that mentioned benzodiazepines. The content of each tweet and the characteristics of the users were analyzed using a mixed-method approach, including manual analysis and semi-supervised machine learning. RESULTS:Over half of the Twitter users highlighted the efficacy of benzodiazepines, with minimal discussion of their side effects. The most active participants in these conversations were patients and their families, with health professionals and institutions being notably absent. Additionally, the drugs most frequently mentioned corresponded with those most commonly prescribed by healthcare professionals. CONCLUSIONS:Social media platforms offer valuable insights into users' experiences and opinions regarding medications. Notably, the sentiment towards benzodiazepines is predominantly positive, with users viewing them as effective while rarely mentioning side effects. This analysis underscores the need to educate physicians, patients, and their families about the potential risks associated with benzodiazepine use and to promote clinical guidelines that support the proper management of these medications. CLINICAL TRIAL NUMBER/BACKGROUND:Not applicable.

INTRODUCTION/BACKGROUND:Autonomy during residency is crucial to the training and development of competent surgeons. An essential component of this process is the 'teaching assistant (TA)' case, an indispensable opportunity for residents to gain confidence and hone intraoperative skills. However, high-quality data on the volume and diversity of cases that graduates perform are scarce. METHODS:A retrospective analysis was performed from publicly collected data of operative case logs from general surgery residents graduating from ACGME-accredited programs from 2006 to 2023. Data on the median overall number of surgeon chief and TA cases were retrieved. Collected data were organized based on sub-specialties. The Mann-Kendall trend test was used to investigate trends in TA cases and surgeon chief operative volume. RESULTS:Between 2007 and 2023, the surgeon chief cases gradually increased from 229 to 274 (19.6 ​% increase; τ ​= ​0.610, p ​= ​0.001). There was a concurrent 72.7 ​% increase in TA cases from a median of 22-38 (τ ​= ​0.574, p ​= ​0.001). Surgeon chief (283 per resident) and TA cases (43 per resident) peaked in 2018-2019 and 2016-2017. The uptrend in TA cases was associated with the significant increase in colorectal (τ ​= ​0.559, p ​= ​0.001), general surgery-other (τ ​= ​0.404, p ​= ​0.018), and hepatopancreaticobiliary (HPB) (τ ​= ​0.596, p ​= ​0.001) subspecialties. Trauma and vascular surgery did not change significantly. With respect to total chief cases, general surgery-other (τ ​= ​0.956, p=<0.001), HPB (τ ​= ​0.713, p=<0.001) and colorectal (τ ​= ​0.522, p ​= ​0.004) volume increased. There was no significant change in trauma and foregut volume, while the volume of endocrine (τ ​= ​-0.485, p ​= ​0.006) and vascular surgery (τ ​= ​0.603, p ​= ​0.001) dropped significantly. The procedural category with the highest chief and TA volume was 'colorectal tract - large intestine.' Most procedural categories (53.49 ​%) retained a median of 0 teaching cases. No chief cases were logged for the specialties generally not considered part of general surgery (genitourinary, nervous system, orthopedics, and gynecology), although a median of 1 surgeon chief genitourinary case was recorded from 2018 to 2023. CONCLUSIONS:Over the past seventeen years, there has been a gradual uptrend in the number of surgeon chief and TA cases. While this is a positive indicator of improved autonomy, further research must focus on strategies to improve resident autonomy to train well-rounded surgeons safely.

In the present work, phytoconstituents from Citrus limon are computationally tested against SARS-CoV-2 target protein such as Mpro - (5R82.pdb), Spike - (6YZ5.pdb) &RdRp - (7BTF.pdb) for COVID-19. Docking was done by glide model, QikProp was performed by in silico ADMET screening & Prime MM-GB/SA modules were used to define binding energy. When compared with approved COVID-19 drugs such as Remdesivir, Ritonavir, Lopinavir, and Hydroxychloroquine, plant-based constituents such as Quercetin, Rutoside, Naringin, Eriocitrin, and Hesperidin. bind with significant G-scores to the active SARS-CoV-2 place. The constituents Rutoside and Eriocitrin were studied in each MD simulation in 100 ns against 3 proteins 5R82.pdb, 6YZ5.pdb and 7BTF.pdb.We performed an assay with significant natural compounds from contacts and in silico results (Rutin, Eriocitrin, Naringin, Hesperidin) using 3CL protease assay kit (B.11529 Omicron variant). This kit contained 3CL inhibitor GC376 as Control. The IC₅₀ value of the test compound was found to be Rutin -17.50 μM, Eriocitrin-37.91 μM, Naringin-39.58 μM, Hesperidine-140.20 μM, the standard inhibitory concentration of GC376 was 38.64 μM. The phytoconstituents showed important interactions with SARS-CoV-2 targets, and potential modifications could be beneficial for future development.

The astrocyte, a major glial cell type in the central nervous system (CNS), is widely regarded as a functionally diverse mediator of homeostasis. During development and throughout adulthood, astrocytes have essential roles, such as providing neuron metabolic support, modulating synaptic function, and maintaining the blood-brain barrier (BBB). Recent evidence continues to underscore their functional heterogeneity and importance for CNS maintenance, as well as how these cells ensure optimal CNS and immune responses to disease, acute trauma, and infection. Advances in our understanding of neuroimmune interactions complement our knowledge of astrocyte functional heterogeneity, where astrocytes are now regarded as key effectors and propagators of immune signaling. This shift in perspective highlights the role of astrocytes not merely as support cells, but as active participants in CNS immune responses.

BACKGROUND:The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Masters Program includes eight distinct clinical pathways. The Bariatric Surgery Pathway focuses on three anchoring procedures, including the laparoscopic sleeve gastrectomy (LSG) which is the most commonly performed bariatric procedure in the United States. In this article, we present and discuss the top 10 seminal articles regarding the LSG. METHODS:The literature was systematically searched to identify the most cited papers on LSG. The SAGES Metabolic and Bariatric Surgery committee reviewed the most cited article list, and using expert consensus elected the seminal articles deemed most pertinent to LSG. These articles were reviewed in detail by committee members and are presented here. RESULTS:The top 10 most cited sentinel papers on LSG focus on operative safety, outcomes, surgical technique, and physiologic changes after the procedure. A summary of each paper is presented, including expert appraisal and commentary. CONCLUSIONS:The seminal articles presented support the widespread acceptance and use of the LSG by bolstering the understanding of its mechanism of action and by demonstrating its safety and excellent patient outcomes. All bariatric surgeons should be familiar with these 10 landmark articles.