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Medical students are increasingly choosing nonsurgical specialties; observership programs can address factors influencing them toward surgical careers by allowing preclerkship exposure and mentorship, and correcting misconceptions. The aims of this study were to assess the influence of a peer-led observership program at the Université de Montréal on the career choices of preclinical medical students and to determine the factors associated with a positive observership experience. We used a quasi-experimental convergent mixed-methods questionnaire design. From Nov. 19 to Dec. 31, 2018, and Mar. 1 to Apr. 4, 2019, all medical students participating in the observership program were eligible for the study; there were no ineligibility criteria. Using a prospective purposive sampling method, we recruited students via the email sent to confirm their observership. In the week after their observership, we invited the students by email to complete a postintervention survey. We used nonparametric tests to evaluate the impact of the observership on participants’ career choices and an inductive data-driven thematic analysis to analyze their responses. Of the 204 students who participated, 157 provided consent, of whom 85 (54.1%) completed questionnaires both before and after the observership. The majority of participants were interested in a surgical specialty before (72 [85%]) and after (68 [84%]) the observership. There was no significant change in the students’ choices of surgical specialties after the observership. However, most (68 [81%]) reported being more interested in a surgical career as a result of the observership, which allowed them to see that the type of practice they considered was congruent with a surgical career. Their perceptions of the field of surgery became positive, particularly regarding its pace and atmosphere and the humanistic patient–doctor relationship it required. The experience was influenced by surgeons’ and teams’ attitudes toward students, knowledge-sharing and quality of exposure. Participants mentioned that their willingness to participate was in part responsible for the success of their experience. This observership program allowed an early, positive introduction of students to surgery while challenging stereotypes. It provided a better understanding of surgery, enabling participants to consider this field and potentially influencing their residency application. De plus en plus d’étudiants en médecine choisissent des spécialités non chirurgicales; les stages d’observation peuvent servir à leur rendre la carrière de chirurgien plus attirante en leur offrant une exposition et un mentorat précliniques et en corrigeant certaines idées préconçues. Cette étude avait pour but d’évaluer l’influence d’un stage d’observation mené par des pairs à l’Université de Montréal sur les choix de carrière chez les étudiants en médecine à l’étape préclinique et déterminer quels facteurs sont associés à une expérience positive lors du stage d’observation. Nous avons utilisé un type de questionnaire à méthodes mixtes convergent quasi-expérimental. Du 19 novembre au 31 décembre 2018 et du 1er mars au 4 avril 2019, tous les étudiants en médecine participant au stage d’observation étaient admissibles à l’étude; il n’y avait aucun critère d’exclusion. À l’aide d’une méthode d’échantillonnage dirigé prospectif, nous avons recruté les étudiants à même le courriel de confirmation de leur stage d’observation. La semaine suivant leur stage d’observation, nous les avons invités par courriel à répondre à un questionnaire. Nous avons utilisé des tests non paramétriques pour mesurer l’impact du stage d’observation sur leurs choix de carrière et une analyse thématique inductive guidée par des données pour analyser leurs réponses. Parmi les 204 étudiants qui ont participé, 157 ont fourni leur consentement, dont 85 (54,1 %) ont répondu aux questionnaires avant et après le stage d’observation. La majorité des participants étaient intéressés par une spécialité chirurgicale avant (72 [85 %]) et après (68 [84 %]) le stage d’observation. On n’a noté aucun changement significatif dans les choix de spécialité chirurgicale des étudiants après le stage d’observation. Par contre, la plupart (68 [81 %]) se sont dits plus intéressés par une carrière en chirurgie par suite du stage d’observation, qui leur a permis de voir que le type de pratique auquel ils aspiraient s’harmonisait bien avec une carrière en chirurgie. Leurs perceptions du domaine de la chirurgie sont devenues positives, particulièrement au plan du rythme, de l’ambiance et du lien patient–médecin empreint d’humanité qui est requis. Leur expérience a été influencée par l’attitude des chirurgiens et des équipes qui les ont accueillis, par le partage des connaissances et la qualité de leur présence. Les participants ont mentionné que leur volonté de participer était en partie responsable de la réussite de leur expérience. Pour les étudiants, ce stage d’observation a constitué une introduction positive au milieu chirurgical tout en ébranlant leurs préjugés. Il leur a permis de mieux comprendre ce qu’est la chirurgie et d’envisager de faire carrière dans ce domaine, et pourrait avoir influé sur leur choix de résidence.

Evaluate the impact of deep neuromuscular blockade on intraoperative nociception Deep neuromuscular blockade has been shown to improve surgical conditions and postoperative outcomes compared to moderate neuromuscular blockade in laparoscopic surgery. Still, its impact on intraoperative nociception and opioid requirement has never been assessed. Monocentric randomised controlled trial. Operating room. We included 100 ASA I to III patients who underwent colorectal laparoscopic surgery with desflurane-remifentanil anesthesia. Patients were randomised into two groups to achieve either moderate (1–3 train of four response) or deep (1–2 post-tetanic count) neuromuscular block (NMB) with repeated boluses of rocuronium. The Nociception Level (NOL) index guided intraoperative remifentanil administration in both groups. The primary endpoint was total intraoperative remifentanil administration per hour of surgery. Secondary endpoints included, Leiden Surgical Rating Scale (L-SRS), intra-abdominal pressure, postoperative pain scores and opioids' consumption. Ninety-three patients were analysed. Forty-five in the deep group and 48 patients in moderate group. Intraoperative administration of remifentanil was 348 (228–472) μg.h−1 in the deep NMB group compared to 494 (392–618) μg.h−1 in the moderate NMB group (P < 0.001). Lowest L-SRS was 5 (4–5) in the deep NMB group versus 3 (2–5) (P < 0.001) in the moderate NMB group. Mean intra-abdominal pressure was 11.9 (1.3) in the deep NMB group versus 13 (1.3) (P < 0.001) in the moderate NMB group. Secondary postoperative outcomes including pain scores and analgesics administration were not significantly different. This study shows that deep neuromuscular blockade reduces intraoperative NOL-guided administration of remifentanil in colorectal laparoscopic surgeries. It also improves surgical conditions. The study was registered at ClinicalTrials.gov under NCT03910998. •Deep neuromuscular block NMB reduces NOL-guided remifentanil administration by 30 % during laparoscopic colorectal surgery.•Deep neuromuscular block improves surgical satisfaction and reduces intra-abdominal pressure during laparoscopic surgery.•Postoperative outcomes including postoperative pain scores and opioids' consumption were similar between groups.

A cholecystoenteric fistula (CEF) is a rare complication of cholelithiasis with cholecystitis. Cholecystocolonic fistulas (CCFs) account for 8-26.5% of all CEFs. CCFs can cause colonic bleeding, obstruction or perforation, with such complications being mainly reported in the narrower sigmoid colon. Colonic biliary ileus, or obstruction due to the colonic gallstone impaction, is extremely rare in the proximal colon and its best management is yet to be elucidated. We present the case of a 73-year-old male patient with multiple comorbidities and previous abdominal surgeries who presented with hematochezia and intestinal obstructive symptoms. Imaging revealed a giant 5 × 7 cm gallstone in the proximal transverse colon. Laparotomy and stone extraction via colotomy were performed. Complicated proximal colonic gallstones are exceedingly rare with several operative and non-operative treatments already described. A time-saving surgery in a patient with serious comorbidities is reasonable when compared to a more extensive procedure including enterolithotomy, cholecystecomy and fistula closure.

We draw on a five-year longitudinal data set to investigate the influence of performance measurement in the processual dynamics of strategic change, particularly in enacting effective strategic change. Our model examines the role of performance measurement in driving strategy-consistent operational changes and in ensuring that the desired objectives of the strategic change process are achieved. We investigate these roles for performance measurement over time and empirically document lags between changes in strategic priorities, changes in operational processes, and subsequent changes in firm performance. We find that performance measurement supports the implementation of strategic change by influencing the extent to which changes to operational tasks and activities are made in response to new strategic priorities, as well as influencing the quality and impact of these operational changes, as reflected in improved contemporaneous and future firm performance. This paper was accepted by Suraj Srinivasan, accounting .

Skeletal muscle regeneration depends on satellite cells. After injury these muscle stem cells exit quiescence, proliferate and differentiate to regenerate damaged fibres. We show that this progression is accompanied by metabolic changes leading to increased production of reactive oxygen species (ROS). Using Pitx2/3 single and double mutant mice that provide genetic models of deregulated redox states, we demonstrate that moderate overproduction of ROS results in premature differentiation of satellite cells while high levels lead to their senescence and regenerative failure. Using the ROS scavenger, N-Acetyl-Cysteine (NAC), in primary cultures we show that a physiological increase in ROS is required for satellite cells to exit the cell cycle and initiate differentiation through the redox activation of p38α MAP kinase. Subjecting cultured satellite cells to transient inhibition of P38α MAP kinase in conjunction with NAC treatment leads to their rapid expansion, with striking improvement of their regenerative potential in grafting experiments.

We report multiple lines of evidence for a stochastic signal that is correlated among 67 pulsars from the 15 yr pulsar timing data set collected by the North American Nanohertz Observatory for Gravitational Waves. The correlations follow the Hellings–Downs pattern expected for a stochastic gravitational-wave background. The presence of such a gravitational-wave background with a power-law spectrum is favored over a model with only independent pulsar noises with a Bayes factor in excess of 1014, and this same model is favored over an uncorrelated common power-law spectrum model with Bayes factors of 200–1000, depending on spectral modeling choices. We have built a statistical background distribution for the latter Bayes factors using a method that removes interpulsar correlations from our data set, finding p = 10−3 (≈3σ) for the observed Bayes factors in the null no-correlation scenario. A frequentist test statistic built directly as a weighted sum of interpulsar correlations yields p = 5 × 10−5 to 1.9 × 10−4 (≈3.5σ–4σ). Assuming a fiducial f −2/3 characteristic strain spectrum, as appropriate for an ensemble of binary supermassive black hole inspirals, the strain amplitude is 2.4−0.6+0.7×10−15 (median + 90% credible interval) at a reference frequency of 1 yr−1. The inferred gravitational-wave background amplitude and spectrum are consistent with astrophysical expectations for a signal from a population of supermassive black hole binaries, although more exotic cosmological and astrophysical sources cannot be excluded. The observation of Hellings–Downs correlations points to the gravitational-wave origin of this signal.

Base editing can be applied to characterize single nucleotide variants of unknown function, yet defining effective combinations of single guide RNAs (sgRNAs) and base editors remains challenging. Here, we describe modular base-editing-activity ‘sensors’ that link sgRNAs and cognate target sites in cis and use them to systematically measure the editing efficiency and precision of thousands of sgRNAs paired with functionally distinct base editors. By quantifying sensor editing across >200,000 editor-sgRNA combinations, we provide a comprehensive resource of sgRNAs for introducing and interrogating cancer-associated single nucleotide variants in multiple model systems. We demonstrate that sensor-validated tools streamline production of in vivo cancer models and that integrating sensor modules in pooled sgRNA libraries can aid interpretation of high-throughput base editing screens. Using this approach, we identify several previously uncharacterized mutant TP53 alleles as drivers of cancer cell proliferation and in vivo tumor development. We anticipate that the framework described here will facilitate the functional interrogation of cancer variants in cell and animal models. Improved base editing libraries enable high-throughput functional analysis of single-nucleotide variants in cancer.

BackgroundProgrammed cell death receptor-1 (PD-1)-blocking antibodies are approved to treat metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) cases ineligible for curative surgery or radiation. Notwithstanding, some patients experience inadequate responses or severe immune-related adverse events (AEs), indicating the need for improved therapies. Cosibelimab is a high-affinity programmed cell death-ligand 1 (PD-L1)-blocking antibody that activates innate and adaptive immunity by blocking PD-L1 interaction with PD-1 and B7-1 receptors. It is an unmodified immunoglobulin G1 subtype with a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Here, we present results of the pivotal study of patients with metastatic CSCC from an open-label, multicenter, multiregional, multicohort, phase 1 trial of cosibelimab.MethodsIn this trial, participants with metastatic CSCC received cosibelimab 800 mg intravenously every 2 weeks. Primary endpoint was objective response rate (ORR) by independent central review using Response Evaluation Criteria in Solid Tumors, V.1.1. Secondary endpoints included duration of response (DOR) and safety.ResultsObjective response was observed in 37 of 78 participants (47.4% (95% CI: 36.0% to 59.1%)), with median follow-up of 15.4 months (range: 0.4 to 40.5) as of data cut-off. Median DOR was not reached (range: 1.4+ to 34.1+ months), with response ongoing in 73.0% of participants. Common treatment-emergent AEs (≥15%) were fatigue (26.9%), rash (16.7%), and anemia (15.4%). Eighteen participants (23.1%) experienced immune-related AEs (grade 3: n=2 (2.6%); no grade 4/5). No treatment-related deaths were reported.ConclusionsCosibelimab demonstrated clinically meaningful ORR and DOR and was associated with a manageable safety profile.Trial registration numberNCT03212404.

There is a debate in the literature as to whether employee selection is a substitute or complement to incentive contracting. We argue that incentive contracts and selection can be both complements and substitutes conditional on the contracting difficulty faced by the firm. We examine these control choices in a setting where contracting difficulties arise due to the firm's choice of strategy and from the volatility created by the firm's external environment. We select a firm's commitment to organizational learning (OL) as our strategic choice variable as this provides a useful proxy for identifying settings where explicit incentive contracting is difficult. The results show that, as firms become increasingly committed to OL, incentive contracts and employee selection operate as complements. However, with a high commitment to OL and an increasing level of external volatility, contracting on performance measures will become less effective. In this context, our results indicate that there is a substitution effect toward employee selection.