What would you do? A survey of HPB surgeons practice patterns.

BACKGROUND: The surgical decision making for pancreatic adenocarcinoma is complex. Although practice guidelines exist for many scenarios, these do not cover many common eventualities that may be encountered during these cases. We sought to identify the practice pattern variations amongst pancreatic surgeons in response to commonly experienced clinical scenarios. METHODS: A multiple-choice questionnaire was distributed to all full members of the IHPBA. Participant demographics, training history, and clinical practice information were obtained. The survey provided various operative scenarios and participants were asked how they would likely proceed. Responses were collected and stored anonymously in a secure database. Statistical analysis was performed using Stata 16.0. RESULTS: 164 responses were submitted. Most of the respondents were male and had been in practice for over 10 years. The median age range was 40-50 years old. When asked about staging laparoscopy, the majority performed it selectively. For most respondents a pathological aorto-caval nodes was a reason to abort the procedure but most would have continued in the setting of a positive hepatic artery node. When encountering a single Segment 2 liver metastasis, participants who practiced in Europe were significantly more likely to resect and proceed compared to those in Asia and North America. Participants who had undergone only a Surgical Oncology fellowship were most likely to abort. With respect to direct colonic invasion, most participants would resect the specimen en bloc. Respondents who participated in fewer that 20 PDAC operations/year were most likely to abort. CONCLUSIONS: Surgical decision making in PDAC surgery is complex and there is significant disagreement on the correct management. While formal guidelines cannot exist for all situations, this survey highlights the need for consensus on commonly encountered operative scenarios.

Is it resectable? A survey regarding tumor classification and vascular involvement.

INTRODUCTION: The anatomic location of the pancreas can result in involvement of major vasculature, which may act as a contraindication to resection. Several classification systems have been developed. We sought to discover the variations in the HPB community determining PDAC resectability. METHODS: The multiple-choice survey was distributed to all full members of the IHPBA. Questions were asked regarding demographics and clinical scenarios regarding tumor resectability. RESULTS: 164 responses were submitted. Most of the respondents were male and had been in practice for over 10 years. The median age range was 40-50 years old. Most practiced in either Asia (n = 57,35.9%), North America (n = 52,32.7%), or Europe (n = 32,20.1%). Classification systems used to determine resectability were: NCCN (n = 42,26.3%), JPS (n = 35,21.9%), International consensus (n = 33,20.6%), AHPBA/SSO (n = 23,14.4%), Alliance (n = 3,1.9%), and other/no-classification (n = 23,14.5%). There was significant variation in the frequency of the most common answer within the scenarios (84.7%-33.5%). Participant concordance with their stated classification system found a median rate of 62.5%. Participant decision of tumor resectability was not dependent on their adopted classification system. CONCLUSION: When classifying PDAC resectability, there is significant variation between surgeons as to how they would classify a specific tumour, independent of the classification system they use. In addition, surgeons do not show high concordance with the definitions within that classification system.

Listening to depression and suicide risk in medical students: the Healer Education Assessment and Referral (HEAR) Program.

OBJECTIVE: A growing body of literature documents high rates of burnout, depression, and suicidal ideation among physicians and medical students. Barriers to seeking mental health treatment in this group include concerns about time, stigma, confidentiality, and potential career impact. The authors describe a 4-year trial of the Healer Education Assessment and Referral (HEAR) program, designed to increase mental health services utilization (MHSU) and decrease suicide risk (SR) as assessed by an Interactive Screening Program (ISP)at one US medical school. METHODS: Over a 4-year period, medical students were engaged in face-to-face, campus-wide, educational group programs and were invited to complete an individual, online, and anonymous survey. This survey contained the 9-item Patient Health Questionnaire (PHQ-9) scale to assess depression and items to identify suicidal thoughts and behaviors, substance use, distressing emotional states, and the use of mental health treatment. Students who engaged in this ISP by corresponding electronically with a counselor after completing the survey were assessed and when indicated, referred to further treatment. RESULTS: The HEAR program was delivered to 1,008 medical students. Thirty-four percent (343/1,008) completed the online screening portion. Almost 8 % of respondents met the criteria for high/significant SR upon analysis of the completed screens. Ten out of 13 of the students with SR who dialogued with a counselor were not already receiving mental health treatment, indicating that this anonymous ISP identified a high proportion of an untreated, at risk, and potentially suicidal population. MHSU among medical students who completed the survey was 11.5 % in year 1 and 15.0 % by year 4. SR among medical students was 8.8 % in year 1 and 6.2 % in year 4 as assessed by the ISP. CONCLUSIONS: This novel interventional program identified at risk, potentially suicidal medical students at one institution. Based on this single-site experience, we suggest that future multisite studies incorporate a comparison group, acquire baseline (prematriculation) data regarding MHSU and SR, and use an individualized yet anonymous identification system to measure changes in individual participants' mental health status over time.

The multiple shark Ig H chain genes rearrange and hypermutate autonomously.

Sharks and skates are representatives of the earliest vertebrates with an immune system based on V(D)J rearrangement. They possess a unique Ig gene organization consisting of 15 to >50 individual IgM loci, each with one VH, two DH, one JH, and one set of constant region exons. The present study attempts to understand how multiple Ig genes are regulated with respect to rearrangement initiation and to targeting during somatic hypermutation. The linkage of three single-copy IgH genes was determined, and single-cell genomic PCR studies in a neonatal animal were used to examine any relationship between relative gene position and likelihood of rearrangement. Our results show that one to three IgH genes are activated independently of linkage or allelic position and the data best fit with a probability model based on the hypothesis that V(D)J rearrangement occurs as a sequence of trials within the B cell. In the neonatal cell set, two closely related IgH, G2A, and G2B, rearranged at similar frequencies, and their membrane forms were expressed at similar levels, like in other young animals. However, older animals displayed a bias in favor of the G2A isotype, which suggests that although rearrangement at G2A and G2B was randomly initiated during primary repertoire generation, the two very similar IgM sequences appear to be differentially expressed with age and exposure to Ag. We performed genomic single-cell PCR on B cells from an immunized individual to study activation-induced cytidine deaminase targeting and found that hypermutation, like V(D)J rearrangement, occurred independently among the many shark IgH.

Understanding risk factors and microbial trends implicated in the development of Whipple-related surgical-site infections.

Objective: The purpose of this study is to understand the role of risk factors and postoperative complications seen in patients undergoing Whipple procedures in the development of surgical site infections. Our secondary goal was to evaluate whether microbial patterns differed between preoperative antibiotic classes, offering insight into the effectiveness of current practices while promoting antibiotic stewardship. Design: We performed a retrospective cohort study comparing patients with and without SSIs. Setting: This study was conducted at a tertiary-care center in the southeastern United States. Participants: Patients who underwent a Whipple procedure between 2012 and 2021 were acquired from the National Surgical Quality Improvement Program (NSQIP) database. Results: Patients with a bleeding disorder reported higher SSI rates (P = .04), whereas patients with a biliary stent reported lower surgical site infection (SSI) rates (P = .02) Those with postoperative complications had higher SSI rates, including delayed gastric emptying (P < .001) and pancreatic fistula (P < .001). Patients with longer operative times were 1.002 times more likely to develop SSIs (adjusted odds ratio [aOR], 1.002; 95% confidence interval [CI], 1.001-1.004; P = .006) whereas surgical indications for malignancy correlated with decreased SSIs risk (aOR, 0.578; 95% CI, 0.386-866) when adjusting for body mass index, surgical indication, and duration of surgical procedure. Conclusions: Optimizing preoperative management of modifiable risk factors for patients undergoing pancreatoduodenectomies and decreasing operative times may reduce SSI rates and patient and hospital burden. Further research is needed to understand whether stent placement reduces SSI risk in pancreatoduodenectomy.

Immunoglobulin heavy chain exclusion in the shark.

The adaptive immune system depends on specific antigen receptors, immunoglobulins (Ig) in B lymphocytes and T cell receptors (TCR) in T lymphocytes. Adaptive responses to immune challenge are based on the expression of a single species of antigen receptor per cell; and in B cells, this is mediated in part by allelic exclusion at the Ig heavy (H) chain locus. How allelic exclusion is regulated is unclear; we considered that sharks, the oldest vertebrates possessing the Ig/TCR-based immune system, would yield insights not previously approachable and reveal the primordial basis of the regulation of allelic exclusion. Sharks have an IgH locus organization consisting of 15-200 independently rearranging miniloci (VH-D1-D2-JH-Cmu), a gene organization that is considered ancestral to the tetrapod and bony fish IgH locus. We found that rearrangement takes place only within a minilocus, and the recombining gene segments are assembled simultaneously and randomly. Only one or few H chain genes were fully rearranged in each shark B cell, whereas the other loci retained their germline configuration. In contrast, most IgH were partially rearranged in every thymocyte (developing T cell) examined, but no IgH transcripts were detected. The distinction between B and T cells in their IgH configurations and transcription reveals a heretofore unsuspected chromatin state permissive for rearrangement in precursor lymphocytes, and suggests that controlled limitation of B cell lineage-specific factors mediate regulated rearrangement and allelic exclusion. This regulation may be shared by higher vertebrates in which additional mechanistic and regulatory elements have evolved with their structurally complex IgH locus.

LIN37-DREAM prevents DNA end resection and homologous recombination at DNA double-strand breaks in quiescent cells.

DNA double-strand break (DSB) repair by homologous recombination (HR) is thought to be restricted to the S- and G2- phases of the cell cycle in part due to 53BP1 antagonizing DNA end resection in G1-phase and non-cycling quiescent (G0) cells. Here, we show that LIN37, a component of the DREAM transcriptional repressor, functions in a 53BP1-independent manner to prevent DNA end resection and HR in G0 cells. Loss of LIN37 leads to the expression of HR proteins, including BRCA1, BRCA2, PALB2, and RAD51, and promotes DNA end resection in G0 cells even in the presence of 53BP1. In contrast to 53BP1-deficiency, DNA end resection in LIN37-deficient G0 cells depends on BRCA1 and leads to RAD51 filament formation and HR. LIN37 is not required to protect DNA ends in cycling cells at G1-phase. Thus, LIN37 regulates a novel 53BP1-independent cell phase-specific DNA end protection pathway that functions uniquely in quiescent cells.

Inpatient Telehealth and Coronavirus Disease 2019 Outcomes: Experiences in Alabama.

Background: During the early months of the coronavirus disease 2019 (COVID-19) pandemic, hospitals were concerned about preserving personal protective equipment. UAB Hospital Medicine designed a strategy to outfit acute care patient rooms on a COVID-19 unit with telemedicine technology to allow for remote clinician rounding. Objective: To describe one hospital's experience with inpatient telehealth and compare outcomes between patients with and without inpatient telehealth visits. Design and Methods: Retrospective chart review of patients admitted to UAB Hospital Medicine with COVID-19 between March 16, 2020 and April 24, 2020. Logistic and negative binomial regression models were used to examine the relationship between telehealth visits and the likelihood of a subsequent transfer to the intensive care unit (ICU), ventilation, and number of ICU days. Clinician interviews provided additional insight into the telehealth implementation. Findings: One-quarter of the patients received a telehealth visit. Half were admitted to the ICU, and one-third received ventilation. Regression models did not identify statistically significant differences in transfer to the ICU, number of ICU days, and ventilation between patients with and without telehealth visits. Older age and increased respiratory rate were associated with higher odds of ICU admission. Patients with a cough were associated with lower odds of ventilation and fewer ICU days. Discussion: Implementation challenges included difficulties associated with assisting patients with operating the tablets. However, clinicians noted that there was a great benefit to patients being able to see an unmasked physician. Furthermore, the telehealth program proved to be a viable strategy for connecting patients in isolation with their families. Findings can inform the future development of inpatient telemedicine strategies.

Evaluation of retinal nerve fiber layer thickness and optic nerve functions in fellow eye of neuromyelitis optica with unilateral optic neuritis.

PURPOSE: Peripapillary retinal nerve fibre layer (RNFL) thickness might be useful in monitoring ongoing subclinical structural damage especially in eyes with no history of optic neuritis (ON) in neuromyelitis optica (NMO). OBJECTIVE: To evaluate the peripapillary RNFL thickness and optic nerve functions in fellow eye of NMO with unilateral optic neuritis. MATERIALS AND METHODS: A comparative cross-sectional study was conducted in 2 tertiary hospitals from August 2017 to May 2019. RNFL thickness and optic nerve functions were evaluated. Statistical analysis was performed using Statistical Package for Social Science version 24. RESULTS: A total of 26 NMO patients and 26 controls were involved in this study. The median age (IQR) of NMO patients was 32.5 (12) years old. The RNFL thickness was significantly reduced in NMO patients with non-ON eyes as compared to control group. Best corrected visual acuity between the 2 groups were comparable (0.20 vs 0.00, p=0.071). Contrast sensitivity was also reduced in NMO patients (non-ON eyes) at all 5 spatial frequencies. In NMO group, 34.6% have normal colour vision. The mean deviation (MD) of Humphrey visual field (HVF) was higher in NMO group (p<0.001). There was a moderate correlation between RNFL thickness and contrast sensitivity. Weak correlation was found between the RNFL thickness with visual acuity and mean deviation of visual field test. CONCLUSION: Our study showed that the fellow eye of NMO patients with unilateral ON revealed a significant reduction in RNFL thickness and all the optic nerve functions have subtle early changes that signify a subclinical retinal damage.

ß-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3ß/tau cascade.

The brain noradrenergic system is critical for normal cognition and is affected at early stages in Alzheimer's disease (AD). Here, we reveal a previously unappreciated direct role of norepinephrine signaling in connecting ß-amyloid (Aß) and tau, two key pathological components of AD pathogenesis. Our results show that Aß oligomers bind to an allosteric site on α2A adrenergic receptor (α2AAR) to redirect norepinephrine-elicited signaling to glycogen synthase kinase 3ß (GSK3ß) activation and tau hyperphosphorylation. This norepinephrine-dependent mechanism sensitizes pathological GSK3ß/tau activation in response to nanomolar accumulations of extracellular Aß, which is 50- to 100-fold lower than the amount required to activate GSK3ß by Aß alone. The significance of our findings is supported by in vivo evidence in two mouse models, human tissue sample analysis, and longitudinal clinical data. Our study provides translational insights into mechanisms underlying Aß proteotoxicity, which might have strong implications for the interpretation of Aß clearance trial results and future drug design and for understanding the selective vulnerability of noradrenergic neurons in AD.

The effectiveness of air-free warming systems on perioperative hypothermia in total hip and knee arthroplasty: A systematic review and meta-analysis.

BACKGROUND: Perioperative hypothermia is a common and serious complication during surgery. Different warming systems are used to prevent perioperative hypothermia. However, there have been no previous meta-analyses of the effectiveness of air-free warming systems on perioperative hypothermia in patients undergoing joint arthroplasty. METHODS: We systematically searched PubMed, EMBASE, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases to collect randomized controlled trials (RCTs) from inception to August 2018. These RCTs compared the effects of air-free warming with forced-air (FA) warming system in patients undergoing joint arthroplasty. Postoperative temperature, core temperature during surgery, thermal comfort, blood loss and incidence of shivering and hypothermia were analyzed. RESULTS: A total of 287 patients from 6 clinical studies were included in the analysis. In summary, there was no significant difference in the postoperative temperature (WMD -0.043, 95% CI -0.32 to 0.23, P = .758) between the air-free warming and FA warming groups. No statistical difference (WMD 0.058, 95% CI -0.10 to 0.22, P = .475) was found in core temperatures at 0 minutes during surgery between the air-free warming and FA warming groups. Furthermore, there was no statistical difference in thermal comfort, blood loss or incidence of shivering and hypothermia between the air-free warming and FA warming groups. CONCLUSIONS: Air-free warming system was as effective as FA warming system in patients undergoing joint arthroplasty.

Dorsolateral septum somatostatin interneurons gate mobility to calibrate context-specific behavioral fear responses.

Adaptive fear responses to external threats rely upon efficient relay of computations underlying contextual encoding to subcortical circuits. Brain-wide analysis of highly coactivated ensembles following contextual fear discrimination identified the dorsolateral septum (DLS) as a relay of the dentate gyrus-CA3 circuit. Retrograde monosynaptic tracing and electrophysiological whole-cell recordings demonstrated that DLS somatostatin-expressing interneurons (SST-INs) receive direct CA3 inputs. Longitudinal in vivo calcium imaging of DLS SST-INs in awake, behaving mice identified a stable population of footshock-responsive SST-INs during contextual conditioning whose activity tracked and predicted non-freezing epochs during subsequent recall in the training context but not in a similar, neutral context or open field. Optogenetic attenuation or stimulation of DLS SST-INs bidirectionally modulated conditioned fear responses and recruited proximal and distal subcortical targets. Together, these observations suggest a role for a potentially hard-wired DLS SST-IN subpopulation as arbiters of mobility that calibrate context-appropriate behavioral fear responses.

Dopamine D2 Receptors in the Paraventricular Thalamus Attenuate Cocaine Locomotor Sensitization.

Alterations in thalamic dopamine (DA) or DA D2 receptors (D2Rs) have been measured in drug addiction and schizophrenia, but the relevance of thalamic D2Rs for behavior is largely unknown. Using in situ hybridization and mice expressing green fluorescent protein (GFP) under the Drd2 promoter, we found that D2R expression within the thalamus is enriched in the paraventricular nucleus (PVT) as well as in more ventral midline thalamic nuclei. Within the PVT, D2Rs are inhibitory as their activation inhibits neuronal action potentials in brain slices. Using Cre-dependent anterograde and retrograde viral tracers, we further determined that PVT neurons are reciprocally interconnected with multiple areas of the limbic system including the amygdala and the nucleus accumbens (NAc). Based on these anatomical findings, we analyzed the role of D2Rs in the PVT in behaviors that are supported by these areas and that also have relevance for schizophrenia and drug addiction. Male and female mice with selective overexpression of D2Rs in the PVT showed attenuated cocaine locomotor sensitization, whereas anxiety levels, fear conditioning, sensorimotor gating, and food-motivated behaviors were not affected. These findings suggest the importance of PVT inhibition by D2Rs in modulating the sensitivity to cocaine, a finding that may have novel implications for human drug use.