This review highlights noteworthy literature published in 2023 and pertinent to anesthesiologists and critical care physicians caring for patients undergoing abdominal organ transplantation. We feature 9 studies from 593 peer-reviewed papers on pancreatic transplantation, 3 from 194 on intestinal transplantation, and 28 from over 4513 on kidney transplantation. The liver transplantation section includes a special focus on 20 studies from 5666 clinical trial publications. We explore a broad range of topics, including donor management, perioperative recipient management, and innovative pharmacologic and mechanical interventions tested for the improvement of patient and graft outcomes and survival.

Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719). Various biological pathway analyses are performed, along with bulk and single-cell RNA sequencing, to demonstrate the likely physiological relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of Ashkenazi Jewish adult IBD displays significant overlap with very early onset-IBD genetics. Moreover, by performing biobank phenome-wide analyses, we find that IBD genes have pleiotropic effects that involve other immune responses. Finally, we show that polygenic risk score analyses based on genome-wide high impact variants have high power to predict IBD susceptibility.

Anatomy is an essential component of clinical anesthesiology. The use of simulated patients and alternative materials, including embalmed human bodies, have become increasingly common during resident physician training due to the deemphasis on anatomical education during undergraduate medical training. In this report, the need for a more extensive review of relevant anatomy for the practice of anesthesiology was addressed by the design, evaluation, and dissemination of a human dissection course for procedural training of anesthesiology residents. The course utilized "freedom art" embalmed human bodies that allowed trainees to perform ultrasound-based regional and neuraxial techniques followed by detailed dissections of critical anatomy. One hundred and four residents participated in workshops and small group discussions and were evaluated using pre- and post-course assessments. A variety of clinical techniques were performed on the bodies, including regional blocks and neuraxial catheter placement. Insertion of peripheral/neuraxial catheters was successful, with dissections demonstrating the expected placement. Assessment scores improved following the course (pre-course mean 52.7%, standard deviation (σ) 13.1%; post-course mean 72.2%, σ 11.6%; t-test p < 0.0001) and feedback highlighted the usefulness and clinical relevance of course content. The ability to correlate ultrasound imaging with subsequent dissections of the "blocked" area and visualization of dye staining was extremely relevant for spatial understanding of the anatomy relevant for the clinical practice of these techniques. This manuscript demonstrates successful implementation of a comprehensive course for anesthesiology resident physicians to address gaps in undergraduate anatomical education and suggests that broader adoption of dissection courses may be beneficial for training anesthesiologists.

INTRODUCTION:Liver transplantation surgeries are challenging cases for anesthesiologists. While intra-operative teaching is paramount, simulation has emerged as an educational tool to augment clinical training. A variety of simulation modalities have been described in the literature, but no study has aimed to assess the use of simulation in liver transplantation fellowship training.METHODS:A 20-question survey detailing the use of simulation, including simulation modalities used and barriers to simulation use, was developed and distributed to 22 program directors for liver transplantation anesthesiology fellowships. An exploratory analysis was performed on multiple-choice and free-text responses.RESULTS:Thirteen program directors completed the survey and were included in our analysis. Most programs (61.5%) did not report the use of simulation for liver transplantation fellow training. Of the programs that did use simulation, four required it as a mandatory component of their curriculum. Task trainers and screen-based simulators were more commonly used by these programs. Faculty availability and interest, as well as a lack of an established curriculum, were cited as major limitations to simulation use.CONCLUSIONS:Simulation is an important component of anesthesiology trainee education, as evidenced by the requirement for simulation during residency by the American Council for Graduate Medical Education. Our findings suggest that simulation is an underutilized educational tool that we believe could greatly augment the training of liver transplantation anesthesiology fellows by providing exposure to a wide range of clinical challenges.

Transcription factor (TF) networks determine cell fate in hematopoiesis. However, how TFs cooperate with other regulatory mechanisms to instruct transcription remains poorly understood. Here we show that in small pre-B cells, the lineage restricted epigenetic reader BRWD1 closes early development enhancers and opens the enhancers of late B lymphopoiesis to TF binding. BRWD1 regulates over 7000 genes to repress proliferative and induce differentiation programs. However, BRWD1 does not regulate the expression of TFs required for B lymphopoiesis. Hypogammaglobulinemia patients with BRWD1 mutations have B-cell transcriptional profiles and enhancer landscapes similar to those observed in Brwd1 -/- mice. These data indicate that, in both mice and humans, BRWD1 is a master orchestrator of enhancer accessibility that cooperates with TF networks to drive late B-cell development.

High-throughput genomic technologies yield about 20,000 variants in the protein-coding exome of each individual. A commonly used approach to select candidate disease-causing variants is to test whether the associated gene has been previously reported to be disease-causing. In the absence of known disease-causing genes, it can be challenging to associate candidate genes with specific genetic diseases. To facilitate the discovery of novel gene-disease associations, we determined the putative biologically closest known genes and their associated diseases for 13,005 human genes not currently reported to be disease-associated. We used these data to construct the closest disease-causing genes (CDG) server, which can be used to infer the closest genes with an associated disease for a user-defined list of genes or diseases. We demonstrate the utility of the CDG server in five immunodeficiency patient exomes across different diseases and modes of inheritance, where CDG dramatically reduced the number of candidate genes to be evaluated. This resource will be a considerable asset for ascertaining the potential relevance of genetic variants found in patient exomes to specific diseases of interest. The CDG database and online server are freely available to non-commercial users at: http://lab.rockefeller.edu/casanova/CDG.

Computational analyses of human patient exomes aim to filter out as many nonpathogenic genetic variants (NPVs) as possible, without removing the true disease-causing mutations. This involves comparing the patient's exome with public databases to remove reported variants inconsistent with disease prevalence, mode of inheritance, or clinical penetrance. However, variants frequent in a given exome cohort, but absent or rare in public databases, have also been reported and treated as NPVs, without rigorous exploration. We report the generation of a blacklist of variants frequent within an in-house cohort of 3,104 exomes. This blacklist did not remove known pathogenic mutations from the exomes of 129 patients and decreased the number of NPVs remaining in the 3,104 individual exomes by a median of 62%. We validated this approach by testing three other independent cohorts of 400, 902, and 3,869 exomes. The blacklist generated from any given cohort removed a substantial proportion of NPVs (11-65%). We analyzed the blacklisted variants computationally and experimentally. Most of the blacklisted variants corresponded to false signals generated by incomplete reference genome assembly, location in low-complexity regions, bioinformatic misprocessing, or limitations inherent to cohort-specific private alleles (e.g., due to sequencing kits, and genetic ancestries). Finally, we provide our precalculated blacklists, together with ReFiNE, a program for generating customized blacklists from any medium-sized or large in-house cohort of exome (or other next-generation sequencing) data via a user-friendly public web server. This work demonstrates the power of extracting variant blacklists from private databases as a specific in-house but broadly applicable tool for optimizing exome analysis.

We report the molecular, cellular, and clinical features of 5 patients from 3 kindreds with biallelic mutations in the autosomal LIG1 gene encoding DNA ligase 1. The patients exhibited hypogammaglobulinemia, lymphopenia, increased proportions of circulating γδT cells, and erythrocyte macrocytosis. Clinical severity ranged from a mild antibody deficiency to a combined immunodeficiency requiring hematopoietic stem cell transplantation. Using engineered LIG1-deficient cell lines, we demonstrated chemical and radiation defects associated with the mutant alleles, which variably impaired the DNA repair pathway. We further showed that these LIG1 mutant alleles are amorphic or hypomorphic, and exhibited variably decreased enzymatic activities, which lead to premature release of unligated adenylated DNA. The variability of the LIG1 genotypes in the patients was consistent with that of their immunological and clinical phenotypes. These data suggest that different forms of autosomal recessive, partial DNA ligase 1 deficiency underlie an immunodeficiency of variable severity.

Whole exome sequencing (WES) has proven an effective tool for the discovery of genetic defects in patients with primary immunodeficiencies (PIDs). However, success in dissecting the genetic etiology of common variable immunodeficiency (CVID) has been limited. We outline a practical framework for using WES to identify causative genetic defects in these subjects. WES was performed on 50 subjects diagnosed with CVID who had at least one of the following criteria: early onset, autoimmune/inflammatory manifestations, low B lymphocytes, and/or familial history of hypogammaglobulinemia. Following alignment and variant calling, exomes were screened for mutations in 269 PID-causing genes. Variants were filtered based on the mode of inheritance and reported frequency in the general population. Each variant was assessed by study of familial segregation and computational predictions of deleteriousness. Out of 433 variations in PID-associated genes, we identified 17 probable disease-causing mutations in 15 patients (30%). These variations were rare or private and included monoallelic mutations in NFKB1, STAT3, CTLA4, PIK3CD, and IKZF1, and biallelic mutations in LRBA and STXBP2. Forty-two other damaging variants were found but were not considered likely disease-causing based on the mode of inheritance and/or patient phenotype. WES combined with analysis of PID-associated genes is a cost-effective approach to identify disease-causing mutations in CVID patients with severe phenotypes and was successful in 30% of our cohort. As targeted therapeutics are becoming the mainstay of treatment for non-infectious manifestations in CVID, this approach will improve management of patients with more severe phenotypes.

The Structures course at the Icahn School of Medicine at Mount Sinai is a combination of three courses taken by first year medical students: Gross Anatomy, Histology, and Embryology. Functioning as a single unit, this course allows integration of these three areas to enhance student learning and offer a unique perspective for medical students. In previous years, we have reported our efforts to increase Teaching Assistant (TA) involvement in the course. Senior TAs (4 th year medical students, scholarly year medical students, or PhD phase MD/PhD students) have become responsible for a broad range of activities in the course, notably organizing and presenting content at a variety of review sessions, and proctoring table conferences. Table conferences, a substitute for traditional practical exams in Gross Anatomy that have normally been conducted by faculty members, were transitioned entirely to Senior Teaching Assistants last year. These conferences are an oral assessment of students’ practical and conceptual knowledge, meant to model interactions students may have with residents or attendings later in their medical education. It is our hope that students thus become comfortable with this format in preparation for these future interactions. Table conferences are conducted by student TAs four times during the course and result in a group grade of 6 (below average), 8 (average), or 10 (above average). After each conference, TAs record the table's grade and then give formative feedback about the group's performance. This year, we seek to explore the dynamics of post‐table conference formative feedback. This feedback is meant to give students a chance to reflect on their table conference performance and analyze their strengths and weaknesses. TAs are instructed to give students a chance to explain how they felt about a conference before discussing their own thoughts. Students do not receive their grade on the day of the conference, so as to avoid discussions focusing on quantitative grades rather than qualitative feedback. To assess the effectiveness of feedback, we have surveyed the TAs that have led table conferences, and in addition, are conducting group sessions with first year medical students to solicit their opinions about conferences. Overall, response to table conferences and conference feedback from students and TAs has been very positive. However, some responses we have already obtained indicate that the withholding of numerical grades during post‐conference feedback may actually have an opposite effect than desired, leaving students to attempt to “read into” TA feedback to determine the grade instead of qualitatively critiquing their own performance. In addition, when giving feedback to a table who has received a grade of below average, TAs have noted difficulty with finding a balance between being too upbeat, giving a false sense of optimism as to the grade, and being too negative. Regardless, the act of giving table conferences and formative feedback to students is excellent preparation for future medical education, and TAs often feel better prepared for other teaching positions having been a TA for Structures.

BACKGROUNDCommon variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells.METHODSWe used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates.RESULTSSix different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients.CONCLUSIONSHeterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.).

The United States Immunodeficiency Network (USIDNET) patient registry was used to characterize the presentation, genetics, phenotypes, and treatment of patients with Hyper IgM Syndrome (HIGM). The USIDNET Registry was queried for HIGM patient data collected from October 1992 to July 2015. Data fields included demographics, criteria for diagnosis, pedigree analysis, mutations, clinical features, treatment and transplant records, laboratory findings, and mortality. Fifty-two physicians entered data from 145 patients of ages 2 months to 62 years (median 12 years); 131 were males. Using patients' age at last entry, data from 2072 patient years are included. Mutations were recorded for 85 subjects; 82 were in CD40LG. Eighteen subjects had non-X-linked HIGM. 40 % had a normal serum IgM and 15 %, normal IgA. Infections were reported for 91 %, with pulmonary, ear, and sinus infections being the most common. 42 % had Pneumocystis jirovecii pneumonia; 6 % had Cryptosporidium. 41 % had neutropenia. 78 % experienced non-infectious complications: chronic diarrhea (n = 22), aphthous ulcers (n = 28), and neoplasms (n = 8) including colon cancer, adrenal adenoma, liver adenocarcinoma, pancreatic carcinoid, acute myeloid leukemia, hepatoma, and, in a female with an autosomal dominant gain of function mutation in PIK3CD, an ovarian dysgerminoma. Thirteen patients had a hematopoietic marrow or stem cell transplant; three had solid organ transplants. Thirteen were known to have died (median age = 14 years). Analysis of the USIDNET Registry provides data on the common clinical features of this rare syndrome, and in contrast with previously published data, demonstrates longer survival times and reduced gastrointestinal manifestations.

The Structures course at Mount Sinai is a combination of three courses taken by first year medical students: Anatomy, Histology, and Embryology. Functioning as a single unit, this course allows integration of these areas to enhance student learning and offer a unique perspective for medical students. Last year, we reported our efforts to reshape how Teaching Assistants (TAs) function within our course. This year, with the second iteration of Structures and as part of a continued effort to increase the role of student TAs, TAs became responsible for a broader range of activities. Notably, table conferences, a substitute for practical exams in Anatomy normally conducted by faculty members, were transitioned entirely to Senior TAs (4th year or scholarly year medical students, or PhD phase MD/PhD students). Second year medical student TAs became responsible for organizing and teaching a number of review sessions, including weekly review sessions, midterm/final examination reviews, and in‐lab review sessions before each table conference. Course evaluations have been completed and are being analyzed. Feedback on TAs and their role in the course was overwhelmingly positive. In addition, focus groups consisting of first year students are being organized to solicit feedback and suggestions. Of equal importance, TAs have responded favorably to increased involvement in the course and have cited the value of increased opportunities to teach and of strengthening their understanding of topics taught. Overall, we have found that an increase in the role and responsibilities of TAs in medical education have been extremely positive for both students and TAs alike.

As much of the education of medical students in their clinical years is now conducted by residents, it is becoming increasingly important that medical students at all levels learn the importance of various aspects of teaching, from in‐class instruction to conducting evaluations. The following report will discuss the changes implemented in our first year medical school “Structures” course, a new entity at the Icahn School of Medicine at Mount Sinai consisting of Gross Anatomy, Histology, and Embryology.Approximately 70 TAs take part in teaching for this course, with roles ranging from organizing review sessions, to assisting in the preparation of exams and in‐lab assessment of students. In an effort to integrate TAs more into the teaching process, Structures TAs became responsible for organizing weekly review sessions, comprehensive midterm and final exam review sessions, and, especially of note, became a larger part of the course’s evaluations. Over the past few years, the anatomy course at Mount Sinai has adopted an assessment strategy called “table conferences” in place of practical examinations. Traditionally, in these table conferences, a group of five or six students are questioned about aspects of their dissection, both practical and conceptual, by an evaluator. While historically done by faculty members, this year, in Structures, Senior TAs became responsible for conducting the majority of these table conferences.Overall, we found that increased TA involvement in all aspects of the course has been an overwhelmingly positive experience for students, TAs, and faculty alike. It is our hope to completely shift table conferences to Senior TAs and to further increase the involvement of both Senior TAs and second year TAs in the course in the future. We believe participating in this TA paradigm will play a major role in shaping our students as educators.

About half of all subjects with common variable immune deficiency (CVID) are afflicted with inflammatory complications including hematologic autoimmunity, granulomatous infiltrations, interstitial lung disease, lymphoid hyperplasia and/or gastrointestinal inflammatory disease. The pathogenesis of these conditions is poorly understood but singly and in aggregate, these lead to significantly increased (11 fold) morbidity and mortality, not experienced by CVID subjects without these complications. To explore the dysregulated networks in these subjects, we applied whole blood transcriptional profiling to 91 CVID subjects, 47 with inflammatory conditions and 44 without, in comparison to subjects with XLA and healthy controls. As compared to other CVID subjects, males with XLA or healthy controls, the signature of CVID subjects with inflammatory complications was distinguished by a marked up-regulation of IFN responsive genes. Chronic up-regulation of IFN pathways is known to occur in autoimmune disease due to activation of TLRs and other still unclarified cytoplasmic sensors. As subjects with inflammatory complications were also more likely to be lymphopenic, have reduced B cell numbers, and a greater reduction of B, T and plasma cell networks, we suggest that more impaired adaptive immunity in these subjects may lead to chronic activation of innate IFN pathways in response to environmental antigens. The unbiased use of whole blood transcriptome analysis may provides a tool for distinguishing CVID subjects who are at risk for increased morbidity and earlier mortality. As more effective therapeutic options are developed, whole blood transcriptome analyses could also provide an efficient means of monitoring the effects of treatment of the inflammatory phenotype.