The Influence of Obesity on Outcomes Following Arthroscopic Rotator Cuff Repair: A Systematic Review and Meta-Analysis of 118,331 Patients Internationally.

Background: Given the rising prevalence of obesity, the number of patients with obesity undergoing arthroscopic rotator cuff repair (RCR) will likely increase; however, there have been mixed results in the existing literature with regard to the effect of elevated body mass index (BMI) on functional outcomes and complications. Methods: The patient-reported outcome measures included the visual analog scale (VAS) pain score, the American Shoulder and Elbow Surgeons (ASES) score, range of motion, and adverse events. Results: Fourteen studies (118,331 patients) were included. There were significant decreases in VAS pain scores for both patients with obesity (mean difference, -3.8 [95% confidence interval (CI), -3.9 to -3.7]; p < 0.001) and patients without obesity (mean difference, -3.2 [95% CI, -3.3 to -3.1]; p < 0.001). There were also significant increases in ASES scores for both patients with obesity (mean difference, 24.3 [95% CI, 22.5 to 26.1]; p < 0.001) and patients without obesity (mean difference, 24.3 [95% CI, 21.4 to 26.0]; p < 0.001). There were also significant increases in ASES scores for both patients with obesity (mean difference, 24.3 [95% CI, 22.5 to 26.1]; p < 0.001) and patients without obesity (mean difference, 24.3 [95% CI, 21.4 to 26.0]; p < 0.001). However, there were no significant differences in final VAS pain scores, ASES scores, or range of motion between the groups. The mean rates of complications were higher among patients with obesity (1.2% ± 1.7%) than among patients without obesity (0.59% ± 0.11%) (p < 0.0001), and the mean rates of postoperative admissions were also higher among patients with obesity (5.9%) than patients without obesity (3.7%) (p < 0.0001). Although the mean rates of reoperation were similar between groups (5.2% ± 2.8% compared with 5.2% ± 4.2%), the meta-analysis revealed lower odds of reoperation in patients without obesity (odds ratio [OR], 0.76 [95% CI, 0.71 to 0.82]). Conclusions: No significant or clinically important differences in postoperative pain, ASES scores, or range of motion were found between patients with and without obesity following arthroscopic RCR. However, populations with obesity had higher rates of complications, postoperative admissions, and reoperation following arthroscopic RCR. Level of Evidence: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Disparities in Access to Outpatient Surgery Related to Removal of Procedures from Medicare's Inpatient Only List.

OBJECTIVE: We assessed the shift from inpatient to outpatient surgical care related to changes to the Inpatient Only List in 2020 and 2021 compared to 2019. SUMMARY BACKGROUND DATA: The extent to which procedures shift from the inpatient to outpatient setting following removal from Medicare's Inpatient Only List is unknown. Many health systems also encouraged a shift from inpatient to outpatient surgery during the COVID-19 pandemic. Assessing the relative change in outpatient surgical utilization for procedures removed from the Inpatient Only List during COVID-19 would provide empirical data on whether reimbursement policy changes or inpatient capacity needs during the pandemic were more likely to shift care from the inpatient to outpatient setting. METHODS: We used administrative data from the PINC AI Healthcare Database across 723 hospitals to determine the within-facility relative change in outpatient vs inpatient procedural volume in 2020 and 2021 compared to 2019 using a multivariable conditional fixed-effects Poisson regression model. We also assessed whether outpatient surgical utilization varied by race and ethnicity. Using a multivariable linear probability model, we assessed the absolute change in risk-adjusted 30-day complication, readmission, and mortality rates for inpatient and outpatient surgical procedures. RESULTS: In 2020 and 2021 compared to 2019 respectively, there was a 5.3% (95% CI, 1.4% to 9.5%) and 41.3% (95% CI 33.1% to 50.0%) relative increase in outpatient elective procedural volume. Outpatient procedural volume increased most significantly for hip replacement which was removed from the Inpatient Only List in 2020 (increase in outpatient surgical utilization of 589.3% (95% CI, 524.9% to 660.3%)). The shift to outpatient hip replacement procedures was concentrated among White patients; in 2021, hip replacement procedural volume increased by 271.1% (95% CI, 241.2% and 303.7%) for White patients and 29.5% (95% CI, 24.4% and 34.9%) for Black patients compared to 2019 levels. There were no consistent or large changes in 30-day complication, readmission, or mortality risk in 2020 and 2021 compared to 2019. CONCLUSION: There was a modest increase in elective outpatient surgeries and a pronounced increase in outpatient orthopedic surgeries which were removed from the Inpatient Only List during the COVID-19 pandemic. Utilization of outpatient surgical procedures was concentrated among White patients.

Association between physician-hospital integration and inpatient care delivery in accountable care organizations: An instrumental variable analysis.

OBJECTIVE: To investigate the relationship between physician-hospital integration within accountable care organizations (ACOs) and inpatient care utilization and expenditure. DATA SOURCES: The primary data were Massachusetts All-Payer Claims Database (2009-2013). STUDY SETTING: Fifteen provider organizations that entered a commercial ACO contract with a major private payer in Massachusetts between 2009 and 2013. STUDY DESIGN: Using an instrumental variable approach, the study compared inpatient care delivery between patients of ACOs demonstrating high versus low integration. We measured physician-hospital integration within ACOs by the proportion of primary care physicians in an ACO who billed for outpatient services with a place-of-service code indicating employment or practice ownership by a hospital. The study sample comprised non-elderly adults who had continuous insurance coverage and were attributed to one of the 15 ACOs. Outcomes of interest included total medical expenditure during an episode of inpatient care, length of stay (LOS) of the index hospitalization, and 30-day readmission. An inpatient episode was defined as 30, 45, and 60 days from the admission date. DATA COLLECTION/EXTRACTION METHODS: Not applicable. PRINCIPAL FINDINGS: The study examined 33,535 admissions from patients served by the 15 ACOs. Average medical expenditure within 30 days of admission was $24,601, within 45 days was $26,447, and within 60 days was $28,043. Average LOS was 3.5 days, and 5.4% of patients were readmitted within 30 days. Physician-hospital integration was associated with a 10.6% reduction in 30-day expenditure (95% CI, -15.1% to -5.9%). Corresponding estimates for 45 and 60 days were - 9.7% (95%CI, -14.2% to -4.9%) and - 9.6% (95%CI, -14.3% to -4.7%). Integration was associated with a 15.7% decrease in LOS (95%CI, -22.6% to -8.2%) but unrelated to 30-day readmission rate. CONCLUSIONS: Our instrumental variable analysis shows physician-hospital integration with ACOs was associated with reduced inpatient spending and LOS, with no evidence of elevated readmission rates.

Iterative assay for transposase-accessible chromatin by sequencing to isolate functionally relevant neuronal subtypes.

The Drosophila brain contains tens of thousands of distinct cell types. Thousands of different transgenic lines reproducibly target specific neuron subsets, yet most still express in several cell types. Furthermore, most lines were developed without a priori knowledge of where the transgenes would be expressed. To aid in the development of cell type-specific tools for neuronal identification and manipulation, we developed an iterative assay for transposase-accessible chromatin (ATAC) approach. Open chromatin regions (OCRs) enriched in neurons, compared to whole bodies, drove transgene expression preferentially in subsets of neurons. A second round of ATAC-seq from these specific neuron subsets revealed additional enriched OCR2s that further restricted transgene expression within the chosen neuron subset. This approach allows for continued refinement of transgene expression, and we used it to identify neurons relevant for sleep behavior. Furthermore, this approach is widely applicable to other cell types and to other organisms.

Virtual Access to STEM Careers: In the Field Experiments.

The Virtual Access to STEM Careers (VASC) project is an intertwined classroom and virtual reality (VR) curricular program for third through fourth graders. Elementary school students learn about and take on the roles and responsibilities of STEM occupations through authentic, problem-based tasks with physical kits and immersive VR environments. This article reports on a round of curriculum and virtual environment development and in-classroom experimentation that was guided by preliminary results gathered from our initial VASC prototyping and testing. This specific iteration focuses on curriculum for learning about sea turtles and tasks regularly completed by park rangers and marine biologists who work with these creatures and a new backend data collection component to analyze participant behavior. Our results showed that educators were able to setup and integrate VASC into their classrooms with relative ease. Elementary school students were able to learn how to interface with our system quickly and enjoyed being in the environment, making a positive link to STEM education.

Association between weight-for-length percentile and ICU length of stay in patients with a single ventricle undergoing bidirectional Glenn repair: A retrospective cohort study.

BACKGROUND: Poor weight gain has been identified as an independent risk factor for increased surgical morbidity and mortality for patients with single-ventricle physiology undergoing staged surgical palliation. Conversely, excessive weight gain has also emerged as an independent risk factor predicting increased morbidity and mortality in a single-center study. Given this novel single-center concept, we investigated the impact of excessive weight on patients with single-ventricle physiology undergoing bidirectional Glenn palliation in a multicenter study model. METHODS: Patients from the Pediatric Heart Network Single Ventricle Reconstruction Trial (n = 387) were analyzed in a retrospective cohort study examining the independent effect of weight percentile on intensive care unit (ICU) length of stay (LOS) and ventilator days. Locally estimated scatterplot smoothing (LOESS) regression was used to plot weight-for-length (WFL) percentiles by ICU LOS and ventilator days. Unadjusted and adjusted ordinal regression was used to model ICU LOS and ventilator days. RESULTS: Scatterplots and LOESS regression curves demonstrated increasing ICU LOS and ventilator days for increasing WFL percentiles. Unadjusted ordinal regression analysis of ICU LOS demonstrated a trend of increasing ICU LOS for increasing WFL percentiles that was not statistically significant (P = 0.11). A similar trend was demonstrated in adjusted ordinal regression that was not statistically significant (P = 0.48). Unadjusted and adjusted ordinal regression analysis of ventilator days did not reach statistical significance (P = 0.07). CONCLUSION: Excessive weight gain has a clinically relevant but not statistically significant association with increased ICU LOS and ventilator days for those patients in the >90th WFL percentile for age.

Surgery for nonlocalizing hyperparathyroidism in high volume center.

BACKGROUND: Patients with nonlocalizing hyperparathyroidism pose a significant challenge to surgeons when undergoing neck exploration for parathyroidectomy. METHODS: We evaluated 536 patients that had parathyroidectomy for primary hyperparathyroidism (PHPT) from 2005 to 2018 at a single tertiary academic center, and 155 (29%) had standard nonlocalizing preoperative imaging (negative ultrasound and sestamibi scans). RESULTS: There were a total of 102 (66%) non-ectopic single adenomas in the nonlocalizing group and 325 (85%) single adenomas in the localizing group. There was no significant difference (p = 0.09) in adenoma quadrant between localizing and nonlocalizing single adenomas, but the most common location in both groups was right inferior. Patients with nonlocalizing scans were more likely to have double adenomas (21% vs. 9%, p < 0.001), ectopic glands (10% vs. 5%, p = 0.052), and multi-gland disease (13% vs. 8%, p = 0.002). CONCLUSION: Nonlocalizing PHPT patients experienced similar cure and complication rates as localizing PHPT, but required more bilateral explorations and increased operative time.

Potential inequities in access to in-person SHIP counseling services.

OBJECTIVES: Counseling and education on Medicare coverage options are available through the federal State Health Insurance Assistance Program (SHIP), but little is known about the population that SHIP reaches. STUDY DESIGN: Cross-sectional study. METHODS: Using a novel data source on SHIP counseling site locations, we characterized the availability of in-person SHIP counseling by zip code tabulation area (ZCTA) and used linear regression and t tests to evaluate whether SHIP counseling sites are disproportionately located in higher-income communities. RESULTS: Our sample included 1511 SHIP counseling sites. More than half (63%) of the localities in our sample have a SHIP site within the ZCTA or county. Twenty-four percent do not have a SHIP site within the county but have one in an adjacent county. The remaining 13% do not have a nearby SHIP site. There is a disproportionate number of individuals eligible for Medicare in localities without a SHIP site. Moreover, the population living in areas without in-person SHIP sites is more likely to have low income and fewer years of education than the population living in areas with a SHIP site. CONCLUSIONS: These results suggest that there are areas where in-person SHIP service expansion or other additional navigation support may be warranted.

Strikingly High Activity of 15-Lipoxygenase Towards Di-Polyunsaturated Arachidonoyl/Adrenoyl-Phosphatidylethanolamines Generates Peroxidation Signals of Ferroptotic Cell Death.

The vast majority of membrane phospholipids (PLs) include two asymmetrically positioned fatty acyls: oxidizable polyunsaturated fatty acids (PUFA) attached predominantly at the sn2 position, and non-oxidizable saturated/monounsaturated acids (SFA/MUFA) localized at the sn1 position. The peroxidation of PUFA-PLs, particularly sn2-arachidonoyl(AA)- and sn2-adrenoyl(AdA)-containing phosphatidylethanolamines (PE), has been associated with the execution of ferroptosis, a program of regulated cell death. There is a minor subpopulation (≈1-2 mol %) of doubly PUFA-acylated phospholipids (di-PUFA-PLs) whose role in ferroptosis remains enigmatic. Here we report that 15-lipoxygenase (15LOX) exhibits unexpectedly high pro-ferroptotic peroxidation activity towards di-PUFA-PEs. We revealed that peroxidation of several molecular species of di-PUFA-PEs occurred early in ferroptosis. Ferrostatin-1, a typical ferroptosis inhibitor, effectively prevented peroxidation of di-PUFA-PEs. Furthermore, co-incubation of cells with di-AA-PE and 15LOX produced PUFA-PE peroxidation and induced ferroptotic death. The decreased contents of di-PUFA-PEs in ACSL4 KO A375 cells was associated with lower levels of di-PUFA-PE peroxidation and enhanced resistance to ferroptosis. Thus, di-PUFA-PE species are newly identified phospholipid peroxidation substrates and regulators of ferroptosis, representing a promising therapeutic target for many diseases related to ferroptotic death.

Conserved chromatin and repetitive patterns reveal slow genome evolution in frogs.

Frogs are an ecologically diverse and phylogenetically ancient group of anuran amphibians that include important vertebrate cell and developmental model systems, notably the genus Xenopus. Here we report a high-quality reference genome sequence for the western clawed frog, Xenopus tropicalis, along with draft chromosome-scale sequences of three distantly related emerging model frog species, Eleutherodactylus coqui, Engystomops pustulosus, and Hymenochirus boettgeri. Frog chromosomes have remained remarkably stable since the Mesozoic Era, with limited Robertsonian (i.e., arm-preserving) translocations and end-to-end fusions found among the smaller chromosomes. Conservation of synteny includes conservation of centromere locations, marked by centromeric tandem repeats associated with Cenp-a binding surrounded by pericentromeric LINE/L1 elements. This work explores the structure of chromosomes across frogs, using a dense meiotic linkage map for X. tropicalis and chromatin conformation capture (Hi-C) data for all species. Abundant satellite repeats occupy the unusually long (~20 megabase) terminal regions of each chromosome that coincide with high rates of recombination. Both embryonic and differentiated cells show reproducible associations of centromeric chromatin and of telomeres, reflecting a Rabl-like configuration. Our comparative analyses reveal 13 conserved ancestral anuran chromosomes from which contemporary frog genomes were constructed.

Measuring restrictiveness of Medicare Advantage networks: A claims-based approach.

OBJECTIVE: To develop and validate a measure of provider network restrictiveness in the Medicare Advantage (MA) population. DATA SOURCES: Prescription drug event data and beneficiary information for Part D enrollees from the Center for Medicare and Medicaid Services, along with prescriber identifiers; geographic variables from the Area Health Resources Files. STUDY DESIGN: A prediction model was used to predict the unique number of primary care providers that would have been seen by MA beneficiaries absent network restrictions. The model was trained and validated on Traditional Medicare (TM) beneficiaries. A pseudo-Poisson and a random forest model were evaluated. An observed-to-expected (O/E) ratio was calculated as the number of unique providers seen by MA beneficiaries divided by the number expected based the TM prediction model. Multivariable linear models were used to assess the relationship between network restrictiveness and plan and market factors. DATA COLLECTION/EXTRACTION METHODS: Prescription drug event data were obtained for a 20% random sample of beneficiaries enrolled in prescription drug coverage from 2011 to 2017. PRINCIPAL FINDINGS: Health Maintenance Organization plans were more restrictive (O/E = 55.5%; 95% CI 55.3%-55.7%) than Health Maintenance Organization-Point of Service plans (67.2%; 95% CI 66.7%-67.8%) or Preferred Provider Organization plans (74.7%; 95% CI 74.3%-75.1%), and rural areas had more restrictive networks (31.6%; 95% CI 29.0%-34.2%) than metropolitan areas (61.5%; 95% CI 61.3%-61.7%). Multivariable results confirmed these findings, and also indicated that increased provider supply was associated with less restrictive networks. CONCLUSIONS: We developed a means of estimating provider network restrictiveness in MA from claims data. Our results validate the approach, providing confidence for wider application (e.g., for other markets and specialties) and use for regulation.

Clinical effectiveness and cost-impact after 2 years of a ketogenic diet and virtual coaching intervention for patients with diabetes.

AIM: We previously evaluated the impacts at 5 months of a digitally delivered coaching intervention in which participants are instructed to adhere to a very low carbohydrate, ketogenic diet. With extended follow-up (24 months), we assessed the longer-term effects of this intervention on changes in clinical outcomes, health care utilization and costs associated with outpatient, inpatient and emergency department use in the Veterans Health Administration. MATERIALS AND METHODS: We employed a difference-in-differences model with a waiting list control group to estimate the 24-month change in glycated haemoglobin, body mass index, blood pressure, prescription medication use, health care utilization rates and associated costs. The analysis included 550 people with type 2 diabetes who were overweight or obese and enrolled in the Veterans Health Administration for health care. Data were obtained from electronic health records from 2018 to 2021. RESULTS: The virtual coaching and ketogenic diet intervention was associated with significant reductions in body mass index [-1.56 (SE 0.390)] and total monthly diabetes medication usage [-0.35 (SE 0.054)]. No statistically significant differences in glycated haemoglobin, blood pressure, outpatient visits, inpatient visits, or emergency department visits were observed. The intervention was associated with reductions in per-patient, per-month outpatient spending [-USD286.80 (SE 97.175)] and prescription drug costs (-USD105.40 (SE 30.332)]. CONCLUSIONS: A virtual coaching intervention with a ketogenic diet component offered modest effects on clinical and cost parameters in people with type 2 diabetes and with obesity or overweight. Health care systems should develop methods to assess participant progress and engagement over time if they adopt such interventions, to ensure continued patient engagement and goal achievement.

Sequencing by avidity enables high accuracy with low reagent consumption.

We present avidity sequencing, a sequencing chemistry that separately optimizes the processes of stepping along a DNA template and that of identifying each nucleotide within the template. Nucleotide identification uses multivalent nucleotide ligands on dye-labeled cores to form polymerase-polymer-nucleotide complexes bound to clonal copies of DNA targets. These polymer-nucleotide substrates, termed avidites, decrease the required concentration of reporting nucleotides from micromolar to nanomolar and yield negligible dissociation rates. Avidity sequencing achieves high accuracy, with 96.2% and 85.4% of base calls having an average of one error per 1,000 and 10,000 base pairs, respectively. We show that the average error rate of avidity sequencing remained stable following a long homopolymer.

Differences in adverse outcomes across race and ethnicity among Veterans with similar predicted risks of an overdose or suicide-related event.

OBJECTIVE: To evaluate the degree to which differences in incidence of mortality and serious adverse events exist across patient race and ethnicity among Veterans Health Administration (VHA) patients receiving outpatient opioid prescriptions and who have similar predicted risks of adverse outcomes. Patients were assigned scores via the VHA Stratification Tool for Opioid Risk Mitigation (STORM), a model used to predict the risk of experiencing overdose- or suicide-related health care events or death. Individuals with the highest STORM risk scores are targeted for case review. DESIGN: Retrospective cohort study of high-risk veterans who received an outpatient prescription opioid between 4/2018-3/2019. SETTING: All VHA medical centers. PARTICIPANTS: In total, 84 473 patients whose estimated risk scores were between 0.0420 and 0.0609, the risk scores associated with the top 5%-10% of risk in the STORM development sample. METHODS: We examined the expected probability of mortality and serious adverse events (SAEs; overdose or suicide-related events) given a patient's risk score and race. RESULTS: Given a similar risk score, Black patients were less likely than White patients to have a recorded SAE within 6 months of risk score calculation. Black, Hispanic, and Asian patients were less likely than White patients with similar risk scores to die within 6 months of risk score calculation. Some of the mortality differences were driven by age differences in the composition of racial and ethnic groups in our sample. CONCLUSIONS: Our results suggest that relying on the STORM model to identify patients who may benefit from an interdisciplinary case review may identify patients with clinically meaningful differences in outcome risk across race and ethnicity.

Thyroid hormones mediate the impact of early-life stress on ventral tegmental area gene expression and behavior.

Proper thyroid function is essential to the developing brain, including dopamine neuron differentiation, growth, and maintenance. Stress across the lifespan impacts thyroid hormone signaling and anxiety disorders and depression have been associated with thyroid dysfunction (both hypo- and hyper-active). However, less is known about how stress during postnatal development impacts thyroid function and related brain development. Our previous work in mice demonstrated that early-life stress (ELS) transiently impinged on expression of a transcription factor in dopamine neurons, Otx2, shown to be regulated by thyroid hormones. We hypothesized that thyroid hormone signaling may link experience of ELS with transcriptional dysregulation within the dopaminergic midbrain, and ultimately behavior. Here, we find that ELS transiently increases thyroid-stimulating hormone levels (inversely related to thyroid signaling) in both male and female mice at P21, an effect which recovers by adolescence. We next tested whether transient treatment of ELS mice with synthetic thyroid hormone (levothyroxine, LT4) could ameliorate the impact of ELS on sensitivity to future stress, and on expression of genes related to dopamine neuron development and maintenance, thyroid signaling, and plasticity within the ventral tegmental area. Among male mice, but not females, juvenile LT4 treatment prevented hypersensitivity to adult stress. We also found that rescuing developmental deficits in thyroid hormone signaling after ELS restored levels of some genes altered directly by ELS, and prevented alterations in expression of other genes sensitive to the second hit of adult stress. These findings suggest that thyroid signaling mediates the deleterious impact of ELS on VTA development, and that temporary treatment of hypothyroidism after ELS may be sufficient to prevent future stress hypersensitivity.

Characterization of Higher Order Structural Changes of a Thermally Stressed Monoclonal Antibody via Mass Spectrometry Footprinting and Other Biophysical Approaches.

Characterizing changes in the higher order structure (HOS) of monoclonal antibodies upon stressed conditions is critical to gaining a better understanding of the product and process. One single biophysical approach may not be best suited to assess HOS comprehensively; thus, the synergy from multiple, complementary approaches improves characterization accuracy and resolution. In this study, we employed two mass spectrometry (MS )-based footprinting techniques, namely, fast photochemical oxidation of proteins (FPOP)-MS and hydrogen-deuterium exchange (HDX)-MS, supported by dynamic light scattering (DLS), differential scanning calorimetry (DSC), circular dichroism (CD), and nuclear magnetic resonance (NMR) to study changes to the HOS of a mAb upon thermal stress. The biophysical techniques report a nuanced characterization of the HOS in which CD detects no changes to the secondary or tertiary structure, yet DLS measurements show an increase in the hydrodynamic radius. DSC indicates that the stability decreases, and chemical or conformational changes accumulate with incubation time according to NMR. Furthermore, whereas HDX-MS does not indicate HOS changes, FPOP-MS footprinting reveals conformational changes at residue resolution for some amino acids. The local phenomena observed with FPOP-MS indicate that several residues show various patterns of degradation during thermal stress: no change, an increase in solvent exposure, and a biphasic response to solvent exposure. All evidences show that FPOP-MS efficiently resolves subtle structural changes and novel degradation pathways upon thermal stress treatment at residue-level resolution.

Distinct disease mutations in DNMT3A result in a spectrum of behavioral, epigenetic, and transcriptional deficits.

Phenotypic heterogeneity in monogenic neurodevelopmental disorders can arise from differential severity of variants underlying disease, but how distinct alleles drive variable disease presentation is not well understood. Here, we investigate missense mutations in DNA methyltransferase 3A (DNMT3A), a DNA methyltransferase associated with overgrowth, intellectual disability, and autism, to uncover molecular correlates of phenotypic heterogeneity. We generate a Dnmt3aP900L/+ mouse mimicking a mutation with mild to moderate severity and compare phenotypic and epigenomic effects with a severe R878H mutation. P900L mutants exhibit core growth and behavioral phenotypes shared across models but show subtle epigenomic changes, while R878H mutants display extensive disruptions. We identify mutation-specific dysregulated genes that may contribute to variable disease severity. Shared transcriptomic disruption identified across mutations overlaps dysregulation observed in other developmental disorder models and likely drives common phenotypes. Together, our findings define central drivers of DNMT3A disorders and illustrate how variable epigenomic disruption contributes to phenotypic heterogeneity in neurodevelopmental disease.

Stereospecific and Regioselective Synthesis of E-Allylic Alcohols through Reductive Cross Coupling of Terminal Alkynes.

We have developed a convergent method for the synthesis of allylic alcohols that involves a reductive coupling of terminal alkynes with α-chloro boronic esters. The new method affords allylic alcohols with excellent regioselectivity (anti-Markovnikov) and an E/Z ratio greater than 200:1. The reaction can be performed in the presence of a wide range of functional groups and has a substrate scope that complements the stoichiometric alkenylation of α-chloro boronic esters performed using alkenyl lithium and Grignard reagents. The transformation is stereospecific and allows for the robust and highly selective synthesis of chiral allylic alcohols. Our studies support a mechanism that involves hydrocupration of the alkyne and cross-coupling of the alkenyl copper intermediate with α-chloro boronic esters. Experimental evidence excludes a radical mechanism of the cross-coupling step and is consistent with the formation of a boron-ate intermediate and a 1,2-metalate shift.