A neural network solves, explains, and generates university math problems by program synthesis and few-shot learning at human level.

We demonstrate that a neural network pretrained on text and fine-tuned on code solves mathematics course problems, explains solutions, and generates questions at a human level. We automatically synthesize programs using few-shot learning and OpenAI's Codex transformer and execute them to solve course problems at 81% automatic accuracy. We curate a dataset of questions from Massachusetts Institute of Technology (MIT)'s largest mathematics courses (Single Variable and Multivariable Calculus, Differential Equations, Introduction to Probability and Statistics, Linear Algebra, and Mathematics for Computer Science) and Columbia University's Computational Linear Algebra. We solve questions from a MATH dataset (on Prealgebra, Algebra, Counting and Probability, Intermediate Algebra, Number Theory, and Precalculus), the latest benchmark of advanced mathematics problems designed to assess mathematical reasoning. We randomly sample questions and generate solutions with multiple modalities, including numbers, equations, and plots. The latest GPT-3 language model pretrained on text automatically solves only 18.8% of these university questions using zero-shot learning and 30.8% using few-shot learning and the most recent chain of thought prompting. In contrast, program synthesis with few-shot learning using Codex fine-tuned on code generates programs that automatically solve 81% of these questions. Our approach improves the previous state-of-the-art automatic solution accuracy on the benchmark topics from 8.8 to 81.1%. We perform a survey to evaluate the quality and difficulty of generated questions. This work automatically solves university-level mathematics course questions at a human level and explains and generates university-level mathematics course questions at scale, a milestone for higher education.

Antimicrobial use and appropriateness in neutropenic fever: a study of the Hospital National Antimicrobial Prescribing Survey data.

BACKGROUND: Neutropenic fever (NF) is a common complication in patients receiving chemotherapy. Judicious antimicrobial use is paramount to minimize morbidity and mortality and to avoid antimicrobial-related harms. OBJECTIVES: To use an Australian national dataset of antimicrobial prescriptions for the treatment of NF to describe antimicrobial use, prescription guideline compliance and appropriateness; and to compare these findings across different healthcare settings and patient demographics. We also aimed to identify trends and practice changes over time. METHODS: Data were extracted from the Hospital National Antimicrobial Prescribing Survey (Hospital NAPS) database from August 2013 to May 2022. Antimicrobial prescriptions with a NF indication were analysed for antimicrobial use, guideline compliance and appropriateness according to the Hospital NAPS methodology. Demographic factors, hospital classifications and disease characteristics were compared. RESULTS: A total of 2887 (n = 2441 adults, n = 441 paediatric) NF prescriptions from 254 health facilities were included. Piperacillin-tazobactam was the most prescribed antimicrobial. Overall, 87.4% of prescriptions were appropriate. Piperacillin-tazobactam and cefepime had the highest appropriateness though incorrect piperacillin-tazobactam dosing was observed. Lower appropriateness was identified for meropenem, vancomycin, and gentamicin prescribing particularly in the private hospital and paediatric cohorts. The most common reasons for inappropriate prescribing were spectrum too broad, incorrect dosing or frequency, and incorrect duration. CONCLUSIONS: This study provides insights into antimicrobial prescribing practices for NF in Australia. We have identified three key areas for improvement: piperacillin-tazobactam dosing, paediatric NF prescribing and private hospital NF prescribing. Findings from this study will inform the updated Australian and New Zealand consensus guidelines for the management of neutropenic fever in patients with cancer.

Cardiogenic Shock Intravascular Cooling Trial (CHILL-SHOCK).

BACKGROUND: Cardiogenic shock (CS) is complicated by high mortality rates. Targeted temperature control (TTC) has been proposed as an adjunct therapy in CS. This study aims to examine the safety of TTC in patients presenting with CS. METHODS AND RESULTS: In this open-label, randomized controlled pilot trial, 20 patients with hemodynamic criteria for CS were assigned to standard of care plus TTC vs standard of care alone. The primary outcome was a composite safety outcome, including well-described complications of TTC. Secondary outcomes included mortality at 90 days, invasive hemodynamic and echocardiographic parameters, electrocardiographic measurements, and inotrope dosing. There were no significant differences in the composite analysis of prespecified safety outcomes (3 events in the TTC group vs 0 events in the control group; P = 0.24). Patients randomized to TTC demonstrated a statistically significant increase in cardiac index and cardiac power index compared to the control group at 48-96 hours after randomization (3.6 [3.1, 3.9] L/min/m2 vs 2.6 [2.5, 3.15] L/min/m2; P = 0.029 and 0.61 [0.55, 0.7] W/m2 vs 0.53 [0.435, 0.565] W/m2; P = 0.029, respectively). CONCLUSION: TTC may be a safe adjunct therapy for patients presenting with CS and may yield improvement in specific hemodynamic parameters.

Fluoroquinolone prophylaxis in patients with neutropenia at high risk of serious infections: Exploring pros and cons.

BACKGROUND: The use of fluoroquinolones to prevent infections in neutropenic patients with cancer or undergoing hematopoietic stem cell transplantation (HSCT) is a controversial issue, with international guidelines providing conflicting recommendations. Although potential benefits are clear, concerns revolve around efficacy, potential harms, and antimicrobial resistance (AMR) implications. DISCUSSION: Fluoroquinolone prophylaxis reduces neutropenic fever (NF) bloodstream infections and other serious bacterial infections, based on evidence from systematic reviews, randomized controlled trials, and observational studies in adults and children. Fluoroquinolone prophylaxis may also reduce infection-related morbidity and healthcare costs; however, evidence is conflicting. Adverse effects of fluoroquinolones are well recognized in the general population; however, studies in the cancer cohort where it is used for a defined period of neutropenia have not reflected this. The largest concern for routine use of fluoroquinolone prophylaxis remains AMR, as many, but not all, observational studies have found that fluoroquinolone prophylaxis might increase the risk of AMR, and some studies have suggested negative impacts on patient outcomes as a result. CONCLUSIONS: The debate surrounding fluoroquinolone prophylaxis calls for individualized risk assessment based on patient characteristics and local AMR patterns, and prophylaxis should be restricted to patients at the highest risk of serious infection during the highest risk periods to ensure that the risk-benefit analysis is in favor of individual and community benefit. More research is needed to address important unanswered questions about fluoroquinolone prophylaxis in neutropenic patients with cancer or receiving HSCT.

Approach to diagnostic evaluation and prevention of invasive fungal disease in patients prior to allogeneic hematopoietic stem cell transplant.

In recent years, advancements in the treatment landscape for hematological malignancies, such as acute myeloid leukemia and acute lymphoblastic leukemia, have significantly improved disease prognosis and overall survival. However, the treatment landscape is changing and the emergence of targeted oral therapies and immune-based treatments has brought forth new challenges in evaluating and preventing invasive fungal diseases (IFDs). IFD disproportionately affects immunocompromised hosts, particularly those undergoing therapy for acute leukemia and allogeneic hematopoietic stem cell transplant. This review aims to provide a comprehensive overview of the pretransplant workup, identification, and prevention of IFD in patients with hematological malignancy. The pretransplant period offers a critical window to assess each patient's risk factors and implement appropriate prophylactic measures. Risk assessment includes evaluation of disease, host, prior treatments, and environmental factors, allowing a dynamic evaluation that considers disease progression and treatment course. Diagnostic screening, involving various biomarkers and radiological modalities, plays a crucial role in early detection of IFD. Antifungal prophylaxis choice is based on available evidence as well as individual risk assessment, potential for drug-drug interactions, toxicity, and patient adherence. Therapeutic drug monitoring ensures effective antifungal stewardship and optimal treatment. Patient education and counselling are vital in minimizing environmental exposures to fungal pathogens and promoting medication adherence. A well-structured and individualized approach, encompassing risk assessment, prophylaxis, surveillance, and patient education, is essential for effectively preventing IFD in hematological malignancies, ultimately leading to improved patient outcomes and overall survival.

Genome-wide association mapping reveals genes underlying population-level metabolome diversity in a fungal crop pathogen.

BACKGROUND: Fungi produce a wide range of specialized metabolites (SMs) involved in biotic interactions. Pathways for the production of SMs are often encoded in clusters of tightly arranged genes identified as biosynthetic gene clusters. Such gene clusters can undergo horizontal gene transfers between species and rapid evolutionary change within species. The acquisition, rearrangement, and deletion of gene clusters can generate significant metabolome diversity. However, the genetic basis underlying variation in SM production remains poorly understood. RESULTS: Here, we analyzed the metabolite production of a large population of the fungal pathogen of wheat, Zymoseptoria tritici. The pathogen causes major yield losses and shows variation in gene clusters. We performed untargeted ultra-high performance liquid chromatography-high resolution mass spectrometry to profile the metabolite diversity among 102 isolates of the same species. We found substantial variation in the abundance of the detected metabolites among isolates. Integrating whole-genome sequencing data, we performed metabolite genome-wide association mapping to identify loci underlying variation in metabolite production (i.e., metabolite-GWAS). We found that significantly associated SNPs reside mostly in coding and gene regulatory regions. Associated genes encode mainly transport and catalytic activities. The metabolite-GWAS identified also a polymorphism in the 3'UTR region of a virulence gene related to metabolite production and showing expression variation. CONCLUSIONS: Taken together, our study provides a significant resource to unravel polymorphism underlying metabolome diversity within a species. Integrating metabolome screens should be feasible for a range of different plant pathogens and help prioritize molecular studies.

Comparing the Efficacy of Postoperative Antibiotic Regimens in the Treatment of Maxillofacial Fractures: A Prospective Study.

AIM: The present study was designed to investigate the difference in the effectiveness of a 3 day postoperative course and a single perioperative dose of antibiotics on the incidence of postoperative infection in the management of maxillofacial trauma patients. MATERIALS AND METHODS: About 183 maxillofacial trauma patients requiring open reduction and internal fixation (ORIF) under general anesthesia were divided based on the type of fracture sustained, i.e., mandibular fractures, Le Fort fractures, and zygomaticomaxillary complex fractures. Patients from each fracture type were randomized into two groups, A and B. All patients were administered amoxicillin/clavulanate 1.2 grams intravenously 8 hours from the time of admission till the patient was taken up for surgery. Once the patients were taken up for surgery, a perioperative dose was administered. No antibiotics beyond this point were given to patients in Group A. Patients in Group B were administered the same antibiotic for 3 postoperative days additionally. Outcomes in terms of purulent discharge from the surgical site, an abscess or any other sign of infection, and wound dehiscence requiring reopening of the surgical site were considered. Patients were reviewed at 1 week, 2 weeks, 1 month, 2 months, and 3 months. RESULTS: No statistically significant difference was found between the two groups across all three fracture types in terms of postoperative outcomes. However, increased numbers of complications were noted in the patients treated with an intra-oral approach in each fracture type irrespective of group. All complications were managed with local measures. CONCLUSION: A single perioperative dose of antibiotics is effective in minimizing postoperative complications following ORIF of maxillofacial fractures and there is no significant benefit in prolonging the course of antibiotics postoperatively with the need for further studies to be conducted considering comminuted, complex fractures and old fractures. CLINICAL SIGNIFICANCE: In maxillofacial trauma, fractures frequently communicate with contaminated indigenous flora on the skin surface, oral cavities, or sinus cavities. Surgery is frequently performed using an approach across a contaminated area, even in closed fractures. Postoperative infections can be significantly decreased by using antibiotics in surgical procedures to treat facial fractures.

Contemporary treatment of below-the-knee peripheral arterial disease in patients with chronic limb threatening ischemia: Observations from the Vascular Quality Initiative.

OBJECTIVE: We sought to determine trends in percutaneous transluminal angioplasty (PTA) versus non-PTA interventions over time, as well as factors that influence the decision for non-PTA intervention. BACKGROUND: Although the optimal strategy for revascularization in patients with below-the-knee (BTK) chronic limb-threatening ischemia (CLTI) remains under investigation, PTA has been the preferred endovascular approach. Recently, there has been an increase in the use of non-PTA approaches for revascularization. METHODS: We performed a retrospective analysis of the Vascular Quality Initiative. Between 2011 and 2020, a total of 23,850 procedures corresponding to 33,098 arteries in 19,404 patients with CLTI were included. After application of exclusion criteria and removal of missing variables, 18,644 arteries were included in the study cohort. The primary analysis was factors associated with receiving non-PTA intervention. Secondary analysis included trends in PTA versus non-PTA intervention over time. RESULTS: Throughout the study period, the majority of interventions (72%) were PTA alone. The percentage of non-PTA interventions, on a per-artery basis, increased over the study period from 18% to 33%, p < 0.01. Advanced age, increasing TransAtlantic Inter-Society Consensus classification, and concomitant above-the-knee disease were associated with an increased likelihood for non-PTA intervention. In contrast, longer lesion length, insulin-dependent diabetes mellitus, bilateral disease, and discharge to location other than home were associated with an increased likelihood of PTA. CONCLUSIONS: We observed a significant increase in the percentage of non-PTA interventions for patients with CLTI requiring BTK interventions over the last decade, with lesion- and patient-specific characteristics associated with the type of endovascular approach.

Functional performance status and risk of cardiovascular events and mortality following endovascular repair of thoracic and abdominal aortic pathology.

OBJECTIVE: To characterize the association of preoperative functional performance status based on Eastern Cooperative Oncology Group (ECOG) scoring with the risk of adverse cardiovascular events, vascular events, and mortality in patients undergoing EVAR and TEVAR. METHODS: Retrospective review of the Society for Vascular Surgery Vascular Quality Initiative, a large, multi-center, registry database was performed. All individuals undergoing EVAR (n = 18,730) and TEVAR (n = 6595) for non-ruptured aortic pathologies between 2014 and 2018 were eligible for analysis. Multivariable logistic regression was used to determine the association of pre-procedure ECOG functional performance status on risk of in-hospital adverse cardiovascular events, vascular events, and mortality. RESULTS: The number of operations complicated by adverse cardiovascular and vascular events was 480 (2.6%) and 190 (1.0%) for EVAR and 733 (11.1%) and 219 (3.3%) for TEVAR, respectively. There were 118 (0.6%) and 240 (3.6%) in-hospital deaths following EVAR and TEVAR, respectively. Patients with ECOG grades 3 or 4 undergoing EVAR were at increased risk of cardiovascular events (OR = 1.62; 95% CI = 1.09, 2.41) and one-year mortality (HR = 2.62; 95% CI = 1.92, 3.57) compared to those with ECOG grade 0. Patients undergoing TEVAR with ECOG grade 3 or 4 were at increased risk for both inpatient death (OR = 2.77; 95% CI = 1.56, 4.9) and one-year mortality (HR = 3.27, 95% CI = 2.06, 5.21). ECOG status was not associated with an increased risk of adverse vascular events following either EVAR or TEVAR. CONCLUSIONS: Poor preoperative functional status as assessed by ECOG score is associated with an increased risk of adverse postoperative cardiovascular events following EVAR and a higher mortality risk following both EVAR and TEVAR. Functional status assessment may be useful for risk stratification and determining procedural candidacy prior to EVAR and TEVAR.

Rapid sequence evolution driven by transposable elements at a virulence locus in a fungal wheat pathogen.

BACKGROUND: Plant pathogens cause substantial crop losses in agriculture production and threaten food security. Plants evolved the ability to recognize virulence factors and pathogens have repeatedly escaped recognition due rapid evolutionary change at pathogen virulence loci (i.e. effector genes). The presence of transposable elements (TEs) in close physical proximity of effector genes can have important consequences for gene regulation and sequence evolution. Species-wide investigations of effector gene loci remain rare hindering our ability to predict pathogen evolvability. RESULTS: Here, we performed genome-wide association studies (GWAS) on a highly polymorphic mapping population of 120 isolates of Zymoseptoria tritici, the most damaging pathogen of wheat in Europe. We identified a major locus underlying significant variation in reproductive success of the pathogen and damage caused on the wheat cultivar Claro. The most strongly associated locus is intergenic and flanked by genes encoding a predicted effector and a serine-type endopeptidase. The center of the locus contained a highly dynamic region consisting of multiple families of TEs. Based on a large global collection of assembled genomes, we show that the virulence locus has undergone substantial recent sequence evolution. Large insertion and deletion events generated length variation between the flanking genes by a factor of seven (5-35 kb). The locus showed also strong signatures of genomic defenses against TEs (i.e. RIP) contributing to the rapid diversification of the locus. CONCLUSIONS: In conjunction, our work highlights the power of combining GWAS and population-scale genome analyses to investigate major effect loci in pathogens.

The complex genomic basis of rapid convergent adaptation to pesticides across continents in a fungal plant pathogen.

Convergent evolution leads to identical phenotypic traits in different species or populations. Convergence can be driven by standing variation allowing selection to favour identical alleles in parallel or the same mutations can arise independently. However, the molecular basis of such convergent adaptation remains often poorly resolved. Pesticide resistance in agricultural ecosystems is a hallmark of convergence in phenotypic traits. Here, we analyse the major fungal pathogen Zymoseptoria tritici causing serious losses on wheat and with fungicide resistance emergence across several continents. We sampled three population pairs each from a different continent spanning periods early and late in the application of fungicides. To identify causal loci for resistance, we combined knowledge from molecular genetics work and performed genome-wide association studies (GWAS) on a global set of isolates. We discovered yet unknown factors in azole resistance including a gene encoding membrane associated functions. We found strong support for the "hotspot" model of resistance evolution with convergent changes in a small set of loci but additional loci showed more population-specific allele frequency changes. Genome-wide scans of selection showed that half of all known resistance loci were overlapping a selective sweep region. Hence, the application of fungicides was one of the major selective agents acting on the pathogen over the past decades. Furthermore, loci identified through GWAS showed the highest overlap with selective sweep regions underlining the importance to map phenotypic trait variation in evolving populations. Our population genomic analyses highlighted that both de novo mutations and gene flow contributed to convergent pesticide adaptation.

Soil composition and plant genotype determine benzoxazinoid-mediated plant-soil feedbacks in cereals.

Plant-soil feedbacks refer to effects on plants that are mediated by soil modifications caused by the previous plant generation. Maize conditions the surrounding soil by secretion of root exudates including benzoxazinoids (BXs), a class of bioactive secondary metabolites. Previous work found that a BX-conditioned soil microbiota enhances insect resistance while reducing biomass in the next generation of maize plants. Whether these BX-mediated and microbially driven feedbacks are conserved across different soils and response species is unknown. We found the BX-feedbacks on maize growth and insect resistance conserved between two arable soils, but absent in a more fertile grassland soil, suggesting a soil-type dependence of BX feedbacks. We demonstrated that wheat also responded to BX-feedbacks. While the negative growth response to BX-conditioning was conserved in both cereals, insect resistance showed opposite patterns, with an increase in maize and a decrease in wheat. Wheat pathogen resistance was not affected. Finally and consistent with maize, we found the BX-feedbacks to be cultivar-specific. Taken together, BX-feedbacks affected cereal growth and resistance in a soil and genotype-dependent manner. Cultivar-specificity of BX-feedbacks is a key finding, as it hides the potential to optimize crops that avoid negative plant-soil feedbacks in rotations.

Perianeurysmal retroperitoneal fibrosis presenting as acute kidney injury: A case report.

Retroperitoneal fibrosis and chronic periaortitis describe overlapping groups of rare diseases characterized by inflammation and fibrosis involving the aorta. The presentation is often non-specific, and while obstructive nephropathy is a common complication, these entities are an uncommon cause of renal failure necessitating dialysis. A 57-year-old man presented multiple times with acute kidney injury, even requiring hemodialysis, with repeated abrupt resolution. Renal ultrasound repeatedly did not reveal acute hydronephrosis. Renal biopsy on his first admission showed acute tubular injury attributed to hypovolemia. Computed tomography finally revealed a retroperitoneal soft tissue mass encasing the infrarenal abdominal aorta and partially encasing the bilateral ureters. Bilateral nephrostomy tubes were placed, steroids were initiated, and the patient experienced rapid and remarkable improvement in renal function. Chronic periaortitis should be considered in older patients with acute kidney injury, even in the absence of ultrasonographic evidence of obstruction. Additional studies are needed to describe the test characteristics of renal sonography for periaortitis, the long-term sequelae of acute kidney injury secondary to periaortitis, and the optimal management to preserve long-term renal function.

High sensitivity Troponin-T for prediction of adverse events in patients with COVID-19.

BACKGROUND: High sensitivity cardiac troponin-T (hs-TnT) has been associated with mortality in patients hospitalized with COVID-19. We aimed to determine if hs-TnT levels and their timing are independent predictors of adverse events in these patients. DESIGN: Retrospective chart review was performed for all patients hospitalized at our institution between 23 March 2020 and 13 April 2020 who were found to be COVID-19-positive. Clinical, demographic, and laboratory variables including initial and peak hs-TnT were recorded. Univariable and multivariable analyses were completed for a primary composite endpoint of in-hospital death, intubation, need for critical care, or cardiac arrest. RESULTS: In the 276 patients analysed, initial hs-TnT above the median (≥17 ng/L) was associated with increased length of stay, need for vasoactive medications, and death, along with the composite endpoint (OR 3.92, p < 0.001). Multivariable analysis demonstrated that elevated initial hs-TnT was independently associated with the primary endpoint (OR 2.92, p = 0.01). Late-peaking hs-TnT (OR 2.19 for each additional day until peak, p < 0.001) was also independently associated with the composite endpoint. CONCLUSIONS: In patients hospitalized with COVID-19, hs-TnT identifies patients at high risk for adverse in-hospital events, and trends of hs-TnT over time, particularly during the first day, provide additional prognostic information.

Preoperative hemoglobin A1c levels and increased risk of adverse limb events in diabetic patients undergoing infrainguinal lower extremity bypass surgery in the Vascular Quality Initiative.

BACKGROUND: The impact of preoperative glycemic control on the risk of adverse perioperative outcomes in diabetic patients undergoing lower extremity bypass (LEB) surgery is not well-understood. We determined whether higher preoperative hemoglobin A1c (HbA1c) levels are associated with an increased risk of major adverse limb events, major adverse cardiovascular events, and mortality in diabetic patients undergoing infrainguinal LEB. METHODS: A retrospective review of all infrainguinal LEB surgeries in the Vascular Quality Initiative registry from January 2012 to February 2017 was performed. Only surgeries performed on diabetic patients with complete demographic and clinical data, including HbA1c value at the time of LEB, were included for analysis (n = 7727). Entries were stratified according to the following HbA1c levels: 6 or less (n = 1087), greater than 6 to 7 or less (n = 2137), greater than 7 to 8 or less (n = 1657), and greater than 8 (n = 2846). Multivariate logistic regression was used to determine the association of preoperative HbA1c levels on the risk of in-hospital major adverse limb events (above ankle amputation, loss of primary graft patency), major adverse cardiovascular events (myocardial infarction, stroke, congestive heart failure, cardiac arrhythmia), and mortality. RESULTS: The number of surgeries complicated by adverse limb and cardiovascular events were 356 (4.6%) and 1314 (17.0%), respectively. There were 72 in-hospital deaths (0.9%). After adjustment for clinical and demographic variables, patients with high HbA1c values (≥8%) were at an increased risk of adverse limb events (odds ratio [OR], 1.37; 95% confidence interval [CI], 1.01-1.86) compared with those with a normal HbA1c (>6% to ≤7%). High HbA1c values were not associated with an increased risk of cardiovascular events (OR, 1.07; 95% CI, 0.81-1.43) or mortality (OR, 1.57; 95% CI, 0.83-3.03). Patients with low HbA1c values (≤6%) did not experience a significantly higher risk for any of the three outcomes. In a stratified analysis, the association of high HbA1c values with adverse limb events was only present in those presenting without critical limb ischemia (OR 1.82; 95% CI, 1.05-3.16). CONCLUSIONS: Poor preoperative glycemic control in diabetic individuals undergoing infrainguinal LEB, particularly in those without critical limb ischemia, is associated with an increased risk of in-hospital limb events. Further study should evaluate whether improved efforts to identify individuals with poorly controlled diabetes and subsequent interventions to better optimize glycemic control during the preoperative period improve limb outcomes after LEB.

The long-term prognostic value of the Q wave criteria for prior myocardial infarction recommended in the universal definition of myocardial infarction.

BACKGROUND: We sought to characterize the prognostic value of the third universal definition of myocardial infarction (UDMI) and ≥40msec Q wave criteria. METHODS: We evaluated hazard ratios (HR) with 95% confidence intervals (CI) for cardiovascular (CV) death for computerized Q wave measurements from the electrocardiograms of 43,661 patients collected from 1987 to 1999 at the Palo Alto VA. There were 3929 (9.0%) CV deaths over a mean follow-up of 7.6 (±3.8) years. RESULTS: The risk of CV death for Q waves ≥40msec in any two contiguous leads in any lead group was equivalent to or higher than that for contiguous UDMI Q waves, with HR 2.44 (95% CI 2.15-4.11) and HR 2.42 (95% CI (2.18-3.42), respectively. CONCLUSIONS: The UDMI Q wave criteria do not provide an advantage over ≥40msec Q waves at predicting CV death.

Murine craniofacial development requires Hdac3-mediated repression of Msx gene expression.

Craniofacial development is characterized by reciprocal interactions between neural crest cells and neighboring cell populations of ectodermal, endodermal and mesodermal origin. Various genetic pathways play critical roles in coordinating the development of cranial structures by modulating the growth, survival and differentiation of neural crest cells. However, the regulation of these pathways, particularly at the epigenomic level, remains poorly understood. Using murine genetics, we show that neural crest cells exhibit a requirement for the class I histone deacetylase Hdac3 during craniofacial development. Mice in which Hdac3 has been conditionally deleted in neural crest demonstrate fully penetrant craniofacial abnormalities, including microcephaly, cleft secondary palate and dental hypoplasia. Consistent with these abnormalities, we observe dysregulation of cell cycle genes and increased apoptosis in neural crest structures in mutant embryos. Known regulators of cell cycle progression and apoptosis in neural crest, including Msx1, Msx2 and Bmp4, are upregulated in Hdac3-deficient cranial mesenchyme. These results suggest that Hdac3 serves as a critical regulator of craniofacial morphogenesis, in part by repressing core apoptotic pathways in cranial neural crest cells.

Patterns and prognosis of all components of the J-wave pattern in multiethnic athletes and ambulatory patients.

BACKGROUND: Despite recent concern about the significance of the J-wave pattern (also often referred to as early repolarization) and the importance of screening in athletes, there are limited rigorous prognostic data characterizing the 3 components of the J-wave pattern (ST elevation, J waves, and QRS slurs). We aim to assess the prevalence, patterns, and prognosis of the J-wave pattern among both stable clinical and athlete populations. METHODS: We retrospectively studied 4,041 electrocardiograms from a multiethnic clinical population from 1997 to 1999 at the Veterans Affairs Palo Alto Health Care System. We also examined preparticipation electrocardiograms of 1,114 Stanford University varsity athletes from 2007 to 2008. Strictly defined criteria for components of the J-wave pattern were examined. In clinical subjects, prognosis was assessed using the end point of cardiovascular death after 7 years of follow-up. RESULTS: Components of the J-wave pattern were most prevalent in males; African Americans; and, particularly, athletes, with the greatest variations demonstrated in the lateral leads. ST elevation was the most common. Inferior J waves and slurs, previously linked to cardiovascular risk, were observed in 9.6% of clinical subjects and 12.3% of athletes. J waves, slurs, or ST elevation was not associated with time to cardiovascular death in clinical subjects, and ST-segment slope abnormalities were not prevalent enough in conjunction with them to reach significance. CONCLUSIONS: J waves, slurs, or ST elevation was not associated with increased hazard of cardiovascular death in our large multiethnic, ambulatory population. Even subsets of J-wave patterns, recently proposed to pose a risk of arrhythmic death, occurred at such a high prevalence as to negate their utility in screening.

Adverse Metal Reaction in a Case of Metal-on-Polyethylene Hip Arthroplasty.

Soft tissue inflammatory responses to metal debris from prostheses, categorised as adverse reactions to metal debris (ARMD), are frequent complications of total hip arthroplasty (THA) and often result in implant failure. Introducing modular implant designs in modern orthopaedics has brought benefits to total hip replacements but has also increased patients' susceptibility to corrosion-related risks. ARMD can develop from various metal articulating surfaces, including ceramic-on-polyethylene (CoP), ceramic-on-ceramic (CoC), metal-on-metal (MoM), and metal-on-polyethylene (MoP) configurations. In this case study, a 68-year-old male who underwent a MoP implant for osteoarthritis of the right hip 16 years ago presented with pain and difficulty walking, exacerbated over the past three months. Clinical examination revealed tenderness around the implant and a limited range of motion. Imaging studies, including X-rays and ultrasound-guided aspiration, coupled with normal serum and urinary cobalt (Co) and chromium (Cr) levels, confirmed the diagnosis of ARMD. Given the severity of symptoms and radiographic findings, surgical intervention was warranted, leading to a two-stage revision with implant augmentation using a Burch-Schneider cage. Three months post operation, the patient experienced significant improvements in pain levels, range of motion (ROM), and hip function. This case underscores the importance of vigilant surveillance for ARMD in patients undergoing non-MoM THA, even years post surgery. Prompt recognition and management of ARMD are crucial to mitigate the risk of long-term complications and optimise patient outcomes. Further research is needed to understand the risk factors and mechanisms underlying ARMD in MoP THA, aiding in developing preventive strategies and refined treatment protocols.

Histone deacetylase 3 regulates smooth muscle differentiation in neural crest cells and development of the cardiac outflow tract.

RATIONALE: The development of the cardiac outflow tract (OFT) and great vessels is a complex process that involves coordinated regulation of multiple progenitor cell populations. Among these populations, neural crest cells make important contributions to OFT formation and aortic arch remodeling. Although numerous signaling pathways, including Notch, have been implicated in this process, the role of epigenetics in OFT development remains largely unexplored. OBJECTIVE: Because histone deacetylases (Hdacs) play important roles in the epigenetic regulation of mammalian development, we have investigated the function of Hdac3, a class I Hdac, during cardiac neural crest development in mouse. METHODS AND RESULTS: Using 2 neural crest drivers, Wnt1-Cre and Pax3(Cre), we show that loss of Hdac3 in neural crest results in perinatal lethality and cardiovascular abnormalities, including interrupted aortic arch type B, aortic arch hypoplasia, double-outlet right ventricle, and ventricular septal defect. Affected embryos are deficient in aortic arch artery smooth muscle during midgestation, despite intact neural crest cell migration and preserved development of other cardiac and truncal neural crest derivatives. The Hdac3-dependent block in smooth muscle differentiation is cell autonomous and is associated with downregulation of the Notch ligand Jagged1, a key driver of smooth muscle differentiation in the aortic arch arteries. CONCLUSIONS: These results indicate that Hdac3 plays a critical and specific regulatory role in the neural crest-derived smooth muscle lineage and in formation of the OFT.