Ash1 l loss-of-function results in structural birth defects and altered cortical development.

The histone methyltransferase ASH1L plays a crucial role in regulating gene expression across various organ systems during development, yet its role in brain development remains largely unexplored. Over 130 individuals with autism harbour heterozygous loss-of-function ASH1L variants, and population studies confirm it as a high-risk autism gene. Previous studies on Ash1 l deficient mice have reported autistic-like behaviours and provided insights into the underlying neuropathophysiology. In this study, we used mice with a cre-inducible deletion of Ash1 l exon 4, which results in a frame shift and premature stop codon (p.V1693Afs*2). Our investigation evaluated the impact of Ash1 l loss-of-function on survival and craniofacial skeletal development. Using a tamoxifen-inducible cre strain, we targeted Ash1 l knockout early in cortical development (Emx1-Cre-ERT2; e10.5). Immunohistochemistry was utilized to assess cortical lamination, while EdU incorporation aided in birthdating cortical neurons. Additionally, single-cell RNA sequencing was employed to compare cortical cell populations and identify genes with differential expression. At e18.5, the proportion of homozygous Ash1 l germline knockout embryos appeared normal; however, no live Ash1 l null pups were present at birth (e18.5: n = 77, P = 0.90; p0: n = 41, P = 0.00095). Notably, Ash1l-/- exhibited shortened nasal bones (n = 31, P = 0.017). In the cortical-specific knockout model, SATB2 neurons showed increased numbers (n = 6/genotype, P = 0.0001) and were distributed through the cortical plate. Birthdating revealed generation of ectopically placed deep layer neurons that express SATB2 (e13.5 injection: n = 4/genotype, P = 0.0126). Single cell RNA sequencing revealed significant differences in gene expression between control and mutant upper layer neurons, leading to distinct clustering. Pseudotime analysis indicated that the mutant cluster followed an altered cell differentiation trajectory. This study underscores the essential role of Ash1 l in postnatal survival and normal craniofacial development. In the cortex, ASH1L exerts broad effects on gene expression and is indispensable for determining the fate of upper layer cortical neurons. These findings provide valuable insights into the potential mechanisms of ASH1L neuropathology, shedding light on its significance in neurodevelopmental disorders like autism.

Assessment of Coronary Stenoses for Percutaneous Coronary Intervention: A Systematic Review and Network Meta-Analysis of Randomized Trials.

Evidence regarding the comparative efficacy of the different methods to determine the significance of coronary stenoses in the catheterization laboratory is lacking. We aimed to compare all available methods guiding the decision to perform percutaneous coronary intervention (PCI). We searched Medline, Embase, and CENTRAL until October 5, 2023. We included trials that randomized patients with greater than 30% stenoses who were considered for PCI and reported major adverse cardiovascular events (MACE). We performed a frequentist random-effects network meta-analysis and assessed the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. We included 15 trials with 16,333 participants with a mean weighted follow-up of 34 months. The trials contained a median of 49.3% (interquartile range: 32.6%, 100%) acute coronary syndrome participants. Quantitative flow ratio (QFR) was associated with a decreased risk of MACE compared with coronary angiography (CA) (risk ratio [RR] 0.68, 95% confidence interval [CI] 0.56 to 0.82, high certainty), fractional flow reserve (FFR) (RR 0.73, 95% CI 0.58 to 0.92, moderate certainty), and instantaneous wave-free ratio (iFR) (RR 0.63, 95% CI 0.49 to 0.82, moderate certainty), and ranked first for MACE (88.1% probability of being the best). FFR (RR 0.93, 95% CI 0.82 to 1.06, moderate certainty) and iFR (RR 1.07, 95% CI 0.90 to 1.28, moderate certainty) likely did not decrease the risk of MACE compared with CA. Intravascular imaging may not be associated with a significant decrease in MACE compared with CA (RR 0.85, 95% CI 0.62 to 1.17, low certainty) when used to guide the decision to perform PCI. In conclusion, a decision to perform PCI based on QFR was associated with a decreased risk of MACE compared with CA, FFR, and iFR in a mixed stable coronary disease and acute coronary syndrome population. These hypothesis-generating findings should be validated in large, randomized, head-to-head trials.

Abnormal Glucose Tolerance in Women Diagnosed With Gestational Diabetes (WHO 2013) 10 Years After Index Pregnancy.

Context: It is not clear if the risk of abnormal glucose tolerance (AGT) is attenuated in the long-term in women diagnosed with gestational diabetes (GDM) using the World Health Organization (WHO) 2013 criteria and who have received appropriate treatment during pregnancy. Objective: We aimed to assess the long-term prevalence of AGT and other cardiovascular disease (CVD) risk factors in this cohort. Methods: A retrospective cohort follow-up study was conducted of 37 and 107 women diagnosed with and without GDM respectively using the WHO 2013 criteria between June 2010 and December 2010. Women were invited to attend our center, where they underwent a 75-g oral glucose tolerance test, blood and urine collection, body measurements, and electrocardiography. Main outcome measure included the development of AGT using the American Diabetes Association criteria. Results: Sixteen (43.2%) women with GDM compared to 5 (4.7%) women with normal glucose tolerance (NGT) at index pregnancy had AGT (P < .001). In the GDM group, 10 (27.0%), 7 (18.9%), and 4 (10.8%) women had impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM), respectively. In the NGT group, 2 (1.9%), 3 (2.8%), and 1 (0.9%) woman had IFG, IGT, and T2DM, respectively. Women with AGT also had an unfavorable metabolic profile including obesity, hypertension, insulin resistance, and dyslipidemia. Conclusion: Women treated for GDM (WHO 2013 criteria) remain at increased risk for developing AGT and adverse CVD risk factors as early as a decade after diagnosis. Continued efforts are needed to accurately follow this population to address modifiable risk factors.

Development and Pilot Testing of a Programmatic System for Competency Assessment in US Anesthesiology Residency Training.

BACKGROUND: In 2018, a set of entrustable professional activities (EPAs) and procedural skills assessments were developed for anesthesiology training, but they did not assess all the Accreditation Council for Graduate Medical Education (ACGME) milestones. The aims of this study were to (1) remap the 2018 EPA and procedural skills assessments to the revised ACGME Anesthesiology Milestones 2.0, (2) develop new assessments that combined with the original assessments to create a system of assessment that addresses all level 1 to 4 milestones, and (3) provide evidence for the validity of the assessments. METHODS: Using a modified Delphi process, a panel of anesthesiology education experts remapped the original assessments developed in 2018 to the Anesthesiology Milestones 2.0 and developed new assessments to create a system that assessed all level 1 through 4 milestones. Following a 24-month pilot at 7 institutions, the number of EPA and procedural skill assessments and mean scores were computed at the end of the academic year. Milestone achievement and subcompetency data for assessments from a single institution were compared to scores assigned by the institution's clinical competency committee (CCC). RESULTS: New assessment development, 2 months of testing and feedback, and revisions resulted in 5 new EPAs, 11 nontechnical skills assessments (NTSAs), and 6 objective structured clinical examinations (OSCEs). Combined with the original 20 EPAs and procedural skills assessments, the new system of assessment addresses 99% of level 1 to 4 Anesthesiology Milestones 2.0. During the 24-month pilot, aggregate mean EPA and procedural skill scores significantly increased with year in training. System subcompetency scores correlated significantly with 15 of 23 (65.2%) corresponding CCC scores at a single institution, but 8 correlations (36.4%) were <30.0, illustrating poor correlation. CONCLUSIONS: A panel of experts developed a set of EPAs, procedural skill assessment, NTSAs, and OSCEs to form a programmatic system of assessment for anesthesiology residency training in the United States. The method used to develop and pilot test the assessments, the progression of assessment scores with time in training, and the correlation of assessment scores with CCC scoring of milestone achievement provide evidence for the validity of the assessments.

Clostridioides difficile toxin is infrequently detected in inflammatory bowel disease and does not associate with clinical outcomes.

INTRODUCTION: Clostridioides difficile infection (CDI) rates and outcomes can vary based on differences in testing strategy. Our aim was to assess the prevalence of toxin detection in inflammatory bowel disease (IBD) when compared to those without IBD. Secondly, the clinical outcomes of CDI in IBD were assessed using two-step testing strategies. METHODS: We included patients undergoing CDI testing from four academic centers in the United States between January 1, 2018 and June 30, 2020. First the prevalence of toxin detection was compared between individuals with IBD and those without IBD. Secondly, among patients with IBD a primary composite outcome of abdominal colectomy, admission to an intensive care unit (ICU) or death within 30 days of C. difficile testing was assessed across the three categorical groups (screen positive/toxin positive, screen positive/toxin negative and screen negative assay) resulting from the two-step testing strategy. RESULTS: When comparing individuals with a positive screening assay, patients with IBD were less likely to have toxin detected by enzyme immunoassay (EIA) as compared to the non-IBD population (22/145 (15.2%) vs. 413/1144 (36.1%), p < 0.0001). Among all patients with IBD (n = 300), twenty-five (8.3%) had a screen positive assay/toxin positive assay, 136 (45.3%) had a screen positive/toxin negative assay and 139 (46.3%) had a negative screening assay. No significant difference in the primary composite outcome was detected across the three groups (p = 0.566). CONCLUSION: When compared to those without IBD, patients with IBD have a reduced proportion of cases of C. difficile with toxin positivity. Differences in clinical outcomes among patients with IBD were not detected and limited by the infrequent detection of expressed toxin.

Development and Pilot Testing of Entrustable Professional Activities for US Anesthesiology Residency Training.

BACKGROUND: Modern medical education requires frequent competency assessment. The Accreditation Council for Graduate Medical Education (ACGME) provides a descriptive framework of competencies and milestones but does not provide standardized instruments to assess and track trainee competency over time. Entrustable professional activities (EPAs) represent a workplace-based method to assess the achievement of competency milestones at the point-of-care that can be applied to anesthesiology training in the United States. METHODS: Experts in education and competency assessment were recruited to participate in a 6-step process using a modified Delphi method with iterative rounds to reach consensus on an entrustment scale, a list of EPAs and procedural skills, detailed definitions for each EPA, a mapping of the EPAs to the ACGME milestones, and a target level of entrustment for graduating US anesthesiology residents for each EPA and procedural skill. The defined EPAs and procedural skills were implemented using a website and mobile app. The assessment system was piloted at 7 anesthesiology residency programs. After 2 months, faculty were surveyed on their attitudes on usability and utility of the assessment system. The number of evaluations submitted per month was collected for 1 year. RESULTS: Participants in EPA development included 18 education experts from 11 different programs. The Delphi rounds produced a final list of 20 EPAs, each differentiated as simple or complex, a defined entrustment scale, mapping of the EPAs to milestones, and graduation entrustment targets. A list of 159 procedural skills was similarly developed. Results of the faculty survey demonstrated favorable ratings on all questions regarding app usability as well as the utility of the app and EPA assessments. Over the 2-month pilot period, 1636 EPA and 1427 procedure assessments were submitted. All programs continued to use the app for the remainder of the academic year resulting in 12,641 submitted assessments. CONCLUSIONS: A list of 20 anesthesiology EPAs and 159 procedural skills assessments were developed using a rigorous methodology to reach consensus among education experts. The assessments were pilot tested at 7 US anesthesiology residency programs demonstrating the feasibility of implementation using a mobile app and the ability to collect assessment data. Adoption at the pilot sites was variable; however, the use of the system was not mandatory for faculty or trainees at any site.

Transcatheter Aortic Valve Replacement With the LOTUS Edge System: Early European Experience.

OBJECTIVES: The aim of this study was to evaluate the short-term safety and efficacy of transcatheter aortic valve replacement (TAVR) with the LOTUS Edge system. BACKGROUND: The LOTUS Edge system was commercially re-released in April 2019. The authors report the first European experience with this device. METHODS: A multicenter, single-arm, retrospective registry was initiated to evaluate short-term clinical outcomes. Included cases are the first experience with this device and new implantation technique in Europe. Clinical, echocardiographic, and computed tomographic data were analyzed. Endpoints were defined according to Valve Academic Research Consortium-2 and were site reported. RESULTS: Between April and November 2019, 286 consecutive patients undergoing TAVR with the LOTUS Edge system at 18 European centers were included. The mean age and Society of Thoracic Surgeons score were 81.2 ± 6.9 years and 5.2 ± 5.4%, respectively. Nearly one-half of all patients (47.9%) were considered to have complex anatomy. Thirty-day major adverse events included death (2.4% [n = 7]) and stroke (3.5% [n = 10]). After TAVR, the mean aortic valve area was 1.9 ± 0.9 cm2, and the mean transvalvular gradient was 11.9 ± 5.7 mm Hg. None or trace paravalvular leak (PVL) occurred in 84.4% and moderate PVL in 2.0%. There were no cases of severe PVL. New permanent pacemaker (PPM) implantation was required in 25.9% among all patients and 30.8% among PPM-naive patients. CONCLUSIONS: Early experience with the LOTUS Edge system demonstrated satisfactory short-term safety and efficacy, favorable hemodynamic data, and very low rates of PVL in an anatomically complex cohort. New PPM implantation remained high. Further study will evaluate if increasing operator experience with the device and new implantation technique can reduce the incidence of PPM implantation.

Delayed Tension Symptomatic Pneumoperitoneum After POEM Requiring Needle Decompression.

INTRODUCTION: Per-oral endoscopic myotomy (POEM) is an effective modality for the management of achalasia. Tension pneumoperitoneum is a significant complication that causes hemodynamic instability, generally within the periprocedural period. METHODS: Here, we report 2 cases of delayed tension pneumoperitoneum that was recognized and treated several hours after uncomplicated POEM. RESULTS: These cases illustrate the importance of continued vigilance for this complication outside of the immediate periprocedural period as well as the utility of computed tomography-guided aspiration in managing it. DISCUSSION: When discharging patients after POEM, caregivers should be aware of this rare complication and alert patients to return for immediate care when it happens.

Isolated Diastolic Hypertension in the UK Biobank: Comparison of ACC/AHA and ESC/NICE Guideline Definitions.

The 2017 American College of Cardiology/American Heart Association guideline defines hypertension as a blood pressure ≥130/80 mm Hg, whereas the 2018 European Society of Cardiology (ESC) and 2019 National Institute for Health and Care Excellence (NICE) guidelines use a ≥140/90 mm Hg threshold. Our objective was to study the associations between isolated diastolic hypertension (IDH), diagnosed using these 2 blood pressure thresholds, and cardiovascular disease (CVD) in a large cohort of UK adults. We analyzed data from UK Biobank, which enrolled participants between 2006 and 2010 with follow-up through March 2019. We excluded persons with systolic hypertension or baseline CVD. We defined incident CVD as a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. We used Cox regression to quantify associations between IDH and CVD, as well as the individual outcomes included in the composite outcome. We studied 151 831 participants with normal systolic blood pressure (mean age 54 years, 40% male). Overall, 24.5% had IDH by the American College of Cardiology/American Heart Association definition compared with 6% by the ESC/NICE definition. Compared with normal diastolic blood pressure, IDH by the American College of Cardiology/American Heart Association definition was not significantly associated with CVD risk (hazard ratio, 1.08 [95% CI, 0.98-1.18]) whereas IDH by the ESC/NICE definition was significantly associated with a modest increase in CVD (hazard ratio, 1.15 [95% CI, 1.04-1.29]). Similar results were found by sex and among participants not taking baseline antihypertensives. Furthermore, neither IDH definition was associated with the individual outcomes of nonfatal myocardial infarction or stroke. In conclusion, the proportion of UK Biobank participants with IDH was significantly higher by the American College of Cardiology/American Heart Association definition compared with the ESC/NICE definitions; however, only the ESC/NICE definition was statistically associated with increased CVD risk.

A casein hydrolysate increases GLP-1 secretion and reduces food intake.

In an effort to control weight gain, much attention has focused on the identification of bioactive peptides from food sources that induce satiety hormone secretion and increase the feeling of fullness. In this study, a screening platform identified a sodium caseinate hydrolysate, LFC25, that significantly increased calcium signalling in the enteroendocrine cell line, STC-1, and as a result increased secretion of the satiety hormone, GLP-1, in a dose-dependent manner. Administration of this hydrolysate to mice reduced the cumulative food intake over an eight hour period. To determine the feasibility of LFC25 as a food ingredient, production was scaled up to 10 L and spray-dried or freeze-dried without loss of bioactivity.

LMWF-5A for the Treatment of Severe Osteoarthritis of the Knee: Integrated Analysis of Safety and Efficacy.

The low-molecular-weight fraction of 5% human serum albumin (LMWF-5A) is being developed to treat the signs and symptoms of severe osteoarthritis of the knee. This study was a post hoc pooled analysis of 3 randomized placebo-controlled trials of a single intra-articular injection of LMWF-5A, focusing on the subset of patients with severe osteoarthritis of the knee (Kellgren-Lawrence grade 4). Patients were randomized 1:1 to receive a single 4-mL intra-articular knee injection of either LMWF-5A or saline. Safety was assessed as the incidence and severity of adverse events. Efficacy was assessed as the change from baseline to week 12 on the Western Ontario and McMaster Universities Osteoarthritis Index pain (primary outcome), stiffness, and physical function subscores and on patient global assessment scores and was presented as the least squares mean difference and 95% confidence interval. The proportion of responders was defined with the Outcome Measures in Rheumatology-Osteoarthritis Research Society International criteria for scenario D and examined with Pearson's chi-square test. For 417 patients with severe osteoarthritis of the knee, treatment with LMWF-5A resulted in a significant decrease in pain at 12 weeks compared with saline (mean difference, -0.19; 95% confidence interval, -0.34 to -0.04; P=.016), with improvements in function (mean difference, -0.15; 95% confidence interval, -0.31 to 0.01) and patient global assessment (mean difference, -0.30; 95% confidence interval, -0.49 to -0.12) and higher responder rates (64.25% vs 50.90%, P=.006). No drug-related serious adverse events and no deaths occurred, and the incidence and severity of adverse events were similar across treatment groups. This pooled analysis supports the use of LMWF-5A as a safe therapeutic agent for relief of the signs and symptoms of severe osteoarthritis of the knee. [Orthopedics. 2018; 41(1):e77-e83.].

Histone H2A Monoubiquitination in Neurodevelopmental Disorders.

Covalent histone modifications play an essential role in gene regulation and cellular specification required for multicellular organism development. Monoubiquitination of histone H2A (H2AUb1) is a reversible transcriptionally repressive mark. Exchange of histone H2A monoubiquitination and deubiquitination reflects the succession of transcriptional profiles during development required to produce cellular diversity from pluripotent cells. Germ-line pathogenic variants in components of the H2AUb1 regulatory axis are being identified as the genetic basis of congenital neurodevelopmental disorders. Here, we review the human genetics findings coalescing on molecular mechanisms that alter the genome-wide distribution of this histone modification required for development.

Pediatric sleep-disordered breathing: an update on diagnostic testing.

PURPOSE OF REVIEW: Recent advances in diagnostic testing for obstructive sleep apnea in children have refined the standard tests while identifying several new tools that hold promise to radically change how we diagnose sleep apnea. RECENT FINDINGS: Studies have demonstrated that the polysomnogram may be modified to permit home assessment of sleep disturbed breathing in children to ensure more widespread access to the test. Alternately, questionnaires, nocturnal oximetry, and diagnostic urinary biomarkers have shown great promise as both sensitive and specific tools to diagnose sleep apnea in children as well as track the severity of the disease. SUMMARY: The gold standard polysomnogram has been refined to permit its application in a modified form at home and for brief examinations in children. This standard has been challenged on several fronts, including questionnaires, nocturnal oximetry, drug-induced sleep endoscopy, and noninvasive urinary biomarkers that may ultimately supplant polysomnography as the gold standard to diagnose obstructive sleep apnea syndrome in children.

Unique aspects of pain reduction in osteoarthritis of the knee with LMWF-5A.

Osteoarthritis of the knee (OAK) is a common form of arthritis that can lead to substantial pain and disability. This commentary highlights key aspects of the recently published phase 3 A Efficacy and Safety Study of Two Doses of Intra-Articular Injection of Ampion™ in Adults With Pain Due to Osteoarthritis of the Knee (SPRING) study. SPRING (NCT01839331) was a multicenter, randomized, vehicle-controlled, double-blind trial that evaluated the safety and efficacy of the low-molecular-weight fraction of 5% human serum albumin (LMWF-5A) for treatment of pain, measured by the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) pain scale, in patients with symptomatic OAK (N=329). Patients in this study reflected many characteristics of "real-world" individuals with OAK, with a broad range of disease severity and disability. The most important finding from this study was that treatment with a single intra-articular injection of LMWF-5A led to significant pain reduction in the patients with objective radiographic evidence of severe disease and joint deterioration (Kellgren-Lawrence grade 3; P=0.04 and Kellgren-Lawrence grade 4; P=0.02). The magnitude of pain reduction in the entire cohort treated with LMWF-5A was 42% from baseline and the treatment effect compared with vehicle control (estimated difference in WOMAC pain, -0.25; P=0.004) was also notable, especially relative to a previously reported study of hyaluronic acid, in which only a marginally significant treatment effect was observed (mean difference in WOMAC pain compared with control, -0.15; P=0.047). Significant improvement in physical function observed with LMWF-5A (P=0.04) was also noted and suggests that LMWF-5A may provide therapeutic benefit for those who are limited in the activities of daily living. Intra-articular injection of LMWF-5A was well tolerated, and the adverse event profile was similar to that of control. These results demonstrate significant benefit of LMWF-5A for patients with greatest disability (Kellgren-Lawrence grades 3 and 4) and highest therapeutic need who have limited pharmacologic options for relief of pain associated with OAK.

A case of long term survival with skeletal only metastatic breast cancer.

INTRODUCTION: The prognosis of patients with metastatic breast cancer is very poor. Because of this, treatment of skeletal metastasis is often palliative with limited goals rather than cure. However, there are those patients, such as presented here, who survive for an extended time. PRESENTATION OF CASE: This thirty-six year old female presented with lytic lesions to one ulna and rib five years after mastectomy for breast cancer. Despite radiation and chemotherapy, the ulnar lesion expanded and resulted in an elbow dislocation. The rib lesion was resected and the arm amputated above the elbow. She developed local recurrence in both her above elbow amputation stump and chest wall and a more proximal below shoulder amputation was performed with resection of chest wall lesion. Even though she had locally aggressive disease, she has survived for 31 years after diagnosis without any evidence of disease. DISCUSSION: Reports of metastatic breast cancer survival indicate the five year survival to be 15%. There have been few reports indicating that those patients with skeletal only or oligometastatic disease have improved prognosis. It is not clear what biological properties of these tumors results in the improved survival. CONCLUSION: This case highlights the challenges of giving patients the optimal treatment in the light of limited ability to predict prognosis. It also highlights the need to further investigate the phenotypes of breast cancer that can, despite metastatic disease and with modern treatment go on to long survival. In addition this case demonstrates the importance of long term followup.