A novel missense variant in the ATPase domain of ATP8A2 and review of phenotypic variability of ATP8A2-related disorders caused by missense changes.

ATPase, class 1, type 8 A, member 2 (ATP8A2) is a P4-ATPase with a critical role in phospholipid translocation across the plasma membrane. Pathogenic variants in ATP8A2 are known to cause cerebellar ataxia, impaired intellectual development, and disequilibrium syndrome 4 (CAMRQ4) which is often associated with encephalopathy, global developmental delay, and severe motor deficits. Here, we present a family with two siblings born from a consanguineous, first-cousin union from Sudan presenting with global developmental delay, intellectual disability, spasticity, ataxia, nystagmus, and thin corpus callosum. Whole exome sequencing revealed a homozygous missense variant in the nucleotide binding domain of ATP8A2 (p.Leu538Pro) that results in near complete loss of protein expression. This is in line with other missense variants in the same domain leading to protein misfolding and loss of ATPase function. In addition, by performing diffusion-weighted imaging, we identified bilateral hyperintensities in the posterior limbs of the internal capsule suggesting possible microstructural changes in axon tracts that had not been appreciated before and could contribute to the sensorimotor deficits in these individuals.

An Evaluation of Critical Factors for the Cost-Effectiveness of Real-Time Computer-Aided Detection: Sensitivity and Threshold Analyses Using a Microsimulation Model.

BACKGROUND & AIMS: The use of computer-aided detection (CAD) increases the adenoma detection rates (ADRs) during colorectal cancer (CRC) screening/surveillance. This study aimed to evaluate the requirements for CAD to be cost-effective and the impact of CAD on adenoma detection by endoscopists with different ADRs. METHODS: We developed a semi-Markov microsimulation model to compare the effectiveness of traditional colonoscopy (mean ADR, 26%) to colonoscopy with CAD (mean ADR, 37%). CAD was modeled as having a $75 per-procedure cost. Extensive 1-way sensitivity and threshold analysis were performed to vary cost and ADR of CAD. Multiple scenarios evaluated the potential effect of CAD on endoscopists' ADRs. Outcome measures were reported in incremental cost-effectiveness ratios, with a willingness-to-pay threshold of $100,000/quality-adjusted life year. RESULTS: When modeling CAD improved ADR for all endoscopists, the CAD cohort had 79 and 34 fewer lifetime CRC cases and deaths, respectively, per 10,000 persons. This scenario was dominant with a cost savings of $143 and incremental effectiveness of 0.01 quality-adjusted life years. Threshold analysis demonstrated that CAD would be cost-effective up to an additional cost of $579 per colonoscopy, or if it increases ADR from 26% to at least 30%. CAD reduced CRC incidence and mortality when limited to improving ADRs for low-ADR endoscopists (ADR <25%), with 67 fewer CRC cases and 28 CRC deaths per 10,000 persons compared with traditional colonoscopy. CONCLUSIONS: As CAD is implemented clinically, it needs to improve mean ADR from 26% to at least 30% or cost less than $579 per colonoscopy to be cost-effective when compared with traditional colonoscopy. Further studies are needed to understand the impact of CAD when used in community practice.

Dynamic Mueller matrix polarimetry using generalized measurements.

Mueller matrices provide a complete description of a medium's response to excitation by polarized light, and their characterization is important across a broad range of applications from ellipsometry in material science to polarimetry in biochemistry, medicine and astronomy. Here we introduce single-shot Mueller matrix polarimetry based on generalized measurements performed with a Poincaré beam. We determine the Mueller matrix of a homogeneous medium with unknown optical activity by detecting its optical response to a Poincaré beam, which across its profile contains all polarization states, and analyze the resulting polarization pattern in terms of four generalized measurements, which are implemented as a path-displaced Sagnac interferometer. We illustrate the working of our Mueller matrix polarimetry on the example of tilted and rotated wave plates and find excellent agreement with predictions as well as alternative Stokes measurements. After initial calibration, the alignment of the device stays stable for up to 8 hours, promising suitability for the dynamic characterization of Mueller matrices that change in time. Unlike traditional rotating waveplate polarimetry, our method allows the acquisition of a sample's dynamic Mueller matrix. We expect that our feasibility study could be developed into a practical and versatile tool for the real-time analysis of optical activity changes, with applications in biomedical and biochemical research and industrial monitoring.

A Lower Bound on Dark Matter Mass.

We argue that there is a lower bound of order 10^{-19} eV on dark matter mass if it is produced after inflation via a process with finite correlation length. We rely on nondetection of free-streaming suppression and white-noise enhancement of density perturbations as the observational inputs.

Measuring the Optical Concurrence of Vector Beams with an Atomic-State Interferometer.

We investigate the transmission of vector beams, correlated in their polarization and spatial degrees of freedom, through cold atoms in the presence of a transverse magnetic coupling field. The resulting phase-dependent dynamics allow us to imprint the spatially varying polarization of a vector beam onto atomic spin polarizations, thereby establishing a direct link between optical space-polarization correlations and atomic-state interference. We find that the resulting absorption profiles show interference fringes whose modulation strength is given by the squared concurrence of the vector beam, letting us identify optical concurrence from a single absorption image. We expect impact across a diverse range of applications, including spintronics, quantum memories, metrology, and clocks.

Bidirectional relationship between acute pancreatitis and pancreatic cancer.

PURPOSE OF REVIEW: The burdens of pancreatic ductal adenocarcinoma (PDAC) and acute pancreatitis are increasing globally. We reviewed current literature on whether acute pancreatitis is a causal factor for PDAC and examined clinical manifestations of PDAC-associated acute pancreatitis. RECENT FINDINGS: Recent findings detail the timing of acute pancreatitis before and after PDAC occurrence, further solidifying the evidence for PDAC-associated acute pancreatitis and for acute pancreatitis as a causal risk factor for PDAC. The risk of PDAC remains elevated above the general population in patients with distant history of acute pancreatitis. PDAC risk also increases with recurrent acute pancreatitis episodes, independent of smoking and alcohol. Mechanisms linking acute pancreatitis to PDAC include inflammation and neutrophil infiltration, which can be attenuated by suppressing inflammation and/or epigenetic modulation, thus slowing the progression of acinar-to-ductal metaplasia. Clinical presentation and management of acute pancreatitis in the context of PDAC are discussed, including challenges acute pancreatitis poses in the diagnosis and treatment of PDAC, and novel interventions for PDAC-associated acute pancreatitis. SUMMARY: PDAC risk may be reduced with improved acute pancreatitis prevention and treatment, such as antiinflammatories or epigenetic modulators. Increased acute pancreatitis and PDAC burden warrant more research on better diagnosis and management of PDAC-associated acute pancreatitis.

Low delayed bleeding and high complete closure rate of mucosal defects with the novel through-the-scope dual-action tissue clip after endoscopic resection of large nonpedunculated colorectal lesions (with video).

BACKGROUND AND AIMS: Complete closure after endoscopic resection of large nonpedunculated colorectal lesions (LNPCLs) can reduce delayed bleeding but is challenging with conventional through-the-scope (TTS) clips alone. The novel dual-action tissue (DAT) clip has clip arms that open and close independently of each other, facilitating tissue approximation. We aimed to evaluate the rate of complete closure and delayed bleeding with the DAT clip after endoscopic resection of LNPCLs. METHODS: This was a multicenter prospective cohort study of all patients who underwent defect closure with the DAT clip after EMR or endoscopic submucosal dissection (ESD) of LNPCLs ≥20 mm from July 2022 to May 2023. Delayed bleeding was defined as a bleeding event requiring hospitalization, blood transfusion, or any intervention within 30 days after the procedure. Complete closure was defined as apposition of mucosal defect margins without visible submucosal areas <3 mm along the closure line. RESULTS: One hundred seven patients (median age, 64 years; 42.5% women) underwent EMR (n = 63) or ESD (n = 44) of LNPCLs (median size, 40 mm; 74.8% right-sided colon) followed by defect closure. Complete closure was achieved in 96.3% (n = 103) with a mean of 1.4 ± .6 DAT clips and 2.9 ± 1.8 TTS clips. Delayed bleeding occurred in 1 patient (.9%) without requiring additional interventions. CONCLUSIONS: The use of the DAT clip in conjunction with TTS clips achieved high complete defect closure after endoscopic resection of large LNPCLs and was associated with a .9% delayed bleeding rate. Future comparative trials and formal cost-analyses are needed to validate these findings. (Clinical trial registration number: NCT05852457.).

Index admission cholecystectomy for biliary acute pancreatitis or choledocholithiasis reduces 30-day readmission rates in children.

BACKGROUND: Adult patients with biliary acute pancreatitis (BAP) or choledocholithiasis who do not undergo cholecystectomy on index admission have worse outcomes. Given the paucity of data on the impact of cholecystectomy during index hospitalization in children, we examined readmission rates among pediatric patients with BAP or choledocholithiasis who underwent index cholecystectomy versus those who did not. METHODS: Retrospective study of children (< 18 years old) admitted with BAP, without infection or necrosis (ICD-10 K85.10), or choledocholithiasis (K80.3x-K80.7x) using the 2018 National Readmission Database (NRD). Exclusion criteria were necrotizing pancreatitis with or without infected necrosis and death during index admission. Multivariable logistic regression was performed to identify factors associated with 30-day readmission. RESULTS: In 2018, 1122 children were admitted for index BAP (n = 377, 33.6%) or choledocholithiasis (n = 745, 66.4%). Mean age at admission was 13 (SD 4.2) years; most patients were female (n = 792, 70.6%). Index cholecystectomy was performed in 663 (59.1%) of cases. Thirty-day readmission rate was 10.9% in patients who underwent cholecystectomy during that index admission and 48.8% in those who did not (p < 0.001). In multivariable analysis, patients who underwent index cholecystectomy had lower odds of 30-day readmission than those who did not (OR 0.16, 95% CI 0.11-0.24, p < 0.001). CONCLUSIONS: Index cholecystectomy was performed in only 59% of pediatric patients admitted with BAP or choledocholithiasis but was associated with 84% decreased odds of readmission within 30 days. Current guidelines should be updated to reflect these findings, and future studies should evaluate barriers to index cholecystectomy.

Index admission cholecystectomy for acute cholecystitis reduces 30-day readmission rates in pediatric patients.

BACKGROUND: Adult patients with cholecystitis who do not undergo cholecystectomy on index admission have worse outcomes, however, there is a paucity of data of the role of cholecystectomy during index hospitalization in the pediatric population. Our aim was to determine outcomes and readmission rates among pediatric patients with cholecystitis who underwent index cholecystectomy versus those who did not. METHODS: We performed a retrospective study of pediatric (< 18 years old) admitted with acute cholecystitis (AC) requiring hospitalization using the 2018 National Readmission Database (NRD). Exclusion criteria included age ≥ 18 years and death on index admission. Multivariable logistic regression was performed to identify factors associated with 30-day readmissions. RESULTS: We identified 550 unique index acute cholecystitis admissions. Mean age was 14.6 ± 3.0 years. Majority of patients were female (n = 372, 67.6%). Index cholecystectomy was performed in (n = 435, 79.1%) of cases. Thirty-day readmission rate was 2.8% in patients who underwent index cholecystectomy and 22.6% in those who did not (p < 0.001). On multivariable analysis, patients who did not undergo index cholecystectomy had higher odds of 30-day readmission than those who did not (OR 10.66, 95% CI 5.06-22.45, p < 0.001). Female patients also had higher odds of 30-day readmission compared to males (OR 3.37, 95% CI 1.31-8.69). CONCLUSIONS: Patients who did not undergo index cholecystectomy had over tenfold increase in odds of 30-day readmission. Further research is required to understand the barriers to index cholecystectomy despite society recommendations and clear clinical benefit.

Global 30-day morbidity and mortality of surgery for perforated peptic ulcer: GRACE study.

BACKGROUND: There is little international data on morbidity and mortality of surgery for perforated peptic ulcer (PPU). This study aimed to understand the global 30-day morbidity and mortality of patients undergoing surgery for PPU and to identify variables associated with these. METHOD: We performed an international study of adults (≥ 18 years) who underwent surgery for PPU from 1st January 2022 to 30th June 2022. Patients who were treated conservatively or had an underlying gastric cancer were excluded. Patients were divided into subgroups according to age (≤ 50 and > 50 years) and time from onset of symptoms to hospital presentation (≤ 24 and > 24 h). Univariate and Multivariate analyses were carried out to identify factors associated with higher 30-day morbidity and mortality. RESULTS:  1874 patients from 159 centres across 52 countries were included. 78.3% (n = 1467) of the patients were males and the median (IQR) age was 49 years (25). Thirty-day morbidity and mortality were 48.5% (n = 910) and 9.3% (n = 174) respectively. Median (IQR) hospital stay was 7 (5) days. Open surgery was performed in 80% (n = 1505) of the cohort. Age > 50 years [(OR = 1.7, 95% CI 1.4-2), (OR = 4.7, 95% CI 3.1-7.6)], female gender [(OR = 1.8, 95% CI 1.4-2.3), (OR = 1.9, 95% CI 1.3-2.9)], shock on admission [(OR = 2.1, 95% CI 1.7-2.7), (OR = 4.8, 95% CI 3.2-7.1)], and acute kidney injury [(OR = 2.5, 95% CI 1.9-3.2), (OR = 3.9), 95% CI 2.7-5.6)] were associated with both 30-day morbidity and mortality. Delayed presentation was associated with 30-day morbidity [OR = 1.3, 95% CI 1.1-1.6], but not mortality. CONCLUSIONS: This study showed that surgery for PPU was associated with high 30-day morbidity and mortality rate. Age, female gender, and signs of shock at presentation were associated with both 30-day morbidity and mortality.

Application of Global Trigger Tools in University Hospital and Comparison to Volunteer Adverse Events Reporting System.

BACKGROUND: A voluntary reporting system (VRS) is still used to detect adverse events (AEs) in health-care services in many countries. We attempted to apply the Global Trigger Tool (GTT) for the first time in our country and searched for an answer to the question of whether there could be new triggers. METHODS: Two hundred and forty inpatient records were selected from total of 1,807 inpatient files in the university obstetrics and gynecology clinic between 2018 and 2020. Twenty files per month were reviewed retrospectively using GTT, an approach developed by the American Institute for Health Development. VRS records of the same period were examined. The data were evaluated according to the National Coordinating Council for Medication Error Reporting and Prevention scale and those in the E, F, G, H, I categories were included. RESULTS: The number of AEs per 1,000 patient days was 47.81, AEs per 1,000 patient hospitalizations was 95.83, and hospitalizations with AEs was 9.58%. In the VRS data, 10 of 85 reporting cases were listed in the E category (Damage is temporary and requires intervention), 6 of them were related to fall of the patient, and 4 of them were related to medical device and material safety. By applying GTT, 45 cases in category E and 35 cases in category F (Damage is temporary and requires hospitalization or prolonged hospitalization) AEs were detected in 23 patients (9.58%). The number of AEs reported was 8.3 times higher in the GTT than with VRS. Healthcare related infection, development of complications from any procedure, APTT>100 Seconds, INR>6, Organ Injury - Repair or Removal, All Kinds of Operative Complications were found to be the most sensitive triggers (PPV = 100). There was no difference between the patients with and without AEs in terms of age and number of hospitalization days (p: 0.707, p: 0.618). The sensitivity rate of vaginal dinoprostone use and CRP elevation (30% and 22%, respectively) was higher than the mean sensitivity rate of GTT triggers (15.6%). CONCLUSIONS: The GTT is more effective than VRS in detecting AEs. Using vaginal dinoprostone (propess) and high CRP levels could be used as a trigger. The GTT is a credible and fruitful instrument for determining AEs when adapted to the departmental practices.

Common Genetic Variants in SIRT1 Gene Promoter and Type 2 Diabetes Mellitus in Saudi Arabia.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is common in Saudi Arabia and represents a major health concern. Silent information regulator of transcription-1 (SIRT1) positively influences insulin sensitivity and might contribute to the pathogenesis of T2DM. This study aimed to investigate the frequency of two common functional single nucleotide polymorphisms (SNPs) in the promoter region of SIRT1; rs12778366 (T>C) and rs3758391 (T>C) in Saudi Arabian population and examine any association with T2DM. METHODS: A total of 445 volunteers were divided into 224 healthy controls and 221 patients previously diagnosed with T2DM. Genomic DNA was extracted from all samples and genotyped for SIRT1 rs12778366 and rs3758391 SNPs by TaqMan RT-PCR allelic discrimination assay. Logistic regression analysis was used to establish any relationship between these polymorphisms and T2DM. RESULTS: In the total study population, rs12778366 genotype frequencies were TT (89.2%), TC (10.3%), and CC (0.45%) and for the rs3758391 they were TT (16.4%), TC (44.5%), and CC (39.1%). The distribution of these genotypes, in both polymorphisms, were similar among T2DM and controls. Logistic regression analysis confirmed the lack of association between the presence of CC or CT variants and T2DM for rs12778366 and rs3758391 SNP (OR = 0.98 [CI]: 0.55 - 1.75; p = 0.999 and OR= 0.75; [CI]: 0.45 - 1.24; p = 0.313), respectively. CONCLUSIONS: This study revealed the frequency of SIRT1 rs12778366 and rs3758391 SNPs in our population and reported no association between these polymorphisms and the risk for T2DM. This finding might add to the growing body of literature exploring the genetics of T2DM.

Axillary compared to brachial access for endovascular procedures.

OBJECTIVES: Limited knowledge exists regarding access site complication rates between trans-axillary and trans-brachial approaches with sheath sizes ≥6Fr. We retrospectively reviewed our institution experience with access site complications for percutaneous trans-axillary and trans-brachial arterial interventions using sheath sizes ranging from 6Fr to 10Fr. METHODS: We examined 67 endovascular interventions performed over 18 months, restricted to sheath sizes of 6Fr to 10Fr. Procedures utilizing trans-brachial (41 cases) and trans-axillary (26 cases) approaches under sonographic guidance were included. Cases involving hemodialysis accesses and those requiring surgical cut-down were excluded. The primary outcome measure was the occurrence of major access site complications (SIR grade-II/III) within 30 days, with data collected on hemostasis method, sheath size, and complications. Statistical analysis involved ANCOVA and Fisher's exact tests, with significance set at p < .05. RESULTS: Successful percutaneous arterial access was achieved in all cases using either approach (trans-axillary or trans-brachial). Closure devices were employed in all axillary punctures and in 71% of brachial punctures. Major access site complications occurred in 7 out of 41 cases (17%) in the trans-brachial group and in 4 out of 26 cases (15%) in the trans-axillary group. However, there was no statistically significant difference in complication rates between the two groups, regardless of access site or sheath size. CONCLUSION: Trans-axillary access serves as a safe and effective upper limb access method for percutaneous endovascular procedures requiring sheath size of 7Fr or larger when compared to trans-brachial approach.

Accelerometer Thresholds for Estimating Physical Activity Intensity Levels in Infants: A Preliminary Study.

Lack of physical activity (PA) at a young age can result in health issues. Thus, monitoring PA is important. Wearable accelerometers are the preferred tool to monitor PA in children. Validated thresholds are used to classify activity intensity levels, e.g., sedentary, light, and moderate-to-vigorous, in ambulatory children. No previous work has developed accelerometer thresholds for infancy (pre-ambulatory children). Therefore, this work aims to develop accelerometer thresholds for PA intensity levels in pre-ambulatory infants. Infants (n = 10) were placed in a supine position and allowed free movement. Their movements were synchronously captured using video cameras and accelerometers worn on each ankle. The video data were labeled by activity intensity level (sedentary, light, and moderate-to-vigorous) in two-second epochs using observational rating (gold standard). Accelerometer thresholds were developed for acceleration and jerk using two optimization approaches. Four sets of thresholds were developed for dual (two ankles) and for single-worn (one ankle) accelerometers. Of these, for a typical use case, we recommend using acceleration-based thresholds of 1.00 m/s to distinguish sedentary and light activity and 2.60 m/s to distinguish light and moderate-to-vigorous activity. Acceleration and jerk are both suitable for measuring PA.

Activated carbon and their nanocomposites derived from vegetable and fruit residues for water treatment.

Water pollution remains a pressing environmental issue, with diverse pollutants such as heavy metals, pharmaceuticals, dyes, and aromatic hydrocarbon compounds posing a significant threat to clean water access. Historically, biomass-derived activated carbons (ACs) have served as effective adsorbents for water treatment, owing to their inherent porosity and expansive surface area. Nanocomposites have emerged as a means to enhance the absorption properties of ACs, surpassing conventional AC performance. Biomass-based activated carbon nanocomposites (ACNCs) hold promise due to their high surface area and cost-effectiveness. This review explores recent advancements in biomass-based ACNCs, emphasizing their remarkable adsorption efficiencies and paving the way for future research in developing efficient and affordable ACNCs. Leveraging real-time communication for ACNC applications presents a viable approach to addressing cost concerns.

Effect of Air Pollutants Particulate Matter PM2.5, PM10, Carbon Monoxide (CO), Nitrogen Dioxide (NO2), Sulfur Dioxide (SO2), and Ozone (O3) on Fractional Exhaled Nitric Oxide (FeNO).

Objectives: This study aimed to investigate the effect of Environmental Pollutants Particulate Matter PM2.5, PM10, Carbon Monoxide (CO), Nitrogen Dioxide (NO2), Sulfur Dioxide (SO2), and Ozone (O3) on lung airway inflammation by assessing the Fractional Exhaled Nitric Oxide (FeNO) in students studying in schools located in or away from air-polluted areas. Methods: This matched case-control cross-sectional study was conducted in the Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia from August 2022 to July 2023. In this study, two schools were selected, one was located near a traffic-polluted area (School #1), and the second was located away from the traffic-polluted area (School #2). A total of 300 students were recruited, 150 (75 male and 75 female) students from the school located in a traffic-polluted area, and 150 students (75 male and 75 female) from the school located away from a traffic-polluted area. Environmental pollutants PM2.5, PM10, CO, NO2, O3, and SO2, were recorded. The Fractional Exhaled Nitric Oxide (FeNO) was measured using a Niox Mino. Results: The mean concentration of PM2.5, PM10, CO, NO2, O3, and SO2 were 35.00±0.65 significantly higher in a school located in motor vehicle polluted area compared to a school located away from a motor vehicle-polluted area (29.95±0.32) (p=0.001). The mean values for FeNO were significantly higher (18.75±0.90) among students studying in a school located in the motor vehicle-polluted area compared to students studying in a school located away from the motor vehicle-polluted area (11.26±0.56) (p=0.001). Conclusions: Environmental pollution can cause lung inflammation among students in schools located in traffic-polluted areas.

Clinical, genetic, and functional characterization of the glycine receptor ß-subunit A455P variant in a family affected by hyperekplexia syndrome.

Hyperekplexia is a rare neurological disorder characterized by exaggerated startle responses affecting newborns with the hallmark characteristics of hypertonia, apnea, and noise or touch-induced nonepileptic seizures. The genetic causes of the disease can vary, and several associated genes and mutations have been reported to affect glycine receptors (GlyRs); however, the mechanistic links between GlyRs and hyperekplexia are not yet understood. Here, we describe a patient with hyperekplexia from a consanguineous family. Extensive genetic screening using exome sequencing coupled with autozygome analysis and iterative filtering supplemented by in silico prediction identified that the patient carries the homozygous missense mutation A455P in GLRB, which encodes the GlyR ß-subunit. To unravel the physiological and molecular effects of A455P on GlyRs, we used electrophysiology in a heterologous system as well as immunocytochemistry, confocal microscopy, and cellular biochemistry. We found a reduction in glycine-evoked currents in N2A cells expressing the mutation compared to WT cells. Western blot analysis also revealed a reduced amount of GlyR ß protein both in cell lysates and isolated membrane fractions. In line with the above observations, coimmunoprecipitation assays suggested that the GlyR α1-subunit retained coassembly with ßA455P to form membrane-bound heteromeric receptors. Finally, structural modeling showed that the A455P mutation affected the interaction between the GlyR ß-subunit transmembrane domain 4 and the other helices of the subunit. Taken together, our study identifies and validates a novel loss-of-function mutation in GlyRs whose pathogenicity is likely to cause hyperekplexia in the affected individual.

A Prospective Cohort Study Evaluating PAN-PROMISE, a Patient-reported Outcome Measure to Detect Post-ERCP Morbidity.

BACKGROUND & AIMS: The Cotton Consensus (CC) criteria for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) may not capture post-ERCP morbidity. PAN-PROMISE, a patient-reported outcome measure (PROM), was developed to quantify acute pancreatitis-related morbidity. This study aims to determine the value of PAN-PROMISE in independently defining ERCP-related morbidity. METHODS: We conducted a prospective cohort study of patients undergoing ERCP at 2 academic centers from September 2021 to August 2022. We administered PAN-PROMISE and assessed quality of life and work productivity at baseline, 48 to 72 hours, 7 days, and 30 days following ERCP. PEP was defined by a 3-physician committee using the CC criteria. We defined high morbidity following ERCP (elevated PROM) by an increase of PAN-PROMISE score of >7 at 7 days post-procedure. The McNemar test assessed discordance between PEP and elevated-PROM. RESULTS: A total of 679 patients were enrolled. Choledocholithiasis (30%) and malignant biliary obstruction (29%) were the main indications for ERCP. Thirty-two patients (4.7%) developed PEP. One hundred forty-seven patients (21.6%) had an elevated PROM, whereas only 20 of them (13.4%) had PEP by the CC criteria (P < .001 for discordance). An elevated PROM strongly correlated with lower physical quality of life and increased direct and indirect health care costs ($80 and $25 per point increase in PAN-PROMISE, respectively). Patients with pancreatic cancer (odds ratio, 4.52; 95% confidence interval, 1.68-10.74) and primary sclerosing cholangitis (odds ratio, 1.79; 95% confidence interval, 1.29-2.45) had the highest odds of elevated PROM. CONCLUSIONS: A substantial number of patients experience significant morbidity after ERCP despite not developing PEP or other adverse events. Future studies are needed to characterize better the reasons behind this increase in symptoms and potential interventions to reduce the symptom burden post-ERCP. CLINICALTRIALS: gov number, NCT05310409.

Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders.

PURPOSE: Missense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy with early-onset seizures and severe intellectual disability. METHODS: By international collaboration, we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders. By western blotting, we investigated the consequences of missense variants in vitro. RESULTS: In accordance with previous observations, de novo heterozygous missense variants in the BTB domain region led to a severe developmental and epileptic encephalopathy in 16 individuals. Now, we also identified de novo missense variants in the GTPase domain in 6 individuals with apparently more variable neurodevelopmental phenotypes with or without epilepsy. In contrast to variants in the BTB domain region, variants in the GTPase domain do not impair proteasomal degradation of RHOBTB2 in vitro, indicating different functional consequences. Furthermore, we observed biallelic splice-site and truncating variants in 9 families with variable neurodevelopmental phenotypes, indicating that complete loss of RHOBTB2 is pathogenic as well. CONCLUSION: By identifying genotype-phenotype correlations regarding location and consequences of de novo missense variants in RHOBTB2 and by identifying biallelic truncating variants, we further delineate and expand the molecular and clinical spectrum of RHOBTB2-related phenotypes, including both autosomal dominant and recessive neurodevelopmental disorders.

Delineation of the clinical profile of CNOT2 haploinsufficiency and overview of the IDNADFS phenotype.

CNOT2 haploinsufficiency underlies a rare neurodevelopmental disorder named Intellectual Developmental disorder with NAsal speech, Dysmorphic Facies, and variable Skeletal anomalies (IDNADFS, OMIM 618608). The condition clinically overlaps with chromosome 12q15 deletion syndrome, suggesting a major contribution of CNOT2 haploinsufficiency to the latter. CNOT2 is a member of the CCR4-NOT complex, which is a master regulator of multiple cellular processes, including gene expression, RNA deadenylation, and protein ubiquitination. To date, less than 20 pathogenic 12q15 microdeletions encompassing CNOT2, together with a single truncating variant of the gene, and two large intragenic deletions have been reported. Due to the small number of affected subjects described so far, the clinical profile of IDNADFS has not been fully delineated. Here we report five unrelated individuals, three of which carrying de novo intragenic CNOT2 variants, one presenting with a multiexon intragenic deletion, and an additional case of 12q15 microdeletion syndrome. Finally, we assess the features of IDNADFS by reviewing published and present affected individuals and reevaluate the clinical phenotype of this neurodevelopmental disorder.