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Background: The clinical significance and incidence of phosphate abnormalities in cardiac surgery have not been investigated extensively. We hypothesize that phosphate abnormalities are associated with a longer time to tracheal extubation., Methods: This was a single-center, retrospective cohort study in patients who underwent nontransplant cardiac surgery with cardiopulmonary bypass between August 2009 and December 2020. Serum phosphate levels were measured within 6 hours of arrival to the intensive care unit (ICU). Select clinical outcomes were extracted from an intramural database: time to tracheal extubation, hospital length of stay, and in-hospital mortality. The lactate level within 6 hours of arrival to the ICU was extracted as well., Results: A total of 2659 patients were included. There were 502 (18.9%) patients who were found to be hypophosphatemic (phosphate <2.5 mg/dL), 1905 (71.6%) had normal phosphate levels (phosphate 2.5-4.5 mg/dL), and 252 (9.5%) were hyperphosphatemic (phosphate >4.5 mg/dL). Hyperphosphatemia was associated with 26% longer time to tracheal extubation (incident rate ratio, 1.26, 95% confidence interval [CI], 10%, 44%, P = .001), 37% longer hospital length of stay (acceleration factor = 0.63, 95% CI, -43% to -30%); P < .001), and increased in-hospital mortality (odds ratio, 4.0; 95% CI, 2.3-7.1; P < .001) when compared to patients with normal phosphate levels. These associations were not found for hypophosphatemia., Conclusions: Hyperphosphatemia in the immediate postoperative period after cardiac surgery is associated with adverse clinical outcomes. Future studies will need to investigate if actively correcting the phosphate level has an impact on clinical outcomes., Competing Interests: Conflicts of Interest, Funding: Please see DISCLOSURES at the end of this article., (Copyright © 2024 International Anesthesia Research Society.)

Importance: General-domain large language models may be able to perform risk stratification and predict postoperative outcome measures using a description of the procedure and a patient's electronic health record notes., Objective: To examine predictive performance on 8 different tasks: prediction of American Society of Anesthesiologists Physical Status (ASA-PS), hospital admission, intensive care unit (ICU) admission, unplanned admission, hospital mortality, postanesthesia care unit (PACU) phase 1 duration, hospital duration, and ICU duration., Design, Setting, and Participants: This prognostic study included task-specific datasets constructed from 2 years of retrospective electronic health records data collected during routine clinical care. Case and note data were formatted into prompts and given to the large language model GPT-4 Turbo (OpenAI) to generate a prediction and explanation. The setting included a quaternary care center comprising 3 academic hospitals and affiliated clinics in a single metropolitan area. Patients who had a surgery or procedure with anesthesia and at least 1 clinician-written note filed in the electronic health record before surgery were included in the study. Data were analyzed from November to December 2023., Exposures: Compared original notes, note summaries, few-shot prompting, and chain-of-thought prompting strategies., Main Outcomes and Measures: F1 score for binary and categorical outcomes. Mean absolute error for numerical duration outcomes., Results: Study results were measured on task-specific datasets, each with 1000 cases with the exception of unplanned admission, which had 949 cases, and hospital mortality, which had 576 cases. The best results for each task included an F1 score of 0.50 (95% CI, 0.47-0.53) for ASA-PS, 0.64 (95% CI, 0.61-0.67) for hospital admission, 0.81 (95% CI, 0.78-0.83) for ICU admission, 0.61 (95% CI, 0.58-0.64) for unplanned admission, and 0.86 (95% CI, 0.83-0.89) for hospital mortality prediction. Performance on duration prediction tasks was universally poor across all prompt strategies for which the large language model achieved a mean absolute error of 49 minutes (95% CI, 46-51 minutes) for PACU phase 1 duration, 4.5 days (95% CI, 4.2-5.0 days) for hospital duration, and 1.1 days (95% CI, 0.9-1.3 days) for ICU duration prediction., Conclusions and Relevance: Current general-domain large language models may assist clinicians in perioperative risk stratification on classification tasks but are inadequate for numerical duration predictions. Their ability to produce high-quality natural language explanations for the predictions may make them useful tools in clinical workflows and may be complementary to traditional risk prediction models.

Background: Intraoperative events and clinical management of deceased organ donors after brain death are poorly characterized and may consequently vary between hospitals and organ procurement organization (OPO) regions. In a multicenter cohort, we sought to estimate the incidence of hypotension and anesthetic and nonanesthetic medication use during organ recovery procedures., Methods: We used data from electronic anesthetic records generated during organ recovery procedures from brain-dead adults across a Multicenter Perioperative Outcomes Group (MPOG) cohort of 14 US hospitals and 4 OPO regions (2014-2020). Hypotension, defined as mean arterial pressure or MAP <60 mm Hg for at least 10 cumulative minutes was the primary outcome of interest. The associations between hypotension and age, sex, race, anesthesia time, OPOs, and OPO case volume were examined using multivariable mixed-effects Poisson regression analyses with robust standard error estimates. We calculated intraclass correlation coefficients (ICCs) to describe the variation between-MPOG centers and the OPO regions in the use of medications, time of the operation, and duration of the operation., Results: We examined 1338 brain-dead adult donors, with a mean age of 42± (standard deviation [SD] 15) years; 60% (n = 801) were males and 67% (n = 891) non-Hispanic White. During the entire intraoperative monitoring period, 321 donors (24%, 95% confidence interval [CI], 22%-26%) had hypotension for a median of 13.8% [quartile1-quartile 3: 9.4%-21%] of the monitoring period and a minimum of 10 minutes to a maximum of 96 minutes [(median: 17, quartile1-quartile 3: 12-24]). The probability having hypotension in donors 35 to 64 years and 65 years and older were approximately 30% less than in donors 18 to 34 years of age (adjusted relative risk ratios, aRR, 0.68, 95% CI, 0.55-0.82, aRR, 0.63, 95% CI, 0.42-0.94, respectively). Donors received intravenous heparin (96.4%, n = 1291), neuromuscular blockers (89.5%, n = 1198), vasoactive medications (82.7%, n = 1108), crystalloids (76.2%, n = 1020), halogenated anesthetic gases (63.5%, n = 850), diuretics (43.8%, n = 587), steroids (16.7%, n = 224), and opioids (23.2%, n = 310). The largest practice heterogeneity observed between the MPOG center and OPO regions was steroids (between-center ICCs = 0.65, 95% CI, 0.62-0.75, between-region ICCs = 0.39, 95% CI, 0.27-0.63) and diuretics (between-center ICCs = 0.44, 95% CI, 0.36-0.6, between-region ICCs = 0.30, 95% CI, 0.22-0.49)., Conclusions: Despite guidelines recommending maintenance of MAP >60 mm Hg in adult brain-dead organ donors, hypotension during recovery procedures was common. Future research is needed to clarify the relationship between intraoperative events with donation and transplantation outcomes and to identify best practices for the anesthetic management of brain-dead donors in the operating room., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2024 International Anesthesia Research Society.)

Background: We report adherence to 6 Anesthesiology Performance Improvement and Reporting Exchange (ASPIRE) quality metrics (QMs) relevant to patients undergoing decompressive craniectomy or endoscopic clot evacuation after spontaneous supratentorial intracerebral hemorrhage (sICH)., Methods: In this retrospective observational study, we describe adherence to the following ASPIRE QMs: acute kidney injury (AKI-01); mean arterial pressure < 65 mm Hg for less than 15 minutes (BP-03); myocardial injury (CARD-02); treatment of high glucose (> 200 mg/dL, GLU-03); reversal of neuromuscular blockade (NMB-02); and perioperative hypothermia (TEMP-03)., Result: The study included 95 patients (70% male) with median (interquartile range) age 55 (47 to 66) years and ICH score 2 (1 to 3) undergoing craniectomy (n=55) or endoscopic clot evacuation (n=40) after sICH. In-hospital mortality attributable to sICH was 23% (n=22). Patients with American Society of Anesthesiologists physical status class 5 (n=16), preoperative reduced glomerular filtration rate (n=5), elevated cardiac troponin (n=21) and no intraoperative labs with high glucose (n=71), those who were not extubated at the end of the case (n=62) or did not receive a neuromuscular blocker given (n=3), and patients having emergent surgery (n=64) were excluded from the analysis for their respective ASPIRE QM based on predetermined ASPIRE exclusion criteria. For the remaining patients, the adherence to ASPIRE QMs were: AKI-01, craniectomy 34%, endoscopic clot evacuation 1%; BP-03, craniectomy 72%, clot evacuation 73%; CARD-02, 100% for both groups; GLU-03, craniectomy 67%, clot evacuation 100%; NMB-02, clot evacuation 79%, and; TEMP-03, clot evacuation 0% with hypothermia., Conclusion: This study found variable adherence to ASPIRE QMs in sICH patients undergoing decompressive craniectomy or endoscopic clot evacuation. The relatively high number of patients excluded from individual ASPIRE metrics is a major limitation., Competing Interests: A.V.L. reports receiving salary support from LifeCenter Northwest, which is not relevant to this study. M.R.L. reports receiving research support from Medtronic and Stryker, Consulting for Medtronic, Metis Innovative, and Aegean Advisers, and equity interest in Proprio, Cerebrotech, Synchron, Fluid Biomed, and Hyperion Surgical, none of which are relevant to this study. M.J.S. reports salary support to the University of Washington from Life Center Northwest and consulting for Teleflex Medical, neither of which are relevant to this study. The remaining authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective There is growing interest in the use of phenobarbital for alcohol withdrawal syndrome in critically ill patients, though experience in neurologically injured patients is limited. The purpose of this study was to compare the safety and effectiveness of phenobarbital-containing alcohol withdrawal regimens versus benzodiazepine monotherapy in the neurocritical care unit. Methods We conducted a retrospective cohort study of adult patients admitted to the neurocritical care unit from January 2014 through November 2021 who received pharmacologic treatment for alcohol withdrawal. Treatment groups were defined as benzodiazepine monotherapy versus phenobarbital alone or in combination with benzodiazepines. The primary outcome was the percentage of patients requiring intubation after receiving alcohol withdrawal treatment. Secondary outcomes included all-cause, in-hospital mortality, intensive care unit length of stay, discharge disposition, change in Glasgow Coma Scale (GCS) score, and the use of adjunctive agents. Results We analyzed data from 156 patients, with 77 (49%) in the benzodiazepine group and 79 (51%) in the phenobarbital combination group. The groups were well-balanced for baseline characteristics, though more males (67, 85%) were in the phenobarbital group. Only three (1.9%) patients received phenobarbital monotherapy, and the rest (153, 98.1%) received combination therapy. The percentage of patients requiring mechanical ventilation was significantly higher in the phenobarbital combination group compared to benzodiazepine monotherapy (39% (n=31) versus 13% (n=10); OR: 4.33, 95% CI: 1.94-9.66; p<0.001). The use of adjunctive propofol and dexmedetomidine was higher in the phenobarbital group (propofol 35% (n= 28) versus 9% (n=7) and dexmedetomidine 30% (n=24) versus 5% (n=4), respectively). Patients in the phenobarbital group also had lower GCS scores and higher Clinical Institute Withdrawal Assessment of Alcohol (CIWA-Ar) scores during their intensive care unit admission, possibly suggesting more severe alcohol withdrawal. There was no difference in intensive care unit length of stay, all-cause, in-hospital mortality, discharge disposition, or therapeutic adjuncts. Conclusions Combination therapy of phenobarbital plus benzodiazepines was associated with higher odds of requiring mechanical ventilation. Few patients received phenobarbital monotherapy. Additional studies are needed to better compare the effects of phenobarbital monotherapy versus benzodiazepines in neurocritical patients., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. University of Washington issued approval STUDY 00014298. The study (STUDY 00014298) was approved (14 February 2022) by the University of Washington Medical Center institutional review board (IRB), and a waiver of informed consent was in place. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: Abhijit V. Lele declare(s) personal fees from LifeCenter Northwest. Medical Advisor. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Norris et al.)

Introduction: Patients with traumatic intracranial hemorrhage (tICH) are at increased risk of venous thromboembolism and may require anticoagulation. We evaluated the utility of surveillance computed tomography (CT) in patients with tICH who required therapeutic anticoagulation., Methods: This single institution, retrospective study included adult patients with tICH who required anticoagulation within 4 weeks and had a surveillance head CT within 24 hours of reaching therapeutic anticoagulation levels. The primary outcome was hematoma expansion (HE) detected by the surveillance CT. Secondary outcomes included 1) changes in management in patients with HE on the surveillance head CT, 2) HE in the absence of clinical changes, and 3) mortality due to HE. We also compared mortality between patients who did and did not have a surveillance CT., Results: Of 175 patients, 5 (2.9%) were found to have HE. Most (n = 4, 80%) had changes in management including anticoagulation discontinuation (n = 4), reversal (n = 1), and operative management (n = 1). Two patients developed symptoms or exam changes prior to the head CT. Of the 3 patients (1.7%) without preceding exam changes, each had only very minor HE and did not require operative management. No patient experienced mortality directly attributed to HE. There was no difference in mortality between patients who did and those who did not have a surveillance scan., Conclusions: Our findings suggest that most patients with tICH who are started on anticoagulation could be followed clinically, and providers may reserve CT imaging for patients with changes in exam/symptoms or those who have a poor clinical examination to follow., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: to examine factors associated with cardiac evaluation and associations between cardiac test abnormalities and clinical outcomes in patients with acute brain injury (ABI) due to acute ischemic stroke (AIS), spontaneous subarachnoid hemorrhage (SAH), spontaneous intracerebral hemorrhage (sICH), and traumatic brain injury (TBI) requiring neurocritical care. Methods : In a cohort of patients ≥18 years, we examined the utilization of electrocardiography (ECG), beta-natriuretic peptide (BNP), cardiac troponin (cTnI), and transthoracic echocardiography (TTE). We investigated the association between cTnI, BNP, sex-adjusted prolonged QTc interval, low ejection fraction (EF < 40%), all-cause mortality, death by neurologic criteria (DNC), transition to comfort measures only (CMO), and hospital discharge to home using univariable and multivariable analysis (adjusted for age, sex, race/ethnicity, insurance carrier, pre-admission cardiac disorder, ABI type, admission Glasgow Coma Scale Score, mechanical ventilation, and intracranial pressure [ICP] monitoring). Results : The final sample comprised 11,822 patients: AIS (46.7%), sICH (18.5%), SAH (14.8%), and TBI (20.0%). A total of 63% ( n = 7472) received cardiac workup, which increased over nine years ( p < 0.001). A cardiac investigation was associated with increased age, male sex (aOR 1.16 [1.07, 1.27]), non-white ethnicity (aOR), non-commercial insurance (aOR 1.21 [1.09, 1.33]), pre-admission cardiac disorder (aOR 1.21 [1.09, 1.34]), mechanical ventilation (aOR1.78 [1.57, 2.02]) and ICP monitoring (aOR1.68 [1.49, 1.89]). Compared to AIS, sICH (aOR 0.25 [0.22, 0.29]), SAH (aOR 0.36 [0.30, 0.43]), and TBI (aOR 0.19 [0.17, 0.24]) patients were less likely to receive cardiac investigation. Patients with troponin 25th-50th quartile (aOR 1.65 [1.10-2.47]), troponin 50th-75th quartile (aOR 1.79 [1.22-2.63]), troponin >75th quartile (aOR 2.18 [1.49-3.17]), BNP 50th-75th quartile (aOR 2.86 [1.28-6.40]), BNP >75th quartile (aOR 4.54 [2.09-9.85]), prolonged QTc (aOR 3.41 [2.28; 5.30]), and EF < 40% (aOR 2.47 [1.07; 5.14]) were more likely to be DNC. Patients with troponin 50th-75th quartile (aOR 1.77 [1.14-2.73]), troponin >75th quartile (aOR 1.81 [1.18-2.78]), and prolonged QTc (aOR 1.71 [1.39; 2.12]) were more likely to be associated with a transition to CMO. Patients with prolonged QTc (aOR 0.66 [0.58; 0.76]) were less likely to be discharged home. Conclusions : This large, single-center study demonstrates low rates of cardiac evaluations in TBI, SAH, and sICH compared to AIS. However, there are strong associations between electrocardiography, biomarkers of cardiac injury and heart failure, and echocardiography findings on clinical outcomes in patients with ABI. Findings need validation in a multicenter cohort.

Purpose: Uncorrected hearing loss can result in detrimental sequelae. Research addressing clinical presentation and genetic testing would inform clinical decision making., Method: A retrospective chart review of 96 patients aged 1 month to 46 years (median age = 6 years) diagnosed with hearing loss or deafness and who underwent genetic testing at University of Rochester Medical Center from 2011 to 2021. Chi-square and Fisher's exact tests examined the relationship between a diagnostic positive genetic test result and various characteristics of hearing loss, including congenital ( n = 52), noncongenital ( n = 34), prelingual ( n = 53), postlingual ( n = 33), progressive ( n = 13), not progressive ( n = 47), bilateral ( n = 67), unilateral ( n = 26), sensorineural ( n = 68), conductive ( n = 14), mixed ( n = 5), syndromic ( n = 10), and nonsyndromic ( n = 87) hearing loss. We also examined the number of patients with presence of developmental disabilities ( n = 35), having a first-degree relative with hearing loss ( n = 19), having hearing aids or cochlear implants ( n = 45), and having a multisystem presentation prior to diagnosis ( n = 45)., Results: Patients with sensorineural hearing loss (44.1%) had significantly more diagnostic positive results than those with mixed (0%) or conductive hearing loss (21.4%), p = .004. However, significantly fewer patients with disabilities (19.4%) had diagnostic positive tests than those without disabilities (43.3%), p < .05. More patients with a multisystem presentation were also found to have syndromic causes of hearing loss (23.3%) than patients who did not have a multisystem presentation, p < .05., Conclusions: Our study suggests a significant association between sensorineural type of hearing loss and a diagnostic positive genetic test result, while the presence of disabilities was significantly associated with a nondiagnostic genetic test result. Knowledge of these findings is critical for understanding the cause of the hearing loss, identifying other associated symptoms, and determining risk to family members.

Background: To examine the association between external ventricular drain (EVD) placement, critical care utilization, complications, and clinical outcomes in hospitalized adults with spontaneous subarachnoid hemorrhage (SAH)., Methods: A single-center retrospective study included SAH patients 18 years and older, admitted between 1 January 2014 and 31 December 2022. The exposure variable was EVD. The primary outcomes of interest were (1) early mortality (<72 h), (2) overall mortality, (3) improvement in modified-World Federation of Neurological Surgeons (m-WFNSs) grade between admission and discharge, and (4) discharge to home at the end of the hospital stay. We adjusted for admission m-WFNS grade, age, sex, race/ethnicity, intraventricular hemorrhage, aneurysmal cause of SAH, mechanical ventilation, critical care utilization, and complications within a multivariable analysis. We reported adjusted odds ratios (aORs) and 95% confidence intervals (CI)., Results: The study sample included 1346 patients: 18% (n = 243) were between the ages of 18 and 44 years, 48% (n = 645) were between the age of 45-64 years, and 34% (n = 458) were 65 years and older, with other statistics of females (56%, n = 756), m-WFNS I-III (57%, n = 762), m-WFNS IV-V (43%, n = 584), 51% mechanically ventilated, 76% White (n = 680), and 86% English-speaking (n = 1158). Early mortality occurred in 11% (n = 142). Overall mortality was 21% (n = 278), 53% (n = 707) were discharged to their home, and 25% (n = 331) improved their m-WFNS between admission and discharge. Altogether, 54% (n = 731) received EVD placement. After adjusting for covariates, the results of the multivariable analysis demonstrated that EVD placement was associated with reduced early mortality (aOR 0.21 [0.14, 0.33]), an improvement in m-WFNS grade (aOR 2.06 [1.42, 2.99]) but not associated with overall mortality (aOR 0.69 [0.47, 1.00]) or being discharged home at the end of the hospital stay (aOR 1.00 [0.74, 1.36]). EVD was associated with a higher rate of ventilator-associated pneumonia (aOR 2.32 [1.03, 5.23]), delirium (aOR 1.56 [1.05, 2.32]), and a longer ICU (aOR 1.33 [1.29;1.36]) and hospital length of stay (aOR 1.09 [1.07;1.10]). Critical care utilization was also higher in patients with EVD compared to those without., Conclusions: The study suggests that EVD placement in hospitalized adults with spontaneous subarachnoid hemorrhage (SAH) is associated with reduced early mortality and improved neurological recovery, albeit with higher critical care utilization and complications. These findings emphasize the potential clinical benefits of EVD placement in managing SAH. However, further research and prospective studies may be necessary to validate these results and provide a more comprehensive understanding of the factors influencing clinical outcomes in SAH.

Background and Objectives : We analyzed delirium testing, delirium prevalence, critical care associations outcomes at the time of hospital discharge in patients with acute brain injury (ABI) due to acute ischemic stroke (AIS), non-traumatic subarachnoid hemorrhage (SAH), non-traumatic intraparenchymal hemorrhage (IPH), and traumatic brain injury (TBI) admitted to an intensive care unit. Materials and Methods : We examined the frequency of assessment for delirium using the Confusion Assessment Method for the intensive care unit. We assessed delirium testing frequency, associated factors, positive test outcomes, and their correlations with clinical care, including nonpharmacological interventions and pain, agitation, and distress management. Results : Amongst 11,322 patients with ABI, delirium was tested in 8220 (726%). Compared to patients 18-44 years of age, patients 65-79 years (aOR 0.79 [0.69, 0.90]), and those 80 years and older (aOR 0.58 [0.50, 0.68]) were less likely to undergo delirium testing. Compared to English-speaking patients, non-English-speaking patients (aOR 0.73 [0.64, 0.84]) were less likely to undergo delirium testing. Amongst 8220, 2217 (27.2%) tested positive for delirium. For every day in the ICU, the odds of testing positive for delirium increased by 1.11 [0.10, 0.12]. Delirium was highest in those 80 years and older (aOR 3.18 [2.59, 3.90]). Delirium was associated with critical care resource utilization and with significant odds of mortality (aOR 7.26 [6.07, 8.70] at the time of hospital discharge. Conclusions : In conclusion, we find that seven out of ten patients in the neurocritical care unit are tested for delirium, and approximately two out of every five patients test positive for delirium. We demonstrate disparities in delirium testing by age and preferred language, identified high-risk subgroups, and the association between delirium, critical care resource use, complications, discharge GCS, and disposition. Prioritizing equitable testing and diagnosis, especially for elderly and non-English-speaking patients, is crucial for delivering quality care to this vulnerable group.

The calcium/calmodulin-dependent protein kinase type 2 (CAMK2) family consists of four different isozymes, encoded by four different genes-CAMK2A, CAMK2B, CAMK2G, and CAMK2D-of which the first three have been associated recently with neurodevelopmental disorders. CAMK2D is one of the major CAMK2 proteins expressed in the heart and has been associated with cardiac anomalies. Although this CAMK2 isoform is also known to be one of the major CAMK2 subtypes expressed during early brain development, it has never been linked with neurodevelopmental disorders until now. Here we show that CAMK2D plays an important role in neurodevelopment not only in mice but also in humans. We identified eight individuals harboring heterozygous variants in CAMK2D who display symptoms of intellectual disability, delayed speech, behavioral problems, and dilated cardiomyopathy. The majority of the variants tested lead to a gain of function (GoF), which appears to cause both neurological problems and dilated cardiomyopathy. In contrast, loss-of-function (LoF) variants appear to induce only neurological symptoms. Together, we describe a cohort of individuals with neurodevelopmental disorders and cardiac anomalies, harboring pathogenic variants in CAMK2D, confirming an important role for the CAMK2D isozyme in both heart and brain function., Competing Interests: Declaration of interests The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories. A.B. and I.M.W. are employees of GeneDx, LLC; H.S. is a consultant for Vasa Therapeutics (Poland)., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background Managing neurocritical care patients encompasses many complex challenges, necessitating specialized care and continuous quality improvement efforts. In recent years, the focus on enhancing patient outcomes in neurocritical care may have led to the development of dedicated quality improvement programs. These programs are designed to systematically evaluate and refine care practices, aligning them with the latest clinical guidelines and research findings. Objective To describe the structure, processes, and outcomes of a dedicated Neurocritical Care Quality Improvement Program (NCC-QIP) at Harborview Medical Center, United States; a quaternary academic medical center, level I trauma, and a comprehensive stroke center. Materials and methods We describe the development of the NCC-QIP, its structure, function, challenges, and evolution. We examine our performance with several NCC-QI quality measures as proposed by the Joint Commission, the American Association of Neurology, and the Neurocritical Care Society, self-reported quality improvement (QI) concerns and QI initiatives undertaken because of the information obtained during our event/measure reporting process for patients admitted between 1/1/2014 and 06/30/2023. Results The NCC-QI reviewed data from 20,218 patients; mean age 57.9 (standard deviation 18.1) years, 56% (n=11,326) males, with acute ischemic stroke (AIS; 22.3%, n=4506), spontaneous intracerebral hemorrhage (ICH; 14.8%, n=2,996), spontaneous subarachnoid hemorrhage (SAH; 8.9%, n=1804), and traumatic brain injury (TBI; 16.6%, n=3352) among other admissions, 37.4% (n=7,559) were mechanically ventilated, and 13.6% (n=2,753) received an intracranial pressure monitor. The median intensive care unit length of stay was two days (Quartile 1-Quartile 3: 2-5 days), and the median hospital length of stay was seven days (Quartile 1-Quartile 3: 3-14 days); 53.9% (n=10,907) were discharged home while 11.4% (2,309) died. The three most commonly reported QI concerns were related to care coordination/communication/handoff (40.4%, n=283), medication-related concerns (14.9%, n=104), and equipment/devices-related concerns (11.7%, n=82). Hospital-acquired infections were in the form of ventilator-associated pneumonia (16.3%, n=419/2562), ventriculostomy catheter-associated infections (4%, n=102/2246), and deep venous thrombosis/pulmonary embolism (3.2%, n=647). The quality metrics documentation was as follows: nimodipine after SAH (99.8%, 1802/1810), Hunt and Hess score (36%, n=650/1804), and ICH score (58.4% n=1752/2996). In comparison, 72% (n=3244/4506) of patients with AIS had a documented National Institute of Health Stroke Scale. Admission Glasgow Coma Score was recorded in 99% of patients with SAH, ICH, and TBI. Educational modules were implemented in response to event reporting. Conclusion A dedicated NCC-QIP can be successfully implemented at a quaternary medical medical center. It is possible to monitor and review a large volume of neurocritical care patients, The three most reported NCC-QI concerns may be related to care coordination-communication/handoff, medication-related concerns, and equipment/devices-related complications. The documentation of illness severity scores and stroke measures depends upon the type of measure and ability to reliably and accurately abstract and can be challenging. The quality improvement process can be enhanced by educational modules that reinforce quality and safety., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2024, Lele et al.)

Purpose: BCL11B-related disorder (BCL11B-RD) arises from rare genetic variants within the BCL11B gene, resulting in a distinctive clinical spectrum encompassing syndromic neurodevelopmental disorder, with or without intellectual disability, associated with facial features and impaired immune function. This study presents an in-depth clinico-biological analysis of 20 newly reported individuals with BCL11B-RD, coupled with a characterization of genome-wide DNA methylation patterns of this genetic condition., Methods: Through an international collaboration, clinical and molecular data from 20 individuals were systematically gathered, and a comparative analysis was conducted between this series and existing literature. We further scrutinized peripheral blood DNA methylation profile of individuals with BCL11B-RD, contrasting them with healthy controls and other neurodevelopmental disorders marked by established episignature., Results: Our findings unveil rarely documented clinical manifestations, notably including Rubinstein-Taybi-like facial features, craniosynostosis, and autoimmune disorders, all manifesting within the realm of BCL11B-RD. We refine the intricacies of T cell compartment alterations of BCL11B-RD, revealing decreased levels naive CD4 + T cells and recent thymic emigrants while concurrently observing an elevated proportion of effector-memory expressing CD45RA CD8 + T cells (TEMRA). Finally, a distinct DNA methylation episignature exclusive to BCL11B-RD is unveiled., Conclusion: This study serves to enrich our comprehension of the clinico-biological landscape of BCL11B-RD, potentially furnishing a more precise framework for diagnosis and follow-up of individuals carrying pathogenic BCL11B variant. Moreover, the identification of a unique DNA methylation episignature offers a valuable diagnosis tool for BCL11B-RD, thereby facilitating routine clinical practice by empowering physicians to reevaluate variants of uncertain significance within the BCL11B gene., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. All rights reserved.)

Background: Electronic health records (EHR) contain large volumes of unstructured free-form text notes that richly describe a patient's health and medical comorbidities. It is unclear if perioperative risk stratification can be performed directly from these notes without manual data extraction. We conduct a feasibility study using natural language processing (NLP) to predict the American Society of Anesthesiologists Physical Status Classification (ASA-PS) as a surrogate measure for perioperative risk. We explore prediction performance using four different model types and compare the use of different note sections versus the whole note. We use Shapley values to explain model predictions and analyze disagreement between model and human anesthesiologist predictions., Methods: Single-center retrospective cohort analysis of EHR notes from patients undergoing procedures with anesthesia care spanning all procedural specialties during a 5 year period who were not assigned ASA VI and also had a preoperative evaluation note filed within 90 days prior to the procedure. NLP models were trained for each combination of 4 models and 8 text snippets from notes. Model performance was compared using area under the receiver operating characteristic curve (AUROC) and area under the precision recall curve (AUPRC). Shapley values were used to explain model predictions. Error analysis and model explanation using Shapley values was conducted for the best performing model., Results: Final dataset includes 38,566 patients undergoing 61,503 procedures with anesthesia care. Prevalence of ASA-PS was 8.81% for ASA I, 31.4% for ASA II, 43.25% for ASA III, and 16.54% for ASA IV-V. The best performing models were the BioClinicalBERT model on the truncated note task (macro-average AUROC 0.845) and the fastText model on the full note task (macro-average AUROC 0.865). Shapley values reveal human-interpretable model predictions. Error analysis reveals that some original ASA-PS assignments may be incorrect and the model is making a reasonable prediction in these cases., Conclusions: Text classification models can accurately predict a patient's illness severity using only free-form text descriptions of patients without any manual data extraction. They can be an additional patient safety tool in the perioperative setting and reduce manual chart review for medical billing. Shapley feature attributions produce explanations that logically support model predictions and are understandable to clinicians., (© 2023. BioMed Central Ltd., part of Springer Nature.)

We examined the associations between the Neurological Pupillary Index (NPi) and disposition at hospital discharge in patients admitted to the neurocritical care unit with acute brain injury (ABI) due to acute ischemic stroke (AIS), spontaneous intracerebral hemorrhage (sICH), aneurysmal subarachnoid hemorrhage (SAH), and traumatic brain injury (TBI). The primary outcome was discharge disposition (home/acute rehabilitation vs. death/hospice/skilled nursing facility). Secondary outcomes were tracheostomy tube placement and transition to comfort measures. Among 2258 patients who received serial NPi assessments within the first seven days of ICU admission, 47.7% (n = 1078) demonstrated NPi ≥ 3 on initial and final assessments, 30.1% (n = 680) had initial NPI < 3 that never improved, 19% (n = 430) had initial NPi ≥ 3, which subsequently worsened to <3 and never recovered, and 3.1% (n = 70) had initial NPi < 3, which improved to ≥3. After adjusting for age, sex, admitting diagnosis, admission Glasgow Coma Scale score, craniotomy/craniectomy, and hyperosmolar therapy, NPi values that remained <3 or worsened from ≥3 to <3 were associated with poor outcomes (adjusted odds ratio, aOR 2.58, 95% CI [2.03; 3.28]), placement of a tracheostomy tube (aOR 1.58, 95% CI [1.13; 2.22]), and transition to comfort measures only (aOR 2.12, 95% CI [1.67; 2.70]). Our study suggests that serial NPi assessments during the first seven days of ICU admission may be helpful in predicting outcomes and guiding clinical decision-making in patients with ABI. Further studies are needed to evaluate the potential benefit of interventions to improve NPi trends in this population.

Objective To describe Harborview Medical Center's experience with the involvement of caseworker cultural mediators (CCM) for patients requiring neurocritical care. Methods Using univariate and multivariate analysis (model adjusted for age, Glasgow Coma Scale score (GCS), Sequential Organ Failure Assessment (SOFA) Scores, mechanical ventilation, transition to comfort measures only (CMO), and death by neurologic criteria), we examined CCM team members' involvement in the care of Amharic/Cambodian/Khmer/Somali/Spanish/Vietnamese patients admitted to our neurocritical care service between 2014-2022, factors associated with CCM utilization, and changes in CCM utilization after a QI initiative was implemented in 2020 to encourage healthcare providers to consult the CCM team. Results Compared to eligible patients (n=827) who did not receive CCM referral, patients with CCM involvement (n=121) were younger (49 [interquartile range, IQR 38,63] vs. 56 [IQR 42,68] years, p = 0.002), had greater illness severity (admission GCS 8.5 [IQR 3,14] vs. 14 [IQR 7,15], p < 0.001, SOFA scores (5 [IQR 2,8] vs. 4 [IQR2,6], p = 0.007), and more frequently required mechanical ventilation (67% vs. 40%, odds ratio, OR 3.07, 95% CI 2.06,4.64), with higher all-cause mortality (20% vs. 12%, RR 1.83, 95% CI 1.09, 2.95), and with a higher rate of transition to CMO (11.6% vs. 6.2%, OR 2.00, 95% CI 1.03;3.66). The CCM QI initiative was independently associated with increased CCM involvement (aOR 4.22, 95% CI [2.32;7.66]). Overall, 4/10 attempts made by CCMs to reach out to the family to provide support were declined by the family. CCMs reported providing cultural/emotional support (n=96, 79%), end-of-life counseling (n=16, 13%), conflict mediation (n=15, 12.4%), and facilitating goals of care meetings (n=4, 3.3%). Conclusions Among eligible patients, CCM consultations appeared to occur in patients with higher disease severity. Our QI initiative increased CCM involvement., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2023, Lele et al.)

Objectives: The clinical significance of hypophosphatemia in cardiac surgery has not been investigated extensively. The aim of this study was to evaluate the association of postoperative hypophosphatemia and lactic acidosis in cardiac surgery patients at the time of intensive care unit (ICU) admission., Design: A retrospective cohort study., Setting: At a single academic center., Participants: Patients who underwent nontransplant cardiac surgery with cardiopulmonary bypass between August 2009 and December 2020., Interventions: None., Measurements and Main Results: Serum phosphate and lactate levels were measured upon ICU admission in patients undergoing nontransplant cardiac surgery with cardiopulmonary bypass. There were 681 patients in the low-phosphate (<2.5 mg/dL) group and 2,579 patients in the normal phosphate group (2.5-4.5 mg/dL). A higher proportion of patients in the low phosphate group (26%; 179 of 681; 95% CI: 23-30) had severe lactic acidosis compared to patients in the normal phosphate group (16%; 417 of 2,579; 95% CI: 15-18). In an unadjusted logistic regression model, patients in the low phosphate group had 1.9-times the odds of having severe lactic acidosis (serum lactate ≥4.0 mmol/L) when compared to patients in the normal phosphate group (95% CI: 1.5-2.3), and still 1.4-times the odds (95% CI: 1.1-1.7) after adjusting for several possible confounders., Conclusions: Hypophosphatemia is associated with lactic acidosis in the immediate postoperative period in cardiac surgery patients. Future studies will need to investigate it as a potential treatment target for lactic acidosis., Competing Interests: Conflict of Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Alternative polyadenylation (APA) creates distinct transcripts from the same gene by cleaving the pre-mRNA at poly(A) sites that can lie within the 3' untranslated region (3'UTR), introns, or exons. Most studies focus on APA within the 3'UTR; however, here, we show that CPSF6 insufficiency alters protein levels and causes a developmental syndrome by deregulating APA throughout the transcript. In neonatal humans and zebrafish larvae, CPSF6 insufficiency shifts poly(A) site usage between the 3'UTR and internal sites in a pathway-specific manner. Genes associated with neuronal function undergo mostly intronic APA, reducing their expression, while genes associated with heart and skeletal function mostly undergo 3'UTR APA and are up-regulated. This suggests that, under healthy conditions, cells toggle between internal and 3'UTR APA to modulate protein expression.

Background and objective: There is no report of the rate of opioid prescription at the time of hospital discharge, which may be associated with various patient and procedure-related factors. This study examined the prevalence and factors associated with prescribing opioids for head/neck pain after elective craniotomy for tumor resection/vascular repair. Methods: We performed a retrospective cohort study on adults undergoing elective craniotomy for tumor resection/vascular repair at a large quaternary-care hospital. We used univariable and multivariable analysis to examine the prevalence and factors (pre-operative, intraoperative, and postoperative) associated with prescribing opioids at the time of hospital discharge. We also examined the factors associated with discharge oral morphine equivalent use. Results: The study sample comprised 273 patients with a median age of 54 years [IQR 41,65], 173 females (63%), 174 (63.7%) tumor resections, and 99 (36.2%) vascular repairs. The majority (n = 264, 96.7%) received opioids postoperatively. The opiate prescription rates were 72% (n = 196/273) at hospital discharge, 23% (19/83) at neurosurgical clinical visits within 30 days of the procedure, and 2.4% (2/83) after 30 days from the procedure. The median oral morphine equivalent (OME) at discharge use was 300 [IQR 175,600]. Patients were discharged with a median supply of 5 days [IQR 3,7]. On multivariable analysis, opioid prescription at hospital discharge was associated with pre-existent chronic pain (adjusted odds ratio, aOR 1.87 [1.06,3.29], p = 0.03) and time from surgery to hospital discharge (compared to patients discharged within days 1−4 postoperatively, patients discharged between days 5−12 (aOR 0.3, 95% CI [0.15; 0.59], p = 0.0005), discharged at 12 days and later (aOR 0.17, 95% CI [0.07; 0.39], p < 0.001)). There was a linear relationship between the first 24 h OME (p < 0.001), daily OME (p < 0.001), hospital OME (p < 0.001), and discharge OME. Conclusions: This single-center study finds that at the time of hospital discharge, opioids are prescribed for head/neck pain in as many as seven out of ten patients after elective craniotomy. A history of chronic pain and time from surgery to discharge may be associated with opiate prescriptions. Discharge OME may be associated with first 24-h, daily OME, and hospital OME use. Findings need further evaluation in a large multicenter sample. The findings are important to consider as there is growing interest in an early discharge after elective craniotomy.

To investigate the pandemic's impact on critically ill patients with neurological emergencies, we compared care metrics and outcomes of patients with severe acute brain injury (SABI) before and during the initial COVID-19 surge at our institution. We included adult patients with SABI during two separate three-month time periods: 'pre-COVID vs COVID'. We further stratified the COVID cohort to characterize outcomes in patients requiring COVID-19 precautions (Patient Under Investigation, 'PUI'). The primary endpoint was in-hospital mortality; secondary endpoints included length of stay (LOS), diagnostic studies performed, time to emergent decompressive craniectomies (DCHC), ventilator management, and end-of-life care. We included 394 patients and found the overall number of admissions for SABI declined by 29 % during COVID (pre-COVID n = 231 vs COVID, n = 163). Our primary outcome of mortality and most secondary outcomes were similar between study periods. There were more frequent extubation attempts (72.1 % vs 76 %) and the mean time to extubation was shorter during COVID (55.5 h vs 38.2 h). The ICU LOS (6.10 days vs 4.69 days) and hospital LOS (15.32 days vs 11.74 days) was shorter during COVID. More PUIs died than non-PUIs (51.7 % vs 11.2 %), but when adjusted for markers of illness severity, this was not significant. We demonstrate the ability to maintain a consistent care delivery for patients with SABI during the pandemic at our institution. PUIs represent a population with higher illness severity at risk for delays in care. Multicenter, longitudinal studies are needed to explore the impact of the pandemic on patients with acute neurological emergencies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Claire Creutzfeldt has received research support from the NINDS (K23 NS099421). Abhijit Lele receives ongoing salary support from LifeCenter Northwest. Sarah Livesay receives consulting fees via Stroke Challenges through Lombardi Hill. Sherry Chou has received research support from the NIH (UL1 TR001857, R21NS113037) and University of Pittsburgh Dean’s Faculty Achievement Award as well as has a leadership role in the Neurocritical Care Society. Robert Bonow received in-kind research support from Butterfly Network. The remaining authors have no relevant financial disclosures or conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: The objective is to examine the relationship between transcranial Doppler cerebral vasospasm (TCD-vasospasm), and clinical outcomes in aneurysmal subarachnoid hemorrhage (aSAH)., Methods: In a retrospective cohort study, using univariate and multivariate analysis, we examined the association between TCD-vasospasm (defined as Lindegaard ratio >3) and patient's ability to ambulate without assistance, the need for tracheostomy and gastrostomy tube placement, and the likelihood of being discharged home from the hospital., Results: We studied 346 patients with aSAH; median age 55 years (Interquartile range IQR 46,64), median Hunt and Hess 3 [IQR 1-5]. Overall, 68.6% (n=238) had TCD-vasospasm, and 28% (n=97) had delayed cerebral ischemia. At hospital discharge, 54.3% (n=188) were able to walk without assistance, 5.8% (n=20) had received a tracheostomy, and 12% (n=42) had received a gastrostomy tube. Fifty-three percent (n=183) were discharged directly from the hospital to their home. TCD-vasospasm was not associated with ambulation without assistance at discharge (adjusted odds ratio, aOR 0.54, 95% 0.19,1.45), tracheostomy placement (aOR 2.04, 95% 0.23,18.43), gastrostomy tube placement (aOR 0.95, 95% CI 0.28,3.26), discharge to home (aOR 0.36, 95% CI 0.11,1.23)., Conclusion: This single-center retrospective study finds that TCD-vasospasm is not associated with clinical outcomes such as ambulation without assistance, discharge to home from the hospital, tracheostomy, and gastrostomy feeding tube placement. Routine screening for cerebral vasospasm and its impact on vasospasm diagnostic and therapeutic interventions and their associations with improved clinical outcomes warrant an evaluation in large, prospective, case-controlled, multi-center studies., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2022, Lele et al.)

Background: In medical genetics, discovery and characterization of disease trait contributory genes and alleles depends on genetic reasoning, study design, and patient ascertainment; we suggest a segmental haploid genetics approach to enhance gene discovery and molecular diagnostics., Methods: We constructed a genome-wide map for nonallelic homologous recombination (NAHR)-mediated recurrent genomic deletions and used this map to estimate population frequencies of NAHR deletions based on large-scale population cohorts and region-specific studies. We calculated recessive disease carrier burden using high-quality pathogenic or likely pathogenic variants from ClinVar and gnomAD. We developed a NIRD (NAHR deletion Impact to Recessive Disease) score for recessive disorders by quantifying the contribution of NAHR deletion to the overall allele load that enumerated all pairwise combinations of disease-causing alleles; we used a Punnett square approach based on an assumption of random mating. Literature mining was conducted to identify all reported patients with defects in a gene with a high NIRD score; meta-analysis was performed on these patients to estimate the representation of NAHR deletions in recessive traits from contemporary human genomics studies. Retrospective analyses of extant clinical exome sequencing (cES) were performed for novel rare recessive disease trait gene and allele discovery from individuals with NAHR deletions., Results: We present novel genomic insights regarding the genome-wide impact of NAHR recurrent segmental variants on recessive disease burden; we demonstrate the utility of NAHR recurrent deletions to enhance discovery in the challenging context of autosomal recessive (AR) traits and biallelic variation. Computational results demonstrate new mutations mediated by NAHR, involving recurrent deletions at 30 genomic regions, likely drive recessive disease burden for over 74% of loci within these segmental deletions or at least 2% of loci genome-wide. Meta-analyses on 170 literature-reported patients implicate that NAHR deletions are depleted from the ascertained pool of AR trait alleles. Exome reanalysis of personal genomes from subjects harboring recurrent deletions uncovered new disease-contributing variants in genes including COX10, ERCC6, PRRT2, and OTUD7A., Conclusions: Our results demonstrate that genomic sequencing of personal genomes with NAHR deletions could dramatically improve allele and gene discovery and enhance clinical molecular diagnosis. Moreover, results suggest NAHR events could potentially enable human haploid genetic screens as an approach to experimental inquiry into disease biology., (© 2022. The Author(s).)

Objectives: Literature supporting best practice of perioperative buprenorphine management for opioid use disorder is evolving with more recent studies trending toward maintenance of home dose. To guide treatment protocols at our institution, we evaluated patients taking medication for opioid use disorder (MOUD) undergoing similar surgeries. Patients were maintained on either their outpatient buprenorphine or methadone., Patients and Participants: Data were collected on 46 patients maintained on buprenorphine MOUD who underwent surgery. A subset of these patients (n = 24) was compared with 24 patients maintained on methadone MOUD, matched on surgical procedure, admission date, age, and sex., Design: This is a retrospective matched control study., Setting: An academic, tertiary, Level 1 trauma center., Main Outcome Measures: Primary outcomes were post-operative opioid use and post-anesthesia care unit (PACU) length of stay., Results: No significant differences in demographic characteristics, physical status, comorbid psychiatric diagnoses, or illicit substance use history were observed between patient groups. A higher proportion of patients taking methadone was admitted due to infection (41.7 percent vs 16.7 percent, p = 0.031) and underwent nonelective surgery (75.0 percent vs 45.8 percent, p = 0.039). No significant differences were observed between patients taking buprenorphine versus methadone with respect to PACU length of stay, post-operative opioid consumption, time-to-transition to oral opioids, or discharge opioid prescriptions. Patients taking buprenorphine were more likely to receive intravenous lidocaine (25.0 percent vs 0.0 percent, p = 0.031) and ketamine (83.3 percent vs 54.2 percent, p = 0.039)., Conclusion: Findings from this study support accumulating evidence that patients should be maintained on buprenorphine MOUD throughout the perioperative period.

MEIS2 (Meis homeobox 2) encodes a homeobox protein in the three amino acid loop extension (TALE) family of highly conserved homeodomain-containing transcription regulators important for development. MEIS2 deletions/mutations have been associated with cleft lip/palate, dysmorphic facial features, cardiac defects, as well as intellectual disability at a variable severity. Here we report on one familial case that two affected siblings carry the same non-mosaic ~ 423 kb genomic deletion at 15q14 encompassing the entirety of CDIN1 and the last three exons (ex. 10, 11, 12) of the MEIS2 gene, while their unaffected father is mosaic for the same deletion in about 10% lymphocytes. Both siblings presented with mild developmental delay and bifid uvula, while no congenital cardiac abnormalities were identified. The elder sister also showed syncopal episodes and mild speech delay and the father had atrial septal defects. This is the first report showing multiple family members inherit a genomic deletion resulting in a MEIS2 partial truncation from a mosaic parent. Taken all together, this study has important implications for genetic counseling regarding recurrence risk and also points to the importance of offering MEIS2 gene tests covering both point mutations and microdeletions to individuals with milder bifid uvula and developmental delay., (© 2021. The Author(s).)

The histone H3 variant H3.3, encoded by two genes H3-3A and H3-3B, can replace canonical isoforms H3.1 and H3.2. H3.3 is important in chromatin compaction, early embryonic development, and lineage commitment. The role of H3.3 in somatic cancers has been studied extensively, but its association with a congenital disorder has emerged just recently. Here we report eleven de novo missense variants and one de novo stop-loss variant in H3-3A (n = 6) and H3-3B (n = 6) from Baylor Genetics exome cohort (n = 11) and Matchmaker Exchange (n = 1), of which detailed phenotyping was conducted for 10 individuals (H3-3A = 4 and H3-3B = 6) that showed major phenotypes including global developmental delay, short stature, failure to thrive, dysmorphic facial features, structural brain abnormalities, hypotonia, and visual impairment. Three variant constructs (p.R129H, p.M121I, and p.I52N) showed significant decrease in protein expression, while one variant (p.R41C) accumulated at greater levels than wild-type control. One H3.3 variant construct (p.R129H) was found to have stronger interaction with the chaperone death domain-associated protein 6., (© 2021. The Author(s).)

Nance-Horan syndrome (NHS) is a rare X-linked dominant disorder caused by mutation in the NHS gene on chromosome Xp22.13. (OMIM 302350). Classic NHS manifested in males is characterized by congenital cataracts, dental anomalies, dysmorphic facial features and occasionally intellectual disability. Females typically have a milder presentation. The majority of reported cases of NHS are the result of nonsense mutations and small deletions. Isolated X-linked congenital cataract is caused by non-recurrent rearrangement-associated aberrant NHS transcription. Classic NHS in females associated with gene disruption by balanced X-autosome translocation has been infrequently reported. We present a familial NHS associated with translocation t(X;19) (Xp22.13;q13.1). The proband, a 28-year-old female, presented with intellectual disability, dysmorphic features, short stature, primary amenorrhea, cleft palate, and horseshoe kidney, but no NHS phenotype. A karyotype and chromosome microarray analysis (CMA) revealed partial monosomy Xp/partial trisomy 19q with the breakpoint at Xp22.13 disrupting the NHS gene. Family history revealed congenital cataracts and glaucoma in the patient's mother, and congenital cataracts in maternal half-sister and maternal grandmother. The same balanced translocation t(X;19) was subsequently identified in both the mother and maternal half-sister, and further clinical evaluation of the maternal half-sister made a diagnosis of NHS. This study describes the clinical implication of NHS gene disruption due to balanced X-autosome translocations as a unique mechanism causing Nance-Horan syndrome, refines dose effects of NHS on disease presentation and phenotype expressivity, and justifies consideration of karyotype and fluorescence in situ hybridization (FISH) analysis for female patients with familial NHS if single-gene analysis of NHS is negative., (© 2021. The Author(s).)

Objectives: To evaluate factors predictive of clinical progression among coronavirus disease 2019 patients following admission, and whether continuous, automated assessments of patient status may contribute to optimal monitoring and management., Design: Retrospective cohort for algorithm training, testing, and validation., Setting: Eight hospitals across two geographically distinct regions., Patients: Two-thousand fifteen hospitalized coronavirus disease 2019-positive patients., Interventions: None., Measurements and Main Results: Anticipating Respiratory failure in Coronavirus disease (ARC), a clinically interpretable, continuously monitoring prognostic model of acute respiratory failure in hospitalized coronavirus disease 2019 patients, was developed and validated. An analysis of the most important clinical predictors aligns with key risk factors identified by other investigators but contributes new insights regarding the time at which key factors first begin to exhibit aberrency and distinguishes features predictive of acute respiratory failure in coronavirus disease 2019 versus pneumonia caused by other types of infection. Departing from prior work, ARC was designed to update continuously over time as new observations (vitals and laboratory test results) are recorded in the electronic health record. Validation against data from two geographically distinct health systems showed that the proposed model achieved 75% specificity and 77% sensitivity and predicted acute respiratory failure at a median time of 32 hours prior to onset. Over 80% of true-positive alerts occurred in non-ICU settings., Conclusions: Patients admitted to non-ICU environments with coronavirus disease 2019 are at ongoing risk of clinical progression to severe disease, yet it is challenging to anticipate which patients will develop acute respiratory failure. A continuously monitoring prognostic model has potential to facilitate anticipatory rather than reactive approaches to escalation of care (e.g., earlier initiation of treatments for severe disease or structured monitoring and therapeutic interventions for high-risk patients)., Competing Interests: Dr. Saria is a founder of, and holds equity in, Bayesian Health. Dr. Saria also holds equity in and is a member of the scientific advisory board for PatientPing. This arrangement has been reviewed and approved by Johns Hopkins University in accordance with its conflict-of-interest policies. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS., (© 2021 Wiley Periodicals LLC.)

Objectives: The objective of this retrospective practice-based study was to evaluate the survival of molar teeth and endodontic success after complex endodontic treatment up to 89 months., Methods: Endodontically (Endodontic Treatment Classification (ETC) scores II and III) treated first and second molars treated between January 2011-October 2017 within a referral setting were included. Open apices, combined surgical treatment, ETC score I, patients <18 years or with an ASA-score >2 were excluded. Cumulative survival estimates and Cox regression analysis were performed for tooth survival and endodontic healing according to the Glossary of Endodontic Terms. Restoration quality was assessed using the FDI criteria. Alpha was set at 0.05., Results: 279 endodontically treated molars in 245 patients were included for survival analysis and 268 molars for endodontic success. After 89 months, the cumulative survival was 91.7 % [95 % CI: 86.8 %-94.9 %]. Absence of adjacent teeth and deviance in root canal morphology significantly decreased the probability of tooth survival. Cumulative endododontic healing rates after 48 and 89 months were 82.2 % [95 %CI: 75.7 %-87.1 %] and 51.1 [95 % CI: 20.2 %-75.5 %] respectively. Deviance in root canal morphology and inadequate coronal seal significantly decreased the probability of endodontic healing. Indirect restorations obtained higher esthetic and biological FDI scores, however no difference between direct and indirect restorations was found concerning the functional FDI score., Conclusions: After 89 months, cumulative survival of molars in need of complex endodontic treatment was 91.7 % [95 % CI: 86.8 %-94.9 %]., Clinical Significance: Within daily clinical practice, the dilemma of performing a complex endodontic (re)treatment or to explore other treatment options for molar teeth in need of reintervention is still urgent. Tooth survival of molar teeth with complex endodontic (re)treatment seems satisfactory up to 89 months., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To assess the functional independence of a group of patients with mucopolysaccharidosis using the Functional Independence Measure as a tool that accomplishes this purpose., Methods: This is a cross-sectional study of patients with mucopolysaccharidosis. Our data was collected between June 2015 and July 2016. In addition to history of present illness and physical examination each study participant was asked to answer a questionnaire to specifically evaluate their functional independence using the functional independence measure. the internal consistency of the functional independence measure was assessed using Cronbach's alpha coefficient., Results: We collected data on 20 patients with mucopolysaccharidosis. The average age was 10.8 (8.67-13.03) years, the average weight was 23.6 (19.91-27.37) kg and the average height was 1 (0.83-1.17) m. The most prevalent type of mucopolysaccharidosis in the study was type VI (n= 14). The average total functional independence measure score was 104.4 (97.61-111.19), the average for the mobility domain was 73.50 (68.22-78.78) and the average for the cognitive function domain was 30.90 (28.68-33.13). The internal consistency of the entire questionnaire was 0.859, with values of 0.966 for the mobility domain and 0.624 for the cognitive function domain., Conclusion: The lowest functional independence measure scores were obtained in the following sub-domains: self-care, locomotion and cognitive function. The functional independence measure questionnaire demonstrated internal consistency for the evaluation of functional independence in patients with mucopolysaccharidosis, being able to value all the affected sub-domains separately., (Copyright © 2020 Colombia Medica.)

Background: The FOXG1 gene plays a vital role in mammalian brain differentiation and development. Intra- and intergenic mutations resulting in loss of function or altered expression of the FOXG1 gene cause FOXG1 syndrome. The hallmarks of this syndrome are severe developmental delay with absent verbal language, post-natal growth restriction, post-natal microcephaly, and a recognizable movement disorder characterized by chorea and dystonia., Case Presentation: Here we describe a case of a 7-year-old male patient found to have a de novo balanced translocation between chromosome 3 at band 3q14.1 and chromosome 14 at band 14q12 via G-banding chromosome and Fluorescence In Situ Hybridization (FISH) analyses. This rearrangement disrupts the proximity of FOXG1 to a previously described smallest region of deletion overlap (SRO), likely resulting in haploinsufficiency., Conclusions: This case adds to the growing body of literature implicating chromosomal structural variants in the manifestation of this disorder and highlights the vital role of cis-acting regulatory elements in the normal expression of this gene. Finally, we propose a protocol for reflex FISH analysis to improve diagnostic efficiency for patients with suspected FOXG1 syndrome.

Opioids play a critical role in acute postoperative pain management. Our objective was to develop machine learning models to predict postoperative opioid requirements in patients undergoing ambulatory surgery. To develop the models, we used a perioperative dataset of 13,700 patients (≥ 18 years) undergoing ambulatory surgery between the years 2016-2018. The data, comprising of patient, procedure and provider factors that could influence postoperative pain and opioid requirements, was randomly split into training (80%) and validation (20%) datasets. Machine learning models of different classes were developed to predict categorized levels of postoperative opioid requirements using the training dataset and then evaluated on the validation dataset. Prediction accuracy was used to differentiate model performances. The five types of models that were developed returned the following accuracies at two different stages of surgery: 1) Prior to surgery-Multinomial Logistic Regression: 71%, Naïve Bayes: 67%, Neural Network: 30%, Random Forest: 72%, Extreme Gradient Boost: 71% and 2) End of surgery-Multinomial Logistic Regression: 71%, Naïve Bayes: 63%, Neural Network: 32%, Random Forest: 72%, Extreme Gradient Boost: 70%. Analyzing the sensitivities of the best performing Random Forest model showed that the lower opioid requirements are predicted with better accuracy (89%) as compared with higher opioid requirements (43%). Feature importance (% relative importance) of model predictions showed that the type of procedure (15.4%), medical history (12.9%) and procedure duration (12.0%) were the top three features contributing to model predictions. Overall, the contribution of patient and procedure features towards model predictions were 65% and 35% respectively. Machine learning models could be used to predict postoperative opioid requirements in ambulatory surgery patients and could potentially assist in better management of their postoperative acute pain., Competing Interests: The authors have read the journal's policy and the authors of this manuscript have the following competing interests: BGN owns equity in Perimatics LLC and serves as its advisor. The University of Washington provided support in the form of salaries for some of the authors [BGN, JDL, CTF]. Perimatics LLC provided support in the form of salaries for some of the authors [NV, RV, LB]. VA Puget Sound Health System provided support in the form of salaries for the author [MH]. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: To investigate the opioid requirements and prevalence of chronic postsurgical pain (CPSP) in liver transplant (LT) recipients and to evaluate the association of opioid use with postoperative survival., Design: Retrospective analysis., Setting: A large academic medical center., Patients: Cadaveric liver transplants recipients from 2008 to 2016., Interventions: Analysis of demographic, perioperative, and outcome data., Measurements and Main Results: This study measured the incidence and quantity of preoperative opioid use, postoperative opioid requirements, the incidence of CPSP, and survival in patients with and without CPSP. Opioid requirements were calculated in morphine milligram equivalents. In total, 322 LT recipients satisfied the inclusion criteria. The cohort of interest included 61 patients (18.9%) who were prescribed opioids before LT, compared to the control group of 261. Postoperative opioid requirements were significantly higher in the cohort of interest in the first 24 hours (205.9 ± 318.5 v 60.4 ± 33.6 mg, p < 0.0001) and at 7 days after transplant (57.0 ± 70.6 mg v 19.2 ± 15.4 mg, p < 0.0001). Incidence of CPSP was significantly higher in the cohort of interest at 3 months (70.5% v 45.5%, p < 0.0001), at 2 years (38% v 12%), and at 5 years (29.8% v 6.9%) postoperatively. CPSP was a significant risk factor for patient mortality after transplantation (p = 0.038, HR 1.26)., Conclusions: Opioid use is relatively frequent in patients waiting for LT. It significantly affects the postoperative opioid requirements and the incidence of CSPS. CPSP may significantly affect survival after LT., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Predictive analytics systems may improve perioperative care by enhancing preparation for, recognition of, and response to high-risk clinical events. Bradycardia is a fairly common and unpredictable clinical event with many causes; it may be benign or become associated with hypotension requiring aggressive treatment. Our aim was to build models to predict the occurrence of clinically significant intraoperative bradycardia at 3 time points during an operative course by utilizing available preoperative electronic medical record and intraoperative anesthesia information management system data., Methods: The analyzed data include 62,182 scheduled noncardiac procedures performed at the University of Washington Medical Center between 2012 and 2017. The clinical event was defined as severe bradycardia (heart rate <50 beats per minute) followed by hypotension (mean arterial pressure <55 mm Hg) within a 10-minute window. We developed models to predict the presence of at least 1 event following 3 time points: induction of anesthesia (TP1), start of the procedure (TP2), and 30 minutes after the start of the procedure (TP3). Predictor variables were based on data available before each time point and included preoperative patient and procedure data (TP1), followed by intraoperative minute-to-minute patient monitor, ventilator, intravenous fluid, infusion, and bolus medication data (TP2 and TP3). Machine-learning and logistic regression models were developed, and their predictive abilities were evaluated using the area under the ROC curve (AUC). The contribution of the input variables to the models were evaluated., Results: The number of events was 3498 (5.6%) after TP1, 2404 (3.9%) after TP2, and 1066 (1.7%) after TP3. Heart rate was the strongest predictor for events after TP1. Occurrence of a previous event, mean heart rate, and mean pulse rates before TP2 were the strongest predictor for events after TP2. Occurrence of a previous event, mean heart rate, mean pulse rates before TP2 (and their interaction), and 15-minute slopes in heart rate and blood pressure before TP2 were the strongest predictors for events after TP3. The best performing machine-learning models including all cases produced an AUC of 0.81 (TP1), 0.87 (TP2), and 0.89 (TP3) with positive predictive values of 0.30, 0.29, and 0.15 at 95% specificity, respectively., Conclusions: We developed models to predict unstable bradycardia leveraging preoperative and real-time intraoperative data. Our study demonstrates how predictive models may be utilized to predict clinical events across multiple time intervals, with a future goal of developing real-time, intraoperative, decision support.

Objective: To examine if attending surgeon presence at the preinduction briefing is associated with a shorter time to incision., Study Design: Retrospective cohort study and survey., Setting: Tertiary academic medical center., Subjects and Methods: A retrospective cohort study was conducted of 22,857 operations by 141 attending surgeons across 12 specialties between August 3, 2016, and June 21, 2018. The independent variable was attending surgeon presence at the preinduction briefing. Linear regression models compared time from room entry to incision overall, by service line, and by surgeon. We hypothesized a shorter time to incision when the attending surgeon was present and a larger effect for cases with complex surgical equipment or positioning. A survey was administered to evaluate attending surgeons' perceptions of the briefing, with a response rate of 68% (64 of 94 attending surgeons)., Results: Cases for which the attending surgeon was present at the preinduction briefing had a statistically significant yet operationally minor reduction in mean time to incision when compared with cases when the attending surgeon was absent. After covariate adjustment, the mean time to incision was associated with an efficiency gain of 1.8 ± 0.5 minutes (mean ± SD; P < .001). There were no statistically significant differences in the subgroups of complex surgical equipment and complex positioning or in secondary analysis comparing service lines. The surgeon was the strongest confounding variable. Survey results demonstrated mild support: 55% of attending surgeons highly prioritized attending the preinduction briefing., Conclusion: Attending surgeon presence at the preinduction briefing has only a minor effect on efficiency as measured by time to incision.

Objectives: To analyze preoperative tumor thrombus progression and occurrence of perioperative pulmonary embolism (PE) in patients with inferior vena cava tumor thrombus resection., Design: Retrospective analysis., Settings: University of Washington Medical Center., Participants: Patients who had undergone inferior vena cava tumor resection with thrombectomy from 2014 to 2017., Interventions: Analysis of demographic, perioperative, and outcome data. Variables were compared between groups according to the level of tumor thrombus, the timing of the preoperative imaging, and the occurrence of perioperative PE., Measurements and Main Results: Incidence, outcomes, and variables associated with perioperative PE and sensitivity/specificity analyses for optimized preoperative imaging timing, broken into 7-day increments, were assessed. Fifty-six patients were included in this analysis. Perioperative PE was observed in 6 (11%) patients, intraoperatively in 5 patients and in the early postoperative period in 1 patient. Of the 5 patients with intraoperative PE, 2 died intraoperatively. Perioperative PE occurred in 1 patient with tumor thrombus level I, in 2 patients with level II, in 2 patients with level III, and in 1 patient with level IV. Risks of preoperative tumor thrombus progression were minimized if the imaging study was performed within 3 weeks for level I and II tumor thrombi and within 1 week for level III tumor thrombus., Conclusions: Perioperative PE was observed in patients with all levels of tumor thrombus. Fifty percent of perioperative PE were observed in patients with infrahepatic tumor thrombus. Post-imaging progression of tumor thrombus was unlikely if the surgery was performed within 3 weeks in patients with levels I or II tumor thrombus or within 1 week in patients with level III tumor thrombus., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Accurate estimation of operative case-time duration is critical for optimizing operating room use. Current estimates are inaccurate and earlier models include data not available at the time of scheduling. Our objective was to develop statistical models in a large retrospective data set to improve estimation of case-time duration relative to current standards., Study Design: We developed models to predict case-time duration using linear regression and supervised machine learning. For each of these models, we generated an all-inclusive model, service-specific models, and surgeon-specific models. In the latter 2 approaches, individual models were created for each surgical service and surgeon, respectively. Our data set included 46,986 scheduled operations performed at a large academic medical center from January 2014 to December 2017, with 80% used for training and 20% for model testing/validation. Predictions derived from each model were compared with our institutional standard of using average historic procedure times and surgeon estimates. Models were evaluated based on accuracy, overage (case duration > predicted + 10%), underage (case duration < predicted - 10%), and the predictive capability of being within a 10% tolerance threshold., Results: The machine learning algorithm resulted in the highest predictive capability. The surgeon-specific model was superior to the service-specific model, with higher accuracy, lower percentage of overage and underage, and higher percentage of cases within the 10% threshold. The ability to predict cases within 10% improved from 32% using our institutional standard to 39% with the machine learning surgeon-specific model., Conclusions: Our study is a notable advancement toward statistical modeling of case-time duration across all surgical departments in a large tertiary medical center. Machine learning approaches can improve case duration estimations, enabling improved operating room scheduling, efficiency, and reduced costs., (Copyright © 2019. Published by Elsevier Inc.)

Background: Hyperglycemia or high blood glucose during surgery is associated with poor postoperative outcome. Knowing in advance which patients may develop hyperglycemia allows optimal assignment of resources and earlier initiation of glucose management plan., Objective: To develop predictive models to estimate peak glucose levels in surgical patients and to implement the best performing model as a point-of-care clinical tool to assist the surgical team to optimally manage glucose levels., Methods: Using a large perioperative dataset (6,579 patients) of patient- and surgery-specific parameters, we developed and validated linear regression and machine learning models (random forest, extreme gradient boosting [Xg Boost], classification and regression trees [CART], and neural network) to predict the peak glucose levels during surgery. The model performances were compared in terms of mean absolute percentage error (MAPE), logarithm of the ratio of the predicted to actual value (log ratio), median prediction error, and interquartile error range. The best performing model was implemented as part of a web-based application for optimal decision-making toward glucose management during surgery., Results: Accuracy of the machine learning models were higher (MAPE = 17%, log ratio = 0.029 for Xg Boost) when compared with that of the linear regression model (MAPE = 22%, log ratio = 0.041). The Xg Boost model had the smallest median prediction error (5.4 mg/dL) and the narrowest interquartile error range (-17 to 24 mg/dL) as compared with the other models. The best performing model, Xg Boost, was implemented as a web application, Hyper-G, which the perioperative providers can use at the point of care to estimate peak glucose levels during surgery., Conclusions: Machine learning models are able to accurately predict peak glucose levels during surgery. Implementation of such a model as a web-based application can facilitate optimal decision-making and advance planning of glucose management strategies., Competing Interests: Dr. Nair reports equity in Perimatics LLC unrelated to this project. Other authors have no conflicts of interests to report., (Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange syndrome (CdLS). We aimed to delineate pathogenic variants in known and candidate cohesinopathy genes from a clinical exome perspective., Methods: We retrospectively studied patients referred for clinical exome sequencing (CES, N = 10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization., Results: Pathogenic or likely pathogenic single-nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N = 5), SMC1A (N = 14), SMC3 (N = 4), RAD21 (N = 2), and HDAC8 (N = 8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared with phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N = 3), STAG2 (N = 5), PDS5A (N = 1), and WAPL (N = 1), and one inherited SNV in PDS5A. We also identified copy-number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS., Conclusion: CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.

DNA methylation and Polycomb are key factors in the establishment of vertebrate cellular identity and fate. Here we report de novo missense mutations in DNMT3A, which encodes the DNA methyltransferase DNMT3A. These mutations cause microcephalic dwarfism, a hypocellular disorder of extreme global growth failure. Substitutions in the PWWP domain abrogate binding to the histone modifications H3K36me2 and H3K36me3, and alter DNA methylation in patient cells. Polycomb-associated DNA methylation valleys, hypomethylated domains encompassing developmental genes, become methylated with concomitant depletion of H3K27me3 and H3K4me3 bivalent marks. Such de novo DNA methylation occurs during differentiation of Dnmt3a W326R pluripotent cells in vitro, and is also evident in Dnmt3a W326R/+ dwarf mice. We therefore propose that the interaction of the DNMT3A PWWP domain with H3K36me2 and H3K36me3 normally limits DNA methylation of Polycomb-marked regions. Our findings implicate the interplay between DNA methylation and Polycomb at key developmental regulators as a determinant of organism size in mammals.

PURA syndrome is a recently described developmental encephalopathy presenting with neonatal hypotonia, feeding difficulties, global developmental delay, severe intellectual disability, and frequent apnea and epilepsy. We describe 18 new individuals with heterozygous sequence variations in PURA. A neuromotor disorder starting with neonatal hyptonia, but ultimately allowing delayed progression to walking, was present in nearly all individuals. Congenital apnea was present in 56% during infancy, but all cases in this cohort resolved during the first year of life. Feeding difficulties were frequently reported, with gastrostomy tube placement required in 28%. Epilepsy was present in 50% of the subjects, including infantile spasms and Lennox-Gastaut syndrome. Skeletal complications were found in 39%. Disorders of gastrointestinal motility and nystagmus were also recurrent features. Autism was diagnosed in one individual, potentially expanding the neurodevelopmental phenotype associated with this syndrome. However, we did not find additional PURA sequence variations in a cohort of 120 subjects with autism. We also present the first neuropathologic studies of PURA syndrome, and describe chronic inflammatory changes around the arterioles within the deep white matter. We did not find significant correlations between mutational class and severity, nor between location of the sequence variation in PUR repeat domains. Further studies are required in larger cohorts of subjects with PURA syndrome to clarify these genotype-phenotype associations., (© 2017 Wiley Periodicals, Inc.)

Chromodomain helicase DNA-binding protein 4 (CHD4) is an ATP-dependent chromatin remodeler involved in epigenetic regulation of gene transcription, DNA repair, and cell cycle progression. Also known as Mi2β, CHD4 is an integral subunit of a well-characterized histone deacetylase complex. Here we report five individuals with de novo missense substitutions in CHD4 identified through whole-exome sequencing and web-based gene matching. These individuals have overlapping phenotypes including developmental delay, intellectual disability, hearing loss, macrocephaly, distinct facial dysmorphisms, palatal abnormalities, ventriculomegaly, and hypogonadism as well as additional findings such as bone fusions. The variants, c.3380G>A (p.Arg1127Gln), c.3443G>T (p.Trp1148Leu), c.3518G>T (p.Arg1173Leu), and c.3008G>A, (p.Gly1003Asp) (GenBank: NM&#95;001273.3), affect evolutionarily highly conserved residues and are predicted to be deleterious. Previous studies in yeast showed the equivalent Arg1127 and Trp1148 residues to be crucial for SNF2 function. Furthermore, mutations in the same positions were reported in malignant tumors, and a de novo missense substitution in an equivalent arginine residue in the C-terminal helicase domain of SMARCA4 is associated with Coffin Siris syndrome. Cell-based studies of the p.Arg1127Gln and p.Arg1173Leu mutants demonstrate normal localization to the nucleus and HDAC1 interaction. Based on these findings, the mutations potentially alter the complex activity but not its formation. This report provides evidence for the role of CHD4 in human development and expands an increasingly recognized group of Mendelian disorders involving chromatin remodeling and modification., (Published by Elsevier Inc.)

Background: Proficiency in medical nutrition requires an understanding of food-related biochemistry and the application of this knowledge in the context of culinary, cultural, psychosocial and interprofessional components., Context: Our aim was to develop a teaching format where medical students could learn the biochemistry of nutrition in the context of patient narratives, interactive cooking and dialogues with nutrition professionals., Innovation: We designed and implemented a day-long culinary laboratory intervention (lab), which is taught to first-year medical students at the University of Rochester with the help of dietetic interns from Cornell University. Here, we present the details of the intervention, the resources used and the preliminary outcomes on student attitudes. We designed and implemented a day-long culinary lab, which is taught to first-year medical students, Methods and Results: A questionnaire with quantitative rating scales and open-ended questions was used to probe student attitudes regarding the educational approach used in the lab. Our preliminary findings suggest that the lab was well received and that the dietetic interns were viewed as effective teachers in this context., Implications: A culinary lab is a feasible educational environment for integrating the breadth of topics within the discipline of nutrition. The experiential, food-based format appears to stimulate questions central to current nutritional controversies, particularly challenges related to translating biochemical mechanism into practical nutrition interventions. Close involvement with basic science faculty members, clinical faculty members and allied health professions are essential for this type of endeavour., (© 2015 John Wiley & Sons Ltd.)

Protein phosphatase 2A (PP2A) is a heterotrimeric protein serine/threonine phosphatase and is involved in a broad range of cellular processes. PPP2R5D is a regulatory B subunit of PP2A and plays an important role in regulating key neuronal and developmental regulation processes such as PI3K/AKT and glycogen synthase kinase 3 beta (GSK3β)-mediated cell growth, chromatin remodeling, and gene transcriptional regulation. Using whole-exome sequencing (WES), we identified four de novo variants in PPP2R5D in a total of seven unrelated individuals with intellectual disability (ID) and other shared clinical characteristics, including autism spectrum disorder, macrocephaly, hypotonia, seizures, and dysmorphic features. Among the four variants, two have been previously reported and two are novel. All four amino acids are highly conserved among the PP2A subunit family, and all change a negatively charged acidic glutamic acid (E) to a positively charged basic lysine (K) and are predicted to disrupt the PP2A subunit binding and impair the dephosphorylation capacity. Our data provides further support for PPP2R5D as a genetic cause of ID.