Evaluation of Cochlear Implantation in Children With Cochlear Nerve Absence or Deficiency.

OBJECTIVE: To identify associations between cochleovestibular anatomy findings and hearing outcomes found in children with imaging evidence of an absent or hypoplastic cochlear nerve treated with cochlear implantation (CI). STUDY DESIGN: retrospective review. SETTING: Cochlear implant program at tertiary care center. METHODS: A retrospective review was performed to identify children with imaging evidence of cochlear nerve absence or deficiency who underwent CI evaluation. High-resolution 3-dimensional T2-weighted magnetic resonance imaging in the oblique sagittal and axial planes were reviewed by a neuroradiologist to identify cochleovestibular anatomy. Hearing was assessed pre and postoperatively with Speech Perception Category scores. RESULTS: Seven CI recipients were identified (n = 10 ears) who had bilateral severe to profound sensorineural hearing loss with lack of auditory development with binaural hearing aid trial and imaging evidence of cochlear nerve aplasia/hypoplasia. All ears had 2 nerves in the cerebellopontine angle (100%, n = 10), half of the ears had evidence of 2 or less nerves in the internal auditory canal (IAC). All children showed large improvement in speech perception after CI. CONCLUSION: Our experience with CIs for children with absent or hypoplastic cochlear nerves demonstrates that CI can be a viable option in select patients who satisfy preoperative audiological criteria. Radiological identification of a hypoplastic or aplastic cochlear nerve does not preclude auditory innervation of the cochlea. CI recipients in this subgroup must be counseled on difficulty in predicting postimplantation language and speech outcomes, and cautioned about facial nerve stimulation.

Predictive Models to Assess Risk of Persistent Opioid Use, Opioid Use Disorder, and Overdose.

BACKGROUND: This systematic review summarizes the development, accuracy, quality, and clinical utility of predictive models to assess the risk of opioid use disorder (OUD), persistent opioid use, and opioid overdose. METHODS: In accordance with Preferred Reporting Items for a Systematic Review and Meta-analysis guidelines, 8 electronic databases were searched for studies on predictive models and OUD, overdose, or persistent use in adults until June 25, 2023. Study selection and data extraction were completed independently by 2 reviewers. Risk of bias of included studies was assessed independently by 2 reviewers using the Prediction model Risk of Bias ASsessment Tool (PROBAST). RESULTS: The literature search yielded 3130 reports; after removing 199 duplicates, excluding 2685 studies after abstract review, and excluding 204 studies after full-text review, the final sample consisted of 41 studies that developed more than 160 predictive models. Primary outcomes included opioid overdose (31.6% of studies), OUD (41.4%), and persistent opioid use (17%). The most common modeling approach was regression modeling, and the most common predictors included age, sex, mental health diagnosis history, and substance use disorder history. Most studies reported model performance via the c statistic, ranging from 0.507 to 0.959; gradient boosting tree models and neural network models performed well in the context of their own study. One study deployed a model in real time. Risk of bias was predominantly high; concerns regarding applicability were predominantly low. CONCLUSIONS: Models to predict opioid-related risks are developed using diverse data sources and predictors, with a wide and heterogenous range of accuracy metrics. There is a need for further research to improve their accuracy and implementation.

Surgeon reported measures of stress and anxiety prior to and after elective gynecological surgery.

INTRODUCTION: Performing surgical procedures is a recognized source of stress for surgeons. Vocational stress is an important contributor to performance, patient care, and burnout with dispositional and environmental factors contributing. Accurately assessing surgeon stress is critical to measuring effectiveness of stress reduction programs. The primary aim was to identify differences between surgeons' self-reported anticipated stress and anxiety prior to gynecological surgery, compared with their recollection of experienced stress and anxiety during surgery. Secondary aims assessed any differences by level of training, surgical type, and surgeon role. MATERIAL AND METHODS: Attending and resident gynecologists performing routine elective surgeries completed a visual analog scale (VAS) assessing perceived stress and the State-Trait Anxiety Inventory (STAI) prior to and immediately after completing 161 elective surgeries including total laparoscopic hysterectomy, laparoscopic excision of moderate-severe endometriosis, or hysteroscopic myomectomy. RESULTS: Eight attending gynecologists and nine residents participated. Residents commenced as primary surgeon in 62/90 (69%) procedures. Stress experienced during surgery was greater than anticipated in 92/161 (57%) surgery episodes (mean VAS increase: 3.9; 95% CI: 1.1-6.8, p = 0.009). State anxiety was greater than anticipated in 99/161 (62%) episodes (mean state anxiety increase: 4.4; 95% CI: 3.0-5.8, p < 0.001). Greater preprocedural anticipatory stress and anxiety was observed in residents vs. attending gynecologists (VAS 51.9 vs. 22.8, p < 0.001; state anxiety 38.3 vs. 28.1, p < 0.001) and in primary vs. assistant surgeons (VAS 47.2 vs. 29.9, p < 0.001; state anxiety 36.9 vs. 28.3, p < 0.001). Intraoperative stress and anxiety were greater in primary surgeons (VAS 50.4 vs. 30.5, p < 0.001; anxiety 41.3 vs. 32.5, p < 0.001) and residents (VAS 43.4 vs. 31.7, p < 0.001; anxiety 53.5 vs. 33.7, p < 0.001) compared with assistants and attending gynecologists. Perceived stress and anxiety were positively correlated at both timepoints (r = 0.68, p < 0.001; r = 0.82, p < 0.001). CONCLUSIONS: When asked to reflect on stress experienced during surgery, our data show that stress during surgery is greater than anticipated for many surgical episodes. Self-reported stress symptoms commence prior to surgery and are more commonly reported by surgeons operating as primary surgeon and by those in training. Future research should focus on determinants of presurgical stress and examine when stressors become inhibitory to performance.

Conformer Generation for Structure-Based Drug Design: How Many and How Good?

Conformer generation, the assignment of realistic 3D coordinates to a small molecule, is fundamental to structure-based drug design. Conformational ensembles are required for rigid-body matching algorithms, such as shape-based or pharmacophore approaches, and even methods that treat the ligand flexibly, such as docking, are dependent on the quality of the provided conformations due to not sampling all degrees of freedom (e.g., only sampling torsions). Here, we empirically elucidate some general principles about the size, diversity, and quality of the conformational ensembles needed to get the best performance in common structure-based drug discovery tasks. In many cases, our findings may parallel "common knowledge" well-known to practitioners of the field. Nonetheless, we feel that it is valuable to quantify these conformational effects while reproducing and expanding upon previous studies. Specifically, we investigate the performance of a state-of-the-art generative deep learning approach versus a more classical geometry-based approach, the effect of energy minimization as a postprocessing step, the effect of ensemble size (maximum number of conformers), and construction (filtering by root-mean-square deviation for diversity) and how these choices influence the ability to recapitulate bioactive conformations and perform pharmacophore screening and molecular docking.

Treatments for Acute Nonarteritic Central Retinal Artery Occlusion: Findings From a Cochrane Systematic Review.

Many interventions for nonarteritic central retinal artery occlusion (CRAO) are associated with serious complications and little effect on visual outcomes. We report on the findings of a Cochrane systematic review that searched seven databases for peer-reviewed articles reporting on treatments for acute nonarteritic CRAO. We assessed six randomized controlled trials, including interventions such as tissue plasminogen activator (t-PA), isovolumic hemodilution, eyeball massage, intraocular pressure reduction, anticoagulation, vasodilation, oxygen inhalation, laser embolysis, transcorneal electrical stimulation, thrombolysis, pentoxifylline, and enhanced external counterpulsation. However, none of the randomized controlled trials demonstrated significant improvement in visual acuity at 1 month compared to observation, and some patients treated with t-PA experienced serious adverse effects including intracranial hemorrhage. Proposed interventions for acute nonarteritic CRAO may not be better than observation, but the evidence is uncertain. Larger, well-designed studies are necessary to determine the most effective management option for acute nonarteritic CRAO. [Ophthalmic Surg Lasers Imaging Retina 2023;54:650-653.].

Behavioral Health Decision Support Systems and User Interface Design in the Emergency Department.

OBJECTIVE: The objective of this qualitative study is to gauge physician sentiment about an emergency department (ED) clinical decision support (CDS) system implemented in multiple adult EDs within a university hospital system. This CDS system focuses on predicting patients' likelihood of ED recidivism and/or adverse opioid-related events. METHODS: The study was conducted among adult emergency physicians working in three EDs of a single academic health system in Rhode Island. Qualitative, semistructured interviews were conducted with ED physicians. Interviews assessed physicians' prior experience with predictive analytics, thoughts on the alert's placement, design, and content, the alert's overall impact, and potential areas for improvement. Responses were aggregated and common themes identified. RESULTS: Twenty-three interviews were conducted (11 preimplementation and 12 postimplementation). Themes were identified regarding each physician familiarity with predictive analytics, alert rollout, alert appearance and content, and on alert sentiments. Most physicians viewed these alerts as a neutral or positive EHR addition, with responses ranging from neutral to positive. The alert placement was noted to be largely intuitive and nonintrusive. The design of the alert was generally viewed positively. The alert's content was believed to be accurate, although the decision to respond to the alert's call-to-action was physician dependent. Those who tended to ignore the alert did so for a few reasons, including already knowing the information the alert contains, the alert offering information that is not relevant to this particular patient, and the alert not containing enough information to be useful. CONCLUSION: Ultimately, this alert appears to have a marginally positive effect on ED physician workflow. At its most beneficial, the alert reminded physicians to deeply consider the care provided to high-risk populations and to potentially adjust their care and referrals. At its least beneficial, the alert did not affect physician decision-making but was not intrusive to the point of negatively impacting workflow.

Cross-cultural Comparison of an American and a Taiwanese Medical School with Longstanding Institutional Ties.

Cross-cultural medical education has been suggested to train students to care for diverse patient populations and reform medical education systems. In this article, the authors conduct a cross-cultural comparison between two medical schools with a long-standing relationship - the Warren Alpert Medical School of Brown University in the United States and the School of Medicine of National Cheng Kung University in Taiwan - focusing on history, admissions, and curriculum.

Acute Biological Changes in Gynecologic Surgeons during Surgery: A Prospective Study.

STUDY OBJECTIVE: To assess changes in biological measures of acute stress in surgeons during surgery in real-world settings DESIGN: A prospective cohort study. SETTING: A tertiary teaching hospital. PATIENTS: 8 consultant and 9 training gynecologists. INTERVENTION: A total of, 161 elective gynecologic surgeries of 3 procedures: laparoscopic hysterectomy, laparoscopic excision of endometriosis, or hysteroscopic myomectomy. MEASUREMENTS AND MAIN RESULTS: Changes in surgeons' biological measures of acute stress while undertaking elective surgery. Salivary cortisol, mean and maximum heart rate (HR), and indices of the HR variability were recorded before and during surgery. From baseline to during surgery over the cohort, salivary cortisol decreased from 4.1 nmol/L to 3.6 nmol/L (p = .03), maximum HR increased from 101.8 beats per min (bpm) to 106.5 bpm (p <.01), root mean square of standard deviation decreased from 51.1 ms to 39.0 ms (p <.01), and standard deviation of beat-to-beat variability decreased from 73.7 to 59.8 ms (p <.01). Analysis of individual changes in stress by participant-surgery event by paired data graphs reveal inconsistent direction of change in all measures of biological stress despite stratification by surgical experience, role in surgery, level of training, or type of surgery performed. CONCLUSION: This study measured biometric stress changes at both a group and individual level in real-world, live surgical settings. Individual changes have not previously been reported and the variable direction of stress change by participant-surgery episode identified in this study demonstrates a problematic interpretation of mean cohort findings previously reported. Results from this study suggest that either live surgery with tight environment control or surgical simulation studies may identify what, if any, biological measures of stress can predict acute stress reactions during surgery.

Immediate versus delayed urinary catheter removal following non-hysterectomy benign gynaecological laparoscopy: a randomised trial.

OBJECTIVE: To compare rates of urinary retention and postoperative urinary tract infection between women with immediate versus women with delayed removal of indwelling catheter following benign non-hysterectomy gynaecological laparoscopic surgery. DESIGN: This randomised clinical trial was conducted between February 2012 and December 2019, with follow-up to 6 weeks. SETTING: Two university-affiliated teaching hospitals in Sydney, Australia. POPULATION: Study participants were 693 women aged 18 years or over, undergoing non-hysterectomy laparoscopy for benign gynaecological conditions, excluding pelvic floor or concomitant bowel surgery. METHODS: Three hundred and fifty-five participants were randomised to immediate removal of urinary catheter and 338 participants were randomised to delayed removal of urinary catheter. MAIN OUTCOME MEASURES: The co-primary outcomes were urinary retention and urinary tract infection. Secondary outcomes included hospital readmission, analgesia requirements, duration of hospitalisation and validated bladder function questionnaires. RESULTS: Urinary retention was higher after immediate compared with delayed removal of the urinary catheter (8.2% vs 4.2%, RR 1.8, 95% CI 1.0-3.0, p = 0.04). Although urinary tract infection was 7.2% following delayed removal of the urinary catheter and 4.7% following immediate removal of the urinary catheter, the difference was not statistically significant (RR 0.7, 95% CI 0.3-1.2, p = 0.2). CONCLUSIONS: There is an increased risk of urinary retention with the immediate compared with the delayed removal of the urinary catheter following benign non-hysterectomy gynaecological laparoscopic surgery. The difference in urinary tract infection was not significant. There is 1/12 risk of re-catheterisation after immediate urinary catheter removal. It is important to ensure that patients report normal voiding and emptying prior to discharge, to reduce the need for readmission for the management of urinary retention.

Interventions for acute non-arteritic central retinal artery occlusion.

BACKGROUND: Acute non-arteritic central retinal artery occlusion (CRAO) occurs as a sudden interruption of the blood supply to the retina and typically results in severe loss of vision in the affected eye. Although many therapeutic interventions have been proposed, there is no generally agreed upon treatment regimen. OBJECTIVES: To assess the effects of treatments for acute non-arteritic CRAO. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2022, Issue 2); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature Database (LILACS); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 15 February 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing any interventions with another treatment in participants with acute non-arteritic CRAO in one or both eyes.  DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology and graded the certainty of the body of evidence for primary (mean change in best-corrected visual acuity [BCVA]) and secondary (quality of life and adverse events) outcomes using the GRADE classification. MAIN RESULTS: We included six RCTs with 223 total participants with acute non-arteritic CRAO; the studies ranged in size from 10 to 84 participants. The included studies varied geographically: one in Australia, one in Austria and Germany, two in China, one in Germany, and one in Italy. We were unable to conduct any meta-analyses due to study heterogeneity. None of the included studies compared the same pair of interventions: 1) tissue plasminogen activator (t-PA) versus intravenous saline; 2) t-PA versus isovolemic hemodilution, eyeball massage, intraocular pressure reduction, and anticoagulation; 3) nitroglycerin, methazolamide, mecobalamin tablets, vitamin B1 and B12 injections, puerarin and compound anisodine (also known as 654-2) along with oxygen inhalation, eyeball massage, tube expansion, and anticoagulation compared with and without intravenous recombinant tissue plasminogen activator (rt-PA); 4) transcorneal electrical stimulation (TES) with 0 mA versus with 66% of the participant's individual electrical phosphene threshold (EPT) at 20 Hz (66%) versus with 150% of the participant's individual EPT (150%) at 20 Hz; 5) ophthalmic artery branch retrograde thrombolysis versus superselective ophthalmic artery thrombolysis; and 6) pentoxifylline versus placebo. There was no evidence of an important difference in visual acuity between participants treated with t-PA versus intravenous saline (mean difference [MD] at 1 month -0.15 logMAR, 95% confidence interval [CI] -0.48 to 0.18; 1 study, 16 participants; low certainty evidence); t-PA versus isovolemic hemodilution, eyeball massage, intraocular pressure reduction, and anticoagulation (MD at 1 month -0.00 logMAR, 95% CI -0.24 to 0.23; 1 study, 82 participants; low certainty evidence); and TES with 0 mA versus TES with 66% of EPT at 20 Hz versus TES with 150% of EPT at 20 Hz. Participants treated with t-PA experienced higher rates of serious adverse effects. The other three comparisons did not report statistically significant differences. Other studies reported no data on secondary outcomes (quality of life or adverse events).  AUTHORS' CONCLUSIONS: The current research suggests that proposed interventions for acute non-arteritic CRAO may not be better than observation or treatments of any kind such as eyeball massage, oxygen inhalation, tube expansion, and anticoagulation, but the evidence is uncertain. Large, well-designed RCTs are necessary to determine the most effective treatment for acute non-arteritic CRAO.

Theoretical Frameworks in Medical Education: Using a Systematic Review of Ophthalmology Education Research to Create a Theory of Change Model.

Background: Theoretical frameworks provide a lens to examine questions and interpret results; however, they are underutilized in medical education. Objective: To systematically evaluate the use of theoretical frameworks in ophthalmic medical education and present a theory of change model to guide educational initiatives. Methods: Six electronic databases were searched for peer-reviewed, English-language studies published between 2016 and 2021 on ophthalmic educational initiatives employing a theoretical framework. Quality of studies was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach; risk of bias was evaluated using the Medical Education Research Study Quality Instrument (MERSQI) and the Accreditation Council for Graduate Medical Education (ACGME) guidelines for evaluation of assessment methods. Abstracted components of the included studies were used to develop a theory of change model. Results: The literature search yielded 1661 studies: 666 were duplicates, 834 studies were excluded after abstract review, and 132 after full-text review; 29 studies (19.2%) employing a theoretical framework were included. The theories used most frequently were the Dreyfus model of skill acquisition and Messick's contemporary validity framework. GRADE ratings were predominantly "low," the average MERSQI score was 10.04, and the ACGME recommendation for all assessment development studies was the lowest recommendation. The theory of change model outlined how educators can select, apply, and evaluate theory-based interventions. Conclusions: Few ophthalmic medical education studies employed a theoretical framework; their overall rigor was low as assessed by GRADE, MERSQI, and ACGME guidelines. A theory of change model can guide integration of theoretical frameworks into educational initiatives.

A longitudinal perspective of hormone replacement therapies (HRTs) on neuromotor capabilities in males with 47,XXY (Klinefelter syndrome).

PURPOSE: The purpose of this study was to delineate the effects of variable hormone replacement therapies on neuromotor function in a large cohort of males with 47,XXY from birth to adulthood. METHODS: A total of 270 participants aged 16 days to 17 years 11 months prenatally diagnosed with 47,XXY were assessed by their pediatric endocrinologist and were administered hormone replacement therapies accordingly. Infants and school-aged children with 47,XXY were administered neuromotor assessments during routine neurodevelopmental evaluations. For statistical analysis, participants were segregated on the basis of treatment status. Two-tailed t tests, 1-way analysis of variance, and post hoc analysis determined significant group differences on each assessment. RESULTS: In infants, the early hormonal treatment (EHT) group performed significantly better than the untreated group on fine motor and motor composite domains. In school-aged children, we observed significantly improved scores on fine motor control, coordination, agility, and strength domains among males treated with EHT (or any combination thereof) compared with those who did not receive early treatment. CONCLUSION: The highest treated combination group was associated with the highest neuromotor function, although the EHT group also often performed better than the other groups. This suggests EHT may be essential in promoting long-term optimal neuromotor outcome in males with an additional X.

A Graphical Toolkit for Longitudinal Dataset Maintenance and Predictive Model Training in Health Care.

BACKGROUND: Predictive analytic models, including machine learning (ML) models, are increasingly integrated into electronic health record (EHR)-based decision support tools for clinicians. These models have the potential to improve care, but are challenging to internally validate, implement, and maintain over the long term. Principles of ML operations (MLOps) may inform development of infrastructure to support the entire ML lifecycle, from feature selection to long-term model deployment and retraining. OBJECTIVES: This study aimed to present the conceptual prototypes for a novel predictive model management system and to evaluate the acceptability of the system among three groups of end users. METHODS: Based on principles of user-centered software design, human-computer interaction, and ethical design, we created graphical prototypes of a web-based MLOps interface to support the construction, deployment, and maintenance of models using EHR data. To assess the acceptability of the interface, we conducted semistructured user interviews with three groups of users (health informaticians, clinical and data stakeholders, chief information officers) and evaluated preliminary usability using the System Usability Scale (SUS). We subsequently revised prototypes based on user input and developed user case studies. RESULTS: Our prototypes include design frameworks for feature selection, model training, deployment, long-term maintenance, visualization over time, and cross-functional collaboration. Users were able to complete 71% of prompted tasks without assistance. The average SUS score of the initial prototype was 75.8 out of 100, translating to a percentile range of 70 to 79, a letter grade of B, and an adjective rating of "good." We reviewed persona-based case studies that illustrate functionalities of this novel prototype. CONCLUSION: The initial graphical prototypes of this MLOps system are preliminarily usable and demonstrate an unmet need within the clinical informatics landscape.

Effect of Fractional Carbon Dioxide Laser vs Sham Treatment on Symptom Severity in Women With Postmenopausal Vaginal Symptoms: A Randomized Clinical Trial.

Importance: Postmenopausal vaginal symptoms are common and frequently detrimental to a woman's quality of life. Fractional carbon dioxide vaginal laser is increasingly offered as a treatment, but the efficacy remains unproven. Objective: To determine the efficacy of fractional carbon dioxide laser for treatment of vaginal symptoms associated with menopause. Design, Setting, and Participants: A double-blind, randomized, sham-controlled trial with 12-month follow-up was undertaken at a single tertiary referral hospital in Sydney, Australia. Enrollment commenced on September 19, 2016, with final follow-up on June 30, 2020. Participants were postmenopausal women with vaginal symptoms substantive enough to seek medical treatment. Of 232 participants approached, 85 were randomized. Interventions: Three treatments using a fractional microablative carbon dioxide laser system performed 4 to 8 weeks apart, with 43 women randomized to the laser group and 42 to the sham group. Main Outcomes and Measures: The co-primary outcomes were symptom severity assessed using a visual analog scale (VAS; range, 0-100; 0 indicates no symptoms and 100 indicates the most severe symptoms) and the Vulvovaginal Symptom Questionnaire (VSQ; range, 0-20; 0 indicates no symptoms and 20 indicates the most severe symptoms) at 12 months. The minimal clinically important difference was specified as a 50% decrease in both VAS and VSQ severity scores. There were 5 prespecified secondary outcomes, including quality of life (range, 0-100; higher scores indicate better quality of life), the Vaginal Health Index Score (range, 5-25; higher scores indicate better health), and vaginal histology (premenopausal or postmenopausal status). Results: Of 85 randomized participants (mean [SD] age, 57 [8] years), 78 (91.7%) completed the 12-month follow-up. From baseline to 12 months, there was no significant difference between the carbon dioxide laser group and the sham group in change in symptom severity (VAS score for overall vaginal symptoms: -17.2 vs -26.6; difference, 9.4 [95% CI, -28.6 to 47.5]; VAS score for the most severe symptom: -24.5 vs -20.4; difference -4.1 [95% CI, -32.5 to 24.3]; VSQ score: -3.1 vs -1.6; difference, -1.5 [95% CI, -5.9 to 3.0]). There were no significant differences between the laser and sham group in the mean quality of life score (6.3 vs 1.4; difference, 4.8 [95% CI, -3.9 to 13.5]) and Vaginal Health Index Score (0.9 vs 1.3; difference, -0.4 [95% CI, -4.3 to 3.6]) or in histological comparisons between laser and sham treatment groups. There were 16 adverse events in the laser group and 17 in the sham group, including vaginal pain/discomfort (44% vs 68%), spotting, discharge, and lower urinary tract symptoms. No severe adverse events were reported in either group. Conclusions and Relevance: Among women with postmenopausal vaginal symptoms, treatment with fractional carbon dioxide laser vs sham treatment did not significantly improve vaginal symptoms after 12 months. Trial Registration: Australian and New Zealand Clinical Trials Registry: ACTRN12616001403426.

DNA methylation and behavioral dysfunction in males with 47,XXY and 49,XXXXY: a pilot study.

BACKGROUND: Equal dosage of X-linked genes between males and females is maintained by the X-inactivation of the second X chromosome in females through epigenetic mechanisms. Boys with aneuploidy of the X chromosome exhibit a host of symptoms such as low fertility, musculoskeletal anomalies, and cognitive and behavioral deficits that are presumed to be caused by the abnormal dosage of these genes. The objective of this pilot study is to assess the relationship between CpG methylation, an epigenetic modification, at several genes on the X chromosome and behavioral dysfunction in boys with supernumerary X chromosomes. RESULTS: Two parental questionnaires, the Behavior Rating Inventory of Executive Function (BRIEF) and Child Behavior Checklist (CBCL), were analyzed, and they showed expected differences in both internal and external behaviors between neurotypical (46,XY) boys and boys with 49,XXXXY. There were several CpGs in AR and MAOA of boys with 49,XXXXY whose methylation levels were skewed from levels predicted from having one active (Xa) and three inactive (Xi) X chromosomes. Further, methylation levels of multiple CpGs in MAOA showed nominally significant association with externalizing behavior on the CBCL, and the methylation level of one CpG in AR showed nominally significant association with the BRIEF Regulation Index. CONCLUSIONS: Boys with 49,XXXXY displayed higher levels of CpG methylation at regulatory intronic regions in X-linked genes encoding the androgen receptor (AR) and monoamine oxidase A (MAOA), compared to that in boys with 47,XXY and neurotypical boys. Our pilot study results suggest a link between CpG methylation levels and behavior in boys with 49,XXXXY.

The effect of early hormonal treatment (EHT) on expressive and receptive language capabilities in boys with 47,XXY (Klinefelter syndrome) during infancy and early childhood.

PURPOSE: 47,XXY is associated with variable neurodevelopmental outcomes including deficits in expressive and receptive language development. Early hormonal treatment (EHT) has been associated with mitigating some deficiencies in boys with 47,XXY. This study investigates these language capabilities of 47,XXY boys in the first five years of life and the associated effects of EHT on these capabilities. METHODS: One hundred and seventy-five boys with 47,XXY between the ages of 0 and 5 years, 11 months completed neurodevelopmental assessments specific to age examining their expressive and receptive language capabilities. Subjects were grouped by treatment (EHT and No-T) and differences were analyzed. RESULTS: In the age groups of under 12 months, 24-35 months, 36-47 months, and 60-71 months, the EHT group scored significantly higher on expressive language assessments than the No-T group (p = 0.09, p = 0.0002, p = 0.009, and p = 0.02, respectively). In the age groups of under 12 months and 24-35 months, the EHT group scored significantly better on the auditory comprehension domain of the PLS-4/5 (p = 0.02 and p = 0.05, respectively) than the No-T group. CONCLUSION: Study data suggest EHT may be essential in optimizing receptive and expressive language development in 47,XXY boys during early childhood, which is critical in fostering reading skills and later academic success.

Case Report: Infant With Congenital Adrenal Hyperplasia and 47,XXY.

Congenital adrenal hyperplasia is a group of autosomal recessive disorders in which enzymes in the cortisol biosynthesis pathways are disrupted by gene mutations. The most common form of congenital adrenal hyperplasia, caused by 21-hydroxylase deficiency, is characterized by decreased cortisol and aldosterone synthesis and excessive androgen production. Adult height is often compromised in affected patients. Intellectual capability remains intact in patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency, based on previous studies. 47,XXY (KS) is a sex chromosomal aneuploidy that manifests with hypergonadotropic hypogonadism, tall stature, and variable intellectual and behavioral dysfunction. This clinical report describes an infant with 21-hydroxylase deficiency congenital adrenal hyperplasia and 47,XXY. The results of his neurodevelopmental, endocrine, neurological, and physical therapy evaluations during his first 22 months are included and were normal. This is the first published case investigating the neurodevelopmental profile of a patient with the combination of these two genetic disorders.

Predictors of Completion of Sublingual Immunotherapy.

OBJECTIVES: Sublingual immunotherapy (SLIT) has emerged as an effective treatment alternative to subcutaneous immunotherapy (SCIT) given its improved safety profile and more convenient dosing. However, SLIT still relies on daily dosing for many years to optimize effectiveness. This study sought to investigate factors that influence patient completion of SLIT. METHODS: We performed an institutional retrospective review of patients who received SLIT (2008-2020). Completion was defined as completing at least 36 months of SLIT. Patient demographics and characteristics, including the number of allergens treated, history of asthma and sinus surgery, number of clinic visits, and total time undergoing SLIT, were documented. Multivariate models were used to analyze predictors of SLIT completion. Subgroup analysis was performed among pediatric patients and patients who discontinued SLIT. RESULTS: Of the 404 total patients, 249 (61.6%) discontinued, 47 (11.6%) completed, and 108 (26.7%) were currently undergoing SLIT. The mean duration of therapy was 11.2 months for those who discontinued and 49.4 months for patients who completed SLIT. The odds of SLIT completion were twice as high with each additional clinic visit (P < .001), and twice as high when the dosage was increased during therapy (P = .06). Pediatric patients younger than age 12 with a history of asthma were over five times more likely to complete therapy (P = .045). Patients with more clinic visits (P < .001) and higher associated costs (P = .003) were less likely to be lost to follow-up. CONCLUSION: Increasing the frequency of clinic visits, improving therapy availability, and mitigating concerns about clinical efficacy may increase patient completion of SLIT. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E2111-E2115, 2021.

The Great Imposter: A Confusing Case of a Rare Renal Cell Carcinoma.

We report a 61-year-old male with sarcomatoid renal cell carcinoma (sRCC) in the context of multiple paraneoplastic syndromes, including thrombocytosis, leukemoid reaction, and paraneoplastic hepatopathy (Stauffer syndrome). The patient's clinical course was complicated by multiple medical challenges, extensive metastases, and persistent infection. This confusing presentation of a rare subtype of renal cell carcinoma (RCC) highlights the diverse and often misleading manifestations of this aggressive malignancy. Clinicians should be aware of the association between RCC, multiple paraneoplastic syndromes, and its propensity to present with systemic, non-renal symptoms.