NF2-related schwannomatosis and other schwannomatosis: an updated genetic and epidemiological study.

OBJECTIVES: New diagnostic criteria for NF2-related schwannomatosis (NF2) were published in 2022. An updated UK prevalence was generated in accordance with these, with an emphasis on the rate of de novo NF2 (a 50% frequency is widely quoted in genetic counselling). The distribution of variant types among de novo and familial NF2 cases was also assessed. METHODS: The UK National NF2 database identifies patients meeting updated NF2 criteria from a highly ascertained population cared for by England's specialised service. Diagnostic prevalence was assessed on 1 February 2023. Molecular analysis of blood and, where possible, tumour specimens for NF2, LZTR1 and SMARCB1 was performed. RESULTS: 1084 living NF2 patients were identified on prevalence day (equivalent to 1 in 61 332). The proportion with NF2 inherited from an affected parent was only 23% in England. If people without a confirmed molecular diagnosis or bilateral vestibular schwannoma are excluded, the frequency of de novo NF2 remains high (72%). Of the identified de novo cases, almost half were mosaic. The most common variant type was nonsense variants, accounting for 173/697 (24.8%) of people with an established variant, but only 18/235 (7.7%) with an inherited NF2 pathogenic variant (p<0.0001). Missense variants had the highest proportion of familial association (56%). The prevalence of LZTR1-related schwannomatosis and SMARCB1-related schwannomatosis was 1 in 527 000 and 1 in 1.1M, respectively, 8.4-18.4 times lower than NF2. CONCLUSIONS: This work confirms a much higher rate of de novo NF2 than previously reported and highlights the benefits of maintaining patient databases for accurate counselling.

Better kidney allograft survival despite higher-risk donor and recipient characteristics between 1995-2014.

BACKGROUND AND HYPOTHESIS: Advances in organ procurement, surgical techniques, immunosuppression regimens and prophylactic antibiotic therapies have dramatically improved short term kidney transplant graft failure. It is unclear how these interventions have affected longer term graft failure. It is hypothesised that graft failure has improved over the last 20 years. METHODS: Data on all first kidney transplants from 1995-2014 were extracted from the Australia and New Zealand Dialysis and Transplant Registry with follow-up as of 31 December, 2021. Primary exposure was transplant era, classified into 5-year intervals. Primary outcome was all-cause 5-year graft failure. Secondary outcomes included all-cause 10-year graft failure and cause-specific graft failure. Kaplan Meier curves and multivariable Cox Proportional Hazards Regression models were used to assess trends in all-cause graft failure. Fine-Gray subdistribution hazard models verified that changes in death rates were not biasing the Cox Proportional Hazards Regression models. Cumulative incidence functions were used to assess temporal trends in cause-specific graft failure. RESULTS: Across 10 871 kidney transplants, there was a shift towards transplanting more recipients aged over 45 years old, with more comorbidities, longer dialysis vintage, body mass index greater than 30 kg/m2 and greater human leukocyte antigen mismatches. Donor age has increased but no clear shift in donor source was observed. Compared to 1995-1999 (reference), the adjusted hazard ratio for 5-year graft failure was 0.78 (95% CI 0.67-0.91), 0.70 (95% CI 0.59-0.83) and 0.60 (95% CI 0.50-0.73) for 2000-2004, 2005-2009, and 2010-2014, respectively. Ten-year graft failure similarly reduced from 0.83 (95% CI 0.74-0.93) for 2000-04 to 0.78 (95% CI 0.68-0.89) for 2010-14, compared to 1995-99. CONCLUSION: Medium and long term all-cause graft failure has improved steadily since 1995-99. Significant reductions in graft failure due to rejection and vascular causes were observed at 5 years, and due to rejection, vascular causes, death and glomerular disease at 10 years.

Reported Hearing Outcome Measures Following Stereotactic Radiosurgery for Vestibular Schwannoma: A Scoping Review.

Background Evidence on hearing outcome measures when assessing hearing preservation following stereotactic radiosurgery (SRS) for adults with vestibular schwannoma (VS) has not previously been collated in a structured review. Objective The objective of the present study was to perform a scoping review of the evidence regarding the choice of hearing outcomes and other methodological characteristics following SRS for adults with VS. Methods The protocol was registered in the International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY) and reported according to the Preferred Reporting Items for Systematic Review and Meta-Analyses extension guidelines for scoping reviews. A systematic search of five online databases revealed 1,591 studies, 247 of which met the inclusion criteria. Results The majority of studies ( n = 213, 86%) were retrospective cohort or case series with the remainder ( n = 34, 14%) prospective cohort. Pure-tone audiometry and speech intelligibility were included in 222 (90%) and 158 (64%) studies, respectively, often summarized within a classification scheme and lacking procedural details. Fifty-nine (24%) studies included self-report measures. The median duration of follow-up, when reported, was 43 months (interquartile range: 29, 4-150). Conclusion Evidence on hearing disability after SRS for VS is based on low-quality studies which are inherently susceptible to bias. This review has highlighted an urgent need for a randomized controlled trial assessing hearing outcomes in patients with VS managed with radiosurgery or radiological observation. Similarly, consensus and coproduction of a core outcome set to determine relevant hearing and communication outcome domains is required. This will ensure that patient priorities, including communication abilities in the presence of background noise and reduced participation restrictions, are addressed.

Using the Socioecological Model to Explore Barriers to Health Care Provision in Underserved Communities in the Philippines: Qualitative Study.

BACKGROUND: The Philippines' primary care is delivered via local health centers called barangay health centers (BHCs). Barangays are the most local government units in the Philippines. Designed to promote and prevent disease via basic health care, these BHCs are staffed mainly by barangay health workers (BHWs). However, there has been limited research on the social and environmental factors affecting underserved communities' access to health care in underserved areas of the Philippines. Given the importance of BHCs in disease prevention and health promotion, it is necessary to identify obstacles to providing their services and initiatives. OBJECTIVE: This study aimed to explore multilevel barriers to accessing and providing basic health care in BHCs. METHODS: We used a qualitative approach and the socioecological model as a framework to investigate the multilevel barriers affecting basic health care provision. A total of 18 BHWs from 6 BHCs nationwide participated in focus group interviews. Traditional thematic content analysis was used to analyze the focus group data. After that, we conducted individual semistructured interviews with 4 public health nurses who supervised the BHWs to confirm findings from focus groups as a data source triangulation. The final stage of thematic analysis was conducted using the socioecological model as the framework. RESULTS: Findings revealed various barriers at the individual (lack of staff motivation and misperceptions of health care needs), interpersonal (lack of training, unprofessional behaviors, and lack of communication), institutional (lack of human resources for health, lack of accountability of staff, unrealistic expectations, and lack of physical space or supplies), community (lack of community support, lack of availability of appropriate resources, and belief in traditional healers), and policy (lack of uniformity in policies and resources and lack of a functional infrastructure) levels. CONCLUSIONS: Examining individual-, interpersonal-, institutional-, community-, and policy-level determinants that affect BHCs can inform community-based health promotion interventions for the country's underserved communities. Given the multidimensional barriers identified, a comprehensive program must be developed and implemented in collaboration with health care providers, community leaders, local and regional health care department representatives, and policy makers.

Response and Outcomes of Maintenance Avelumab After Platinum-Based Chemotherapy (PBC) in Patients With Advanced Urothelial Carcinoma (aUC): "Real World" Experience.

BACKGROUND: Platinum-based chemotherapy (PBC) followed by avelumab switch maintenance in nonprogressors is standard first line (1L) treatment for advanced urothelial carcinoma (aUC). We describe clinical features and outcomes in a "real-world' cohort treated with avelumab maintenance for aUC. MATERIALS AND METHODS: This was a retrospective cohort study of patients (pts) who received 1L switch maintenance avelumab after no progression on PBC for aUC. We calculated progression-free survival (PFS) and overall survival (OS) from initiation of maintenance avelumab. We also described OS and PFS for specific subsets using Cox regression and observed response rate (ORR). RESULTS: A total of 108 pts with aUC from 14 sites treated with maintenance avelumab were included. There was a median of 6 weeks1-30 from end of PBC to avelumab initiation; median follow-up time from avelumab initiation was 8.8 months (1-42.7). Median [m]PFS was 9.6 months (95%CI 7.5-12.1) and estimated 1-year OS was 72.5%. CR/PR (vs. SD) to 1L PBC (HR = 0.33, 95% CI 0.13-0.87) and ECOG PS 0 (vs. ≥1), (HR = 0.15, 95% CI 0.05-0.47) were associated with longer OS. The presence of liver metastases was associated with shorter PFS (HR = 2.32, 95% CI 1.17-4.59). ORR with avelumab maintenance was 28.7% (complete response 17.6%, partial response 11.1%), 29.6% stable disease, 26.9% progressive disease as best response (14.8% best response unknown). CONCLUSIONS: Results seem relatively consistent with findings from JAVELIN Bladder100 trial and recent "real world" studies. Prior response to platinum-based chemotherapy, ECOG PS 0, and absence of liver metastases were favorable prognostic factors. Limitations include the retrospective design, lack of randomization and central scan review, and possible selection/confounding biases.

Saddlepoint approximations to score test statistics in logistic regression for analyzing genome-wide association studies.

We investigate saddlepoint approximations of tail probabilities of the score test statistic in logistic regression for genome-wide association studies. The inaccuracy in the normal approximation of the score test statistic increases with increasing imbalance in the response and with decreasing minor allele counts. Applying saddlepoint approximation methods greatly improve the accuracy, even far out in the tails of the distribution. By using exact results for a simple logistic regression model, as well as simulations for models with nuisance parameters, we compare double saddlepoint methods for computing two-sided P $$ P $$ -values and mid- P $$ P $$ -values. These methods are also compared to a recent single saddlepoint procedure. We investigate the methods further on data from UK Biobank with skin and soft tissue infections as phenotype, using both common and rare variants.

Correlates of Psychological Distress Among Filipino Americans and Filipinos Living in Urban Areas in the United States and the Philippines.

INTRODUCTION: Many Asian immigrants, including Filipino Americans (FilAms), experience psychological distress (PD) due to the challenges in adjusting to their new country and culture. This descriptive comparative study aimed to compare FilAms and Filipinos concerning their levels of PD, sources of stress, and use of health-promotion strategies. METHODS: Data from 89 FilAms and 95 Filipinos living in urban cities, obtained from the I-HELP-FILIPINOS database, measuring cardiometabolic risks, mental health, and environmental stressors in 2017, including PD, were examined. RESULTS: The mean age of all participants (N = 184) was 44.2 ± 22.8 years old. Both groups rated their health as good to excellent, although Filipinos were significantly more likely to be distressed (p < .001). Filipinos were also more likely to ascribe stress to employment (48.3% vs. 68.2%, p =.006) and finances (28.1% vs. 52.6%, p <.001) than FilAms. DISCUSSION: While both groups shared comparative perspectives on health, FilAms reported lower PD than Filipinos. The most significant source of stress was the country of residence. We recommend tailoring interventions to each local context's unique social and environmental circumstances.

Inferring feature importance with uncertainties with application to large genotype data.

Estimating feature importance, which is the contribution of a prediction or several predictions due to a feature, is an essential aspect of explaining data-based models. Besides explaining the model itself, an equally relevant question is which features are important in the underlying data generating process. We present a Shapley-value-based framework for inferring the importance of individual features, including uncertainty in the estimator. We build upon the recently published model-agnostic feature importance score of SAGE (Shapley additive global importance) and introduce Sub-SAGE. For tree-based models, it has the advantage that it can be estimated without computationally expensive resampling. We argue that for all model types the uncertainties in our Sub-SAGE estimator can be estimated using bootstrapping and demonstrate the approach for tree ensemble methods. The framework is exemplified on synthetic data as well as large genotype data for predicting feature importance with respect to obesity.

Genetics of three-dimensional tooth inclination and angulation in orthodontic patients with Class I Occlusion: A cross-sectional study.

PURPOSE: This cross-sectional study aimed to utilize quantitative polymerase chain reaction (qPCR) to investigate the influence of genetic variance over teeth inclination and angulation in orthodontic patients with Class I occlusion. MATERIALS AND METHODS: DNA was extracted from adolescent patients seeking orthodontic treatment in a single institution (from July 2018 to April 2020), who had CBCTs taken as part of initial standardized records. Patients had permanent dentition, Class I skeletal and dental classifications, with normal vertical and transverse skeletal dimensions, normal incisors inclination, no to mild crowding or spacing. qPCR was performed using genetic markers for candidate genes EPB41, TGFß3, GHR and PAX9. Three-dimensional teeth inclinations (TI) and angulations (TA) were evaluated using Invivo6 software and correlated with genotypes. Reliability of TI and TA was assessed using intraclass correlation coefficients (ICC). Mixed models and multiple linear regression analyses were used to assess the association between each single nucleotide polymorphisms (SNP) with tooth inclination (TI) and with tooth angulation (TA). The results were evaluated at the significance level of P<0.05. RESULTS: Twenty four adolescent patients with mean age of 13.4±2.4 years were included in the study. ICC showed adequate intra-examiner reliability for TI and TA (0.806

Relationships Among Rumination, Resilience, Mindfulness, and Perceived PTSD Symptoms in Military Veterans Returning to College: A Cross-Sectional Study.

The influx of military Veterans with posttraumatic stress disorder (PTSD) returning to college following active military service presents an unmanageable trend for many secondary educational institutions in the United States. The current study aimed to determine relationships among rumination, resilience, mindfulness, and perceived PTSD symptoms in college student Veterans. To this end, 133 college student military Veterans registered in a U.S. university responded to an online survey. Results revealed that rumination has a direct effect on perceived PTSD symptoms and mediates the relationship between mindfulness and perceived PTSD symptoms, and that resilience moderates the relationship between mindfulness and perceived PTSD symptoms through rumination as the mediator. These findings imply that designing and developing mindfulness-based interventions for college student Veterans with PTSD requires concerted efforts targeted at improving ruminative thinking and enhancing resilience. [Journal of Psychosocial Nursing and Mental Health Services, 61(6), 43-50.].

Impact of COVID-19 pandemic on surgical residency: Residents' perception.

BACKGROUND: World Health Organization declared COVID-19 outbreak a pandemic, and till the month of March 2023, globally, there have been 761,402,282 confirmed cases of COVID-19, including 6887,000 deaths. In India, almost 44,707,525 cases been recorded till date. Here, almost 30,000,000 cases been recorded after the second wave. The working force fighting this pandemic is majority formed by resident doctors all over the country and globally. MATERIALS AND METHODS: This study was conducted among 110 residents pursuing postgraduation in surgery and allied departments in various training institutions in Tamil Nadu for a duration of 6 months (after the second wave). A pretested and validated questionnaire was formulated to assess the effect of COVID-19 pandemic on surgical trainee's residency program from their perspective. The questionnaire contained basic social-demographic details and general information like the details of surgical specialty they are admitted to, the overall details of changes in their surgical residency experience in the times of COVID pandemic and the changes faced by them in their day-to-day clinical, diagnostic, and surgical learning. The questionnaire also investigated the redeployment status of the surgical trainees to COVID treatment units and their perspective on the changes in their clinical research and surgical skills training. RESULTS: The study participants, 66%, were aged between 25 and 30 years, followed by 30 and 35 years (25.5%). Almost 80% of the participants belong to the final year of postgraduation; 67.3% of surgical trainees strongly perceives and all 100% of them accept the fact that their surgical residency has been affected by the ongoing pandemic. Fifty percent of the trainees were redeployed to COVID duties for 8 h a day shift and rest attended a minimum of 4 h of COVID duties. More than 75% of the residents had COVID duties of 5-10 h/day and more than 90% of these redeployed trainees involved in COVID duties have expressed that they had been suffering from extra stress and more than 60% were suffering from stress grade between 5 and 10 suggestive of high-stress level. Fifty-nine percent of the postgraduates in the current study mentioned that they require extra-surgical or skill-based training after their postgraduation period. CONCLUSION: The influence of COVID-19 on surgical trainees in various institutions of India has been immense due to overburdening of health systems by the large population of the country. Second wave of COVID, especially, has drastically changed the postgraduate surgical trainees' lives. Detrimental effects are not restricted to operative and clinical experience but also the mental health and well-being of them. The observations of the present study make recommendations for the future provision of training through skill-based surgical simulations so that the lost days of their trainings can be compensated and they become the confident surgeons of the future.

Preimplantation genetic testing for aneuploidy: challenges in clinical practice.

Preimplantation genetic testing for aneuploidy (PGT-A) has been used widely during in vitro fertilization procedures in assisted reproductive centers throughout the world. Despite its wide use, concerns arise from the use of PGT-A technology in clinical decision-making. We address knowledge gaps in PGT-A, summarizing major challenges and current professional guidelines. First, PGT-A is a screening test and not a diagnostic test. Second, mosaicism is much higher in the blastocyst stage from PGT-A than had been recognized previously and a mosaic embryo may not accurately represent the genetic disease risk for future fetal disorders. Third, PGT-A was not validated clinically before use in patients; the best use of this technology for selected age-groups remains uncertain. Given these gaps, we believe that current professional policies relying on industry-self-regulation are insufficient. In the USA, the Food and Drug Administration may be the most appropriate agency to provide more definitive guidelines and regulations that are needed for better practice.

Caffeine consumption within British fencing athletes.

The ergogenic effects of caffeine are well documented, yet despite the potential benefits of supplementation, there is a lack of understanding of caffeine habits and supplementation within fencing. British fencers (n = 136) completed a Web-based questionnaire, exploring self-reported caffeine consumption, reasons for use and education. Fencers (94.1%) habitually consumed caffeine, primarily due to the taste of the products (93.8%). Respondents ingested 183.4 ± 137.5 mg of caffeine daily, with a significant difference between age groups (p < 0.05). Many respondents (30.1%) consumed caffeine 60 mins prior/during fencing training and/or competition with the main reason highlighted as cognitive performance enhancement. Respondents ingested 140.8 ± 104.6 mg of caffeine during training/competition, mainly as energy drinks, bars, and powders. Education on caffeine supplementation was low (25.7%), with significant associations between age groups (p < 0.05). Evidence implies caffeine toxicity has been experienced by 35% of fencers, highlighting the need for education on caffeine consumption. To conclude there is evidence of caffeine supplementation in fencing, primarily to magnify cognitive performance. However, there is a requirement for targeted education on caffeine supplementation to fencers, so that negative side effects and potential anti-doping infringements can be avoided.

Long-Term Outcomes of the Electrically Unresponsive, Anatomically Intact Facial Nerve Following Vestibular Schwannoma Surgery.

Objective The study aimed to determine long-term outcomes in patients with intraoperative electrical conduction block in an anatomically intact facial nerve (FN). Methods Single center retrospective review of prospectively collected database of all vestibular schwannoma surgeries between January 1, 2008 and August 25, 2015. Operative notes were reviewed and patients with anatomically intact FNs, but complete conduction block at the end of surgery were included for analysis. Results In total, 371 patients had vestibular schwannoma surgery of which 18 met inclusion criteria. Mean follow-up was 34.28 months and average tumor size was 28.00 mm. Seventeen patients had House-Brackmann Grade VI facial palsy immediately postoperatively and one patient was grade V. At 1 year, three patients remained grade VI (17%), two improved to grade V (11%), seven to grade IV (39%), six to grade III (33%), and one patient to grade II (6%). On extended follow-up, five patients (28%) had additional 1 to 2 score improvement in facial function. Subset analysis revealed no correlation of tumor size, vascularity, adherence to nerve, operative approach, extent of resection, splaying of FN, and recurrent tumor or sporadic tumors to the extent of FN recovery. Conclusion Intraoperative conduction block does not condemn a patient to permanent FN palsy. There is potential for a degree of recovery comparable with those undergoing nerve grafting. Our data do not clearly support a policy of same-surgery or early-postoperative primary nerve grafting in the event of a complete conduction block, and instead we favor monitoring for recovery in an anatomically intact nerve.

Provider reported challenges with completing death certificates: A focus group study demonstrating potential sources of error.

OBJECTIVES: To characterize the experiences of providers in completing the cause of death section on death certificates, with particular reference to deaths in people who have cancer. METHODS: Focus groups were conducted until thematic saturation was reached, resulting in four groups over three months. Participants were from a variety of specialties and levels and types of training. Focus groups were recorded and transcribed verbatim and analyzed using constant comparison analysis. RESULTS: Three types of challenges to case classification were identified. 1) Infrastructural and procedural challenges encountered when completing death certificates, including the rigid structure of the form, lack of training in its completion, and lack of real-time feedback. 2) Clinical uncertainty and the varied approaches providers take to determine the cause of death based on their perception of the purpose of the death certificate. 3) Choosing cause of death in decedents with a history of cancer. CONCLUSIONS: There are specific and substantial challenges in the death certification process that lead to errors in documenting the cause of death, but many of these challenges could be addressed with structural change to the forms or mechanism of training. Using these data to inform change could improve the death certification process and reliability of this data.

Multiple Meningiomas as a Criterion for the Diagnosis of Neurofibromatosis Type 2 and Other Tumor Predisposition Syndromes.

BACKGROUND: Bilateral vestibular schwannomas (VS) are pathognomonic of neurofibromatosis type 2 (NF2), but the diagnostic criteria also include unilateral VS (UVS) in combination with multiple meningiomas (MM) and other schwannomas, as well as MM without VS. OBJECTIVE: To investigate the diagnostic value of these criteria and establish the presence of other genetic conditions in patients presenting in this manner. METHODS: The Manchester International NF2 database was accessed to obtain information on patients presenting with a UVS and MM or ≥2 nonintradermal schwannomas (NIDS). We gathered data on patients diagnosed with NF2 due to MM without VS and on patients presenting with MM without meeting NF2 criteria. Analysis was performed for pathogenic variants (PVs) in NF2, SMARCE1, SMARCB1, and LZTR1. RESULTS: A total of 31 of 131 patients presenting with a UVS and MM had a nonrefuted diagnosis of NF2 after molecular studies, in comparison with 85 of 96 patients presenting with UVS and ≥2 NIDS (P ≤ .00001). Fifty percent of patients presenting with a UVS and ≥2 NIDS with NF2 developed bilateral VS, compared with only 26% of those who presented with a UVS and MM (P = .0046). In total, 11 of 152 patients presenting with MM without fulfilling NF2 criteria were found to have a PV in SMARCE1, and 7 of 152 were confirmed to have mosaic NF2. CONCLUSION: Patients presenting with UVS and MM are significantly more likely to have a nonrefuted diagnosis of NF2 than patients presenting with UVS and ≥2 NIDS, but significantly less likely to develop bilateral VS. Seven percent of those presenting with MM without meeting NF2 criteria had PV in SMARCE1, and 5% had mosaic NF2.

The Moderating Role of Resilience on Mindfulness, Experiential Avoidance, and Posttraumatic Stress Disorder (PTSD) Symptoms of College Student Veterans: A Cross-Sectional Study.

The purpose of the study was to investigate the moderating effect of resilience on the relationship between mindfulness, experiential avoidance, and posttraumatic stress disorder (PTSD) symptom severity. A cross-sectional study design was used on a sample of 133 college student military veterans. We found a direct effect of mindfulness on PTSD and a significant mediating effect of experiential avoidance on the relationship between mindfulness and PTSD. Resilience also had a significant moderating effect on the relationship between mindfulness and PTSD. This study provides preliminary evidence on the usefulness of integrating resilience development in mindfulness-based interventions for trauma-related disorders.

The Process of Learning Mindfulness and Acceptance through the Use of a Mobile App Based on Acceptance and Commitment Therapy: A Grounded Theory Analysis.

This study aimed to explore the process of how college student military veterans with posttraumatic stress disorder (PTSD) symptoms learn mindfulness and acceptance through the use of a mobile app based on acceptance and commitment therapy (ACT). Twenty-three college student veterans with PTSD symptoms participated in the 4-week ACT mobile app-based intervention and took part in three weekly semi-structured interviews. Results of the grounded theory data analysis reveal the core category of Mindful Scaffolding, a process indicating how student veterans cope with the interruptions and intrusions associated with learning mindfulness and acceptance through the use of the ACT-based app. The grounded theory provides a foundational theoretical framework for increasing adherence with using mindfulness- and acceptance-based mobile app interventions for PTSD.