CFTR mutations and phenotypic correlations in people with cystic fibrosis: a retrospective study from a single centre in south India.

Background: Emerging data reveal higher-than-expected prevalence of cystic fibrosis (CF) among non-European populations worldwide including in the Indian subcontinent. Systematic analyses of the CFTR mutation profile, and genotype-phenotype correlations among people with CF from south, east, or northeast India have not been reported before. We wanted to identify CFTR mutations in people with CF, and highlight novel variants, selective phenotypic correlations, and regional variances within India. Methods: A retrospective study was conducted at Christian Medical College, Vellore, India (single tertiary referral hospital) from September 2010 to August 2022, involving 120 people with CF from (i) four south Indian states (Tamil Nadu, Andhra Pradesh, Kerala, Karnataka), (ii) in and nearby regions of West Bengal, India and (iii) Bangladesh. Comprehensive CFTR mutation analyses were done by Next-Generation Sequencing, and variants were categorized per American College of Medical Genetics guidelines and compared with validated Locus-specific databases. Demographic characteristics, mutation profile, novel mutations, selective phenotype correlations, and regional variances were assessed. Findings: In 120 people with CF, 55 CFTR variants were identified, including six novel variants. F508del was the predominant mutation, yet with a lower allele frequency than reported among European populations (27% versus 70%). Phenotypic correlations suggested high mutational pathogenicity causing severe multi-organ morbidity, and death in 27%. Milder variants associated with pancreatic sufficiency were also evident in 23% of people with CF. Statistically significant regional variances were noted in genotype frequency, and clinical phenotype among people with CF from the two regions. Hotspot exons and introns that could potentially help create targeted mutation panels were identified. Interpretation: The identification of 55 different CFTR variants among 120 people with CF describes the diversity of mutations noted in India, while also revealing the challenges that providers may encounter in timely diagnosis and treatment of CF. However, these single-centre data have specific limitations and cannot be generalised to all people with CF from India or to those of non-European origin. Our data on regional CFTR mutations contribute to the emerging national registry on CF epidemiology in India, help formulate diagnostic and newborn screening algorithms, help optimise clinical care, and highlight urgency to improve access to life-changing modulator therapy. Funding: Cystic Fibrosis Foundation, USA (towards the CF-India Demonstration Project) and Christian Medical College, Vellore, India.

Bifactor models of psychopathology using multi-informant and multi-instrument dimensional measures in the ABCD study.

Background: Due to limitations of categorical definitions of mental illness, there is a need for quantitative empirical investigations of the dimensional structure of psychopathology. Using exploratory bifactor methods, this study investigated a comprehensive and representative structure of psychopathology in children to better understand how psychotic-like experiences (PLEs), autism spectrum disorder (ASD) symptoms, impulsivity, and sensitivity to reward and punishment, may be integrated into extant general factor models of psychopathology. Methods: We used seven child-report and three parent-report instruments capturing diverse mental health symptoms in 11,185 children aged 9-10 from the Adolescent Brain Cognitive DevelopmentSM (ABCD) Study. We built on previous modeling frameworks by conducting both split sample and full sample factor analytic approaches that harnessed recent methodological advances in bifactor exploratory structural equation modeling (B-ESEM) to examine a wide range of psychopathology measures not previously integrated into a single analysis. Validity of psychopathology dimensions was examined by investigating associations with sex, age, cognition, imaging measures, and medical service usage. Results: All four factor analytic models showed excellent fit and similar structure within informant. PLEs loaded most highly onto a general psychopathology factor, suggesting that they may reflect non-specific risk for mental illness. ASD symptoms loaded separately from attention/hyperactivity symptoms. Symptoms of impulsivity and sensitivity to reward and punishment loaded onto specific factors, distinct from externalizing and internalizing factors. All identified factors were associated with clinically relevant risk factors, providing preliminary evidence for their construct validity. Conclusion: By integrating diverse child-report and parent-report psychopathology measures for children in the ABCD sample, we deliver data on the quantitative structure of psychopathology for an exceptionally large set of measurements and discuss implications for the field.

Observed rates of surgical instrument errors point to visualization tasks as being a critically vulnerable point in sterile processing and a significant cause of lost chargeable OR minutes.

BACKGROUND: The reporting of surgical instrument errors historically relies on cumbersome, non-automated, human-dependent, data entry into a computer database that is not integrated into the electronic medical record. The limitations of these reporting systems make it difficult to accurately estimate the negative impact of surgical instrument errors on operating room efficiencies. We set out to determine the impact of surgical instrument errors on a two-hospital healthcare campus using independent observers trained in the identification of Surgical Instrument Errors. METHODS: This study was conducted in the 7 pediatric ORs at an academic healthcare campus. Direct observations were conducted over the summer of 2021 in the 7 pediatric ORs by 24 trained student observers during elective OR days. Surgical service line, error type, case type (inpatient or outpatient), and associated length of delay were recorded. RESULTS: There were 236 observed errors affecting 147 individual surgical cases. The three most common errors were Missing+ (n = 160), Broken/poorly functioning instruments (n = 44), and Tray+ (n = 13). Errors arising from failures in visualization (i.e. inspection, identification, function) accounted for 88.6% of all errors (Missing+/Broken/Bioburden). Significantly more inpatient cases (42.73%) had errors than outpatient cases (22.32%) (p = 0.0129). For cases in which data was collected on whether an error caused a delay (103), over 50% of both IP and OP cases experienced a delay. The average length of delays per case was 10.16 min. The annual lost charges in dollars for surgical instrument associated delays in chargeable minutes was estimated to be between $6,751,058.06 and $9,421,590.11. CONCLUSIONS: These data indicate that elimination of surgical instrument errors should be a major target of waste reduction. Most observed errors (88.6%) have to do with failures in the visualization required to identify, determine functionality, detect the presence of bioburden, and assemble instruments into the correct trays. To reduce these errors and associated waste, technological advances in instrument identification, inspection, and assembly will need to be made and applied to the process of sterile processing.

OPTN/SRTR 2022 Annual Data Report: Kidney.

The year 2022 had continued successes and challenges for the field of kidney transplantation, as the community adapted to ongoing surges of the COVID-19 pandemic and broader geographic organ distribution. The total number of kidney transplants in the United States reached a record count of 26,309, driven by continued growth in deceased donor kidney transplants (DDKTs). The total number of candidates listed for DDKT rose slightly in 2022 but remained below 2019 listing levels, with 12.4% of candidates having been waiting 5 years or longer. Following the height of the COVID-19 pandemic, pretransplant mortality in 2022 declined across age, race and ethnicity, sex, and blood type groups. Pretransplant mortality continued to vary substantially by donation service area. The proportion of deceased donor kidneys recovered but not used for transplant (nonuse rate) rose to a high of 26.7% overall, with greater nonuse of biopsied kidneys (39.8%), kidneys from donors aged 55 years or older (54.7%), and kidneys with a kidney donor profile index (KDPI) of 85% or greater (71.3%). Nonuse of kidneys from donors who are hepatitis C virus (HCV) antibody positive rose to 30.2% but only slightly exceeded that of HCV antibody-negative donors. Disparities in access to living donor kidney transplant (LDKT) persist, especially for non-White and publicly insured patients. Delayed graft function continues an upward trend and occurred in 26.3% of adult kidney transplants in 2022. Five-year graft survival after LDKT compared with DDKT was 90.0% versus 81.4% for recipients aged 18-34 years and 80.8% versus 67.8% for recipients aged 65 years or older, respectively. The total number of pediatric kidney transplants performed in 2022 decreased to 705, its lowest point in the past decade; 502 (71.2%) were DDKTs and 203 (28.8%) were LDKTs. Among pediatric recipients, LDKT remains low, with continued racial disparities. The rate of DDKT among pediatric candidates has decreased by almost 25% since 2011. Congenital anomalies of the kidney and urinary tract remain the leading primary kidney disease diagnosis among pediatric candidates with a reported diagnosis. Most pediatric deceased donor recipients received a kidney from a donor with a KDPI of less than 35%. The rate of delayed graft function was 5.8% in 2022 and has been stable over the past decade. Long-term graft survival continues to improve, with superior outcomes for living donor transplant recipients.

Acute Macrocystic Thoracic Schwannoma: Systematic Review and Illustrative Case Example.

BACKGROUND: Schwannomas are benign peripheral nerve sheath tumors arising from myelinating Schwann cells. Although macrocystic changes are regularly encountered in schwannoma variants such as vestibular nerve tumors, they are exceedingly rare among spinal neoplasms. METHODS: Case report and systematic review of 4 databases (Ovid Medline, PubMed, Science Direct, and SCOPUS) from inception to present. All peer-reviewed publications reporting intradural cystic thoracic schwannoma were included. RESULTS: We identified 8 publications documenting 9 cases of cystic thoracic schwannoma. Four were female, 5 male; median age was 41 years (range, 27-80). Presentations ranged from incidental to pain, sensory changes, lower extremity paresis, or bowel/bladder dysfunction. Characteristic radiographic findings included T1 hypointensity, T2 hyperintensity, and cord effacement or compression. The present case followed a similar pattern: a 52-year-old male presented with worsening bilateral lower extremity weakness, low back pain, and gait dysfunction, worsening over 3 days. Examination also revealed decreased left lower extremity sensation. Imaging identified a well-delineated intradural, extramedullary macrocystic extending over T7-T10. The patient underwent a laminectomy resulting in complete tumor resection and restoration of intact neurologic function. Final pathology confirmed benign cystic schwannoma. CONCLUSIONS: Macrocystic thoracic schwannomas are exceedingly rare and lack a comprehensive scheme for clinical classification of their natural history and pathogenesis. We report the 10th case of such a schwannoma, and the first associated systematic review. Although macrocystic thoracic schwannomas are not frequently encountered, accurate diagnosis and appropriate neurosurgical treatment is critical in these vulnerable patients, given the opportunity for excellent functional outcomes following neurosurgical treatment.

Horizontal transfer of miR-383 sensitise cells to cisplatin by targeting VEGFA-Akt signalling loop.

BACKGROUND: Cellular resistance to cisplatin has been one of the major obstacles in the success of combination therapy for many types of cancers. Emerging evidences suggest that exosomes released by drug resistant tumour cells play significant role in conferring resistance to drug sensitive cells by means of horizontal transfer of genetic materials such as miRNAs. Though exosomal miRNAs have been reported to confer drug resistance, the exact underlying mechanisms are still unclear. METHODS AND RESULTS: In the present study, mature miRNAs secreted differentially by cisplatin resistant and cisplatin sensitive HepG2 cells were profiled and the effect of most significantly lowered miRNA in conferring cisplatin resistance when horizontally transferred, was analysed. we report miR-383 to be present at the lowest levels among the differentially abundant miRNAs expressed in exosomes secreted by cisplatin resistant cells compared to that that of cisplatin sensitive cells. We therefore, checked the effect of ectopic expression of miR-383 in altering cisplatin sensitivity of Hela cells. Drug sensitivity assay and apoptotic assays revealed that miR-383 could sensitise cells to cisplatin by targeting VEGF and its downstream Akt mediated pathway. CONCLUSION: Results presented here provide evidence for the important role of miR-383 in regulating cisplatin sensitivity by modulating VEGF signalling loop upon horizontal transfer across different cell types.

Adjusting for race in metrics of organ procurement organization performance.

The Scientific Registry of Transplant Recipients has previously reported the effects of adjusting for demographic variables, including race, in the Centers for Medicare & Medicaid Services (CMS) organ procurement organization (OPO) performance metrics: donation rate and transplant rate. CMS chose not to adjust for most demographic variables other than age (for the transplant rate), arguing that there is no biological reason that these variables would affect the organ donation/utilization decision. However, organ donation is a process based on altruism and trust, not a simple biological phenomenon. Focusing only on biological impacts on health ignores other pathways through which demographic factors can influence OPO outcomes. In this study, we update analyses of demographic adjustment on the OPO metrics for 2020 with a specific focus on adjusting for race. We find that adjusting for race would lead to 8 OPOs changing their CMS tier rankings, including 2 OPOs that actually overperform the national rate among non-White donors improving from a tier 3 ranking (facing decertification without possibility of recompeting) to a tier 2 ranking (allowing the possibility of recompeting). Incorporation of stratified and risk-adjusted metrics in public reporting of OPO performance could help OPOs identify areas for improvement within specific demographic categories.

Impact of Centers for Medicare and Medicaid Services Final Rule on Organ Procurement Organization Metrics and Procedural Trends in the Procurement of Pancreata for Research.

OBJECTIVE: Pancreata recovered for research are included as a success (or positive) in the Centers for Medicare and Medicaid Services' (CMS) donation and organ transplantation rate metrics for recertification of organ procurement organizations (OPOs). MATERIALS AND METHODS: Given these metrics directly incentivize recovery of pancreata for research, this study tracks trends in recovery of pancreata for research across the implementation of the CMS metrics. RESULTS: In the 26 months before the December 2, 2020, publication of the CMS metrics, research pancreata as a percent of organs transplanted, including research pancreata, was 1.7% nationally, including as much as 10.8% of organs transplanted within any OPO. In the 26 months after the CMS metrics were published, research pancreata increased to 5.1% of organs counted as transplants nationally, including as much as 20.3% within any OPO. If research pancreata were excluded from the CMS metrics, 6 OPOs would change their CMS evaluation status for recertification purposes: 2 would move up a tier and 4 would move down a tier. CONCLUSIONS: Procurement of research pancreata has increased since the publication of the CMS performance metrics, OPOs vary in their recovery of pancreata for research, and recovery of pancreata for research can affect recertification of OPOs.

Trends and Characteristics of Terrorist Attacks Against Nightclub Venues Over 5 Decades.

INTRODUCTION: Nightclubs are entertainment and hospitality venues historically vulnerable to terrorist attacks. This study identified and characterized terrorist attacks targeting nightclubs and discotheques documented in the Global Terrorism Database (GTD) over a 50-y period. METHODS: A search of the Global Terrorism Database (GTD) was conducted from 1970 to 2019. Precoded variables for target type "business" and target subtype "entertainment/cultural/stadium/casino" were used to identify attacks potentially involving nightclubs. Nightclub venues were specifically identified using the search terms "club," "nightclub," and "discotheque." Two authors manually reviewed each entry to confirm the appropriateness for inclusion. Descriptive statistics were performed using R (3.6.1). RESULTS: A total of 114 terrorist attacks targeting nightclub venues were identified from January 1, 1970, through December 31, 2019. Seventy-four (64.9%) attacks involved nightclubs, while forty (35.1%) attacks involved discotheques. A bombing or explosion was involved in 84 (73.7%) attacks, followed by armed assault in 14 (12.3%) attacks. The highest number of attacks occurred in Western Europe and Sub-Saharan Africa. In total, 284 persons died, and 1175 persons were wounded in attacks against nightclub venues. CONCLUSIONS: While terrorist attacks against nightclub venues are infrequent, the risk for mass casualties and injuries can be significant, mainly when explosives and armed assaults are used.

Augmenting the Unites States transplant registry with external mortality data: A moving target ripe for further improvement.

The Organ Procurement and Transplantation Network conducts a robust death verification process when augmenting the United States transplant registry with external sources of data. Process enhancements added over 35,000 externally verified deaths across waitlist candidates and transplant recipients for all organs beginning in April 2022. Ninety-four percent of added posttransplant deaths occurred beyond 5 years posttransplant, and over 74% occurred beyond 10 years. Deceased donor solid organ recipients transplanted from January 1, 2010, through October 31, 2020, were analyzed from January and July 2022 Organ Procurement and Transplantation Network Standard Transplant Analysis and Research and the Scientific Registry of Transplant Recipients Standard Analysis Files to quantify the impact of including vs excluding unverified deaths (not releasable to researchers) on posttransplant patient survival estimates. Across all organs, 1- and 5-year posttransplant survival rates were not substantially impacted; meaningful differences were observed in 10-year survival among kidney recipients. These findings bear important implications for anyone who utilized transplant registry data to examine long-term outcomes prior to the updated verification process. Users of transplant surveillance data should interpret results of long-term outcomes cautiously, particularly differences across subpopulations, and the transplant community should identify ways to improve data quality and minimize the reporting burden on transplant institutions.

Terminology for Retinal Findings in Sickle Cell Disease Research: A Scoping Review.

OBJECTIVE: To review the current sickle cell disease (SCD) literature to assess how "retinopathy" has been defined and to identify ocular outcomes that have been measured and described. DESIGN: A systematic scoping review of SCD literature was completed regarding ocular manifestations of SCD and vision outcomes across all medical specialties. SUBJECTS: Participants with SCD and control patients were included in our data extraction. METHODS: We reviewed English-language literature from 2000 to 2021 for eligible studies by searching PubMed, Google Scholar, Embase, and the Cochrane library using terms to encompass SCD and ocular findings. MAIN OUTCOME MEASURES: Data collection included study information, patient characteristics, vision-related findings (inclusion criteria and/or study outcomes), and retinopathy characteristics (definition, when, how and by whom diagnosed). RESULTS: We identified 4006 unique citations and 111 were included in the analysis. Ophthalmologists were senior authors of about half (59/111; 53.2%) of the articles; most articles were published between 2016 and 2021 (71/111; 70.0%). The studies had been conducted primarily in North America (54/111; 48.6%) or Europe (23/111; 20.7%); designs were cross-sectional (51/111; 45.9%), prospective cohort (28/111; 25.2%), retrospective cohort (27/111; 24.3%), and case-control (4/111; 3.6%). Among studies reporting any retinopathy, it was commonly defined as a combination of nonproliferative sickle cell retinopathy and proliferative sickle cell retinopathy (PSR; 52/87; 59.8%), infrequently as PSR only (6/87; 6.9%), or not defined at all (23/87; 26.4%). The Goldberg classification was used to grade retinopathy in almost half of the studies (41/87; 47.1%). Investigators reporting diagnostic methods used clinical fundus examination (56/111; 50.4%), OCT (24/111; 21.6%), fluorescein angiography (20/111; 18.0%), ultrawidefield fundus photographs (15/111; 13.5%), and OCT angiography (10/111; 9.0%), or did not report methods (28/111; 25.2%). CONCLUSIONS: There are inconsistencies in documentation of methods and outcomes in studies of SCD ophthalmic findings. Particularly concerning is the lack of documentation of ophthalmic examination methods, qualifications of examiners, and clarity and specificity of sickle cell retinopathy definitions. With the increase in SCD treatment research and novel systemic therapies available, it is important to adopt clear and consistent descriptions and rigorous data collection and reporting of ophthalmic outcomes in SCD studies. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Long-term stress induced cortisol downregulation, growth reduction and cardiac remodeling in Atlantic salmon.

Stress and elevated plasma cortisol in salmonids have been linked with pathological remodeling of the heart and deterioration of fitness and welfare. However, these associations were based on biomarkers that fail to provide a retrospective view of stress. This study is the first whereby the association of long-term stress, using scale cortisol as a chronic stress biomarker, with cardiac morphology and growth performance of wild Atlantic salmon (Salmo salar) is made. Growth, heart morphology, plasma and scale cortisol levels, and expression of genes involved in cortisol regulation of the hypothalamic-pituitary-interrenal axis of undisturbed fish (control) were compared with those of fish exposed daily to stress for 8 weeks. Though scale cortisol levels showed a time-dependent accumulation in both groups, plasma and scale cortisol levels of stress group fish were 29.1% and 25.0% lower than those of control fish, respectively. These results correlated with the overall upregulation of stress-axis genes involved in the systemic negative feedback of cortisol, and local feedback via 11ß-hydroxysteroid dehydrogenases, glucocorticoid and mineralocorticoid receptors in the stress treatment at the hypothalamus and pituitary level. These lower cortisol levels were, however, counterintuitive in terms of the growth performance as stress group fish grew 33.7% slower than control fish, which probably influenced the 8.4% increase in relative ventricle mass in the stress group. Though compact myocardium area between the treatments was comparable, these parameters showed significant linear correlations with scale cortisol levels, indicating the involvement of chronic stress in cardiac remodeling. These findings underscore the importance of scale cortisol as biomarker when associating chronic stress with long-term processes including cardiac remodeling.

Sequential appetite suppression by oral and visceral feedback to the brainstem.

The termination of a meal is controlled by dedicated neural circuits in the caudal brainstem. A key challenge is to understand how these circuits transform the sensory signals generated during feeding into dynamic control of behaviour. The caudal nucleus of the solitary tract (cNTS) is the first site in the brain where many meal-related signals are sensed and integrated1-4, but how the cNTS processes ingestive feedback during behaviour is unknown. Here we describe how prolactin-releasing hormone (PRLH) and GCG neurons, two principal cNTS cell types that promote non-aversive satiety, are regulated during ingestion. PRLH neurons showed sustained activation by visceral feedback when nutrients were infused into the stomach, but these sustained responses were substantially reduced during oral consumption. Instead, PRLH neurons shifted to a phasic activity pattern that was time-locked to ingestion and linked to the taste of food. Optogenetic manipulations revealed that PRLH neurons control the duration of seconds-timescale feeding bursts, revealing a mechanism by which orosensory signals feed back to restrain the pace of ingestion. By contrast, GCG neurons were activated by mechanical feedback from the gut, tracked the amount of food consumed and promoted satiety that lasted for tens of minutes. These findings reveal that sequential negative feedback signals from the mouth and gut engage distinct circuits in the caudal brainstem, which in turn control elements of feeding behaviour operating on short and long timescales.

Gender diversity in neurosurgical training: an analysis of trends and resident program characteristics.

OBJECTIVE: Recent trends have shown more women entering neurosurgery, but large gender gaps in the number of female trainees continue to persist. A previous study on the gender diversity of residents and faculty in neurosurgery training programs found that only 18.2% of residents and 8.7% of faculty at neurosurgical training programs were female. The goal of this study was to better understand program characteristics that may affect the recruitment of female residents and the gender composition of neurosurgery residency programs. METHODS: The authors assessed publicly available information on websites and social media from 116 Accreditation Council for Graduate Medical Education (ACGME)-accredited neurosurgery residency programs from the 2022-2023 academic year. Data collected on residents included gender and postgraduate year (PGY), geographic region, accreditation year, and complement size for programs. The authors analyzed the distribution of female residents at each program and compared accreditation year, program size, program geographics, PGY, and acceptance rates. RESULTS: There were 1602 residents across the 116 programs included in this study: 1223 (76.3%) male and 379 (23.7%) female residents. The gender distribution of female residents showed 29 programs had 30% or more female residents, 50 programs had between 16% and 30%, and 37 had fewer than 16%, including 8 with none. There were significantly more PGY-1 than PGY-7 female residents (28.9% vs 16.4%, p < 0.01). Programs with ACGME accreditation before 1970 had significantly higher percentages of female residents (26.0%) compared with those accredited after 1970 (18.2%, p < 0.01). Program size was associated with a higher percentage of female residents (large = 25.2%, medium = 24.9%, and small = 19.6%), although the results were not significant. The distribution of female trainees across five geographic regions of the United States was fairly even: Northeast (24.5%), West (25.2%), South Atlantic (23.1%), South Central (21.8%), and North Central (21.2%). Residency acceptance rates were similar between genders. CONCLUSIONS: The underrepresentation of women in neurosurgery residency programs remains a significant issue. While some programs have achieved higher female representation than the overall average proportion of female neurosurgery residents, many still fall short. There are twice as many female PGY-1 compared with PGY-7 residents, suggesting increased recruitment over the past few years. Programs with longer accreditation histories have significantly higher proportions of female residents. Larger program size can also play a role in attracting more female residents, but geographic location did not impact gender composition of resident cohorts in this study.

Erratum: Nurse Practitioner Students' Knowledge Assessment and Perceived Preparedness to Triage Ophthalmology Complaints in a Primary Care Setting: An Educational Intervention.

[This corrects the article DOI: 10.1055/s-0043-1771355.].