Prospective crossover trial of positional and CPAP therapy for the treatment of mild-to-moderate positional obstructive sleep apnea.

STUDY OBJECTIVES: To evaluate efficacy of vibrotactile positional therapy (PT) compared to standard CPAP therapy in mild-to-moderate positional obstructive sleep apnea (pOSA). METHODS: Prospective crossover randomized controlled trial of adult patients with treatment-naïve, symptomatic, mild-to-moderate pOSA - defined as ≥5 total apnea-hypopnea index (AHI) <30 with supine-to-non-supine (s:ns)AHI ratio ≥2. Participants were randomized to in-laboratory treatment initiation polysomnography with either PT or CPAP on sequential nights before an eight-week trial of each therapy. The primary endpoint was symptomatic improvement (Epworth Sleepiness Scale; ΔESS). Secondary endpoints included patient preference, usage, sleep architecture and quality of life (QoL) measures. RESULTS: 52 participants were enrolled and completed both arms of the study. Participants were symptomatic with median ESS 12 (IQR 10-14). Treatment resulted in a significant (p<0.001) symptomatic improvement with both PT and CPAP (ΔESS 4; IQR 6-11) without a significant difference between treatment arms (p=0.782). PT was effective at restricting supine sleep and demonstrated improved sleep efficiency compared with CPAP, although no better than baseline. Both therapies were effective at reducing AHI, although CPAP demonstrated superior AHI reduction. There were otherwise no clinically significant differences in sleep architecture, usage, or secondary outcomes including overall patient preference. CONCLUSIONS: In this cohort, treatment with PT or CPAP resulted in clinically significant symptomatic improvement (ΔESS) that was not significantly different between treatment arms. No real difference was seen in other secondary outcome measures. This study provides further evidence to support the use of PT as an alternative first-line therapy with CPAP in appropriately selected patients with pOSA. CLINICAL TRIAL REGISTRATION: Registry: Australian New Zealand Clinic Trials Registry; Name: Prospective crossover trial of Positional and Continuous positive airway pressure Therapy for the treatment of mild-to-moderate positional obstructive sleep apnoea; Identifier: ACTRN12619000475145; URL: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377221&isReview=true.

Oral anticoagulation in patients with hypertrophic cardiomyopathy and non-valvular atrial fibrillation in Japan.

AIMS: There are limited data to support direct oral anticoagulant (DOAC) use in patients with hypertrophic cardiomyopathy (HCM) and non-valvular atrial fibrillation (NVAF). The current study investigated the safety and effectiveness of DOACs versus warfarin in patients in Japan. METHODS: This retrospective observational study assessed a Japanese cohort of patients diagnosed with HCM and NVAF between July 2011 and June 2021 using a Japanese claims database. Propensity score (PS) matching (2:1 DOAC:warfarin) using the nearest-neighbour method was applied to balance demographic and clinical characteristics between treatment groups. The primary outcomes were the risk of major bleeding and any bleeding (major or minor). Secondary outcomes included describing baseline demographic and clinical characteristics and the risk of stroke/systemic embolism (SE). RESULTS: After PS matching, 2955 DOAC- and 1603 warfarin-treated patients were assessed. The mean [standard deviation (SD)] age in the DOAC and warfarin groups was 74.8 (10.5) and 75.3 (10.2) years, respectively. The majority of patients were male (DOAC, 58.8%; warfarin, 59.6%), had comorbidities (DOAC, 97.5%; warfarin, 96.6%), and were treated with ß-blockers (DOAC, 62.5%; warfarin, 62.3%). The risk of major and any bleeding was similar across cohorts [hazard ratio (HR), 0.80; 95% confidence interval (CI), 0.50-1.27; P = 0.336 and HR, 0.93; 95% CI, 0.78-1.11; P = 0.420] while the risk of stroke/SE was lower among patients treated with DOACs (HR, 0.67; 95% CI, 0.47-0.96; P = 0.027). Factors associated with an increased risk of major bleeding included prior bleeding (HR, 1.97; 95% CI, 1.22-3.17) and chronic kidney disease (HR, 1.87; 95% CI, 1.10-3.18). An increased risk of stroke/SE was associated with prior ischaemic stroke (HR, 2.97; 95% CI, 2.05-4.29), peripheral arterial disease (HR, 1.88; 95% CI, 1.22-2.88) and chronic kidney disease (HR, 1.87; 95% CI, 1.24-2.83). CONCLUSIONS: DOAC-treated patients had a lower risk of stroke/SE and a comparable risk of bleeding compared with warfarin-treated patients. Prior stroke was shown to augment stroke risk by approximately three-fold. This large real-world study suggests that patients diagnosed with HCM and NVAF can be safely and effectively treated with DOACs in Japan.

Patient characteristics, treatment patterns, and survival outcomes for patients with malignant pleural mesothelioma in Denmark between 2011 and 2018: a nationwide population-based cohort study.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare thoracic malignancy with poor prognosis and limited treatment options. Immunotherapy shows potential for improved outcomes; however, real-world evidence on its use will take time to accumulate. This study examined patient characteristics, treatment patterns, overall survival (OS), and predictors of mortality among patients diagnosed with MPM in Denmark prior to the introduction of newer treatments. METHODS: This historical cohort study based on routinely collected Danish National Registry data included adults newly diagnosed with MPM between 01 January 2011 and 31 May 2018. Summary statistics were used to describe patient characteristics and initial treatment. OS was estimated using Kaplan-Meier methods; Cox regression was used to compare patient mortality against the (age/sex-matched) general population and to investigate mortality predictors. RESULTS: Overall, 880 patients were included; 44% had advanced MPM, 37% had non-advanced MPM, and 19% had unknown MPM stage. Median age at diagnosis was 71.9 years, and 82% of the patients were male. Within 180 days of diagnosis, no treatment was recorded for 215 patients (54%) with advanced MPM and 150 (46%) with non-advanced MPM. Median time-to-initial treatment (interquartile range) was 47 days (31-111) overall, 40 days (28-77) in patients with advanced MPM, and 53 days (35-121) with non-advanced MPM. Median OS was 13.7 months overall (non-advanced MPM: 18.0 months vs. advanced MPM: 10.0 months). Predictors of higher mortality were older age at diagnosis, histology, and advanced MPM stage. INTERPRETATION: These findings provide a baseline upon which to evaluate MPM epidemiology as newer treatments are adopted in routine practice.

Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.

One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third (n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations.

The relationship of microvascular inflammation with antibody-mediated rejection in kidney transplantation.

Microvascular inflammation (MVI) is a key diagnostic feature of antibody-mediated rejection (AMR); however, recipients without donor-specific antibodies (DSA) defy etiologic classification using C4d staining of peritubular capillaries (C4dptc) and conventional DSA assignment. We evaluated MVI ≥ 2 (Banff g + ptc ≥ 2) using Banff 2019 AMR (independent of MVI ≥ 2 but including C4dptc) with unconventional endothelial C4d staining of glomerular capillaries (C4dglom) and - arterial endothelium and/or intima (C4dart) using tissue immunoperoxidase, shared-eplet and subthreshold DSA (median fluorescence intensity, [MFI] 100-499), and capillary ultrastructure from 3398 kidney transplant samples for evidence of AMR. MVI ≥ 2 (n = 202 biopsies) from 149 kidneys (12.4% prevalence) correlated with DSA+, C4dptc+, C4dglom+, Banff cg, i, t, ti scores, serum creatinine, proteinuria, and graft failure compared with 202 propensity score matched normal controls. The laboratory reported DSA- MVI ≥ 2 (MFI ≥500) occurred in 34.7%; however, subthreshold (28.6%), eplet-directed (51.4%), and/or misclassified anti-Human leukocyte antigen (HLA) DSA (12.9%) were identified in 67.1% by forensic reanalysis, with vascular C4d+ staining in 67.1%, and endothelial abnormalities in 57.1%, totaling 87.1%. Etiologic analysis attributed 62.9% to AMR (77.8% for MVI with negative reported DSA [DSA- MVI ≥2] with glomerulitis) and pure T cellular rejection in 37.1%. C4dptc-DSA- MVI ≥ 2 was unrecognized AMR in 48.0%. Functional outcomes and graft survival were comparable to normal controls. We concluded that DSA- MVI ≥ 2 frequently signified a mild "borderline" phenotype of AMR which was recognizable using novel serologic and pathological techniques.

Statistical optimization of guest uptake in crystalline sponges: grading structural outcomes.

Investigation of the analyte soaking conditions on the crystalline sponge {[(ZnI2)3(tpt)2·x(solvent)]n} method using a statistical design of experiments model has provided fundamental insights into the influence of experimental variables. This approach focuses on a single analyte tested via 60 experiments (20 unique conditions) to identify the main effects for success and overall guest structure quality. This is employed as a basis for the development of a novel molecular structure grading system that enables the quantification of guest exchange quality.

Identifying erroneous height and weight values from adult electronic health records in the All of Us research program.

INTRODUCTION: Electronic Health Records (EHR) are a useful data source for research, but their usability is hindered by measurement errors. This study investigated an automatic error detection algorithm for adult height and weight measurements in EHR for the All of Us Research Program (All of Us). METHODS: We developed reference charts for adult heights and weights that were stratified on participant sex. Our analysis included 4,076,534 height and 5,207,328 wt measurements from âˆ¼ 150,000 participants. Errors were identified using modified standard deviation scores, differences from their expected values, and significant changes between consecutive measurements. We evaluated our method with chart-reviewed heights (8,092) and weights (9,039) from 250 randomly selected participants and compared it with the current cleaning algorithm in All of Us. RESULTS: The proposed algorithm classified 1.4 % of height and 1.5 % of weight errors in the full cohort. Sensitivity was 90.4 % (95 % CI: 79.0-96.8 %) for heights and 65.9 % (95 % CI: 56.9-74.1 %) for weights. Precision was 73.4 % (95 % CI: 60.9-83.7 %) for heights and 62.9 (95 % CI: 54.0-71.1 %) for weights. In comparison, the current cleaning algorithm has inferior performance in sensitivity (55.8 %) and precision (16.5 %) for height errors while having higher precision (94.0 %) and lower sensitivity (61.9 %) for weight errors. DISCUSSION: Our proposed algorithm outperformed in detecting height errors compared to weights. It can serve as a valuable addition to the current All of Us cleaning algorithm for identifying erroneous height values.

Adjuvant and post-recurrent treatment patterns in patients with resectable gastric cancer in japan: a retrospective database cohort study.

BACKGROUND: This study examined temporal shifts in adjuvant therapy patterns in Japanese patients with resectable gastric cancer (GC) and treatment patterns of first-line and subsequent therapy among those with recurrent disease. METHODS: This retrospective analysis of hospital-based administrative claims data (April 1, 2008 to March 31, 2022) included adults (aged ≥ 20 years) with GC who started adjuvant therapy on or after October 1, 2008 (adjuvant cohort) and patients in the adjuvant cohort with disease recurrence (recurrent cohort), further defined by the time to recurrence (≤ 180 or > 180 days after adjuvant therapy). RESULTS: In the adjuvant cohort (n = 17,062), the most common regimen during October 2008-May 2016 was tegafur/gimeracil/oteracil potassium (S-1; 95.7%). As new standard adjuvant regimen options were established, adjuvant S-1 use decreased to 65.0% and fluoropyrimidine plus oxaliplatin or docetaxel plus S-1 use increased to 15.0% and 20.0%, respectively, in September 2019-March 2022. In the recurrent cohort with no history of trastuzumab/trastuzumab deruxtecan treatment (n = 1257), the most common first-line regimens were paclitaxel plus ramucirumab (34.0%), capecitabine plus oxaliplatin (CapeOX; 17.0%), and nab-paclitaxel plus ramucirumab (10.1%) in patients with early recurrence, and S-1 plus oxaliplatin (26.3%), S-1 plus cisplatin (15.3%), CapeOX (14.0%), S-1 (13.2%), and paclitaxel plus ramucirumab (10.8%) in those with late recurrence. CONCLUSIONS: This study demonstrated temporal shifts in adjuvant treatment patterns that followed the establishment of novel regimens, and confirmed that post-recurrent treatment patterns were consistent with the Japanese Gastric Cancer Association guideline recommendations.

Empowering students to create their dramatizations increases understanding of physiology.

Complex subjects such as physiology can be challenging for students to learn. These challenges are not uncommon in implementing the learning process in physiology and affect learning outcomes. Dramatization is an interactive and effective method to improve learning outcomes. In a project designed by senior medical students, junior medical students were guided in creating dramatizations related to three topics. Senior students were trained and assisted to prepare scenarios and make videos. The dramatizations were then carried out with junior medical students to help them better understand physiology and pathophysiology topics. A group of junior students receiving the same topics in a lecture format served as a control group. Pretest and posttest questionnaires were used to measure the improvement of learning outcomes. Assessment results showed an increase in performance in both groups. This study shows that dramatizations provide an effective alternative to lectures for instructing junior medical students.NEW & NOTEWORTHY The preparation of dramatizations involved students. The ideas, analogies, and dramatizations were originally from students. Dramatization is an alternative form of understanding learning objectives of medical physiology in an interesting way to increase motivation.

Patient Characteristics, Treatment Patterns, and Outcomes for Patients With Renal Cell Carcinoma in England: A Retrospective Cohort Study.

BACKGROUND AND OBJECTIVE: Considering the rapidly evolving treatment landscape of renal cell carcinoma (RCC), recent descriptions of the RCC population in the UK are lacking, as are real-world data on treatment and patient outcomes. To analyse the demographic and clinical characteristics, treatment patterns, and overall survival of patients with RCC using national data sets in England. PATIENTS AND METHODS: This was a retrospective cohort study of patients diagnosed with RCC (all stages) between 2014-2018 using demographic, clinical, cancer registration, and treatment data. Patients were followed until death or study end (December 31, 2020). Treatments administered in each line were described to understand treatment sequencing. Kaplan-Meier methods were used for time-to-event analyses. Factors associated with discontinuation and survival were identified using Cox proportional hazard models. RESULTS AND LIMITATIONS: Among 32,577 included patients, the median age at diagnosis was 66 years, 63.4% were male, and 6,786 (20.8%) had metastatic RCC at diagnosis. Tyrosine kinase inhibitor (TKI) monotherapy was the most common treatment class across lines. Over three quarters of patients (78.5% [95% CI: 78.0-78.9]) were alive one year after diagnosis (93.2% in the non-metastatic at diagnosis subgroup and 37.1% among patients with metastases at diagnosis). At three years post initial diagnosis, 18.0% patients were alive in the metastatic at diagnosis subgroup. Rapid evolution of the treatment landscape limits the results regarding lines of therapy. CONCLUSION: This large-scale study provides insight on characteristics of patients with RCC, and it highlights the need for better treatment options to improve survival.

Immune Checkpoint Inhibitors in Recipients of Renal Allografts.

Kidney transplant recipients are at increased risk of malignancy as a result of immunosuppression and are increasingly exposed to checkpoint inhibitors (CPIs). However, CPI therapy can precipitate allograft rejection. This review aims to summarize the current literature describing the epidemiology, immunological mechanisms, diagnosis, and treatment of CPI-associated allograft rejection.Initial studies of CPIs suggested allograft rejection post commencement of CPIs occured commonly (40-60%), occurring between 2 and 6 weeks after CPI initiation, with a cancer response rate approaching 50%. More recent studies with predefined, structured immunosuppressive regimens have seen rejection rates of 0-12.5%, with rejection occurring later. Allograft biopsy remains the mainstay of diagnosis; however, noninvasive tools are emerging, including donor-derived cell-free DNA, urinary chemokine assessment, and defining alloreactive T-cell clones prior to or during CPI therapy.

PheWAS analysis on large-scale biobank data with PheTK.

Summary: With the rapid growth of genetic data linked to electronic health record data in huge cohorts, large-scale phenome-wide association study (PheWAS), have become powerful discovery tools in biomedical research. PheWAS is an analysis method to study phenotype associations utilizing longitudinal electronic health record (EHR) data. Previous PheWAS packages were developed mostly in the days of smaller biobanks and with earlier PheWAS approaches. PheTK was designed to simplify analysis and efficiently handle biobank-scale data. PheTK uses multithreading and supports a full PheWAS workflow including extraction of data from OMOP databases and Hail matrix tables as well as PheWAS analysis for both phecode version 1.2 and phecodeX. Benchmarking results showed PheTK took 64% less time than the R PheWAS package to complete the same workflow. PheTK can be run locally or on cloud platforms such as the All of Us Researcher Workbench ( All of Us ) or the UK Biobank (UKB) Research Analysis Platform (RAP). Availability and implementation: The PheTK package is freely available on the Python Package Index (PyPi) and on GitHub under GNU Public License (GPL-3) at https://github.com/nhgritctran/PheTK . It is implemented in Python and platform independent. The demonstration workspace for All of Us will be made available in the future as a featured workspace. Contact: PheTK@mail.nih.gov.

Developing and evaluating pediatric phecodes (Peds-Phecodes) for high-throughput phenotyping using electronic health records.

OBJECTIVE: Pediatric patients have different diseases and outcomes than adults; however, existing phecodes do not capture the distinctive pediatric spectrum of disease. We aim to develop specialized pediatric phecodes (Peds-Phecodes) to enable efficient, large-scale phenotypic analyses of pediatric patients. MATERIALS AND METHODS: We adopted a hybrid data- and knowledge-driven approach leveraging electronic health records (EHRs) and genetic data from Vanderbilt University Medical Center to modify the most recent version of phecodes to better capture pediatric phenotypes. First, we compared the prevalence of patient diagnoses in pediatric and adult populations to identify disease phenotypes differentially affecting children and adults. We then used clinical domain knowledge to remove phecodes representing phenotypes unlikely to affect pediatric patients and create new phecodes for phenotypes relevant to the pediatric population. We further compared phenome-wide association study (PheWAS) outcomes replicating known pediatric genotype-phenotype associations between Peds-Phecodes and phecodes. RESULTS: The Peds-Phecodes aggregate 15 533 ICD-9-CM codes and 82 949 ICD-10-CM codes into 2051 distinct phecodes. Peds-Phecodes replicated more known pediatric genotype-phenotype associations than phecodes (248 vs 192 out of 687 SNPs, P < .001). DISCUSSION: We introduce Peds-Phecodes, a high-throughput EHR phenotyping tool tailored for use in pediatric populations. We successfully validated the Peds-Phecodes using genetic replication studies. Our findings also reveal the potential use of Peds-Phecodes in detecting novel genotype-phenotype associations for pediatric conditions. We expect that Peds-Phecodes will facilitate large-scale phenomic and genomic analyses in pediatric populations. CONCLUSION: Peds-Phecodes capture higher-quality pediatric phenotypes and deliver superior PheWAS outcomes compared to phecodes.

Anesthesia and postpartum pain management for placenta accreta spectrum: The healthcare provider perspective.

OBJECTIVE: To explore the management and experiences of healthcare providers around anesthetic care in placenta accreta spectrum (PAS). METHODS: This descriptive survey study was carried out over a 6-week period between January and March 2023. Healthcare providers, both anesthesiologists and those involved in operative care for women with PAS, were invited to participate. Questions invited both quantitative and qualitative responses. Qualitative responses were analyzed using content analysis. RESULTS: In all, 171 healthcare providers responded to the survey, the majority of whom were working in tertiary PAS referral centers (153; 89%) and 116 (70%) had more than 10 years of clinical experience. There was variation in the preferred primary mode of anesthesia for PAS cases; 69 (42%) used neuraxial only, but 58 (35%) used a combined approach of neuraxial and general anesthesia, with only 12 (8%) preferring general anesthesia. Ninety-nine (61%) were offering a routine antenatal anesthesia consultation. Content analysis of qualitative data identified three main themes, which were "variation in approach to primary mode of anesthesia", "perspectives of patient preferences", and "importance of multidisciplinary team care". These findings led to the development of a decision aid provided as part of this paper, which may assist clinicians in counseling women on their options for care to come to an informed decision. CONCLUSIONS: Approach to anesthesia for PAS varied between healthcare providers. The final decision for anesthesia should take into consideration the clinical care needs as well as the preferences of the patient.

Anesthesia and postpartum pain management for placenta accreta spectrum: The patient perspective and recommendations for care.

OBJECTIVE: Placenta accreta spectrum (PAS) is a high-risk complication of pregnancy, which often requires complex surgical intervention. There is limited literature on the patient experience during the perioperative period and postpartum pain management for PAS. Therefore, this study aims to explore the patient perspective of anesthesia care. METHODS: Ethical approval was granted by the hospital ethics committee (EC02.2023). This was a descriptive survey study, including women with a history of pregnancy complicated by PAS who were members of two patient advocacy groups. The survey, consisting of both open and closed questions, was performed over a 6-week period between January and March 2023. Content analysis was performed on qualitative data to identify themes, and recommendations for care are suggested. RESULTS: A total of 347 participants responded to the survey; 76% (n = 252) had a cesarean hysterectomy (n = 252), and general anesthesia was the most common primary mode of anesthesia (39%, n = 130). We identified two overarching themes: experiences of anesthesia and experience of postpartum pain management. Under experiences of anesthesia, three subthemes were identified, namely "communication with the anesthesiologist", "deferring to the expertise of the team", and "consequences of decision around the mode of anesthesia." Under postpartum pain management, two subthemes emerged: "support of specialist PAS team" and "poor pain management following PAS surgery". CONCLUSIONS: Women want to be involved in decisions around their care, but do not always understand the consequences of their decision-making, such as missing the birth of their child. An antenatal anesthesiology consultation is important to provide women with information, explore preferences, and develop a plan of care for the birth.

Bullous Variant of Central Serous Chorioretinopathy in Goodpasture's Disease - A Case Report and Review of Literature.

PURPOSE: To describe a case of bullous variant of central serous chorioretinopathy (CSR) in Goodpasture's disease (GD) compared to an identical twin without GD, and summarize the literature on ocular manifestations of GD. METHODS: Interventional/observational case report and literature review. RESULTS: A 46-year-old white female with a history of GD presented with decreased vision. She demonstrated bilateral multifocal pigment epithelial detachments and a large inferior exudative retinal detachment in the left eye consistent with bilateral CSR with bullous variant CSR (bvCSR) in the left eye. Despite treatment, her disease remained refractory, with final VA of 20/200 in the left eye. The patient's identical twin sister did not have GD and demonstrated milder CSR on presentation with a more typical, self-limited disease course. Her final VA was 20/20 bilaterally. CONCLUSION: GD is associated with severe manifestations of CSR (exudative RD). Additional studies focusing on the association between GD and CSR severity may be of interest.

Next-generation phenotyping: introducing phecodeX for enhanced discovery research in medical phenomics.

MOTIVATION: Phecodes are widely used and easily adapted phenotypes based on International Classification of Diseases codes. The current version of phecodes (v1.2) was designed primarily to study common/complex diseases diagnosed in adults; however, there are numerous limitations in the codes and their structure. RESULTS: Here, we present phecodeX, an expanded version of phecodes with a revised structure and 1,761 new codes. PhecodeX adds granularity to phenotypes in key disease domains that are under-represented in the current phecode structure-including infectious disease, pregnancy, congenital anomalies, and neonatology-and is a more robust representation of the medical phenome for global use in discovery research. AVAILABILITY AND IMPLEMENTATION: phecodeX is available at https://github.com/PheWAS/phecodeX.