Remote-Use Applications of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised Clinical Outcome Assessment Tool: A Scoping Review.

OBJECTIVES: In 2021, the US Congress passed the Accelerating Access to Critical Therapies for Amyotrophic Lateral Sclerosis Act. The law encourages development of "tools, methods, and processes" to improve clinical trial efficiency for neurodegenerative diseases. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is an outcome measure administered during in-person clinic visits and used to support investigational studies for persons living with amyotrophic lateral sclerosis. Availability of a standardized, remote-use version of the ALSFRS-R may promote more inclusive, decentralized clinical trials. A scoping literature review was conducted to identify existing remote-use ALSFRS-R tools, synthesize feasibility and comparability of administration modes, and summarize barriers and facilitators to inform development of a standardized remote-use ALSFRS-R tool. METHODS: Included studies reported comparisons between remote and in-person, clinician-reported, ALSFRS-R administration and were published in English (2002-2022). References were identified by searching peer-reviewed and gray literature. Twelve studies met the inclusion criteria and were analyzed to compare findings within and across modes of administration. RESULTS: Remote modes of ALSFRS-R administration were categorized into 4 nonmutually exclusive categories: telephone (n = 6), videoconferencing (n = 3), computer or online platforms (n = 3), mobile applications and wearables (n = 2), and 1 unspecified telemedicine modality (n = 1). Studies comparing in-person to telephone or videoconferencing administration reported high ALSFRS-R rating correlations and nonsignificant between-mode differences. CONCLUSIONS: There is insufficient information in the ALSFRS-R literature to support remote clinician administration for collecting high quality data. Future research should engage persons living with amyotrophic lateral sclerosis, care partners, and providers to develop a standardized remote-use ALSFRS-R version.

How do features of dynamic postural stability change with age during quiet standing, gait, and obstacle crossing?

Previous research has reported mixed findings regarding age-related changes in dynamic postural stability, quantified by margin of stability (MOS), during gait. However, age-related changes in MOS may be better elicited by tasks imposing greater challenges to the postural control system. Older adults' MOS during obstacle crossing, a destabilizing task, has previously been characterized, although studies comparing MOS during this task between younger and older adults remain sparse. This study investigated age-related changes in dynamic postural stability during quiet standing, gait, and obstacle crossing. Participants aged 20-30 (n = 20), 60-69 (n = 18), 70-79 (n = 15), and 80+ (n = 7; not analyzed statistically) years old performed these tasks while whole-body motion was tracked using motion capture. MOS in each direction was estimated throughout each trial, and integrals, transient ranges, and trial minima were extracted (as applicable). MOS time series were also ensemble averaged across age groups. No age-related differences were identified for quiet standing or gait. However, obstacle crossing metrics revealed greater stability (i.e., more positive MOS) and less instability (i.e., less negative MOS) in older adults, and reduced ranges during transients. These findings potentially arise from shorter step lengths, which may be the result of age-related physical declines; or may reflect a cautious strategy in older adults, which maximizes postural stability in the direction with the greatest consequences for foot-obstacle contact, as it changes throughout the task. This study supports the use of tasks imposing physical challenges and/or voluntary perturbations to study age-related changes in dynamic postural stability. Findings also contribute to our theoretical understanding of the time course of dynamic postural stability during functional tasks in relation to periods of transition in the base of support, and task-specific strategies adopted for obstacle crossing by older adults to maintain dynamic postural stability and mitigate fall risk.

Using differential mobility spectrometry to improve the specificity of targeted measurements of 2,3-dinor 11ß-Prostaglandin F2α.

INTRODUCTION: 2,3-dinor 11ß-Prostaglandin F2α (BPG) is an arachidonic acid derivative and the most abundant metabolic byproduct of prostaglandin D2, which is released during mast cell activation. Therefore, measurements of BPG in urine using liquid chromatography-tandem mass spectrometry (LC-MS/MS) provide a noninvasive method for evaluation and management of mast cell disorders. Measurements obtained by LC-MS/MS exhibit a high prevalence of chromatographic interferences resulting in challenges with optimal determination of BGP. In this investigation, differential mobility spectrometry (DMS) is utilized to overcome the limitations of current testing. METHODS: Urine samples were extracted using an automated solid-phase extraction method. Samples were then analyzed with and without DMS devices installed on two commercially available mass spectrometry platforms to assess the benefits of DMS. Following promising results from a preliminary analytical evaluation, LC-DMS-MS/MS measurements of BPG in urine were fully validated to assess the analytical implications of using this technology. RESULTS AND DISCUSSION: The addition of DMS devices to the LC-MS/MS systems evaluated in this investigation significantly reduced interferences observed in the chromatograms. Concomitantly, DMS reduced the number of discordant quantifier/qualifier fragment ion results that significantly exceeded the ± 20 % limits, suggesting greater analytical specificity. The validation studies yielded low interday imprecision, with %CVs less than 6.5 % across 20 replicate measurements. Validation studies assessing other aspects of analytical performance also met acceptance criteria. CONCLUSIONS: Incorporating DMS devices greatly improved the specificity of BPG measurements by LC-MS/MS, as evidenced by the comparison of chromatograms and fragment ion results. Validation studies showed exceptional performance for established analytical metrics, indicating that this technology can be used to minimize the impact of interferences without adversely impacting other aspects of analytical or clinical performance.

A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research.

Parkinson's disease and dementia with Lewy bodies are currently defined by their clinical features, with α-synuclein pathology as the gold standard to establish the definitive diagnosis. We propose that, given biomarker advances enabling accurate detection of pathological α-synuclein (ie, misfolded and aggregated) in CSF using the seed amplification assay, it is time to redefine Parkinson's disease and dementia with Lewy bodies as neuronal α-synuclein disease rather than as clinical syndromes. This major shift from a clinical to a biological definition of Parkinson's disease and dementia with Lewy bodies takes advantage of the availability of tools to assess the gold standard for diagnosis of neuronal α-synuclein (n-αsyn) in human beings during life. Neuronal α-synuclein disease is defined by the presence of pathological n-αsyn species detected in vivo (S; the first biological anchor) regardless of the presence of any specific clinical syndrome. On the basis of this definition, we propose that individuals with pathological n-αsyn aggregates are at risk for dopaminergic neuronal dysfunction (D; the second biological anchor). Our biological definition establishes a staging system, the neuronal α-synuclein disease integrated staging system (NSD-ISS), rooted in the biological anchors (S and D) and the degree of functional impairment caused by clinical signs or symptoms. Stages 0-1 occur without signs or symptoms and are defined by the presence of pathogenic variants in the SNCA gene (stage 0), S alone (stage 1A), or S and D (stage 1B). The presence of clinical manifestations marks the transition to stage 2 and beyond. Stage 2 is characterised by subtle signs or symptoms but without functional impairment. Stages 2B-6 require both S and D and stage-specific increases in functional impairment. A biological definition of neuronal α-synuclein disease and an NSD-ISS research framework are essential to enable interventional trials at early disease stages. The NSD-ISS will evolve to include the incorporation of data-driven definitions of stage-specific functional anchors and additional biomarkers as they emerge and are validated. Presently, the NSD-ISS is intended for research use only; its application in the clinical setting is premature and inappropriate.

Teaching endoscopic management of gastrointestinal hemorrhage using a modular simulation curriculum.

BACKGROUND: As flexible endoscopy is increasingly adopted as a minimally invasive approach to surgical challenges, an efficient curriculum is needed to train surgeons in therapeutic endoscopy. We developed a simulation-based approach to teaching endoscopic management of gastrointestinal hemorrhage as part of a modular curriculum, complete with task performance pre- and post-testing. METHODS: Two sessions of our advanced flexible endoscopy course were taught using ex vivo porcine models to simulate active gastrointestinal hemorrhage and allow for training in hands-on endoscopic management. The module is composed of hands-on pretesting, didactics, mentored practice sessions, and postcourse assessments. Pre- and postcourse tests and surveys evaluated knowledge, confidence, and performance of participants and results were analyzed using the paired t test. RESULTS: Sixteen practicing surgeons participated in the course. After course completion, overall knowledge-based assessments improved from 3.4 (±1.9) to 5.8 (±2.0) (P < .001). Although participants with glove sizes >7.0 and ≥2 years in practice had higher pretest evaluator scores (P = .045 and P = .020), all participants demonstrated overall improvement in endoscopic management of hemorrhage, with postcourse evaluator score increases from 20.9 (±1.6) to 23.6 (±2.0) (P = .001) and specific improvements in identification of target bleeding (P = .015), endoscopic clip setup (P < .001), and clip deployment (P = .002). Surveys also found increased confidence in competency after curriculum completion, 11.6 (±3.4)-23.0 (±5.5) (P < .001). CONCLUSION: Our simulation-based approach to teaching the endoscopic management of gastrointestinal bleeding emphasizes hands-on pretesting and provides an effective training model to improve the knowledge, confidence, and technical performance of practicing surgeons.

Prospective epigenome and transcriptome analyses of cord and peripheral blood from preterm infants at risk of bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease of prematurity with limited treatment options. To uncover biomarkers of BPD risk, this study investigated epigenetic and transcriptomic signatures of prematurity at birth and during the neonatal period at day 14 and 28. Peripheral blood DNAs from preterm infants were applied to methylation arrays and cell-type composition was estimated by deconvolution. Covariate-adjusted robust linear regression elucidated BPD- and prolonged oxygen (≥ 14 days) exposure-associated CpGs. RNAs from cord and peripheral blood were sequenced, and differentially expressed genes (DEGs) for BPD or oxygen exposure were determined. Estimated neutrophil-lymphocyte ratios in peripheral blood at day 14 in BPD infants were significantly higher than nonBPD infants, suggesting an heightened inflammatory response in developing BPD. BPD-DEGs in cord blood indicated lymphopoiesis inhibition, altered Th1/Th2 responses, DNA damage, and organ degeneration. On day 14, BPD-associated CpGs were highly enriched in neutrophil activation, infection, and CD4 + T cell quantity, and BPD-DEGs were involved in DNA damage, cellular senescence, T cell homeostasis, and hyper-cytokinesis. On day 28, BPD-associated CpGs along with BPD-DEGs were enriched for phagocytosis, neurological disorder, and nucleotide metabolism. Oxygen supplementation markedly downregulated mitochondrial biogenesis genes and altered CpGs annotated to developmental genes. Prematurity-altered DNA methylation could cause abnormal lymphopoiesis, cellular assembly and cell cycle progression to increase BPD risk. Similar pathways between epigenome and transcriptome networks suggest coordination of the two in dysregulating leukopoiesis, adaptive immunity, and innate immunity. The results provide molecular insights into biomarkers for early detection and prevention of BPD.

Recommendations on the Selection, Development, and Modification of Performance Outcome Assessments: A Good Practices Report of an ISPOR Task Force.

In evaluating the clinical benefit of new therapeutic interventions, it is critical that the treatment outcomes assessed reflect aspects of health that are clinically important and meaningful to patients. Performance outcome (PerfO) assessments are measurements based on standardized tasks actively undertaken by a patient that reflect physical, cognitive, sensory, and other functional skills that bring meaning to people's lives. PerfO assessments can have substantial value as drug development tools when the concepts of interest being measured best suit task performance and in cases where patients may be limited in their capacity for self-report. In their development, selection, and modification, including the evaluation and documentation of validity, reliability, usability, and interpretability, the good practice recommendations established for other clinical outcome assessment types should continue to be followed, with concept elicitation as a critical foundation. In addition, the importance of standardization, and the need to ensure feasibility and safety, as well as their utility in patient groups, such as pediatric populations, or those with cognitive and psychiatric challenges, may enhance the need for structured pilot evaluations, additional cognitive interviewing, and evaluation of quantitative data, such as that which would support concept confirmation or provide ecological evidence and other forms of construct evidence within a unitary approach to validity. The opportunity for PerfO assessments to inform key areas of clinical benefit is substantial and establishing good practices in their selection or development, validation, and implementation, as well as how they reflect meaningful aspects of health is critical to ensuring high standards and in furthering patient-focused drug development.

Epigenomic profiling of isolated blood cell types reveals highly specific B cell smoking signatures and links to disease risk.

BACKGROUND: Tobacco smoking alters the DNA methylation profiles of immune cells which may underpin some of the pathogenesis of smoking-associated diseases. To link smoking-driven epigenetic effects in specific immune cell types with disease risk, we isolated six leukocyte subtypes, CD14+ monocytes, CD15+ granulocytes, CD19+ B cells, CD4+ T cells, CD8+ T cells, and CD56+ natural killer cells, from whole blood of 67 healthy adult smokers and 74 nonsmokers for epigenome-wide association study (EWAS) using Illumina 450k and EPIC methylation arrays. RESULTS: Numbers of smoking-associated differentially methylated sites (smCpGs) at genome-wide significance (p < 1.2 × 10-7) varied widely across cell types, from 5 smCpGs in CD8+ T cells to 111 smCpGs in CD19+ B cells. We found unique smoking effects in each cell type, some of which were not apparent in whole blood. Methylation-based deconvolution to estimate B cell subtypes revealed that smokers had 7.2% (p = 0.033) less naïve B cells. Adjusting for naïve and memory B cell proportions in EWAS and RNA-seq allowed the identification of genes enriched for B cell activation-related cytokine signaling pathways, Th1/Th2 responses, and hematopoietic cancers. Integrating with large-scale public datasets, 62 smCpGs were among CpGs associated with health-relevant EWASs. Furthermore, 74 smCpGs had reproducible methylation quantitative trait loci single nucleotide polymorphisms (SNPs) that were in complete linkage disequilibrium with genome-wide association study SNPs, associating with lung function, disease risks, and other traits. CONCLUSIONS: We observed blood cell-type-specific smCpGs, a naïve-to-memory shift among B cells, and by integrating genome-wide datasets, we identified their potential links to disease risks and health traits.

Relative Meaningfulness and Impacts of Symptoms in People with Early-Stage Parkinson's Disease.

BACKGROUND: Patient perspectives on meaningful symptoms and impacts in early Parkinson's disease (PD) are lacking and are urgently needed to clarify priority areas for monitoring, management, and new therapies. OBJECTIVE: To examine experiences of people with early-stage PD, systematically describe meaningful symptoms and impacts, and determine which are most bothersome or important. METHODS: Forty adults with early PD who participated in a study evaluating smartwatch and smartphone digital measures (WATCH-PD study) completed online interviews with symptom mapping to hierarchically delineate symptoms and impacts of disease from "Most bothersome" to "Not present," and to identify which of these were viewed as most important and why. Individual symptom maps were coded for types, frequencies, and bothersomeness of symptoms and their impacts, with thematic analysis of narratives to explore perceptions. RESULTS: The three most bothersome and important symptoms were tremor, fine motor difficulties, and slow movements. Symptoms had the greatest impact on sleep, job functioning, exercise, communication, relationships, and self-concept- commonly expressed as a sense of being limited by PD. Thematically, most bothersome symptoms were those that were personally limiting with broadest negative impact on well-being and activities. However, symptoms could be important to patients even when not present or limiting (e.g., speech, cognition). CONCLUSION: Meaningful symptoms of early PD can include symptoms that are present or anticipated future symptoms that are important to the individual. Systematic assessment of meaningful symptoms should aim to assess the extent to which symptoms are personally important, present, bothersome, and limiting.

Mapping Relevance of Digital Measures to Meaningful Symptoms and Impacts in Early Parkinson's Disease.

BACKGROUND: Adoption of new digital measures for clinical trials and practice has been hindered by lack of actionable qualitative data demonstrating relevance of these metrics to people with Parkinson's disease. OBJECTIVE: This study evaluated of relevance of WATCH-PD digital measures to monitoring meaningful symptoms and impacts of early Parkinson's disease from the patient perspective. METHODS: Participants with early Parkinson's disease (N = 40) completed surveys and 1:1 online-interviews. Interviews combined: 1) symptom mapping to delineate meaningful symptoms/impacts of disease, 2) cognitive interviewing to assess content validity of digital measures, and 3) mapping of digital measures back to personal symptoms to assess relevance from the patient perspective. Content analysis and descriptive techniques were used to analyze data. RESULTS: Participants perceived mapping as deeply engaging, with 39/40 reporting improved ability to communicate important symptoms and relevance of measures. Most measures (9/10) were rated relevant by both cognitive interviewing (70-92.5%) and mapping (80-100%). Two measures related to actively bothersome symptoms for more than 80% of participants (Tremor, Shape rotation). Tasks were generally deemed relevant if they met three participant context criteria: 1) understanding what the task measured, 2) believing it targeted an important symptom of PD (past, present, or future), and 3) believing the task was a good test of that important symptom. Participants did not require that a task relate to active symptoms or "real" life to be relevant. CONCLUSION: Digital measures of tremor and hand dexterity were rated most relevant in early PD. Use of mapping enabled precise quantification of qualitative data for more rigorous evaluation of new measures.

Experience with Impedance Planimetry for Surgical Foregut Disease in 1,097 Cases.

BACKGROUND: The geometry and compliance of gastrointestinal sphincters may be assessed by impedance planimetry using a functional lumen imaging probe (FLIP). We describe our institutional foregut surgeon experience using FLIP in 1,097 cases, highlighting instances where FLIP changed operative decision making. STUDY DESIGN: A retrospective review of an IRB-approved prospective quality database was performed. This included operative and endoscopic suite foregut procedures using FLIP between February 2013 and May 2022. RESULTS: During the study period, FLIP was used a total of 1,097 times in 919 unique patients by 2 foregut surgeons. Intraoperative FLIP was used during 573 antireflux procedures and 272 endoscopic myotomies. FLIP was also used during 252 endoscopic suite procedures. For those undergoing preoperative workup of GERD, starting in 2021, esophageal panometry was performed in addition to standard FLIP measurements at the lower esophageal sphincter. In 77 cases, intraoperative FLIP changed operative decision making. During antireflux procedures, changes included adding or removing crural sutures, adjusting a fundoplication tightness, choice of full vs partial wrap, and magnetic sphincter augmentation sizing. For endoscopic procedures, changes included aborting peroral endoscopic myotomy or Zenker's peroral endoscopic myotomy, performing a myotomy when preoperative diagnosis was unclear, or performing additional myotomy. CONCLUSIONS: FLIP is a useful tool for assessing the upper esophageal sphincter, lower esophageal sphincter, pylorus, and secondary esophageal peristalsis that can be used in a wide variety of clinical situations within a foregut surgeon's practice. It can also function as an adjunct in intraoperative decision making.

Esophagogastric junction compliance on impedance planimetry (EndoFLIP™) following peroral endoscopic myotomy (POEM) predicts improvement in postoperative eckardt score.

BACKGROUND: Peroral endoscopic myotomy (POEM) is a mainstay of treatment for achalasia. Tailored myotomy based on compliance, as measured with impedance planimetry (FLIP), has yet to be described. In this study we describe the associations between Eckardt score, postoperative GERD, and compliance. METHODS: A retrospective review of a prospectively maintained database was performed, evaluating patients who underwent POEM and intraoperative FLIP between January 2019 and November 2021. Group comparisons were made using two-tailed Wilcoxon rank-sum and Fisher's exact tests. Spearman's correlation coefficients (r) were used to assess the relationship between compliance and outcomes, all with two-tailed statistical significance of p < 0.05. RESULTS: Thirty five patients underwent POEM with intraoperative FLIP. At a 30 mL and 40 mL fill, respectively, compliance increased by 80% (180 ± 152%) and 77% (177 ± 131%) from pre to post myotomy. Mean Eckardt score improved from 5.5 ± 2.6 preoperatively to 1.3 ± 1.6 and 1.8 ± 1.9 at first and second follow up, respectively. Median times to first and second follow up were 22 days (IQR 16-23) and 65 days (IQR 58-142). A higher compliance at 40 mL fill was moderately associated with lower Eckardt score at first (r = -0.49, p = 0.012) and second (r = -0.64, p = 0.014) follow up. Post myotomy compliance ≥ 125 mm3/mmHg at 40 mL fill was associated with lower Eckardt scores, < 3, at first (0.4 ± 0.5 vs 1.8 ± 1.3, p = 0.008) and second (0.4 ± 0.5, vs 2.0 ± 1.4, p = 0.027) follow up. Compliance ≥ 125 mm3/mmHg performed better than previously defined ideal ranges of DI and CSA in predicting postoperative Eckardt scores. Compliance was not significantly associated with development of postoperative GERD. CONCLUSIONS: A target post myotomy compliance of ≥ 125 mm3/mmHg at a 40 mL fill is associated with normal Eckardt scores at first and second postoperative visits, and performs better than previously defined ideal ranges of DI and CSA in predicting post-operative Eckardt scores. Compliance is a poor predictor of developing GERD after POEM.

"Into the fire" approach to teaching endoscopic foreign body removal using a modular simulation curriculum.

BACKGROUND: As flexible endoscopy becomes an increasingly valuable minimally invasive approach to surgical challenges, an efficient and comprehensive training curriculum is needed to train surgeons in therapeutic endoscopy. We developed a modular curriculum utilizing a simulation-based, "into the fire" approach to endoscopic foreign body removal for practicing physicians with task performance pre- and post-testing. METHODS: From 2020 to 2021, two sessions of our advanced flexible endoscopy course were taught by two expert surgical endoscopists using ex-vivo porcine models. The course focused on safe removal techniques for various foreign bodies as part of an overall endoscopy curriculum that uses hands-on simulation-based pre-testing, didactics, and mentored practice sessions, followed by post-course examination. Pre- and post-course assessments and surveys were used to evaluate knowledge, performance, and confidence of participants, and subsequently analyzed using the Wilcoxon-signed rank test. RESULTS: Of the 16 practicing physicians who participated in the course, 43.8% were certified in Fundamentals of Endoscopic Surgery, and 62.5% had completed > 200 prior upper endoscopies. Upon course completion, scoring on knowledge-based written examinations improved from 3.4 ± 1.9 to 5.8 ± 2.0 (p < 0.001). Technical facility of each participant demonstrated significant overall improvement with post-course score increased from 15.8 ± 2.5 to 23.6 ± 1.6 (p < 0.001), with skill refinement noted in technical subcategories of appropriate instrument use (p < 0.001), foreign body manipulation (p < 0.001), and successful foreign body removal (p < 0.001). Confidence surveys likewise demonstrated significant increase in confidence after completion of the curriculum 11.6 ± 3.4 to 23.0 ± 5.5 (p < 0.001). CONCLUSIONS: The "into the fire" approach to teaching endoscopic foreign body removal utilizing our simulation module provides an effective curriculum to improve knowledge, confidence, and overall technical performance. Our methodology utilizes hands-on, simulation-based pre-testing prior to instruction. This introduces clinical scenarios and technical challenges, while accounting for and tailoring to provider-specific variation in knowledge and experience, facilitating training efficiency.

Patient-reported outcomes in 645 patients after laparoscopic fundoplication up to 10 years.

BACKGROUND: Laparoscopic fundoplication is the gold-standard surgical management for gastroesophageal reflux disease. Optimal patient outcomes include resolution of symptoms with minimal postoperative side effects of dysphagia or gas-bloat. This study aims to review outcomes at a single institution up to 10 years after surgery. METHODS: This is a retrospective review of a prospectively maintained quality database. Patients who underwent laparoscopic fundoplication from 2009 to 2021 were included. Transition in surgical practice mid-2017 with incorporation of fundoplication algorithm and impedance planimetry. Patient-reported outcome scores include Reflux Symptom Index, gastroesophageal reflux disease-health-related quality of life, and dysphagia score. Comparisons were made using two-tailed Wilcoxon rank sum tests. RESULTS: Six hundred forty-five patients underwent laparoscopic fundoplication (2009-July 2017 n = 355, July 2017-November 2021 n = 290) from January 2009 to November 2021. Patients had an improvement in patient-reported outcomes and did not worsen from 2 to 10 years after surgery. Comparison of each time period showed that the second time period had fewer gas-bloat symptoms at 2 years (P = .04). Paraesophageal hernia was present in 66% of patients. Preoperative patient-reported outcomes in non-paraesophageal hernia include worse Reflux Symptoms Index (P < .01) and gastroesophageal reflux disease-health-related quality of life (P < .01) than the paraesophageal hernia group. Patient-reported outcomes were similar between the 2 except for worse gas-bloat in non-paraesophageal hernia patients at 2 years (P = .02). Endoscopy was performed in 10.9% (n = 58) of the study population at a median of 16 months, with 1.5% of patients (n = 8) from the entire cohort with abnormal DeMeester Scores. Median (interquartile range) preoperative DeMeester Score of 31 (17-51) decreased to 5 (2-14) at postoperative evaluation. CONCLUSION: This single-institution study reports excellent long-term patient-reported outcomes after laparoscopic fundoplication that persist up to 10 years.

Identification of 14 novel susceptibility loci for diaphragmatic hernia development and their biological and clinical implications: results from the UK Biobank.

INTRODUCTION: Genetic contributions to hernia development are incompletely understood. This study performed the first comprehensive genome-wide association study (GWAS) for diaphragmatic hernia using a large population-based cohort in the UK Biobank (UKB). METHODS AND PROCEDURES: Two-stage GWAS (discovery and confirmation) was performed for diaphragmatic hernia in the UKB. Briefly, 275,549 and 91,850 subjects were randomly selected for association tests in Stages 1 and 2, respectively. Association tests between 8,568,156 SNPs (genotyped or imputed with MAF > 0.01) in the autosomal genome and diaphragmatic hernia were performed in Stage 1. SNPs with P < 1 × 10-5 were selected for confirmation in Stage 2, and those with P < 0.05 and the same direction of association as Stage 1 were selected for combined association testing; SNPs with combined P < 5 × 10-8 were considered GWAS-significant. LD clumping analysis identified genetically independent chromosomal regions (loci). A genetic risk score (GRS) measured the cumulative risk of independent SNPs in 91,849 additional subjects using odds ratios (ORs) from Stages 1 and 2. RESULTS: 36,351 patients were identified with diaphragmatic hernia (ICD-10 K44). In Stage 1 analysis, 2654 SNPs were associated (P < 1 × 10-5) with diaphragmatic hernia. Stage 2 analysis confirmed 338 SNPs (P < 0.05). In combined analysis, 245 SNPs reached GWAS significance (P < 5 × 10-8). LD clumping analysis revealed 14 independent loci associated with diaphragmatic hernia. Two loci have been previously associated with inguinal hernia at 2p16 (rs181661155) and 11p13 (rs5030123). eQTL analysis suggested genes CRLF1, UBA52, and CALD1 are also significantly associated with these loci. GRS showed significant increase in cases compared to controls (P < 1 × 10-16) and is associated with increased risk of diaphragmatic hernia (P < 1 × 10-7). CONCLUSIONS: We identified 245 SNPs at 14 susceptibility loci associated with diaphragmatic hernia in a large population-based cohort. These results offer insight into pathogenetic mechanisms of diaphragmatic hernia development and may be used in genetic risk scores for pre-operative risk-stratification and clinical prediction models.

Impedance Planimetry (Endoflip) and Ideal Distensibility Ranges for Optimal Outcomes after Nissen and Toupet Fundoplication.

BACKGROUND: Previous research has shown that impedance planimetry-based functional lumen imaging probe (FLIP) measurements are associated with patient-reported outcomes after laparoscopic antireflux surgery. We hypothesize that Nissen and Toupet fundoplications have different ideal FLIP profiles, such as distensibility. STUDY DESIGN: A retrospective review of a prospectively maintained quality database was performed. Patients who had FLIP measurements during fundoplications between 2013 and 2021 were included. Reflux Symptom Index, Gastroesophageal Reflux Disease-Health Related Quality of Life Questionnaire, and dysphagia score were collected for up to 2 years postoperatively. The Wilcoxon rank-sum test was used to compare FLIP measurements vs outcomes. RESULTS: Two hundred fifty patients (171 Toupet, 79 Nissen) were analyzed. Distensibility ranges were categorized as tight, ideal, or loose. The ideal distensibility index range of Toupet patients with the 30- and 40-mL balloon fills were 2.6 to 3.7 mm2/mmHg. This range was associated with less dysphagia at 1 year compared with the tight group (p = 0.02). For Nissen patients, the 30- and 40-mL ideal threshold was a distensibility index of ≥2.2 mm2/mmHg. Patients with distensibility exceeding this threshold had a better quality of life than the tight group, reporting better Gastroesophageal Reflux Disease-Health Related Quality of Life Questionnaire (p = 0.02) and lower dysphagia scores (p = 0.01) at 2 years. CONCLUSIONS: Impedance planimetry revealed different ideal distensibility ranges after Toupet and Nissen fundoplications that are associated with improved patient-reported outcomes, suggesting that intraoperative FLIP has the potential to tailor fundoplication.

Plasma neurofilament light chain (NfL) reference interval determination in an Age-stratified cognitively unimpaired cohort.

BACKGROUND AND AIMS: Neurofilament light chain (NfL) is an emerging biomarker of neurodegenerative disease progression. As plasma NfL increases with age, characterization of NfL concentrations in an age-stratified cognitively unimpaired population was assessed. MATERIALS AND METHODS: EDTA-plasma samples were measured using the Simoa® NF-light™ Advantage Kit assay. One-sided reference intervals were established from 1100 cognitive normal individuals (588 male, 512 female) aged 20 to 95 years. Of those, 927 samples were obtained from the Mayo Clinic Study of Aging cohort (age > 50 years), and the remainder (age < 50 years) were obtained from individuals without known neurological conditions. All samples were from individuals without known chronic kidney disease, stroke or myocardial infarction, and a body mass index < 30 kg/m2. RESULTS: The 97.5th percentile limits for the following age ranges (in years) were (pg/mL): 20 s: ≤8.4, 30 s: ≤11.4, 40 s: ≤15.4, 50 s: ≤20.8, 60 s: ≤28.0, 70 s: ≤37.9, 80+: ≤51.2. Sex had no significant effect on reference intervals. Observed NfL concentrations increased at a rate of 3.1 % per year of age. CONCLUSIONS: Characterization of the rate of NfL concentration increase and decade-wide reference intervals from a neurologically well-characterized patient population will aid in interpretation of NfL during the clinical evaluation of a potential neurodegenerative disease.

Analytic and Clinical Performance of Major Commercial Severe Acute Respiratory Syndrome Coronavirus 2 Molecular Assays in the United States.

The rapid development of commercially available molecular assays in response to the COVID-19 pandemic has been essential in identifying positive cases and guiding state and national response plans. With over 200 SARS-CoV-2 molecular tests having received emergency use authorization by the US Food and Drug Administration, numerous studies have been conducted to evaluate these methods and compare their analytical and clinical performance. By applying the lessons learned from the rapid development of molecular assays in response to the COVID-19 pandemic, the diagnostic industry will be better prepared to respond to future outbreaks of novel infectious diseases.

Changes in impedance planimetry (EndoFLIP) measurements at follow-up after peroral endoscopic myotomy (POEM).

BACKGROUND: Numerous studies show changes in functional lumen imaging probe (FLIP) measurements after myotomy during peroral endoscopic myotomy (POEM), but few report on FLIP measurements at follow-up esophagogastroduodenoscopy (EGD). The purpose of this study was to compare perioperative FLIP measurements to those at follow-up EGD. METHODS: Patients who underwent POEM with FLIP in the operating room and POEM patients who had EGD with FLIP at follow-up were included. FLIP measurements, including diameter (Dmin), pressure, cross-sectional area (CSA), and distensibility index (DI), were analyzed at a 30-mL balloon fill. Differences between measurements at different timepoints were assessed using a two-tailed Wilcoxon signed-rank test. RESULTS: A total of 97 patients who underwent POEM and 28 who underwent EGD with FLIP were analyzed. The average age was 63 ± 18 years and 46.4% of the patients were male. Mean preoperative Eckardt score was 6.5 ± 4.8, decreasing to 1.6 ± 2.0 at follow-up. EGDs were performed at a median of 15 months after surgery. When compared to mean measurements obtained post-myotomy, at the time of EGD, pressure was found to be significantly lower (p = 0.007) and DI significantly higher (p = 0.045). Of the patients who underwent EGD, 70.8% had an increase in DI, 55.6% had evidence of reflux esophagitis, and 81.0% met diagnostic criteria for reflux on esophageal pH monitoring. However, there was no correlation with the development of esophagitis or reflux and increase or decrease in DI at follow-up. CONCLUSIONS: There are significant changes in FLIP measurements between the time of surgery and at follow-up EGD. These results suggest that esophageal remodeling may cause changes in lower esophageal sphincter geometry after POEM and postoperative FLIP targets immediately post-myotomy may need to be adjusted to account for these changes.