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Lauren M Nelson,1 Valerie SL Williams,1 Sheri E Fehnel,1 Robyn T Carson,2 James MacDougall,3 Mollie J Baird,3 Stavros Tourkodimitris,2 Caroline B Kurtz,3 Jeffrey M Johnston31RTI Health Solutions, Durham, NC, USA; 2Forest Research Institute, Jersey City, NJ, USA; 3Ironwood Pharmaceuticals, Cambridge, MA, USABackground: Measures assessing treatment outcomes in previous CC clinical trials have not met the requirements described in the US Food and Drug Administration's guidance on patient-reported outcomes.Aim: Psychometric analyses using data from one Phase IIb study and two Phase III trials of linaclotide for the treatment of chronic constipation (CC) were conducted to document the measurement properties of patient-reported CC Symptom Severity Measures.Study methods: Each study had a multicenter, randomized, double-blind, placebo-controlled, parallel-group design, comparing placebo to four doses of oral linaclotide taken once daily for 4 weeks in the Phase IIb dose-ranging study (n=307) and to two doses of linaclotide taken once daily for 12 weeks in the Phase III trials (n=1,272). The CC Symptom Severity Measures addressing bowel function (Bowel Movement Frequency, Stool Consistency, Straining) and abdominal symptoms (Bloating, Abdominal Discomfort, Abdominal Pain) were administered daily using interactive voice-response system technology. Intraclass correlations, Pearson correlations, factor analyses, F-tests, and effect sizes were computed.Results: The CC Symptom Severity Measures demonstrated satisfactory test–retest reliability and construct validity. Factor analyses indicated one factor for abdominal symptoms and another for bowel symptoms. Known-groups F-tests substantiated the discriminating ability of the CC Symptom Severity Measures. Responsiveness statistics were moderate to strong, indicating that these measures are capable of detecting change.Conclusion: In large studies of CC patients, linaclotide significantly improved abdominal and bowel symptoms. These psychometric analyses support the reliability, validity, discriminating ability, and responsiveness of the CC Symptom Severity Measures for evaluating treatment outcomes in the linaclotide clinical studies.Keywords: psychometric evaluation, patient-reported outcomes, linaclotide

Claire M Ervin,1 Sheri E Fehnel,1 Mollie J Baird,2 Robyn T Carson,3 Jeffrey M Johnston,2 Steven J Shiff,3 Caroline B Kurtz,2 Allen W Mangel11RTI Health Solutions, Research Triangle Park, NC, USA; 2Ironwood Pharmaceuticals, Inc., Cambridge, MA, USA; 3Forest Research Institute, Jersey City, NJ, USABackground: While chronic constipation (CC) clinical trials have focused primarily on bowel symptoms (symptoms directly related to bowel movements), abdominal symptoms are also prevalent among patients. The United States Food and Drug Administration’s (FDA’s) guidance on the use of patient-reported outcome measures to support product approvals or labeling claims recommends that endpoints be developed with direct patient input and include all symptoms important to patients.Aim: To identify a comprehensive set of CC symptoms that are important to patients for measurement in clinical trials.Methods: Following a targeted literature review to identify CC symptoms previously reported by patients, 28 patient interviews were conducted consistent with the FDA’s guidance on patient-reported outcomes. Subsequent to open-ended questions eliciting descriptions of all symptoms, rating and ranking methods were used to identify those of greatest importance to patients.Results: All 67 studies reviewed included bowel symptoms; more than half also addressed at least one abdominal symptom. Interview participants reported 62 potentially distinct concepts: 12 bowel symptoms; 21 abdominal symptoms; and 29 additional symptoms/impacts. Patients’ descriptions revealed that many symptom terms were highly related and/or could be considered secondary to CC. The rating and ranking task results suggest that both bowel (for example, stool frequency and consistency) and abdominal symptoms (for example, bloating, abdominal pain) comprise patients’ most important symptoms. Further, improvements in both bowel and abdominal symptoms would constitute an improvement in patients’ CC overall.Conclusion: Abdominal symptoms in CC patients are equal in relevance to bowel symptoms and should also be addressed in clinical trials to fully evaluate treatment benefit.Keywords: abdominal symptoms, straining, infrequent bowel movements, incomplete bowel movements, patient-reported outcomes

BACKGROUND: To achieve greater coverage of the elderly smoking population, the provider/client interface could be broadened to include other professional groups who work with the elderly. We evaluated the effectiveness of a 9-h smoking cessation counseling training program for social workers. METHODS: We recruited 177 social workers and used a preintervention/postintervention longitudinal design, analyzed by multilevel, multivariable modeling to adjust for between-subjects covariables and within-subjects correlation in repeated measurements at baseline, 3 months, 6 months, and 12 months after training. RESULTS: Overall, knowledge improved from a mean score of 6.70 +/- 1.03 (+/- SD) at baseline to 7.35 +/- 0.75 at 12 months (range, 0 to 8 correct responses), attitude from 2.84 +/- 0.41 to 3.10 +/- 0.48, and self-perceived competence from 2.49 +/- 0.38 to 2.85 +/- 0.36 (range, 1 to 4, where 4 is best). On multilevel modeling, three of the four 'A's (ask, advice, assist, arrange as per the Agency for Healthcare Research and Quality framework) registered significant gains from baseline to 12 months overall, whereas 'advice' did not show any appreciable change. CONCLUSION: These findings demonstrate that our smoking cessation training program achieved sustained effectiveness in the first year after training in enhancing knowledge, positively shifting attitudes, boosting self-perceived competence, and increasing the self-reported frequency of practicing three of the four As in their routine interaction with elderly clients. [ABSTRACT FROM AUTHOR]

BACKGROUND: By one estimate, 60% of women experiencing the menopause transition perceive that they have memory problems, but most studies that have used cognitive function tests have not substantiated a relation between menopause stage and cognitive performance. We sought to describe the cross-sectional relation between menopause status, estradiol (E(2)), follicle-stimulating hormone (FSH), and measured cognitive function. METHODS: Cross sectional analysis of a community-based cohort of midlife women was used. Cognitive tests were the East Boston Memory Test, Symbol Digit Modalities, and Digits Span Backward. Menopause categories (premenopausal, early perimenopausal, late perimenopausal, and postmenopausal) were defined based on menstrual patterns. One set of general linear models assessed the relations between each cognitive test and menopause transition category, initially adjusted for age, race/ethnicity, education, symptoms, self-rated general health, and body mass index (BMI); next, these were additionally adjusted for FSH and E(2). A second set of models, stratified by menopause status, examined the possible relations between each cognitive test and either E(2) or FSH, adjusted for age, race/ethnicity, education, symptoms, self-related general health, and BMI. RESULTS: The mean age of the analytical sample (n = 1657) was 49.7 years. Only 5% of the sample had less than a high school education, 16% graduated from high school, and the rest had at least some college. The percent of women in each menopause category was premenopausal (9.0%), early perimenopausal (57.0%), late perimenopausal (13.4%), postmenopausal (20.6%). Although clinical-site adjusted models showed moderate differences between menopause transition groups and cognitive performance, no association was found between each of the measured cognitive performance tests and menopause transition status when adjusting for covariates. Similarly, no association between each cognitive test and E(2) or FSH was found. CONCLUSIONS: This study does not support a cross-sectional relation between cognitive test performance and menopause stage, FSH, or E(2). [ABSTRACT FROM AUTHOR]

BACKGROUND: Classification of menopausal status is important for epidemiological and clinical studies as well as for clinicians treating midlife women. Most epidemiological studies, including the Study of Women's Health Across the Nation (SWAN), classify women based on self-reported bleeding history. METHODS: The Women's Ischemia Syndrome Evaluation (WISE) study developed an algorithm using menstrual and reproductive history and serum hormone levels to reproduce the menopausal status classifications assigned by the WISE hormone committee. We applied that algorithm to women participating in SWAN and examined characteristics of women with concordant and discordant SWAN and WISE classifications. RESULTS: Of the 3215 SWAN women with complete information at baseline (1995-1997), 2466 (76.7%) received concordant classifications (kappa = 0.52); at the fifth annual follow-up visit, of the 1623 women with complete information, 1154 (72.7%) received concordant classifications (kappa = 0.57). At each time point, we identified subgroups of women with discordant SWAN and WISE classifications. These subgroups, ordered by chronological age, showed increasing trends for menopausal symptoms and follicle-stimulating hormone (FSH) and a decreasing trend for estrogen (p < 0.001). CONCLUSIONS: The WISE algorithm is a useful tool for studies that have access to blood samples for hormone data unrelated to menstrual cycle phase, with or without an intact uterus, and no resources for adjudication. Future studies may want to combine aspects of the SWAN and WISE algorithms by adding hormonal measures to the series of bleeding questions in order to determine more precisely where women are in the perimenopausal continuum. [ABSTRACT FROM AUTHOR]

The evidence base for most educational initiatives, at least until very recently, is largely composed of low-level evidence. Four major barriers underlie this historical observation, namely: (1) perceived ethical and acceptability problems arising from the unequal treatment of learners in experimental designs; (2) limited choice of outcome measures and validated instruments; (3) time and resource constraints; and (4) methodological issues concerning contextual confounding and small sample sizes. We advocate the adoption of a 'balanced scorecard' approach in the evaluation of education interventions that brings together a comprehensive panel of outcomes under one framework. We require a diversity of rigorously applied methods to generate these outcomes, drawing from the quantitative and qualitative disciplines of epidemiology, psychology and economics. We further suggest that the research community discuss and agree on a standardized set of common metrics or benchmarks. We conclude with a case study examining whether a hand-held computer clinical decision support tool improves clerkship learning of evidence-based medicine. The era of Brownian motion in health education research is over. What we demand in terms of burden of proof for educational effectiveness should be no less rigorous than our call for an ever escalating threshold concerning evidence of clinical care. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Most evidence-based practice (EBP) educational assessment tools evaluated to date have focused on specific knowledge components or technical skills. Other important potential barriers to the adoption of EBP, such as attitudinal, perceptual and behavioural factors, have yet to be studied, especially in the undergraduate setting. Therefore, we developed and validated a knowledge, attitude and behaviour questionnaire designed to evaluate EBP teaching and learning in an undergraduate medical curriculum. METHODS: We derived the questionnaire from a comprehensive literature review, informed by international and local experts and a Year 5 student focus group. We determined its factor structure and refined and validated the questionnaire according to the responses of a cohort of Year 5 and a combined group of Years 2 and 3 students using principal components factor analysis with varimax rotation. Factor reliability was computed using Cronbach's alpha coefficient. We assessed construct validity by correlating the factors with other measures of EBP activity and examined responsiveness through paired t-test of the pre/post factor mean scores. RESULTS: A 43-item questionnaire was developed. Four factors were identified from both student groups. The overall questionnaire as well as each factor had high construct validity (Cronbach's alpha > 0.7 for each scale). No significant correlations were found between the 4 factors, confirming their orthogonality. Positive correlations, however, resulted between factor mean scores and other EBP activities. The responsiveness of the questionnaire was satisfactory. CONCLUSION: A reliable knowledge, attitude and behaviour measure of EBP teaching and learning appropriate for undergraduate medical education has been developed and validated. [ABSTRACT FROM AUTHOR]

Outcome studies of percutaneous coronary intervention (PCI) with conventional balloon angioplasty have established increased in-hospital and 1-year mortality in patients with left ventricular (LV) dysfunction compared with others. It is unclear whether recent PCI practice innovations, including stents and adjunctive pharmacotherapy, have made PCI safer and more effective in patients with LV dysfunction. We evaluated the influence of LV ejection fraction (EF) indexes on in-hospital and 1-year outcomes in 1,458 patients within the National Heart, Lung, and Blood Institute-sponsored Dynamic Registry. Patients (n = 300) with acute myocardial infarction were excluded. The remaining 1,158 patients were subdivided into 3 categories: group 1, EF or=50% (n = 866). We determined the frequency of individual and composite adverse events (death/myocardial infarction [MI]/coronary artery bypass grafting) at discharge and 1 year. In the Dynamic Registry patients, mean EF in the 3 groups was 32%, 45%, and 62% and in-hospital mortality was 3.0%, 1.6%, and 0.1%, respectively (p <0.001). The composite end point of death/MI was also significant, but other in-hospital adverse events did not differ between groups. The respective mortality rates were 11.0%, 4.5%, and 1.9% (p <0.001) after 1 year. The composite end points of death/MI and death/MI/coronary artery bypass grafting also occurred more frequently in group 1 patients. Thus, significant LV dysfunction was still associated with increased in-hospital and 1-year mortality in patients having contemporary PCI. [ABSTRACT FROM AUTHOR]

Objectives: The goal of this study was to determine whether women undergoing contemporary percutaneous coronary intervention (PCI) remain at increased risk in comparison with men and whether the outcomes in women have improved.Background: Previous studies have shown that women treated with coronary angioplasty have a higher incidence of procedural morbidity and mortality than men.Methods: Gender differences in wave 1 of the National Heart, Lung and Blood Institute (NHLBI) Dynamic registry were evaluated. Baseline characteristics and outcomes in women in the Dynamic registry were compared with those in women in the 1985-1986 and 1993-1994 NHLBI Percutaneous Transluminal Coronary Angioplasty (PTCA) registries.Results: Women were older with a higher prevalence of diabetes mellitus, hypertension, congestive heart failure, unstable angina and single vessel disease in comparison with men. Although procedural success and in-hospital death (2.2% vs. 1.3%), myocardial infarction (MI) (2.3% vs. 3.0%) and coronary artery bypass graft surgery (CABG) (1.3% vs. 1.4%) were similar in women and men, respectively, one-year mortality (6.5% vs. 4.3%, p = 0.02) and combined end point of death/MI/CABG (18.3% vs. 14.4%, p = 0.03) were higher in women than in men. After controlling for other factors, gender was not a significant predictor of death or death plus MI at one year. Despite a higher risk profile in women in the Dynamic registry in comparison with women in the 1985-1986 NHLBI PTCA registry, in-hospital death/MI/CABG was lower (6.0% vs. 11.6%, p < 0.001).Conclusions: Despite persistent high-risk characteristics in women, gender differences in outcomes in patients undergoing contemporary PCI have decreased, and outcomes in women have improved. [ABSTRACT FROM AUTHOR]

Context: Despite scientific uncertainties about effectiveness, wearing back belts in the hopes of preventing costly and disabling low back injury in employees is becoming common in the workplace.Objective: To evaluate the effectiveness of using back belts in reducing back injury claims and low back pain.Design and Setting: Prospective cohort study. From April 1996 through April 1998, we identified material-handling employees in 160 new retail merchandise stores (89 required back belt use; 71 had voluntary back belt use) in 30 states (from New Hampshire to Michigan in the north and from Florida to Texas in the south); data collection ended December 1998, median follow-up was 6(1/2) months.Participants: A referred sample of 13,873 material handling employees provided 9377 baseline interviews and 6311 (67%) follow-up interviews; 206 (1.4%) refused baseline interview.Main Outcome Measures: Incidence rate of material-handling back injury workers' compensation claims and 6-month incidence rate of self-reported low back pain.Results: Neither frequent back belt use nor a belt-requirement store policy was significantly associated with back injury claim rates or self-reported back pain. Rate ratios comparing back injury claims of those who reported wearing back belts usually every day and once or twice a week vs those who reported wearing belts never or once or twice a month were 1.22 (95% confidence interval [CI], 0.87-1.70) and 0.95 (95% CI, 0.56-1.59), respectively. The respective odds ratios for low back pain incidence were 0.97 (95% CI, 0.83-1.13) and 0.92 (95% CI, 0.73-1.16).Conclusions: In the largest prospective cohort study of back belt use, adjusted for multiple individual risk factors, neither frequent back belt use nor a store policy that required belt use was associated with reduced incidence of back injury claims or low back pain. JAMA. 2000;284:2727-2732. [ABSTRACT FROM AUTHOR]

Objective: Studies have shown a high prevalence of sleep-disordered breathing (SDB) among children with myelomeningocele (MMC), but there are few published data on the longitudinal care of these patients. The objective of this study was to determine the effectiveness of standard treatments for SDB in children with MMC., Methods: The authors analyzed records from three multidisciplinary spina bifida clinics to identify all patients with both MMC and SDB diagnosed by polysomnography (PSG). The primary outcome of this study was a change in apnea-hypopnea index (AHI; the number of apneic or hypopneic events per hour of sleep) before and after clinically recommended SDB treatments. Clinical and demographic variables were recorded and evaluated for possible association with posttreatment improvement of AHI. Analysis included change in AHI (a continuous variable) and whether SDB improved (defined as an AHI < 2.5 or decrease of AHI by ≥ 50% from baseline)., Results: Seventy-one eligible patients (aged 2 days-21 years, 52% male) had an initial AHI > 2.5 and had follow-up PSG after treatment for SDB. The mean AHI decreased from 20.5 (SD 21.6) at baseline to 11.6 (SD 15.7) after treatment (p = 0.0006). Children treated with supplemental oxygen and with continuous positive airway pressure had improvement on PSG (18 of 25 and 12 of 18, respectively). Children treated with adenotonsillectomy were less likely to improve (7 of 19). Forty-one patients (58%) improved from a baseline AHI > 2.5 to an AHI < 2.5 after treatment., Conclusions: Children with MMC and SDB who undergo standard SDB treatments guided by pediatric sleep medicine physicians show improvement in PSG parameters after treatment.

Introduction: Myelomeningocele (MMC) is the most common neural tube defect, but rarely seen in premature infants. Most centers advocate for closure of MMC within 24 h of birth. However, this is not always possible in severely premature infants. Given the rarity of this patient population, we aimed to share our institutional experience and outcomes of severely premature infants with MMC., Methods: We performed a retrospective, observational review of premature infants (≤ 32 weeks gestational age) identified through our multidisciplinary spina bifida clinic (1995-2021) and surgical logs. Descriptive statistics were compiled about this sample including timing of MMC closure and incidence of adverse events such as sepsis, CSF diversion, meningitis, and death., Results: Eight patients were identified (50% male) with MMC who were born ≤ 32 weeks gestational age. Mean gestational age of the population was 27.3 weeks (SD 3.5). Median time to MMC closure was 1.5 days (IQR = 1-80.8). Five patients were taken for surgery within the recommended 48 h of birth; 2 patients underwent significantly delayed closure (107 and 139 days); and one patient's defect epithelized without surgical intervention. Six of eight patients required permanent cerebrospinal fluid (CSF) diversion (2 patients were treated with ventriculoperitoneal shunting (VPS), three were treated with endoscopic third ventriculostomy (ETV) with choroid plexus cauterization (CPC) and 1 patient treated with ETV; mean of 3 years after birth, ranging from 1 day to 16 years). Two patients required more than one permanent CSF diversion procedure. Two patients developed sepsis (defined as meeting at least 2/4 SIRS criteria). In both cases of sepsis, patients developed signs and symptoms more than 72 h after birth. Notably, both instances of sepsis occurred unrelated to operative intervention as they occurred before permanent MMC closure. Two patients had intraventricular hemorrhage (both grade III). No patients developed meningitis (defined as positive CSF cultures) prior to MMC closure. Median follow up duration was 9.7 years. During this time epoch, 3 patients died: Two before 2 years of age of causes unrelated to surgical intervention. One of the two patients with grade III IVH died within 24 h of MMC closure., Conclusions: In our institutional experience with premature infants with MMC, some patients underwent delayed MMC closure. The overall rate of meningitis, sepsis, and mortality for preterm children with MMC was similar to MMC patients born at term., (© 2024. The Author(s).)

The field of global neurosurgery seeks to improve access to neurosurgery and reduce health disparities worldwide. This process depends on intensive collaboration between partners in high-income and low-to-middle income country (LMIC) settings. Several such collaborations have propelled global neurosurgery forward, and long-standing partnerships in particular have brought subspecialty care and training to new locations. Recently, there have been more reports of collaborations between LMICs themselves. In this narrative study, we summarize the state of collaboration in global neurosurgery and discuss how the field is likely to change moving forward., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pulmonary alveolar proteinosis is a rare diffuse lung disease; diagnosis and treatment of which is often delayed. We present the case study of a 43-year-old male with a six-month history of worsening breathlessness and non-productive cough referred for specialist respiratory input. Rapid investigations, including high-resolution computed tomography (HRCT) and bronchoalveolar lavage, confirmed the diagnosis of pulmonary alveolar proteinosis. Treatment with whole lung lavage significantly improved pulmonary function and quality of life. We discuss the diagnosis and management of this condition and highlight the importance of early recognition and multidisciplinary teamwork in managing pulmonary alveolar proteinosis.

Oncolytic virotherapy or immunovirotherapy is a strategy that utilizes viruses to selectively infect and kill tumor cells while also stimulating an immune response against the tumor. Early clinical trials in both pediatric and adult patients using oncolytic herpes simplex viruses (oHSV) have demonstrated safety and promising efficacy; however, combinatorial strategies designed to enhance oncolysis while also promoting durable T-cell responses for sustaining disease remission are likely required. We hypothesized that combining the direct tumor cell killing and innate immune stimulation by oHSV with a vaccine that promotes T cell-mediated immunity may lead to more durable tumor regression. To this end, we investigated the preclinical efficacy and potential synergy of combining oHSV with a self-assembling nanoparticle vaccine codelivering peptide antigens and Toll-like receptor 7 and 8 agonists (referred to as SNAPvax),which induces robust tumor-specific T-cell immunity. We then assessed how timing of the treatments (i.e., vaccine before or after oHSV) impacts T-cell responses, viral replication, and preclinical efficacy. The sequence of treatments was critical, as survival was significantly enhanced when the SNAPvax vaccine was given prior to oHSV. Increased clinical efficacy was associated with reduced tumor volume and increases in virus replication and tumor antigen-specific CD8+ T cells. These findings substantiate the criticality of combination immunotherapy timing and provide preclinical support for combining SNAPvax with oHSV as a promising treatment approach for both pediatric and adult tumors., (©2024 American Association for Cancer Research.)

Wildfires in western US forests increased over the last two decades, resulting in elevated solid and nutrient loadings to streams, and occasionally threatening drinking water supplies. We demonstrated that a linked LANDIS (LANDscape DIsturbance and Succession)-VELMA (Visualizing Ecosystem Land Management Assessments) modeling approach can simulate wildland fire effects on water quality using the 2002 Colorado Hayman Fire. Utilizing LANDIS-II's forest landscape model to simulate forest composition and VELMA's eco-hydrologic model to simulate pre- and post-fire water quantity and quality, the best calibration performance yielded a Nash-Sutcliffe Efficiency (NSE) of 0.621 during 2000-2006 (most optimal annual - 0.921) in comparison to North American Land Data Assimilation System (NLDAS) runoff. Pre-fire modeled runoff, nitrate, and surface water temperature (SWT) correlated with observations. Simulated post-fire runoff (229%) and SWT (20.6%) were elevated relative to pre-fire, with nitrate concentrations 34 times greater than the aquatic life threshold (0.01 mg N/L)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

GM1 gangliosidosis is an ultra-rare inherited neurodegenerative lysosomal storage disorder caused by biallelic mutations in the GLB1 gene. GM1 is uniformly fatal and has no approved therapies, although clinical trials investigating gene therapy as a potential treatment for this condition are underway. Novel outcome measures or biomarkers demonstrating the longitudinal effects of GM1 and potential recovery due to therapeutic intervention are urgently needed to establish efficacy of potential therapeutics. One promising tool is differential tractography, a novel imaging modality utilizing serial diffusion weighted imaging (DWI) to quantify longitudinal changes in white matter microstructure. In this study, we present the novel use of differential tractography in quantifying the progression of GM1 alongside age-matched neurotypical controls. We analyzed 113 DWI scans from 16 GM1 patients and 32 age-matched neurotypical controls to investigate longitudinal changes in white matter pathology. GM1 patients showed white matter degradation evident by both the number and size of fiber tract loss. In contrast, neurotypical controls showed longitudinal white matter improvements as evident by both the number and size of fiber tract growth. We also corroborated these findings by documenting significant correlations between cognitive global impression (CGI) scores of clinical presentations and our differential tractography derived metrics in our GM1 cohort. Specifically, GM1 patients who lost more neuronal fiber tracts also had a worse clinical presentation. This result demonstrates the importance of differential tractography as an important biomarker for disease progression in GM1 patients with potential extension to other neurodegenerative diseases and therapeutic intervention., Competing Interests: Conflict of Interest Disclosure The authors declare no conflict of interest.

Objective: Cerebral revascularization surgery (CRS) has been used to prevent stroke in children with sickle cell disease (SCD) and cerebral vasculopathy (e.g., moyamoya syndrome). While results suggest that it may be an effective treatment, surgical indications have not been well defined. This study sought to determine indications for offering revascularization surgery in centers with established sickle cell programs in the US., Methods: Three sequential surveys utilizing the Delphi methodology were administered to neurosurgeons participating in the Stroke in Sickle Cell Revascularization Surgery study. Respondents were presented with clinical scenarios of patients with SCD and varying degrees of ischemic presentation and vasculopathy, and the group's agreement to offer surgical revascularization was measured. Consensus was defined as ≥ 75% similar responses., Results: The response rate to all 3 surveys was 100%. Seventeen neurosurgeons from 16 different centers participated. The presence of moyamoya collaterals (MMCs) and arterial stenosis matching an ischemic distribution yielded the strongest recommendations to offer surgery. There was consensus to offer revascularization in the presence of MMCs and at least 50% arterial stenosis matching an ischemic distribution. In contrast, there was no consensus to offer revascularization with 50%-70% stenosis not matching an ischemic presentation in the absence of MMCs. The presence of the ivy sign in the distribution of the stenotic artery also contributed to the consensus to offer surgery in certain scenarios., Conclusions: There were several clinical scenarios that attained consensus to offer surgery; the strongest was moderate to severe arterial stenosis that matched the distribution of ischemic presentation in the presence of MMCs. Radiological findings of decreased cerebral flow or perfusion also facilitated attaining consensus to offer surgery. The findings of this study reflect expert opinion about questions that deserve prospective clinical research. Determination of indications for CRS can guide clinical practice and aid the design of prospective studies.

Purpose: GM1 gangliosidosis (GM1) a lysosomal disorder caused by pathogenic variants in GLB1, is characterized by relentless neurodegeneration. There are no approved treatments., Methods: Forty-one individuals with type II (late-infantile and juvenile) GM1 participated in a single-site prospective observational study., Results: Classification of 37 distinct variants using American College of Medical Genetics and Genomics criteria resulted in the upgrade of 6 and the submission of 4 new variants. In contrast to type I infantile disease, children with type II had normal or near normal hearing and did not have cherry-red maculae or hepatosplenomegaly. Some older children with juvenile onset disease developed thickened aortic and/or mitral valves. Serial magnetic resonance images demonstrated progressive brain atrophy, more pronounced in late infantile patients. Magnetic resonance spectroscopy showed worsening elevation of myo-inositol and deficit of N-acetyl aspartate that were strongly correlated with scores on the Vineland Adaptive Behavior Scale, progressing more rapidly in late infantile compared with juvenile onset disease., Conclusion: Serial phenotyping of type II GM1 patients expands the understanding of disease progression and clarifies common misconceptions about type II patients; these are pivotal steps toward more timely diagnosis and better supportive care. The data amassed through this 10-year effort will serve as a robust comparator for ongoing and future therapeutic trials., Competing Interests: Conflict of Interest Adam L. Hartman receives consulting fees from Teladoc. All other authors declare no conflicts of interest., (Published by Elsevier Inc.)

The late-onset GM2 gangliosidoses, comprising late-onset Tay-Sachs and Sandhoff diseases, are rare, slowly progressive, neurogenetic disorders primarily characterized by neurogenic weakness, ataxia, and dysarthria. The aim of this longitudinal study was to characterize the natural history of late-onset GM2 gangliosidoses using a number of clinical outcome assessments to measure different aspects of disease burden and progression over time, including neurological, functional, and quality of life, to inform the design of future clinical interventional trials. Patients attending the United States National Tay-Sachs & Allied Diseases Family Conference between 2015 and 2019 underwent annual clinical outcome assessments. Currently, there are no clinical outcome assessments validated to assess late-onset GM2 gangliosidoses; therefore, instruments used or designed for diseases with similar features, or to address various aspects of the clinical presentations, were used. Clinical outcome assessments included the Friedreich's Ataxia Rating Scale, the 9-Hole Peg Test, and the Assessment of Intelligibility of Dysarthric Speech. Twenty-three patients participated in at least one meeting visit (late-onset Tay-Sachs, n = 19; late-onset Sandhoff, n = 4). Patients had high disease burden at baseline, and scores for the different clinical outcome assessments were generally lower than would be expected for the general population. Longitudinal analyses showed slow, but statistically significant, neurological progression as evidenced by worsening scores on the 9-Hole Peg Test (2.68%/year, 95% CI: 0.13-5.29; p = 0.04) and the Friedreich's Ataxia Rating Scale neurological examination (1.31 points/year, 95% CI: 0.26-2.35; p = 0.02). Time since diagnosis to study entry correlated with worsening scores on the 9-Hole Peg Test (r = 0.728; p < 0.001), Friedreich's Ataxia Rating Scale neurological examination (r = 0.727; p < 0.001), and Assessment of Intelligibility of Dysarthric Speech intelligibility (r = -0.654; p = 0.001). In summary, patients with late-onset GM2 gangliosidoses had high disease burden and slow disease progression. Several clinical outcome assessments suitable for clinical trials showed only small changes and standardized effect sizes (change/standard deviation of change) over 4 years. These longitudinal natural history study results illustrate the challenge of identifying responsive endpoints for clinical trials in rare, slowly progressive, neurogenerative disorders where arguably the treatment goal is to halt or decrease the rate of decline rather than improve clinical status. Furthermore, powering such a study would require a large sample size and/or a long study duration, neither of which is an attractive option for an ultra-rare disease with no available treatment. These findings support the development of potentially more sensitive late-onset GM2 gangliosidoses-specific rating instruments and/or surrogate endpoints for use in future clinical trials., Competing Interests: Declaration of competing interest JK, CR, PM, and AH are employees of Sanofi and may hold shares and/or stock options in the company. GFC was a former employee of Sanofi through 2016, and since 2019, is the owner of Gerald Cox Rare Care Consulting, LLC and a member of the NTSAD Board of Directors. CDS and FE are neurologists volunteering at the NTSAD. CDS has provided scientific advisory for SwanBio Therapeutics and his institution has received research funding from Sanofi for a study of video oculography in late-onset GM2 gangliosidoses. CDS has received financial support from SwanBio Therapeutics, Encora Therapeutics, Sanofi, Biogen and Biohaven for the conduct of clinical trials. CDS has received honoraria from the International Parkinson's and Movement Disorders Society, the American Academy of Neurology/Continuum and Oakstone CME for the production of educational material. CDS has received grant support from the National Institutes of HealthK23 NS118045-03. FE is co-principal investigator of a gene therapy trial in GM2 sponsored by Sio Pharmaceuticals and site principal investigator of a trial on late onset GM2 sponsored by Sanofi. HL was a former employee of NYU Langone Hospital in New York City, and currently is employed by Ultragenyx and volunteers at NTSAD. JMJ and CT are employees of the Intramural Research Program (IRP) of the National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, Maryland. RK is an employee of IQVIA, which received funding from Sanofi to conduct qualitative research to develop the GM2 gangliosidoses conceptual framework, and to support selection of the COA instruments used in this study. GFC, FE, CDS, HL and CT assessed the patients and did not receive funding for their participation., (Copyright © 2024. Published by Elsevier Inc.)

Neuroglial cysts are rare congenital cysts that seldom require surgical treatment. This case highlights a rare instance when a neurolglial cyst caused acute hydrocephalus in a 10-year old boy. Originally diagnosed and managed as pediatric-onset migraines, the patient presented to the emergency department with nausea, vomiting, and ataxia without clear pathology on neuroradiology. The neurosurgical team took him to the operating room based on his clinical picture and history and the cyst was discovered there. The pathology was benign, and he has had a complete resolution of symptoms., Competing Interests: Conflicts of Interest None to report., (Copyright © 2024 National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.)

Introduction: Pediatric non-galenic pial arteriovenous fistulas (pAVFs) are rare vascular malformations that are characterized by a pial arterial-venous connection without an intervening capillary bed. Outcomes and treatment strategies for pAVFs are highly individualized, owing to the rarity of the disease and lack of large-scale data guiding optimal treatment approaches., Methods: We performed a systematic review of pediatric patients (< 18 years at diagnosis) diagnosed with a pAVF by digital subtraction angiogram (DSA). The demographics, treatment modalities, and outcomes were documented for each patient and clinical outcome data was collected. Descriptive information stratified by outcome scores were classified as follows: 1 = excellent (no deficit and full premorbid activity), 2 = good (mild deficit and full premorbid activity), 3 = fair (moderate deficit and impaired activity), 4 = poor (severe deficit and dependent on others), 5 = death., Results: A total of 87 studies involving 231 patients were identified. Median age at diagnosis was 3 years (neonates to 18 years). There was slight male preponderance (55.4%), and 150 subjects (81.1%*) experienced excellent outcomes after treatment. Of the 189 patients treated using endovascular approaches, 80.3% experienced excellent outcomes and of the 15 patients surgically treated subjects 75% had an excellent outcome. The highest rate of excellent outcomes was achieved in patients treated with Onyx (95.2%) and other forms of EvOH (100%). High output heart failure and comorbid vascular lesions tended to result in worse outcomes, with only 54.2% and 68% of subjects experiencing an excellent outcome, respectively. *Outcomes were reported in only 185 patients., Conclusion: pAVFs are rare lesions, necessitating aggregation of patient data to inform natural history and optimal treatment strategies. This review summarizes the current literature on pAVF in children, where children presenting with heart failure as a result of high flow through the lesion were less likely to experience an excellent outcome. Prospective, large-scale studies would further characterize pediatric pAVFs and enable quantitative analysis of outcomes to inform best treatment practices., (© 2024. The Author(s).)