Search

Objectives: Septic shock in critically ill patients can increases morbidity and mortality. We aimed to study the effect on outcomes when integrating point of care (POC) echocardiography in the management of septic shock patients in the Intensive Care Unit (ICU) who are being treated according to the Surviving Sepsis Campaign (SSC) guidelines., Methods: An electronic search of MEDLINE through PubMed, clinical trials.gov and google scholar was conducted for the period from January 1990-January 2024 to identify studies of septic shock adult and pediatric patients in the ICU managed according to SSC guidelines with or without POC echocardiography. Three reviewers extracted data independent of each other. Cochrane collaboration tool was used for bias assessment. Random effect meta-analysis used to pool data., Results: A total of 1701 articles identified. Seven studies included in the final report with a total of 3885 patients. POC echocardiography guided septic shock management was associated with lower in-hospital and 28-day mortality (sOR = 0.82 [95%CI: 0.71-0.95], p = 0.01), more frequent initiation of inotropic support (sOR = 2.42 [95%CI 1.92-3.03], p < 0.0001) and shorter time to achieve lactate clearance (SMD = - 0.87 h [95%CI - 1.23 h to - 0.51 h], p < 0.0001). Summary estimates did not achieve significance for effect of POC echocardiography on 24-h fluid intake (SMD = - 2.11 ml [95%CI - 5.93 ml to 1.72 ml], p = 0.28) on mechanical ventilation-free days (SMD = 0.03 days [95%CI - 0.04 to 0.10], p = 0.94). Shock reversal time analysis was less meaningful due to the small number of studies reporting outcome., Conclusions: POC echocardiography guided management in septic shock patients in the ICU can lead to a decrease in mortality, increase in initiation of inotropic support, and a decrease in lactate clearance time. Larger cohort studies and data collection and analysis are needed for further understanding and optimizing standardization of protocols for POC echocardiography use in septic shock patients in the ICU., (© 2024. Società Italiana di Ultrasonologia in Medicina e Biologia (SIUMB).)

The Neuronal alpha-Synuclein Disease (NSD) biological definition and Integrated Staging System (NSD-ISS) provide a research framework to identify individuals with Lewy body pathology and stage them based on underlying biology and increasing degree of functional impairment. Utilizing data from the PPMI, PASADENA, and SPARK studies, we developed and applied biologic and clinical data-informed definitions for the NSD-ISS across the disease continuum. Individuals enrolled as Parkinson's disease, Prodromal, or Healthy Controls were defined and staged based on biological, clinical, and functional anchors at baseline. Across the three studies 1741 participants had SAA data and of these 1030 (59%) were S+ consistent with NSD. Among sporadic PD, 683/736 (93%) were NSD, and the distribution for Stages 2B, 3, and 4 was 25%, 63%, and 9%, respectively. Median (95% CI) time to developing a clinically meaningful outcome was 8.3 (6.2, 10.1), 5.9 (4.1, 6.0), and 2.4 (1.0, 4.0) years for baseline stage 2B, 3, and 4, respectively. We propose pilot biologic and clinical anchors for NSD-ISS. Our results highlight the baseline heterogeneity of individuals currently defined as early PD. Baseline stage predicts time to progression to clinically meaningful milestones. Further research on validation of the anchors in longitudinal cohorts is necessary., (© 2024. The Author(s).)

Background: Membranous-like glomerulopathy with masked monoclonal IgG deposits (MGMID) is a newly recognized condition predominantly observed in young females, and its understanding in the pediatric population remains limited., Materials and Methods: Four cases of MGMID are reported, including three pediatric patients., Results: All patients were female, with ages ranging from 12 to 26 years. None of the patients had malignancies. They presented with kidney dysfunction, proteinuria, or hematuria. Kidney biopsies of all cases exhibited a membranous pattern of injury with monoclonal IgG-κ restriction, "unmasked" by pronase digestion. Pediatric cases were treated conservatively, while the adult case underwent immunosuppressive treatment. All patients had favorable outcomes, and none reached end stage kidney disease (ESKD)., Conclusion: MGMID can affect both adult and pediatric patients. Further studies are needed to fully characterize its risk factors, optimal therapy, and outcomes.

Background: Among LRRK2-associated parkinsonism cases with nigral degeneration, over two-thirds demonstrate evidence of pathologic alpha-synuclein, but many do not. Understanding the clinical phenotype and underlying biology in such individuals is critical for therapeutic development. Our objective was to compare clinical and biomarker features, and rate of progression over 4 years follow-up, among LRRK2-associated parkinsonism cases with and without in vivo evidence of alpha-synuclein aggregates., Methods: Data were from the Parkinson's Progression Markers Initiative, a multicenter prospective cohort study. The sample included individuals diagnosed with Parkinson disease with pathogenic variants in LRRK2. Presence of CSF alpha-synuclein aggregation was assessed with seed amplification assay. A range of clinician- and patient- reported outcome assessments were administered. Biomarkers included dopamine transporter SPECT scan, CSF amyloid-beta 1-42 , total tau, phospho-tau 181 , urine bis(monoacylglycerol)phosphate levels, and serum neurofilament light chain. Linear mixed effects models examined differences in trajectory in CSF negative and positive groups., Results: 148 LRRK2-parkinsonism cases (86% with G2019S variant), 46 negative and 102 positive for CSF alpha-synuclein seed amplification assay were included. At baseline, the negative group were older than the positive group (median [interquartile range] 69.1 [65.2-72.3] vs 61.5 [55.6-66.9] years, p<0.001) and a greater proportion were female (28 (61%) vs 43 (42%), p=0.035). Despite being older, the negative group had similar duration since diagnosis, and similar motor rating scale (16 [11-23] vs 16 [10-22], p=0.480) though lower levodopa equivalents. Only 13 (29%) of the negative group were hyposmic, compared to 75 (77%) of the positive group. Lowest putamen dopamine transporter binding expected for age and sex was greater in the negative vs positive groups (0.36 [0.29-0.45] vs 0.26 [0.22-0.37], p<0.001). Serum neurofilament light chain was higher in the negative group compared to the positive group (17.10 [13.60-22.10] vs 10.50 [8.43-14.70]; age-adjusted p-value=0.013). In terms of longitudinal change, the negative group remained stable in functional rating scale score in contrast to the positive group who had a significant increase (worsening) of 0.729 per year (p=0.037), but no other differences in trajectory were found., Conclusion: Among individuals diagnosed with Parkinson disease with pathogenic variants in the LRRK2 gene, we found clinical and biomarker differences in cases without versus with in vivo evidence of CSF alpha-synuclein aggregates. LRRK2 parkinsonism cases without evidence of alpha-synuclein aggregates as a group exhibit less severe motor manifestations and decline may have more significant cognitive dysfunction. The underlying biology in LRRK2-parkinsonism cases without evidence of alpha-synuclein aggregates requires further investigation., Competing Interests: Competing interests The authors report no competing interests.

Introduction: The emerging rise in novel computer technologies and automated data analytics has the potential to change the course of dental education. In line with our long-term goal of harnessing the power of AI to augment didactic teaching, the objective of this study was to quantify and compare the accuracy of responses provided by ChatGPT (GPT-4 and GPT-3.5) and Google Gemini, the three primary large language models (LLMs), to human graduate students (control group) to the annual in-service examination questions posed by the American Academy of Periodontology (AAP)., Methods: Under a comparative cross-sectional study design, a corpus of 1312 questions from the annual in-service examination of AAP administered between 2020 and 2023 were presented to the LLMs. Their responses were analyzed using chi-square tests, and the performance was juxtaposed to the scores of periodontal residents from corresponding years, as the human control group. Additionally, two sub-analyses were performed: one on the performance of the LLMs on each section of the exam; and in answering the most difficult questions., Results: ChatGPT-4 (total average: 79.57%) outperformed all human control groups as well as GPT-3.5 and Google Gemini in all exam years (p < .001). This chatbot showed an accuracy range between 78.80% and 80.98% across the various exam years. Gemini consistently recorded superior performance with scores of 70.65% (p = .01), 73.29% (p = .02), 75.73% (p < .01), and 72.18% (p = .0008) for the exams from 2020 to 2023 compared to ChatGPT-3.5, which achieved 62.5%, 68.24%, 69.83%, and 59.27% respectively. Google Gemini (72.86%) surpassed the average scores achieved by first- (63.48% ± 31.67) and second-year residents (66.25% ± 31.61) when all exam years combined. However, it could not surpass that of third-year residents (69.06% ± 30.45)., Conclusions: Within the confines of this analysis, ChatGPT-4 exhibited a robust capability in answering AAP in-service exam questions in terms of accuracy and reliability while Gemini and ChatGPT-3.5 showed a weaker performance. These findings underscore the potential of deploying LLMs as an educational tool in periodontics and oral implantology domains. However, the current limitations of these models such as inability to effectively process image-based inquiries, the propensity for generating inconsistent responses to the same prompts, and achieving high (80% by GPT-4) but not absolute accuracy rates should be considered. An objective comparison of their capability versus their capacity is required to further develop this field of study., (© 2024 The Author(s). Journal of Periodontal Research published by John Wiley & Sons Ltd.)

Background: Among individuals with recent syncope, recurrence of syncope while driving might incapacitate a driver and cause a motor vehicle crash. Current driving restrictions assume that some forms of syncope transiently increase crash risk. We evaluated whether syncope is associated with a transient increase in crash risk., Methods: We performed a case-crossover analysis of linked administrative health and driving data from British Columbia, Canada (2010 to 2015). We included licensed drivers who visited an emergency department with "syncope and collapse" and who were involved as a driver in an eligible motor vehicle crash, both within the study interval. Using conditional logistic regression, we compared the rate of emergency visits for syncope in the 28 days before crash (the "pre-crash interval") with the rate of emergency visits for syncope in 3 self-matched 28-day control intervals (ending 6, 12, and 18 months before the crash)., Results: Among eligible crash-involved drivers, 47 of 3026 pre-crash intervals and 112 of 9078 control intervals had emergency visits for syncope, indicating syncope was not significantly associated with subsequent crash (1.6% vs 1.2%; adjusted odds ratio [OR], 1.27; 95% confidence interval [CI], 0.90-1.79; P = 0.18). There was no significant association between syncope and crash in subgroups at higher risk for adverse outcomes after syncope (eg, age > 65 years, cardiovascular disease, cardiac syncope)., Conclusions: In the context of prevailing modifications of driving behaviour after syncope, an emergency department visit for syncope did not transiently increase the risk of subsequent traffic collision. Overall crash risks after syncope appear to be adequately addressed by current driving restrictions., (Copyright © 2023 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objective: To describe the epidemiology of reclassification of prehypertensive and unclassified adolescents by 2022 American Heart Association pediatric ambulatory blood pressure monitoring (ABPM) guidelines, and to evaluate the association of the new diagnostic categories with left ventricular hypertrophy (LVH)., Study Design: A single-center, retrospective review of ABPM reports from adolescents 13-21 years old, from 2015 through 2022, was performed. Adolescents with prehypertension or unclassified by 2014 guidelines were reclassified by 2022 definitions. Logistic regression models evaluated the association of reclassification phenotypes with LVH., Results: A majority of prehypertensive adolescents reclassified to hypertension (70%, n = 49/70). More than one-half (57%, n = 28/49) of the hypertension was isolated nocturnal hypertension, and 80% was systolic hypertension. Reclassification to hypertension was more common in males. The majority (55.6%) of unclassified adolescents were reclassified to normotension. No demographic or clinical variables were associated with reclassification categories. LVH was not associated with hypertension in the reclassified prehypertensive or unclassified groups., Conclusions: The 2022 ABPM guidelines clearly define blood pressure phenotypes. However, reclassification to hypertension was not associated with an increased odds of LVH. Because most prehypertensive adolescents reclassified as hypertensive by nighttime BPs alone, this study highlights the lowered threshold for nocturnal hypertension. Prospective studies in larger, well-defined cohorts are needed to describe better the predictive value of 2022 BP phenotypes for target organ damage., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: There is a critical need to develop novel therapies for COVID-19., Methods: We conducted a phase 2, multicentre, placebo-controlled, double-blind, randomised trial; hospitalised patients with hypoxemic respiratory failure due to COVID-19 and at least one poor prognostic biomarker, were given sirolimus (6 mg on Day 1 followed by 2 mg daily for 14 days or hospital discharge, whichever happens first) or placebo, in a 2:1 randomization scheme favouring sirolimus. Primary outcome was the proportion of patients alive and free from advanced respiratory support measures at Day 28., Results: Between April 2020 and April 2021, 32 patients underwent randomization and 28 received either sirolimus (n = 18) or placebo (n = 10). Mean age was 57 years and 75 % of the subjects were men. Twenty-two subjects had at least one co-existing condition (Diabetes, hypertension, obesity, CHF, or asthma/COPD) associated with worse prognosis. Mean FiO 2 requirement was 0.35. There was no difference in the proportion of patients who were alive and free from advanced respiratory support measures in the sirolimus group (n = 15, 83 %) compared with the placebo group (n = 8, 80 %). Although patients in the sirolimus group demonstrated faster improvement in oxygenation and spent less time in the hospital, these differences were not statistically significant. There was no between-group difference in the rate of change in serum biomarkers such as LDH, ferritin, d-dimer or lymphocyte count. There was a decreased risk of thromboembolic complications in patients on sirolimus compared with placebo., Conclusions: Larger studies are warranted to evaluate the role sirolimus in COVID-19 infection., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Published by Elsevier B.V.)

The differential diagnosis for neonatal primary lung masses includes developmental anomalies and congenital lung tumors. Fetal lung interstitial tumor (FLIT) is a rare benign mesenchymal lesion which presents either antenatally or within the first 3 months of age. FLIT is a circumscribed solid-cystic mass which histologically resembles the fetal lung during the canalicular stage at 20-24 weeks of gestation. It is composed of immature mesenchymal cells expanding the interstitium and irregular airspace-like structures. Of all published cases, only 1 identified an α2-macroglobulin ( A2M )::anaplastic lymphoma kinase ( ALK ) fusion and all cases underwent surgical resection in the neonatal or infancy period. We present the second case of FLIT with an A2M::ALK fusion diagnosed postnatally in a neonate which partially regressed spontaneously during conservative management with interim resection at 39 months of age, and provide a review of the literature., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Parkinson's disease (PD) is a progressive neurological disorder that manifests clinically as alterations in movement as well as multiple non-motor symptoms including but not limited to cognitive and autonomic abnormalities. Loss-of-function mutations in the gene encoding the ubiquitin E3 ligase Parkin are causal for familial and juvenile PD. Among several therapeutic approaches being explored to treat or improve the prognosis of patients with PD, the use of small molecules able to reinstate or boost Parkin activity represents a potential pharmacological treatment strategy. A major barrier is the lack of high-throughput platforms for the robust and accurate quantification of Parkin activity in vitro. Here, we present two different and complementary Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry (MALDI-TOF/MS)-based approaches for the quantification of Parkin E3 ligase activity in vitro. Both approaches are scalable for high-throughput primary screening to facilitate the identification of Parkin modulators., Competing Interests: Declaration of interests B.B. is a shareholder and CEO of Vincere Biosciences, Inc., focused on developing therapeutics targeting mitochondrial pathways. When this study was initiated, K.M. was the CSO at Vincere, accountable for drug discovery. K.M. is an advisor to The Michael J. Fox Foundation, serves on advisory panels at the National Institutes of Health, and consults for several biopharmaceutical companies. M.M.K.M. is a member of the scientific advisory board of Montara Therapeutics, Inc and scientific consultant at MSD. R.T. is an employee of the DUB Profiling Service within the MRC-PPU Reagents and Services (https://mrcppureagents.dundee.ac.uk/). C.J.H. is manager of the MRC-PPU Reagents and Services., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Study Objective: Syncope that occurs while driving can result in a motor vehicle crash. Whether individuals with a prior syncope-related crash exhibit an exceptional risk of subsequent crash remains uncertain., Methods: We performed a population-based retrospective observational study of patients diagnosed with 'syncope and collapse' at any of 6 emergency departments in British Columbia, Canada (2010 to 2015). Data were obtained from chart abstraction, administrative health records, insurance claims and police crash reports. We compared crash-free survival among individuals with crash-associated syncope (a crash and an emergency visit for syncope on the same date) to that among controls with syncope alone (no crash on date of emergency visit for syncope)., Results: In the year following their index emergency visit, 13 of 63 drivers with crash-associated syncope and 852 of 9,160 controls with syncope alone experienced a subsequent crash as a driver (crash risk 21% versus 9%). After accounting for censoring and potential confounders, crash-associated syncope was not associated with a significant increase in the risk of subsequent crash (adjusted hazard ratio [aHR] 1.38, 95% confidence interval [CI] 0.78 to 2.47). Individuals with crash-associated syncope were 31-fold more likely to have physician driving advice documented during their index visit (prevalence ratio 31.0, 95% CI, 21.3 to 45.1). In the subgroup without documented driving advice, crash-associated syncope was associated with a significant increase in subsequent crash risk (aHR 1.88, 95% CI 1.06 to 3.36)., Conclusions: Crash risk after crash-associated syncope appears similar to crash risk after syncope alone., (Copyright © 2023 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of interests TSi declares consultancies for 4D Pharma, Acadia, AcureX, AskBio, Amneal, Blue Rock Therapeutics, Caraway, Critical Path for Parkinson's Consortium, Denali, The Michael J Fox Foundation, Neuroderm, Roche, Sanofi, Sinopia, Sunovion, Takeda, UCB, Vanqua Bio, and Voyager. LMC declares research support and consulting fees from The Michael J Fox Foundation. KP declares consultancies for Curasen; was on a scientific advisory board for Curasen and Amprion; honoraria from invited scientific presentations to universities and professional societies not exceeding $5000 per year from California Congress of Clinical Neurology, California Neurological Society, and Johns Hopkins University; and patents or patent applications numbers 17/314,979 and 63/377,293. KP also declares grants to her institution (Stanford University School of Medicine) from NIH/NINDS NS115114, NS062684, NS075097, NIH/NIA U19 AG065156, P30 AG066515, The Michael J Fox Foundation, Lewy Body Dementia Association, Alzheimer's Drug Discovery Foundation, Sue Berghoff LBD Research Fellowship, and the Knight Initiative for Brain Resilience. MB declares travel grants from The Michael J Fox Foundation. SC declares employment for and travel grants from The Michael J Fox Foundation. The Michael J Fox Foundation received funding support from named non-profit institutions (Cure Parkinson's, Lewy Body Dementia Association, Parkinson Canada, Parkinson's UK, and Shake It Up Australia Foundation) to convene an in-person roundtable of experts in April 2023 in which The Michael J Fox Foundation (employer) cost-shared; The Michael J Fox Foundation (employer) provided funding for an in-person meeting in January, 2023. CC declares grants from The Michael J Fox Foundation and NIH/NINDS. LC-M declares employment for, and employee stock options in, Amprion; grants from The Michael J Fox Foundation; and patents or patent applications (numbers US 20210277076A1, US 20210311077A1, US 20190353669A1, and US 20210223268A1). TD declares former employment of and might hold stock or stock options in Biogen. TF declares travel grants and grant payments to her institution (Indiana University) from The Michael J Fox Foundation. MF declares employment for The Michael J Fox Foundation and an unpaid advisory role at Vaxxinity. CG declares research funding to her institution from The Michael J Fox Foundation. DJ declares employment for and employee stock options from Denali Therapeutics. KK declares support to his institution (University of Rochester Medical Center) from The Michael J Fox Foundation. CK declares employment for and travel grants from The Michael J Fox Foundation. KMe declares consultancies for The Michael J Fox Foundation, AcuRx, Caraway, Cerebral Therapeutics, NRG Therapeutics (scientific advisory board), Nitrase Therapeutics (scientific advisory board), Nurabio, Retromer Therapeutics (director on the board, part-time chief scientific officer), Schrodinger, Sinopia Biosciences (scientific advisory board), and Vanqua Biosciences (scientific advisory board); stock ownership for Cognition Therapeutics, Eli Lilly (retiree stock holder), Envisagenics, Nitrase Therapeutics, Sinopia Biosciences, and Retromer Therapeutics; honoraria for the University of Utah; patents or patent applications for Retromer Therapeutics (planned patent); a research grant from The Michael J Fox Foundation; and travel grants from the University of Utah. BM declares consultancies from Roche, Biogen, and The Michael J Fox Foundation; grants from The Michael J Fox Foundation, ASAP, and DFG; honoraria for AbbVie; and travel grants for AbbVie. TM declares support to his institution (Stanford University School of Medicine) from The Michael J Fox Foundation. KN declares support from The Michael J Fox Foundation. GP declares employment for F Hoffmann-La Roche and stock ownership for F Hoffmann-La Roche, Atea, Novartis, and Eli Lilly. JS declares consultancies from Invicro, Biogen, and AbbVie; and stock ownership from RealmIDX, MNI Holdings, and LikeMinds, as well as grants from The Michael J Fox Foundation. TSh declares employment for The Michael J Fox Foundation. ASin declares employment for NIH who received grants from The Michael J Fox Foundation and ASAP. ASin declares Diagnostic for Stroke royalties (unrelated to current work); honoraria from Movement Disorders Society and Nature Publishing Group; travel grants from Chan Zuckerberg Initiative, The Michael J Fox Foundation, and Weill Cornell. Asin's spouse is an employee of GeneDx. DS has no declarations. MS declared consultancies for Mediflix, and Health and Wellness Partners; honoraria from Atria Foundation, International Parkinson and Movement Disorder Society, Neurocrine, Luye Pharma, and Acorda. MS serves on advisory board at Neuroderm, Alexza, Alexion, and Biogen. CS declares employment for Amprion; stock ownership for Amprion; honoraria (will receive royalties for the sale of seed amplification assay) from Amprion; and patents or patent applications, awarded and amplified in conjunction with Amprion for the seed amplification assay. CT declares consultancies for CNS Ratings, Australian Parkinson's Mission, Biogen, Evidera, Cadent (data safety monitoring board), Adamas (steering committee), Biogen (via the Parkinson Study Group steering committee), Kyowa Kirin (advisory board), Lundbeck (advisory board), Jazz–Cavion (steering committee), Acorda (advisory board), Bial (DMC), and Genentech. CT also declares grant support to UCSF from The Michael J Fox Foundation, National Institute of Health, Gateway, Department of Defense, Roche Genentech, Biogen, Parkinson Foundation, and Marcus Program in Precision Medicine. DW declares salary support from The Michael J Fox Foundation for serving on an executive steering committee for the Parkinson Progression Markers Initiative. YX declares employment for and travel grants from The Michael J Fox Foundation. ASid declares consultancies for SPARC Therapeutics, Capsida Therapeutics, and Parkinson Study Group; honoraria from Bial; grants from The Michael J Fox Foundation (member of Parkinson Progression Markers Initiative steering committee), and NIH; and participation on board at Wave Life Sciences, Inhibikase, Prevail and Huntington Study Group, and Massachusetts General Hospital. BD has received consulting fees and travel support for his role as an advisor for Arch Venture Partners, Cerveau Technologies, Epilepsy Foundation, F-PRIME Capital, Loulou Foundation, and The Michael J Fox Foundation. BD has a leadership or fiduciary role in the Virginia Neurological Society (past president) and Prothena (Director). BD holds stock options with Prothena. KM declares support to his institution (Institute for Neurodegenerative Disorders) from The Michael J Fox Foundation. KMa also declares consultancies for Invicro, The Michael J Fox Foundation, Roche, Calico, Coave, Neuron23, Orbimed, Biohaven, Anofi, Koneksa, Merck, Lilly, Inhibikase, Neuramedy, IRLabs, and Prothena. KMa participates on DSMB at Biohaven. TB, MC, PD, and ET and declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Fibroepithelial lesions (FELs) are among the most common breast masses encountered by breast radiologists and pathologists. They encompass a spectrum of benign and malignant lesions, including fibroadenomas (FAs) and phyllodes tumors (PTs). FAs are typically seen in young premenopausal women, with a peak incidence at 20-30 years of age, and have imaging features of oval circumscribed hypoechoic masses. Although some FA variants are especially sensitive to hormonal influences and can exhibit rapid growth (eg, juvenile FA and lactational adenomas), most simple FAs are slow growing and involute after menopause. PTs can be benign, borderline, or malignant and are more common in older women aged 40-50 years. PTs usually manifest as enlarging palpable masses and are associated with a larger size and sometimes with an irregular shape at imaging compared with FAs. Although FA and FA variants are typically managed conservatively unless large and symptomatic, PTs are surgically excised because of the risk of undersampling at percutaneous biopsy and the malignant potential of borderline and malignant PTs. As a result of the overlap in imaging and histologic appearances, FELs can present a diagnostic challenge for the radiologist and pathologist. Radiologists can facilitate accurate diagnosis by supplying adequate tissue sampling and including critical information for the pathologist at the time of biopsy. Understanding the spectrum of FELs can facilitate and guide appropriate radiologic-pathologic correlation and timely diagnosis and management of PTs. Published under a CC BY 4.0 license. Online supplemental material is available for this article. Quiz questions for this article are available through the Online Learning Center.

Phosphatase of regenerating liver 3 (PRL3) is a specific tumor antigen overexpressed in a broad range of adult cancer types. However, its physiological expression in pediatric embryonal and mesenchymal tumors and its association with clinical outcomes in children is unknown. We sought to profile the expression of PRL3 in pediatric tumors in relation to survival outcomes, expression of angiogenesis markers, and G-protein-coupled receptor (GPCR)-mitogen-activated protein kinase (MAPK) signaling targets. PRL3-zumab, a first-in-class humanized antibody, was administered in a dose escalation schedule in a first-in-child clinical trial to study toxicity, pharmacokinetics, and clinical outcomes. Among 64 pediatric tumors, PRL3 was most frequently expressed in neuroblastoma (100%), rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcomas (71%), and renal sarcomas (60%) but absent in paired normal tissues. PRL3 was expressed in 75% of relapsed tumors and associated with shorter median event-free survival. Microarray profiling of PRL3-positive tumors showed elevation of angiogenin, TIMP1 and TIMP2, and GPCR-MAPK signaling proteins that commonly interacted with PRL3. The first use of PRL3-zumab in a pediatric patient saw no adverse events. A 28.6% reduction in maximum target lesion diameter was achieved when PRL3-zumab was administered concurrently with hypofractionated radiation. These findings support wider exploration of PRL3 expression in embryonal and mesenchymal tumors and further clinical application of PRL3-zumab in pediatric patients., Competing Interests: Q.Z. is the founder of Intra-Immu SG Pte Ltd., an A∗STAR spin-off company granted licensing rights to the PRL3-zumab IP portfolio. Intra-Immu SG Pte Ltd. provided PRL3-zumab used in this study., (© 2023 The Author(s).)

Background: Direct-acting antiviral medications have the potential to eliminate the hepatitis C virus (HCV) epidemic among people who inject drugs; yet, suboptimal adherence remains a barrier. Directly observed treatment (DOT), an effective strategy for optimizing adherence, has been frequently implemented in opioid treatment programs but less commonly in community health settings due to the heavy burden of daily visits. An alternative is video-observed therapy (VOT), which uses mobile health technology to monitor adherence. VOT has not been widely studied among people who inject drugs with HCV., Objective: This qualitative study, part of a larger implementation evaluation, investigates stakeholder perceptions and experiences with VOT in Project HERO (Hepatitis C Real Outcomes), a multisite pragmatic trial testing treatment delivery models for people who inject drugs with HCV. Our goal was to understand the potential barriers and facilitators to the implementation of the VOT technology., Methods: Qualitative interviews were conducted with 27 Project HERO study staff and 7 patients. Interviews focused on perceptions and experiences with the VOT app and barriers and facilitators to implementation. Team meeting minutes over the first 2 years of the project were transcribed. A coding system was developed and applied to the data. We summarized thematic data and compared participant perceptions to generate a close understanding of the data., Results: Frequent barriers to VOT included mechanical failure, stolen or lost phones, and a steep learning curve for participants and study staff. In sites with older and less technically skilled participants, staff found it difficult to implement the VOT app. Research staff found that the routine monitoring of app use led to closer engagement with participants. This was both a benefit and a potential threat to the validity of this pragmatic trial. Patient participants reported mixed experiences., Conclusions: VOT may be a useful alternative to DOT for some patients, but it may not be feasible for all. Significant staff involvement may be required., (©Alison Karasz, Krupa Merchant, Julia Arnsten, Judith Feinberg, Arthur Y Kim, Paula J Lum, Melissa Diane McKee, Shruti H Mehta, Paul Meissner, Brianna L Norton, Kimberly Page, Irene Pericot-Valverde, Reena Singh, Ellen Stein, Lynn E Taylor, Judith I Tsui, Katherine Wagner, Alain Litwin. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 02.06.2023.)

Objectives: To identify biopsy rates and indications for BI-RADS 3 lesions in a large cohort of patients and compare with follow-up compliance and malignancy outcomes., Methods: We retrospectively reviewed all BI-RADS category-3 lesions seen on mammography and/or ultrasound between 2013 and 2015. Patient age, lesion size, follow-up rates at 6-, 12-, and 24-months were collected. Biopsy timing, indication, and outcomes (malignant vs benign) were recorded using at least 2-year follow-up or biopsy pathology as endpoint., Results: Of 2319 BI-RADS 3 lesions in 2075 women analyzed, biopsy was performed in 173 (7.5%). Most biopsies were performed upfront (99, 57.2%), followed by at 6 (44, 25.4%), 12 (21, 12.1%), and 24-month follow-up (9, 5.2%; P < .001). Palpable (P < .001) and larger (median 1.4 vs 1.0 cm, P < .001) lesions in women <40 years (15.2% vs 4.8%, P < .001) were more likely to undergo biopsy. Most biopsies were prompted by patient/physician desire (64.5%, P < .001). Of 783 lesions with available endpoint, 5 (0.6%) were cancer. All cancers were identified either at presentation (in 0-5 months, n = 1) or 6-month follow-up (in 5-9 months, n = 4) with biopsy prompted by either morphology change (n = 3) or lesion growth (n = 2). Of the 1855 lesions which were expected for follow up, only 310 (16.7%) underwent all follow-ups, while 482 (26.1%) had two, 489 (26.5%) one, and 565 (30.6%) had no follow-up., Conclusions: In our cohort, BI-RADS category 3 lesions had significantly higher biopsy rates compared with the small malignancy rate, all of which were identified at baseline or first follow-up. Overall patient follow-up compliance low. Imaging follow-up, especially at first 6-month time point, should be encouraged in BI-RADS 3 lesions, instead of upfront biopsies., (© 2022 American Institute of Ultrasound in Medicine.)

Background: Chronic inducible urticaria (CIndU) is characterized by mast cell (MC)-mediated wheals in response to triggers: cold in cold urticaria (ColdU) and friction in symptomatic dermographism (SD). KIT receptor activation by stem cell factor (SCF) is essential for MC function. Barzolvolimab (CDX-0159) is a humanized antibody that inhibits KIT activation by SCF and was well tolerated in healthy volunteers with dose-dependent plasma tryptase suppression indicative of systemic mast cell ablation., Methods: This is an open-label, trial in patients with antihistamine refractory ColdU or SD, receiving one IV dose of barzolvolimab (3 mg/kg), with a 12-week follow-up. Primary endpoint was safety/tolerability; pharmacodynamic (PD)/clinical endpoints included serum tryptase, plasma SCF, skin MC histology, provocation tests, urticaria control test (UCT), and dermatology life quality index (DLQI)., Results: Analysis populations were safety (n = 21) and pharmacodynamics/clinical activity (n = 20). Barzolvolimab was well tolerated; most adverse events were mild and resolved. Treatment resulted in significant depletion of skin MCs, decreased tryptase (

Background: Emerging evidence shows that α-synuclein seed amplification assays (SAAs) have the potential to differentiate people with Parkinson's disease from healthy controls. We used the well characterised, multicentre Parkinson's Progression Markers Initiative (PPMI) cohort to further assess the diagnostic performance of the α-synuclein SAA and to examine whether the assay identifies heterogeneity among patients and enables the early identification of at-risk groups., Methods: This cross-sectional analysis is based on assessments done at enrolment for PPMI participants (including people with sporadic Parkinson's disease from LRRK2 and GBA variants, healthy controls, prodromal individuals with either rapid eye movement sleep behaviour disorder (RBD) or hyposmia, and non-manifesting carriers of LRRK2 and GBA variants) from 33 participating academic neurology outpatient practices worldwide (in Austria, Canada, France, Germany, Greece, Israel, Italy, the Netherlands, Norway, Spain, the UK, and the USA). α-synuclein SAA analysis of CSF was performed using previously described methods. We assessed the sensitivity and specificity of the α-synuclein SAA in participants with Parkinson's disease and healthy controls, including subgroups based on genetic and clinical features. We established the frequency of positive α-synuclein SAA results in prodromal participants (RBD and hyposmia) and non-manifesting carriers of genetic variants associated with Parkinson's disease, and compared α-synuclein SAA to clinical measures and other biomarkers. We used odds ratio estimates with 95% CIs to measure the association between α-synuclein SAA status and categorical measures, and two-sample 95% CIs from the resampling method to assess differences in medians between α-synuclein SAA positive and negative participants for continuous measures. A linear regression model was used to control for potential confounders such as age and sex., Findings: This analysis included 1123 participants who were enrolled between July 7, 2010, and July 4, 2019. Of these, 545 had Parkinson's disease, 163 were healthy controls, 54 were participants with scans without evidence of dopaminergic deficit, 51 were prodromal participants, and 310 were non-manifesting carriers. Sensitivity for Parkinson's disease was 87·7% (95% CI 84·9-90·5), and specificity for healthy controls was 96·3% (93·4-99·2). The sensitivity of the α-synuclein SAA in sporadic Parkinson's disease with the typical olfactory deficit was 98·6% (96·4-99·4). The proportion of positive α-synuclein SAA was lower than this figure in subgroups including LRRK2 Parkinson's disease (67·5% [59·2-75·8]) and participants with sporadic Parkinson's disease without olfactory deficit (78·3% [69·8-86·7]). Participants with LRRK2 variant and normal olfaction had an even lower α-synuclein SAA positivity rate (34·7% [21·4-48·0]). Among prodromal and at-risk groups, 44 (86%) of 51 of participants with RBD or hyposmia had positive α-synuclein SAA (16 of 18 with hyposmia, and 28 of 33 with RBD). 25 (8%) of 310 non-manifesting carriers (14 of 159 [9%] LRRK2 and 11 of 151 [7%] GBA) were positive., Interpretation: This study represents the largest analysis so far of the α-synuclein SAA for the biochemical diagnosis of Parkinson's disease. Our results show that the assay classifies people with Parkinson's disease with high sensitivity and specificity, provides information about molecular heterogeneity, and detects prodromal individuals before diagnosis. These findings suggest a crucial role for the α-synuclein SAA in therapeutic development, both to identify pathologically defined subgroups of people with Parkinson's disease and to establish biomarker-defined at-risk cohorts., Funding: PPMI is funded by the Michael J Fox Foundation for Parkinson's Research and funding partners, including: Abbvie, AcureX, Aligning Science Across Parkinson's, Amathus Therapeutics, Avid Radiopharmaceuticals, Bial Biotech, Biohaven, Biogen, BioLegend, Bristol-Myers Squibb, Calico Labs, Celgene, Cerevel, Coave, DaCapo Brainscience, 4D Pharma, Denali, Edmond J Safra Foundation, Eli Lilly, GE Healthcare, Genentech, GlaxoSmithKline, Golub Capital, Insitro, Janssen Neuroscience, Lundbeck, Merck, Meso Scale Discovery, Neurocrine Biosciences, Prevail Therapeutics, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, VanquaBio, Verily, Voyager Therapeutics, and Yumanity., Competing Interests: Declaration of interests AS declares consultancy for Merck, Parkinson Study Group; and honoraria from Bial. LC-M declares employment for Amprion; stock ownership (employee stock options) for Amprion; and patent or patent applications numbers US 20210277076A1, US 20210311077A1, US 20190353669A1, and US 20210223268A1. CMF declares employment for Amprion; stock ownership (employee stock options) for Amprion; and patent or patent applications numbers US 20210277076A1 and US 20210311077A1. YM declares employment for Amprion; stock ownership (employee stock options) for Amprion; and patent or patent applications number US 20210277076A1. PAU declares employment for Amprion; and stock ownership (employee stock options) for Amprion. HN declares employment for Amprion; and stock ownership (employee stock options) for Amprion. RNA declares consultancies for Janssen, Sanofi, Ono Therapuetics, Avrobio, Takeda, Gain Therapuetics, Merck, GlaxoSmithKline, and Caraway. LMC declares honoraria (royalties) from Elsevier and Wolters Kluwel. TF declares travel grants from the Michael J Fox Foundation. KMe declares consultancies for the Michael J Fox Foundation, AcuRx, Caraway, Cerebral Therapeutics, NRG Therapeutics (scientific advisory board), Nurabio, Retromer Therapeutics (director on the board, part-time chief scientific officer), Schrodinger, Sinopia Biosciences (scientific advisory board), and Vanqua Biosciences (scientific advisory board); stock ownership for Cognition Therapeutics, Eli Lilly (retiree stock holder), Envisagenics, and Retromer Therapeutics; honoraria for the University of Utah; patents or patent applications for Retromer Therapeutics (planned patent); and travel grants from the University of Utah. BM declares consultancies from Roche, Biogen, and the Michael J Fox Foundation; honoraria for Abbvie; and travel grants for Abbvie. KLP declares consultancies for Curasen; was on a scientific advisory board for Curasen and Amprion; honoraria from invited scientific presentations to universities and professional societies not exceeding $5000 per year from California Congress of Clinical Neurology, California Neurological Society, and Johns Hopkins University; and patents or patent applications numbers 17/314,979 and 63/377,293. JS declares consultancies from Invicro, Biogen, and Abbvie; and stock ownership from RealmIDX, MNI Holdings, and LikeMinds. TSi declares consultancies for 4D Pharma, Acadia, AcureX, AskBio, Amneal, Blue Rock Therapeutics, Caraway, Critical Path for Parkinson's Consortium, Denali, Michael J Fox Foundation, Neuroderm, Roche, Sanofi, Sinopia, Sunovion, Takeda, UCB, Vanqua Bio, and Voyager. CMT declares consultancies for CNS Ratings, Australian Parkinson's Mission, Biogen, Evidera, Cadent (data safety monitoring board), Adamas (steering committee), Biogen (via the Parkinson Study Group steering committee), Kyowa Kirin (advisory board), Lundbeck (advisory board), Jazz/Cavion (steering committee), and Acorda (advisory board). DW declares receiving salary support from Michael J Fox Foundation for serving on an Executive Steering Committee for the PPMI. AV declares consultancies for CoA Therapeutics, XW Pharma, and Biogen. MF declares employment for the Michael J Fox Foundation. LMAO declares employment for the Michael J Fox Foundation. SJH declares employment for the Michael J Fox Foundation. TSh declares employment for the Michael J Fox Foundation. KMa declares consultancies for Invicro, MJFF, Roche, Calico, Coave, Neuron23, Orbimed, Neuroderm, Sanofi, Takeda, Merck, Lilly, Inhibikase, and Neuramedy. CS declares employment for Amprion; stock ownership for Amprion; honoraria (will receive royalties for the sale of seed amplification assay [SAA]) from Amprion; and patents or patent applications, awarded and amplified in conjunction with Amprion for the SAA assay., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Little is known about the impact of the dopamine system on development of cognitive impairment (CI) in Parkinson disease (PD)., Objectives: We used data from a multi-site, international, prospective cohort study to explore the impact of dopamine system-related biomarkers on CI in PD., Methods: PD participants were assessed annually from disease onset out to 7 years, and CI determined by applying cut-offs to four measures: (1) Montreal Cognitive Assessment; (2) detailed neuropsychological test battery; (3) Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) cognition score; and (4) site investigator diagnosis of CI (mild cognitive impairment or dementia). The dopamine system was assessed by serial Iodine-123 Ioflupane dopamine transporter (DAT) imaging, genotyping, and levodopa equivalent daily dose (LEDD) recorded at each assessment. Multivariate longitudinal analyses, with adjustment for multiple comparisons, determined the association between dopamine system-related biomarkers and CI, including persistent impairment., Results: Demographic and clinical variables associated with CI were higher age, male sex, lower education, non-White race, higher depression and anxiety scores and higher MDS-UPDRS motor score. For the dopamine system, lower baseline mean striatum dopamine transporter values ( P range 0.003-0.005) and higher LEDD over time ( P range <0.001-0.01) were significantly associated with increased risk for CI., Conclusions: Our results provide preliminary evidence that alterations in the dopamine system predict development of clinically-relevant, cognitive impairment in Parkinson's disease. If replicated and determined to be causative, they demonstrate that the dopamine system is instrumental to cognitive health status throughout the disease course., Trial Registration: Parkinson's Progression Markers Initiative is registered with ClinicalTrials.gov (NCT01141023)., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Hirschsprung's disease (HD) is one of the most well-known gastrointestinal motility disorders. Diagnosis and management of other lesser-known motility disorders are often challenging and tedious. We describe a teenager who was severely constipated from birth and needed intensive care admissions for life-threatening enterocolitis. She also had concomitant anal stenosis. Several rectal biopsies were unable to yield a conclusive diagnosis. Surgical level of resection had to be identified based on the motility of the bowel as determined by transit studies using oral ingestion of a milk feed labelled with Technetium-99m colloid. After completion of all operative stages, histopathological examination of the excised specimens concluded that she had short-segment HD associated with reduced interstitial cells of Cajal in the large bowel. She is currently continent, evacuating voluntarily approximately four times a day and is relieved of all her symptoms., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Neonatal lupus (NL) is a clinical syndrome that develops in the fetus as a result of maternal autoimmune antibodies. Congenital complete heart block (CHB) is the most common manifestation, while extranodal cardiac manifestations of NL, such as endocardial fibroelastosis (EFE) and myocarditis, are rare but more serious. Less is known about this atrioventricular valve rupture due to valvulitis as a consequence of maternal autoantibodies. We have described a case of cardiac neonatal lupus with an antenatally detected CHB patient who developed mitral and tricuspid valve chordal rupture at 45 days of age. We compared the cardiac histopathology and the fetal cardiac echocardiographic findings of this case with another fetus that was aborted after being antenatally diagnosed with CHB but without valvar rupture. A narrative analysis after a systematic review of the literature regarding atrioventricular valve apparatus rupture due to autoimmune etiology along with maternal characteristics, presentation, treatment, and outcome have been discussed in this article., Objectives: To describe published data on atrioventricular valve rupture in neonatal lupus, including clinical presentation, diagnostic evaluation, management, and outcomes., Methods: We conducted a PRISMA-compliant descriptive systematic examination of case reports that included accounts of lupus during pregnancy or in the newborn period that resulted in an atrioventricular valve rupture. We gathered information on the patient's demographics, the details of the valve rupture and other comorbidities, the maternal therapy, the clinical course, and the results. We also used a standardized method to evaluate the cases' quality. A total of 12 cases were investigated, with 11 cases drawn from 10 case reports or case series and 1 from our own experience., Results: Tricuspid valve rupture (50%) is more common than mitral valve rupture (17%). Unlike mitral valve rupture, which occurs postnatally, the timing of tricuspid valve rupture is perinatal. A total of 33% of the patients had concomitant complete heart block, while 75% of the patients had endocardial fibroelastosis on an antenatal ultrasound. Antenatal changes pertaining to endocardial fibroelastosis can be seen as early as 19 weeks of gestation. Patients with both valve ruptures generally have a poor prognosis, especially if they occur at close intervals., Conclusion: Atrioventricular valve rupture in neonatal lupus is rare. A majority of patients with valve rupture had antenatally detected endocardial fibroelastosis in the valvar apparatus. Appropriate and expedited surgical repair of ruptured atrioventricular valves is feasible and has a low mortality risk. Rupture of both atrioventricular valves occurring at close intervals carries a high mortality risk.

Elevated urine bis(monoacylglycerol)phosphate (BMP) levels have been found in gain-of-kinase function LRRK2 G2019S mutation carriers. Here, we have expanded urine BMP analysis to other Parkinson's disease (PD) associated mutations and found them to be consistently elevated in carriers of LRRK2 G2019S and R1441G/C as well as VPS35 D620N mutations. Urine BMP levels are promising biomarkers for patient stratification and potentially target engagement in clinical trials of emerging targeted PD therapies., (© 2023. The Author(s).)

Introduction: Highly effective direct-acting antiviral (DAA) agents have changed the landscape of hepatitis C virus infection (HCV) treatment and have become more available to people who inject drugs (PWID) over the past several years. Although many achieve a sustained virologic response (SVR), a small proportion will become re-infected. This study examined experiences of re-infection among participants in Project HERO, a large multi-site treatment trial designed to test alternative treatment delivery models for DAAs., Methods: Study staff conducted qualitative interviews with twenty-three HERO participants who experienced reinfection following successful treatment for HCV. Interviews focused on life circumstances and experiences with treatment/re-infection. We conducted a thematic analysis, followed by a narrative analysis., Results: Participants described challenging life circumstances. The initial experience of cure was joyful, leading participants to feel that they had escaped a defiled, stigmatized identity. Re-infection was very painful. Feelings of shame were common. Participants with fully developed narratives of re-infection described both a strong emotional response as well as a plan for avoiding re-infection during retreatment. Participants who lack such stories showed signs of hopelessness and apathy., Conclusion: Though the promise of personal transformation through SVR may be motivating for patients, clinicians should be cautious about how they describe the "cure" when educating patients about HCV treatment. Patients should be encouraged to avoid stigmatizing, dichotomizing language of the self, including terms such as "dirty" and "clean." In acknowledging the benefits of HCV cure, clinicians should emphasize that re-infection does not mean failed treatment; and that current treatment guidelines support retreatment of re-infected PWID., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Physicians are often asked to counsel patients about driving safety after syncope, yet little empirical data guides such advice., Methods: We identified a population-based retrospective cohort of 9,507 individuals with a driver license who were discharged from any of six urban emergency departments (EDs) with a diagnosis of 'syncope and collapse'. We examined all police-reported crashes that involved a cohort member as a driver and occurred between 1 January 2010 and 31 December 2016. We categorized crash-involved drivers as 'responsible' or 'non-responsible' for their crash using detailed police-reported crash data and a validated responsibility scoring tool. We then used logistic regression to test the hypothesis that recent syncope was associated with driver responsibility for crash., Results: Over the 7-year study interval, cohort members were involved in 475 police-reported crashes: 210 drivers were deemed responsible and 133 drivers were deemed non-responsible for their crash; the 132 drivers deemed to have indeterminate responsibility were excluded from further analysis. An ED visit for syncope occurred in the three months leading up to crash in 11 crash-responsible drivers and in 5 crash-non-responsible drivers, suggesting that recent syncope was not associated with driver responsibility for crash (adjusted odds ratio, 1.31; 95%CI, 0.40-4.74; p = 0.67). However, all drivers with cardiac syncope were deemed responsible, precluding calculation of an odds ratio for this important subgroup., Conclusions: Recent syncope was not significantly associated with driver responsibility for traffic crash. Clinicians and policymakers should consider these results when making fitness-to-drive recommendations after syncope., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Staples et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The Parkinson's disease (PD) research field has seen the advent of several promising biomarkers and a deeper understanding of the clinical features of the disease from the earliest stages of pathology to manifest disease. Despite progress, a biologically based PD staging system does not exist. Such staging would be a useful framework within which to model the disease, develop and validate biomarkers, guide therapeutic development, and inform clinical trials design. We propose that the presence of aggregated neuronal α-synuclein, dopaminergic neuron dysfunction/degeneration, and clinical signs and symptoms identifies a group of individuals that have Lewy body pathology, which in early stages manifests with what is now referred to as prodromal non-motor features and later stages with the manifestations of PD and related Lewy body diseases as defined by clinical diagnostic criteria. Based on the state of the field, we herein propose a definition and staging of PD based on biology. We present the biologic basis for such a staging system and review key assumptions and evidence that support the proposed approach. We identify gaps in knowledge and delineate crucial research priorities that will inform the ultimate integrated biologic staging system for PD.

Background: Identifying a meaningful progression metric for Parkinson's disease (PD) that reflects heterogeneity remains a challenge., Objective: To assess the frequency and baseline predictors of progression to clinically relevant motor and non-motor PD milestones., Methods: Using data from the Parkinson's Progression Markers Initiative (PPMI) de novo PD cohort, we monitored 25 milestones across six domains ("walking and balance"; "motor complications"; "cognition"; "autonomic dysfunction"; "functional dependence"; "activities of daily living"). Milestones were intended to be severe enough to reflect meaningful disability. We assessed the proportion of participants reaching any milestone; evaluated which occurred most frequently; and conducted a time-to-first-event analysis exploring whether baseline characteristics were associated with progression., Results: Half of participants reached at least one milestone within five years. Milestones within the cognitive, functional dependence, and autonomic dysfunction domains were reached most often. Among participants who reached a milestone at an annual follow-up visit and remained active in the study, 82% continued to meet criteria for any milestone at one or more subsequent annual visits and 55% did so at the next annual visit. In multivariable analysis, baseline features predicting faster time to reaching a milestone included age (p < 0.0001), greater MDS-UPDRS total scores (p < 0.0001), higher GDS-15 depression scores (p = 0.0341), lower dopamine transporter binding (p = 0.0043), and lower CSF total α-synuclein levels (p = 0.0030). Symptomatic treatment was not significantly associated with reaching a milestone (p = 0.1639)., Conclusion: Clinically relevant milestones occur frequently, even in early PD. Milestones were significantly associated with baseline clinical and biological markers, but not with symptomatic treatment. Further studies are necessary to validate these results, further assess the stability of milestones, and explore translating them into an outcome measure suitable for observational and therapeutic studies.

Objective: The role of prophylactic detethering a fibrofatty filum terminale (FFT) remains equivocal. Furthermore, long-term studies focusing on urological outcomes are sparse. The aims of this study were to present an institutional experience on the perioperative and long-term outcomes of FFT surgery and to assess for factors that contribute to postoperative clean intermittent catheterization (CIC)., Methods: This was a single-institution, retrospective study conducted over a 20-year period. Patients younger than 19 years of age who underwent surgery for FFT were included. Variables of interest included patient demographics, clinical presentation, radiological findings, postoperative complications, and long-term need for CIC. Outcomes were measured using the Necker functional score and modified Hoffer Functional Ambulation scale score at 3, 6, and 12 months postdischarge., Results: A total of 164 surgeries were performed for FFT from 2000 to 2020. The median age at surgery was 1.1 years, and the mean follow-up duration was 8.3 years. There were 115 patients (70.1%) who underwent prophylactic-intent surgery and 49 patients (29.9%) who underwent therapeutic-intent surgery. The proportion of therapeutic-intent surgeries increased significantly with age percentiles (0-20th, 21.9%; 20th-40th, 9.1%; 40th-60th, 18.2%; 60th-80th, 36.4%; and 80th-100th, 63.6% [p < 0.001]). Thirty patients (18.3%) had an associated syndrome, the most common (n = 19, 11.6%) being VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities). Forty-eight patients (29.3%) had an associated malformation (anorectal anomaly = 37, urogenital anomaly = 16, and sacral anomaly = 3). Cutaneous manifestation was the most common presentation (n = 96, 58.5%), followed by lower-limb neurological deficits (n = 21, 12.8%). A low-lying conus was present in 36.0% of patients (n = 59), and 16.5% had an associated syrinx (n = 27). There were 26 patients (18.8%) with an abnormal preoperative urodynamic study. Three patients (1.8%) had postoperative complications that required repeat surgery. There were no cases of CSF leakage. One patient (0.6%) developed retethering requiring another surgery. Postoperative CIC was required in 11 patients (6.7%). Multivariable analyses showed that an abnormal preoperative urodynamic study (adjusted OR 5.5 [95% CI 1.27-23.9], p = 0.023) and having an intraspinal syrinx (adjusted OR 5.29 [95% CI 1.06-26.4], p = 0.042) were associated with the need for CIC., Conclusions: The authors' results demonstrate that detethering surgery for FFT is a relatively safe procedure and can be performed prophylactically. Nonetheless, the risks of postoperative CIC should be emphasized during the preoperative counseling process.

Brain diseases are a major cause of death and disability worldwide and contribute significantly to years of potential life lost. Although there have been considerable advances in biological mechanisms associated with brain disorders as well as drug discovery paradigms in recent years, these have not been sufficiently translated into effective treatments. This Special Article expands on Keystone Symposia's pre- and post-pandemic panel discussions on translational neuroscience research. In the article, we discuss how lessons learned from the COVID-19 pandemic can catalyze critical progress in translational research, with efficient collaboration bridging the gap between basic discovery and clinical application. To achieve this, we must place patients at the center of the research paradigm. Furthermore, we need commitment from all collaborators to jointly mitigate the risk associated with the research process. This will require support from investors, the public sector and pharmaceutical companies to translate disease mechanisms into world-class drugs. We also discuss the role of scientific publishing in supporting these models of open innovation. Open science journals can now function as hubs to accelerate progress from discovery to treatments, in neuroscience in particular, making this process less tortuous by bringing scientists together and enabling them to exchange data, tools and knowledge effectively. As stakeholders from a broad range of scientific professions, we feel an urgency to advance brain disease therapies and encourage readers to work together in tackling this challenge., Competing Interests: Competing interests M.-J.B., M.I.L. and K.M. were the organizers of the Keystone Symposia events discussed in this article. J.H. is Senior Editor at DMM but was not involved in any aspect of the editorial handling of the article. S.C. is Head of Research at The Michael J. Fox Foundation for Parkinson's Research and thus has extensive knowledge of this funder's priorities., (© 2022. Published by The Company of Biologists Ltd.)

We examined 2-year longitudinal change in clinical features and biomarkers in LRRK2 non-manifesting carriers (NMCs) versus healthy controls (HCs) enrolled in the Parkinson's Progression Markers Initiative (PPMI). We analyzed 2-year longitudinal data from 176 LRRK2 G2019S NMCs and 185 HCs. All participants were assessed annually with comprehensive motor and non-motor scales, dopamine transporter (DAT) imaging, and biofluid biomarkers. The latter included cerebrospinal fluid (CSF) Abeta, total tau and phospho-tau; serum urate and neurofilament light chain (NfL); and urine bis(monoacylglycerol) phosphate (BMP). At baseline, LRRK2 G2019S NMCs had a mean (SD) age of 62 (7.7) years and were 56% female. 13% had DAT deficit (defined as <65% of age/sex-expected lowest putamen SBR) and 11% had hyposmia (defined as ≤15th percentile for age and sex). Only 5 of 176 LRRK2 NMCs developed PD during follow-up. Although NMCs scored significantly worse on numerous clinical scales at baseline than HCs, there was no longitudinal change in any clinical measures over 2 years or in DAT binding. There were no longitudinal differences in CSF and serum biomarkers between NMCs and HCs. Urinary BMP was significantly elevated in NMCs at all time points but did not change longitudinally. Neither baseline biofluid biomarkers nor the presence of DAT deficit correlated with 2-year change in clinical outcomes. We observed no significant 2-year longitudinal change in clinical or biomarker measures in LRRK2 G2019S NMCs in this large, well-characterized cohort even in the participants with baseline DAT deficit. These findings highlight the essential need for further enrichment biomarker discovery in addition to DAT deficit and longer follow-up to enable the selection of NMCs at the highest risk for conversion to enable future prevention clinical trials., (© 2022. The Author(s).)

There is increasing evidence that lidocaine is toxic to adipocytes and their precursors, which can contribute to the variability in fat graft resorption. Erector spinae plane (ESP) block is a new technique to provide analgesia of the trunk and would avoid lidocaine at the fat graft donor site. The aim of this study was to compare the efficacy of ESP block versus tumescent local anesthesia (TLA)., Methods: A retrospective review was performed for all patients who underwent autologous fat grafting from the abdomen at the University of New Mexico Hospital between February 2016 and March 2019. These patients received either ESP block or TLA during abdominal fat harvest. The primary endpoints were intraoperative, postoperative, and total morphine equivalents., Results: There was no difference in the mean intraoperative, postoperative, and total morphine equivalents administered between the ESP and TLA groups., Conclusions: ESP block is equivalent to TLA for analgesia when using an abdominal donor site for fat harvest. ESP block should be considered in fat-grafting cases to avoid the potential toxicity of lidocaine to the viability of adipocytes and preadipocytes., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Introduction: Increasingly, people who inject drugs (PWID) infected with hepatitis C virus (HCV) are gaining access to highly effective direct-acting antiviral agents (DAAs). Although past studies examined patient experiences with interferon-based treatments, few have explored patient experiences with these new generation therapeutics. Research and real world experience indicate that many PWID can be successfully treated with the new DAAs. Yet a substantial minority fail to complete treatment or achieve only suboptimal adherence. This qualitative study examines experiences with treatment among participants in Project HERO, a large multisite trial designed to compare treatment delivery methods for DAAs. We explored treatment experiences among HERO participants, with the goal of understanding potential barriers to treatment engagement and completion., Methods: We conducted qualitative interviews with a sample of 21 participants, including 14 who completed HCV treatment and 7 participants who discontinued treatment before the end of the 12-week medication course. The first phase of the analysis was descriptive, examining participants' life experiences, histories of disease and treatment seeking, experiences with the program, and barriers to treatment completion. The second phase of the analysis examined differences between completers and noncompleters., Results: Participants offered a variety of reasons for seeking treatment. Both groups of participants reported highly positive experiences of the HERO trial. Participants described research staff as caring, respectful, and nonjudgmental. Substance use was reported by both groups, yet completers described "manageable" substance use, while noncompleters described substance use that sapped their energy and motivation. Shame over drug use was a barrier to treatment completion. Homelessness and a reported lack of social support were much more common in the noncompleter group., Conclusions: Reasons for noncompletion were not related to features of the clinical trial or treatment program. Our results indicate the importance of: 1) recognizing and addressing severe social and economic challenges such as homelessness; and 2) building a program culture of respect and compassion in treatment programs for PWID infected with HCV., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Competing Interests: The authors report no conflict of interest.

Importance: Medical driving restrictions are burdensome, yet syncope recurrence while driving can cause a motor vehicle crash (MVC). Few empirical data inform current driving restrictions after syncope., Objective: To examine MVC risk among patients visiting the emergency department (ED) after first-episode syncope., Design, Setting, and Participants: A population-based, retrospective observational cohort study of MVC risk after first-episode syncope was performed in British Columbia, Canada. Patients visiting any of 6 urban EDs for syncope and collapse were age- and sex-matched to 4 control patients visiting the same ED in the same month for a condition other than syncope. Patients' ED medical records were linked to administrative health records, driving history, and detailed crash reports. Crash-free survival among individuals with syncope was then compared with that among matched control patients. Data analyses were performed from May 2020 to March 2022., Exposures: Initial ED visit for syncope., Main Outcomes and Measures: Involvement as a driver in an MVC in the year following the index ED visit. Crashes were identified using insurance claim data and police crash reports., Results: The study cohort included 43 589 patients (9223 patients with syncope and 34 366 controls; median [IQR] age, 54 [35-72] years; 22 360 [51.3%] women; 5033 [11.5%] rural residents). At baseline, crude MVC incidence rates among both the syncope and control groups were higher than among the general population (12.2, 13.2, and 8.2 crashes per 100 driver-years, respectively). In the year following index ED visit, 846 first crashes occurred in the syncope group and 3457 first crashes occurred in the control group, indicating no significant difference in subsequent MVC risk (9.2% vs 10.1%; adjusted hazard ratio [aHR], 0.93; 95% CI, 0.87-1.01; P = .07). Subsequent crash risk among patients with syncope was not significantly increased in the first 30 days after index ED visit (aHR, 1.07; 95% CI, 0.84-1.36; P = .56) or among subgroups at higher risk of adverse events after syncope (eg, age >65 years; cardiogenic syncope; Canadian Syncope Risk Score ≥1)., Conclusions and Relevance: The findings of this population-based retrospective cohort study suggest that patients visiting the ED with first-episode syncope exhibit a subsequent crash risk no different than the average ED patient. More stringent driving restrictions after syncope may not be warranted.

Purpose: MYCN onco-gene amplification in neuroblastoma confers patients to the high-risk disease category for which prognosis is poor and more aggressive multimodal treatment is indicated. This retrospective study leverages machine learning techniques to develop a computed tomography (CT)-based model incorporating semantic and non-semantic features for non-invasive prediction of MYCN amplification status in pediatric neuroblastoma., Methods: From 2009 to 2020, 54 pediatric patients treated for neuroblastoma at a specialized children's hospital with pre-treatment contrast-enhanced CT and MYCN status were identified (training cohort, n = 44; testing cohort, n = 10). Six morphologic features and 107 quantitative gray-level texture radiomics features extracted from manually drawn volume-of-interest were analyzed. Following feature selection and class balancing, the final predictive model was developed with eXtreme Gradient Boosting (XGBoost) algorithm. Accumulated local effects (ALE) plots were used to explore main effects of the predictive features. Tumor texture maps were also generated for visualization of radiomics features., Results: One morphologic and 2 radiomics features were selected for model building. The XGBoost model from the training cohort yielded an area under the receiver operating characteristics curve (AUC-ROC) of 0.930 (95% CI, 0.85-1.00), optimized F1-score of 0.878, and Matthews correlation coefficient (MCC) of 0.773. Evaluation on the testing cohort returned AUC-ROC of 0.880 (95% CI, 0.64-1.00), optimized F1-score of 0.933, and MCC of 0.764. ALE plots and texture maps showed higher "GreyLevelNonUniformity" values, lower "Strength" values, and higher number of image-defined risk factors contribute to higher predicted probability of MYCN amplification., Conclusion: The machine learning model reliably classified MYCN amplification in pediatric neuroblastoma and shows potential as a surrogate imaging biomarker., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: Paediatric eosinophilic gastritis (EG) is a rare disorder and existing literature on diagnostic criteria and management remains lacking. We aim to describe the clinical spectrum and assess the efficacy of dietary elimination and proton-pump inhibitor (PPI) therapy, with particular emphasis on histologic remission in children with primary EG., Methods: We performed a retrospective study of patients aged 0-18 years diagnosed with EG at a single centre in Singapore from 2013 to 2021. EG was diagnosed based on histological criteria of infiltration of >30 eosinophils per high-power film (HPF) in >5 separate HPFs from gastric biopsies, in the absence of other causes. First-line treatment consisted of PPI therapy and empiric 1-6 food elimination diet (FED). Outcomes measured were clinical, endoscopic and histological remission (defined as eosinophil count <20/HPF in gastric biopsies)., Results: Twenty-one (66.7% females) patients were included with median age at diagnosis of 15 months (range:3-192). Majority presented with vomiting (76.2%) and gastrointestinal bleeding (71.4%). Twenty patients were initiated on FED+PPI and 16 had post-treatment biopsies. Clinical, endoscopic and histologic remissions were achieved in 94.7%, 81.3% and 68.8% respectively following FED+PPI. Histologic remission was significantly associated with younger age (9 vs. 132 months; P = 0.026). Four patients who did not respond to FED+PPI were started on oral viscous budesonide, of whom one achieved histological remission and two had clinical improvement., Conclusions: FED+PPI is effective as first-line treatment in achieving histological remission in paediatric EG particularly in younger patients. Topical corticosteroids can be considered for those who have failed FED+PPI therapy., (© 2022 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Parkinson's disease (PD) is a growing burden worldwide, and there is no reliable biomarker used in clinical routines to date. Cerebrospinal fluid (CSF) is routinely collected in patients with neurological symptoms and should closely reflect alterations in PD patients' brains. Here, we describe a scalable and sensitive mass spectrometry (MS)-based proteomics workflow for CSF proteome profiling. From two independent cohorts with over 200 individuals, our workflow reproducibly quantifies over 1,700 proteins from minimal CSF amounts. Machine learning determines OMD, CD44, VGF, PRL, and MAN2B1 to be altered in PD patients or to significantly correlate with clinical scores. We also uncover signatures of enhanced neuroinflammation in LRRK2 G2019S carriers, as indicated by increased levels of CTSS, PLD4, and HLA proteins. A comparison with our previously acquired urinary proteomes reveals a large overlap in PD-associated changes, including lysosomal proteins, opening up new avenues to improve our understanding of PD pathogenesis., Competing Interests: Declaration of interests The authors declare no conflicts of interest related to this work., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Opioid use disorder (OUD) has led to a staggering death toll in terms of drug-related overdoses. Despite the demonstrated benefits and effectiveness of buprenorphine, retention is suboptimal, and patients typically present with high rates of ongoing polysubstance use during treatment. A pilot trial provided preliminary support for the efficacy of computer-based cognitive-behavioral therapy (CBT4CBT) as an add-on to buprenorphine in reducing substance use. Recovery coaching services provided by individuals with substance use experience and successful recovery have also shown to positively influence recovery outcomes for people with OUD by increasing buprenorphine initiation and reducing opioid use., Methods: The OVERCOME study is a randomized clinical trial (RCT) aimed to tests an integrated intervention combining CBT4CBT and Recovery Coaching relative to treatment- as -usual (TAU) among individuals with OUD on buprenorphine. The primary outcome measure is the percentage of samples with any drug tested as positive at each research visit conducted during treatment (visits 1 to 8). Secondary outcomes include the percentage of samples with any drug tested as positive at 1- and 3- month follow-up and retention to buprenorphine at 3- month follow-up., Results: We describe the rationale, design, and methodology of the OVERCOME Study., Conclusion: This trial will provide evidence of the efficacy of an integrated intervention combining CBT4CBT and Recovery Coaching for reducing substance use and increasing buprenorphine adherence which has the potential to reduce mortality among people with OUD., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work presented in this manuscript., (© 2022 Published by Elsevier Inc.)

Background: Children with frequently relapsing nephrotic syndrome (FRNS) and steroid resistant nephrotic syndrome (SRNS) are exposed to immunosuppressant medications with adverse side effects and variable efficacy. Transcutaneous auricular vagus nerve stimulation (taVNS) modulates the immune system via the inflammatory reflex and has become a therapy of interest for treating immune-mediated illnesses., Methods: An open-label, pilot study of tavNS for five minutes daily for 26 weeks via a TENS 7000 unit was conducted., Results: Three FRNS participants and 4 SRNS participants had a mean age of 9.5±4.2 years (range 4 to 17). Those with FRNS remained relapse-free during the study period; two participants continued treatment and remained in remission for 15 and 21 months, respectively. Three SRNS participants experienced a reduction in first morning UPC (mean of 42%, range 25-76%). Although UPC decreased (13.7%) in one SRNS participant with congenital nephrotic syndrome, UPC remained in nephrotic range. All but one participant (non-compliant with treatment) experienced a reduction in TNF (7.33pg/mL vs. 5.46pg/mL, p=0.03). No adverse events or side effects were reported., Conclusions: taVNS was associated with clinical remission in FRNS and moderately reduced proteinuria in non-congenital SRNS. Further study of taVNS as a treatment for nephrotic syndrome in children is warranted. ClinicalTrials.gov Identifier: NCT04169776, Registered November 20, 2019, https://clinicaltrials.gov/ct2/show/NCT04169776 ., (© 2022. The Author(s).)