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Objective: Some patients treated surgically for grade 1 spondylolisthesis require revision surgery. Outcomes after revision surgery are not well studied. The objective of this study was to determine how revision surgery impacts patient-reported outcomes (PROs) in patients undergoing decompression only or decompression and fusion (D+F) for grade 1 spondylolisthesis within 5 years of the index surgery., Methods: Patients in the 12 highest Quality Outcomes Database (QOD) enrolling sites with a diagnosis of grade 1 spondylolisthesis were identified and the incidence of revision surgery between the decompression-only and D+F patients were compared. PROs were compared between cohorts requiring revision surgery versus a single index procedure., Results: Of 608 patients enrolled, 409 had complete 5-year data available for this study. Eleven (13.3%) of 83 patients underwent revision in the decompression-only group as well as 32 (9.8%) of 326 in the D+F group. For the entire cohort, patients requiring revision had significantly worse PROs at 5 years: Oswestry Disability Index (ODI) 27.4 versus 19.4, p = 0.008; numeric rating scale for back pain (NRS-BP) 4.1 versus 3.0, p = 0.013; and NRS for leg pain (NRS-LP) 3.4 versus 2.1, p = 0.029. In the decompression-only group, the change in 5-year PROs was not impacted by revision status: ODI 31.9 versus 24.2, p = 0.287; NRS-BP 1.9 versus 2.9, p = 0.325; and NRS-LP 6.2 versus 3.7, p = 0.011. In the D+F group, the change in 5-year PROs was diminished if patients required revision: ODI 19.1 versus 29.1, p = 0.001; NRS-BP 3.0 versus 4.0, p = 0.170; and NRS-LP 2.3 versus 4.6, p = 0.001., Conclusions: The most common reasons for reoperation within 5 years in the decompression-only group were repeat decompression and instability, whereas in the D+F group the most common reason was adjacent-segment disease. The need for revision resulted in modestly diminished benefit compared with patients with no revisions. These differences were greater in the fusion cohort compared with the decompression-only cohort. The mean PRO improvement still far exceeded minimal clinically important difference thresholds for all measures for patients who underwent a revision surgery.

Background: Cutaneous leiomyosarcoma (cLMS) is a rare soft tissue neoplasm, showing smooth muscle differentiation, that arises from the mesenchymal cells of the dermis. To-date, genetic investigation of these tumours has involved studies with small sample sizes and limited analyses that identified recurrent somatic mutations in RB1 and TP53, copy number gain of MYCOD and IGF1R, and copy number loss of PTEN., Objectives: To better understand the molecular pathogenesis of cLMS, we comprehensively explored the mutational landscape of these rare tumours to identify candidate driver events., Methods: In this retrospective, multi-institutional study, we performed whole-exome sequencing and RNA sequencing on 38 cases of cLMS., Results: TP53 and RB1 were identified as significantly mutated, thus, represent validated driver genes of cLMS. COSMIC mutational signatures SBS7a/b and DBS1 were recurrent, thus, ultraviolet light exposure may be an aetiological factor driving cLMS. Analysis of significantly recurrent somatic copy number alterations, which represent candidate driver events, found focal (<10Mb) deletions encompassing TP53 and KDM6B, and amplifications encompassing ZMYM2, MYOCD, MAP2K4 and NCOR1. A larger (24 Mb) recurrent deletion encompassing CYLD was also identified as significant. Significantly recurrent broad copy number alterations, involving at least half of a chromosome arm, included deletions of 6p/q, 10p/q, 11q, 12q, 13q and 16p/q, and amplification of 15q. Notably PTEN is located on 10q, RB1 on 13q and IGFR1 on 15q. Fusion gene analysis identified recurrent CRTC1/3::MAML2 fusions, as well as many novel fusions in individual samples., Conclusions: Our analysis of the largest number of cLMS cases to-date highlights the importance of large cohort sizes and the exploration beyond small targeted gene panels when performing molecular analyses, as it allowed a comprehensive exploration of the mutational landscape of these tumours and identification of novel candidate driver events. It also uniquely afforded the opportunity to compare the molecular phenotype of cLMS with LMS of other tissue types, such as uterine and soft tissue LMS. Given that molecular profiling has resulted in the development of novel targeted treatment approaches for uterine and soft tissue LMS, our study now allows the same opportunities to become available for patients with cLMS., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Aims: CIC-rearranged sarcomas (CRS) are clinically aggressive undifferentiated round cell sarcomas (URCS), commonly driven by CIC::DUX4. Due to the repetitive nature of DUX4 and the variability of the fusion breakpoints, CIC::DUX4 fusion may be missed by molecular testing. Immunohistochemical (IHC) stains have been studied as surrogates for the CIC::DUX4 fusion. We aim to assess the performance of DUX4 IHC in the work-up of CRS and its expression in non-CRS round cell or epithelioid neoplasms., Methods and Results: Cases of molecularly confirmed CRS (n = 48) and non-CRS (n = 105) were included. CRS cases consisted of 35 females and 13 males, with ages ranging from less than 1 year to 67 years (median = 41 years). Among the molecularly confirmed non-CRS cases, C-terminal DUX4 expression was investigated in Ewing sarcomas (38 cases), alveolar rhabdomyosarcomas (18 cases), desmoplastic small round cell tumours (12 cases) and synovial sarcomas (n = five), as well as in non-mesenchymal neoplasms such as SMARCA4/SMARCB1-deficient tumours (n = five), carcinomas of unknown primary (n = three) and haematolymphoid neoplasms (four cases). DUX4 IHC was considered positive when strong nuclear expression was detected in more than 50% of neoplastic cells. When used as a surrogate for the diagnosis of CRS, the sensitivity and specificity of DUX4 IHC was 98 and 100%, respectively. Only one CRS case was negative for DUX4 IHC and harboured a CIC::FOXO4 fusion., Conclusions: DUX4 IHC is a highly sensitive and specific surrogate marker for the presence of CIC::DUX4 fusion, demonstrating its utility in establishing a diagnosis of CRS., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

The WHO and International Consensus Classification 2022 classifications of myelodysplastic syndromes enhance diagnostic precision and refine decision-making processes in these diseases. However, some discrepancies still exist and potentially cause inconsistency in their adoption in a clinical setting. We adopted a data-driven approach to provide a harmonisation between these two classification systems. We investigated the importance of genomic features and their effect on the cluster assignment process to define harmonised entity labels. A panel of expert haematologists, haematopathologists, and data scientists who are members of the International Consortium for Myelodysplastic Syndromes was formed and a modified Delphi consensus process was adopted to harmonise morphologically defined categories without a distinct genomic profile. The panel held regular online meetings and participated in a two-round survey using an online voting tool. We identified nine clusters with distinct genomic features. The cluster of highest hierarchical importance was characterised by biallelic TP53 inactivation. Cluster assignment was irrespective of blast count. Individuals with monoallelic TP53 inactivation were assigned to other clusters. Hierarchically, the second most important group included myelodysplastic syndromes with del(5q). Isolated del(5q) and less than 5% of blast cells in the bone marrow were the most relevant label-defining features. The third most important cluster included myelodysplastic syndromes with mutated SF3B1. The absence of isolated del(5q), del(7q)/-7, abn3q26.2, complex karyotype, RUNX1 mutations, or biallelic TP53 were the basis for a harmonised label of this category. Morphologically defined myelodysplastic syndrome entities showed large genomic heterogeneity that was not efficiently captured by single-lineage versus multilineage dysplasia, marrow blasts, hypocellularity, or fibrosis. We investigated the biological continuum between myelodysplastic syndromes with more than 10% bone marrow blasts and acute myeloid leukaemia, and found only a partial overlap in genetic features. After the survey, myelodysplastic syndromes with low blasts (ie, less than 5%) and myelodysplastic syndromes with increased blasts (ie, 5% or more) were recognised as disease entities. Our data-driven approach can efficiently harmonise current classifications of myelodysplastic syndromes and provide a reference for patient management in a real-world setting., Competing Interests: Declaration of interests UG reports speaker honoraria from Novartis, AbbVie, and BMS; and institutional research support from BMS, AbbVie, and Jazz Pharmaceuticals. FE reports consultancy or advisory roles for AbbVie, Incyte, Syros, Novartis, and Jazz Pharmaceuticals. SH reports research support from STORM Therapeutics and AstraZeneca. EAG reports honoraria from AAMDS, MedscapeLIVE!, MediCom Worldwide, MJH Life Sciences, ASH, MDS International Foundation, and Physicians’ Education Resource; consulting fees from AbbVie, Alexion, Apellis, Takeda Oncology, Astex/Taiho Oncology, Alexion/AstraZeneca Rare Disease, Celgene/BMS, CTI BioPharma, Novartis, Partner Therapeutics, Picnic Health, and Servier; and research funding from Alexion, Apellis, Astex /Otsuka/Taiho Oncology, Blueprint Medicines, Celldex Therapeutics, Genentech, and NextCure. MAS reports participation on advisory boards for BMS, Kurome, Schrödinger, and Karyopharm. MD-C reports participation on a data safety monitoring board or advisory board for BMS, Novartis, Blueprint Medicines, GSK, Agios, Hemavan, Syros, Keros, Curis, and Astex/Otsuka; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events for BMS, Novartis, and Keros. UP reports research support and honoraria from BMS, Geron, Curis, AbbVie, and Janssen. RBe reports employment or equity from Aptose Biosciences; participation on advisory boards for BMS, Servier, NeoGenomics, and Geron; being Data Monitoring Committee Chair for Gilead, Ipsen, and Keros; and consultancy for TenSixteen. YM reports honoraria from Nippon Shinyaku, BMS, Novartis, Sumitomo Pharma, Kyowa Kirin, AbbVie, Daiichi Sankyo, Takeda, Janssen, Astellas, Pfizer, Eisai, and Otsuka; and research funding from Chugai. AED reports participation on advisory boards, consultancy, or honoraria from Celgene/BMS, Agios, Novartis, Astellas, and Gilead; and participation on clinical trial committees or data safety monitoring boards for Novartis, AbbVie, Kura, Geron, Servier, Keros, and Celgene/BMS. DPS reports employment by Ajax Therapeutics; former employment by Novartis; and minor equity in Arrowhead and Bluebird. TKK reports consultancy for Agenus and ImmunoBiome. AK reports research support from Novartis and BMS; consulting fees from Alexion, Novartis, Amgen, Agios, Pfizer, Samsung, Celgene, F Hoffmann-La Roche, and Sobi; honoraria from Alexion, Novartis, Pfizer, Amgen, Samsung, Celgene, F Hoffmann-La Roche, BMS, Sobi, and Silence Therapeutics; and speakers fees from Alexion, Novartis, Amgen, Pfizer, Celgene, F Hoffmann-La Roche, and Sobi. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

The northern North American Cordillera is a globally significant center of endemism. In western North America, imperiled arid steppe habitats support a number of unique species, including several endemic lichens. However, processes driving diversification and endemism in this region remain unclear. In this study, we investigate diversity and phylogeography of the threatened wanderlust lichens (mycobiont = Rhizoplaca species) which occur unattached on calcareous soils in steppe habitats in western North America. Wanderlust lichens comprise three species of lichen-forming fungi (LFF) - Rhizoplaca arbuscula, R. haydenii, and R. idahoensis (endangered, IUCN Red List) - which occur in fragmented populations in Idaho and Wyoming, with more limited populations in southeastern Montana and northern Utah. These lichens reproduce almost exclusively via large, asexual vegetative propagules. Here, our aims were to (i) assess the evolutionary origin of this group and identify phylogeographic structure, (ii) infer ancestral geographic distributions for lineages within this clade, and (iii) use species distribution modeling to better understand the distribution of contemporary populations. Using a genome-skimming approach, we generated a 19.1 Mb alignment, spanning ca. half of the complete LFF genome, from specimens collected throughout the entire range of wanderlust lichens. Based on this phylogeny we investigated phylogeographic patterns using RASP. Finally, we used MaxEnt to estimate species distribution models for R. arbuscula and R. haydenii. We inferred a highly structured topology, with clades corresponding to distinct geographic regions and morphologies represented throughout the group's distribution. We found that R. robusta, a sexually reproducing taxon, is clearly nested within this asexual lineage. Phylogeographic analyses suggest that both dispersal and vicariance played a significant role throughout the evolutionary history of the vagrant Rhizoplaca clade, with most of the dispersal events originating from the Salmon Basin in eastern Idaho - the center of diversity for this group. Despite the fact that wanderlust lichens are dispersal limited due to large, unspecialized vegetative propagules, we inferred multiple dispersal events crossing the Continental Divide. Comparing herbarium records with SDMs suggests that wanderlust lichens don't fully occupy the areas of highest distribution probability. In fact, documented records often occur in areas predicted to be only marginally suitable. These data suggest a potential mismatch between contemporary habitats outside of the center of diversity in eastern Idaho with the most suitable habitat, adding to the vulnerability of this imperiled complex of endemic lichens., 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., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Ablation strategies for patients with symptomatic atrial fibrillation and isolated pulmonary veins vary and their effects on arrhythmia recurrence remain unclear. A prospective randomized German multicenter trial sought to compare 2 ablation strategies in this patient cohort., Methods: Patients with atrial fibrillation despite durable pulmonary vein isolation were randomly assigned at 7 centers to undergo low-voltage area ablation using 3-dimensional mapping and irrigated radiofrequency current ablation (group A) or empirical left atrial appendage isolation (LAAI) using the cryoballoon followed by staged interventional left atrial appendage closure (group B). The primary end point was freedom from atrial tachyarrhythmias between 91 and 365 days after index ablation. The study was powered for superiority of LAAI compared with low-voltage area., Results: Patients (40% women; mean age, 68.8±8 years) with paroxysmal (32%) or persistent atrial fibrillation (68%) were randomized to undergo low-voltage area ablation (n=79) or cryoballoon-guided LAAI (n=82). After a planned interim analysis, enrollment was halted for futility on January 10, 2023. In the LAAI group, 77 of 82 left atrial appendages were successfully isolated with subsequent left atrial appendage closure in 57 patients. Procedure-related complications occurred in 4 (5%) and 11 (13.5%) patients in group A and B, respectively ( P =0.10). The median follow-up was 367 days (interquartile range, 359-378). The Kaplan-Meier point estimate for freedom from atrial tachyarrhythmias was 51.7% (CI, 40.9%-65.4%) for group A and 55.5% (CI, 44.4%-69.2%; P =0.8069) for group B., Conclusions: The current study did not detect superiority of cryoballoon-guided LAAI over low-voltage area ablation in patients with atrial fibrillation despite durable PVI., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04056390.

Resupination refers to the developmental orientation changes of flowers through ≈180º, leaving them effectively upside-down. It is a widespread trait present in 14 angiosperm families, including the Orchidaceae, where it is a gravitropic phenomenon actively controlled by auxins. Here, we demonstrate that the passive gravitational pull on flower parts can have an additional influence on resupination. We studied a lady's slipper orchid in which some flowers naturally fail to resupinate. We conducted a manipulative experiment removing floral parts and showed that both the probability of complete resupination and the degree of flower vertical movement (from 0º - 180º) are related to the mass of floral organs. During flower development, the tip of the ovary slightly curves actively (14.75º) due to gravitropism. This promotes a lever arm effect so that the gravitational pull acting on flower mass creates a torque that bends the ovary, orienting the flower into a resupinate position that is accessible to pollinators. The role of the mass of floral organs in resupination provides new insights into flower development and its role in pollination mechanisms., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Impaired episodic memory is the primary feature of early Alzheimer's disease (AD), but not all memories are equally affected. Patients with AD and amnestic Mild Cognitive Impairment (aMCI) remember pictures better than words, to a greater extent than healthy elderly. We investigated neural mechanisms for visual object recognition in 30 patients (14 AD, 16 aMCI) and 36 cognitively unimpaired healthy (19 in the "preclinical" stage of AD). Event-related brain potentials (ERPs) were recorded while participants performed a visual object recognition task. Hippocampal occupancy (integrity), amyloid (florbetapir) PET, and neuropsychological measures of verbal & visual memory, executive function were also collected. A right-frontal ERP recognition effect (500-700 ms post-stimulus) was seen in cognitively unimpaired participants only, and significantly correlated with memory and executive function abilities. A later right-posterior negative ERP effect (700-900 ms) correlated with visual memory abilities across participants with low verbal memory ability, and may reflect a compensatory mechanism. A correlation of this retrieval-related negativity with right hippocampal occupancy (r = 0.55), implicates the hippocampus in the engagement of compensatory perceptual retrieval mechanisms. Our results suggest that early AD patients are impaired in goal-directed retrieval processing, but may engage compensatory perceptual mechanisms which rely on hippocampal function., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background/objectives: The Singing Voice Handicap Index-10 (SVHI-10) is a validated patient-reported outcome measure (PROM) that assesses patients' perception of handicap related to singing voice. A normative value has been established with a score ≥20 being abnormal. However, there is no defined minimal clinically important difference (MCID). This study prospectively determines the MCID of SVHI-10 among a diverse group of singers., Methods: 103 adult singers with and without voice complaints completed SVHI-10 twice, 30 days apart. MCID for the SVHI-10 was determined using distribution-based receiver-operating characteristic (ROC) curve analysis., Results: Twenty-two men (1 transgender), 75 women (1 transgender), and 6 nonbinary individuals participated. The most frequently reported singing genres were classical (44.7%), musical theater (17.5%), and pop (10.7%). Mean initial SVHI-10 score was 13.05 (standard deviation 7.397), and mean follow-up SVHI-10 was 13.13 (7.994). There was a significant positive correlation between initial and follow-up SVHI-10 scores (r = 0.879, p < 0.001). SVHI-10 scores were significantly higher among participants who reported voice changes in the past year (p < 0.001) or sought voice treatment (p = 0.001) compared with participants who did not. SVHI-10 scores varied significantly based on singing type. The area under the ROC curve for SVHI-10 was 0.700 (p = 0.003). The SVHI-10 MCID was determined to be 9.5., Conclusions: An SVHI-10 score change ≥10 should be considered clinically meaningful. This definition has been missing from the literature and will improve understanding of patients' responses to treatment, which will help advance clinical care and track research outcomes., Level of Evidence: 4 Laryngoscope, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: To present a list of key points for good Temporomandibular Disorders (TMDs) clinical practice on behalf of the International Network for Orofacial Pain and Related Disorders Methodology (INfORM) group of the International Association for Dental, Oral and Craniofacial Research (IADR)., Methods: An open working group discussion was held at the IADR General Session in New Orleans (March 2024), where members of the INfORM group finalized the proposal of a list of 10 key points., Results: The key points covered knowledge on the etiology, diagnosis, and treatment. They represent a summary of the current standard of care for management of TMD patients. They are in line with the current need to assist general dental practitioners advance their understanding and prevent inappropriate treatment., Conclusions: The key points can be viewed as a guiding template for other national and international associations to prepare guidelines and recommendations on management of TMDs adapted to the different cultural, social, educational, and healthcare requirements.

The PERFECT study, a randomized, controlled, double-blind study of inhaled treprostinil in patients with COPD and associated pulmonary hypertension (PH-COPD) was a negative trial that was terminated early. The reason(s) for the negative outcome remains uncertain. A post hoc analysis of data from the PERFECT study was undertaken to identify adverse responders and possibly potential responders. The goal was also to provide insight into phenotypes for possible inclusion and exclusion in future PH-COPD clinical trials. An adverse response on active treatment was seen in 36.4% (24/66) of the subjects compared to 27.6% (16/58) on placebo. There was no evidence to suggest that hyperinflation, bronchospasm, or occult heart failure played any role in the untoward outcomes of the study. The patients who died during the study all had baseline diffusing capacity for carbon monoxide ≤25% of predicted. Evidence of a potential response was seen in 10.6% (7/66) of the patients who received inhaled treprostinil. Patients who had evidence of a treatment response had a baseline mean pulmonary artery pressure of ≥40 mmHg and a forced expiratory volume in the first second of ≥40%. Change in N-terminal prohormone of brain natriuretic peptide did not predict clinical response. This post hoc analysis provides information that may potentially enable improved selection of patients for future therapeutic trials in PH-COPD. These analyses are post hoc, observational, and exploratory. The thresholds defining the spectrum of responders are preliminary and may require further refinement and validation in future studies., Competing Interests: Steven D. Nathan, Aaron Waxman, Todd Bull and Victor Tapson are paid consultants for Lung Biotechnology and United Therapeutics. Victoria Lacasse, Heidi Bell, Prakash Sista, and Michael Di Marino are employees of United Therapeutics/Lung Biotechnology, the PERFECT study sponsor., (© 2024 The Author(s). Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Secondary acute myeloid leukemia (sAML) has traditionally been used to designate any AML disease arising from an antecedent hematologic disorder or following prior cytotoxic or radiation therapy. We now know sAML comprises multiple disease entities with distinct clinical and biological features: AML-myelodysplastic related (AML-MR), myeloproliferative neoplasm-blast phase (MPN-BP), and AML post-cytotoxic therapy (AML-pCT). These entities largely represent adverse-risk phenotypes with the majority of patients experiencing suboptimal outcomes with standard therapeutic options. Given the aging general population and the increased lifespan of individuals receiving DNA damaging agents for other medical conditions, the incidence of these diseases is steadily rising and now comprise approximately 25-30% of all new AML diagnoses. Despite the plethora of novel agents approved for AML since 2017, many are either not applicable to sAML (i.e. lacking a targetable mutation), have limited efficacy, or have not been studied in these specific entities. Furthermore, these patients are under-represented in clinical trials, and novel therapeutic options are critically needed. Here we present multiple patient cases exemplifying the new nomenclature and classification of the diseases comprising sAML and highlighting their diverse presentations. We provide our therapeutic approach for each clinical scenario and discuss the challenges of treatment with the currently available armamentarium., (Copyright © 2024 American Society of Hematology.)

Aim: Anastomotic stricture occurs in up to 30% of colorectal resections; however, evidence on risk factors and preventive measures remains scarce. This study aimed to identify technical factors responsible for increasing the risk for colorectal and coloanal anastomotic strictures., Method: This was a retrospective cohort study of patients with anastomotic stricture who underwent resection and/or redo anastomosis between January 1, 2011 and August 1, 2021 in a tertiary referral centre. Patients with anastomotic stricture were compared with an equal number of randomly selected patients without anastomotic complications, who were operated on during the same time period. The main outcome measures were technical risk factors of anastomotic stricture., Results: Each group included 50 patients who were similar for age, sex, American Society of Anesthesiologists score, distance of anastomosis to the dentate line and indication for surgery. Median follow-up was significantly longer in the non-stricture group (38.6 months vs. 12.6 months, p = 0.04). Splenic flexure mobilization [hazard ratio (HR) = 0.18 [2], 95% CI: 0.08-0.39, p < 0.001], high ligation of the inferior mesenteric artery (HR = 0.22, 95% CI: 0.09-0.5, p < 0.001) and high ligation of the inferior mesenteric vein (HR = 0.21, 95% CI: 0.09-0.50, p < 0.001) were associated with a lower likelihood of anastomotic stricture. Conversely, use of a 25-mm-diameter circular stapler (HR = 22.69, 95% CI: 2.69-191.10, p < 0.001), clinically significant anastomotic leak (HR = 3.94, 95% CI: 2.04-7.64, p < 0.001), firing the stapler more than once for rectal division (HR = 24.75, 95% CI: 6.85-89.38, p < 0.001) and diverting stoma (HR = 3.087, 95% CI: 1.736-5.491, p < 0.0001) were predictive of an anastomotic stricture., Conclusion: Failure to mobilize the splenic flexure and to perform high ligation of the inferior mesenteric vessels were associated with higher odds of anastomotic stricture. A small-diameter circular stapler and multiple distal stapler firings were also associated with anastomotic stricture. These data support routine splenic flexure ligation and high ligation of the inferior mesenteric vessels as well as avoidance of both multiple  stapler firings for rectal transection and a 25-mm circular stapler for anastomosis.., (© 2024 The Author(s). Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Background: Children and adolescents with type 1 diabetes require frequent outpatient evaluation to assess glucose trends, modify insulin doses, and screen for comorbidities. Continuous glucose monitoring (CGM) provides a detailed glycemic control assessment. Telemedicine has been increasingly used since the COVID-19 pandemic., Objective: To investigate CGM profile parameter improvement immediately following pediatric outpatient diabetes visits and determine if visit modality impacted these metrics, completion of screening laboratory tests, or diabetic emergency occurrence., Methods: A dual-center retrospective review of medical records assessed the CGM metrics time in range and glucose management indicator for pediatric outpatient diabetes visits during 2021. Baseline values were compared with those at 2 and 4 weeks post visit. Rates of completion of screening laboratory tests and diabetic emergencies following visits were determined., Results: A total of 269 outpatient visits (41.2% telemedicine) were included. Mean time in range increased by 1.63% and 1.35% at 2 and 4 weeks post visit (P=.003 and .01, respectively). Mean glucose management indicator decreased by 0.07% and 0.06% at 2 and 4 weeks post visit (P=.003 and .02, respectively). These improvements in time in range and glucose management indicator were seen across both telemedicine visits and in-person visits without a significant difference. However, patients seen in person were 2.69 times more likely to complete screening laboratory tests (P=.03). Diabetic emergencies occurred too infrequently to analyze., Conclusions: Our findings demonstrate an immediate improvement in CGM metrics following outpatient visits, regardless of modality. While statistically significant, the magnitude of these changes was small; hence, multiple visits over time would be required to achieve clinically relevant improvement. However, completion of screening laboratory tests was found to be more likely after visits occurring in person. Therefore, we suggest a hybrid approach that allows patient convenience with telemedicine but also incorporates periodic in-person assessment., (©Christopher Ferber, Steven D Mittelman, Tannaz Moin, Holly Wilhalme, Rebecca Hicks. Originally published in JMIR Diabetes (https://diabetes.jmir.org), 01.10.2024.)

The most common precursors to synthetic glycoproteins are reducing end glycosyl amines. To afford these amines, a carbohydrate is reacted with an excess of an ammonia source to yield the β-anomer, exclusively, in a reaction known as the Kochetkov amination. Although this process is the state-of-the-art method to synthesize non-functionalized, β-amino (βA) glycans, misconceptions surrounding the stability of these amines has limited their use in subsequent reactions. Here, we investigated the stability of seven amino sugars in the neutral, acidic, and basic conditions they would be subject to in common reactions using amines. In neutral and basic conditions, the amino sugars proved relatively stable with the fastest time to 50% hydrolysis being four days for only one carbohydrate. However, acidic conditions promoted rapid hydrolysis, with all amino sugars reaching over 97% hydrolysis within 2 h. Finally, we performed a bioconjugation using fluorescein isothiocyanate and βA-difucosyllactose, revealing sufficient stability of the amino product for a successful subsequent reaction., 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., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Summary: Immunotherapy for the systemic treatment of cancer offers new treatment possibilities for advanced malignancies. Despite promising initial results, evidence on efficacy of immunotherapy for colon cancer is lacking. Thus, we aimed to assess short-term and long-term outcomes of immunotherapy in patients with advanced colon cancer. A US National Cancer Database was searched for patients with stage III-IV colonic adenocarcinoma between 2010 and 2019. Propensity score matching was used to classify the cohort into 2 groups: patients who received immunotherapy and controls. Main outcome measures were primary outcome was overall survival (OS). A total of 23,778 patients with stage III-IV colonic adenocarcinoma were treated with immunotherapy during the study period compared to 114,753 controls. Immunotherapy treated patients were younger (median age 61 vs. 67 y; P <0.001), more often male (57.3% vs. 50.7%, P <0.001), had more private insurance (44.1% vs. 33.7%; P <0.001), had more left-sided tumors (49.5% vs. 39.1%; P <0.001) and liver metastasis (80.2% vs. 61.7%; P <0.001) than controls. Immunotherapy patients received more standard chemotherapy (49.8% vs. 41.6%; P <0.001). After propensity-score matching, mean OS was significantly shorter in the immunotherapy group compared with controls (34.7 vs. 36.2 mo; P =0.008). Cox regression analysis demonstrated that immunotherapy was associated with increased risk for mortality (HR: 1.1; 95% CI: 1.02-1.18; P =0.005). Patients who received immunotherapy had lower 90-day mortality rates compared with controls (2.3% vs. 3.6%; P =0.004), but the groups had equivalent 30-day mortality rates (0.7% vs. 0.8%; P =0.76). Immunotherapy showed no improvement in OS in patients with stage III-IV colon cancer., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Excessive stimulation of the inositol (1,4,5)-trisphosphate (IP 3 ) signaling pathway has been linked to AF through abnormal calcium handling. However, little is known about the mechanisms involved in this process. We expressed the fluorescence resonance energy transfer (FRET)-based cytosolic cyclic adenosine monophosphate (cAMP) sensor EPAC-S H187 in neonatal rat atrial myocytes (NRAMs) and neonatal rat ventricular myocytes (NRVMs). In NRAMs, the addition of the α 1 -agonist, phenylephrine (PE, 3 µM), resulted in a FRET change of 21.20 ± 7.43%, and the addition of membrane-permeant IP 3 derivative 2,3,6-tri- O - butyryl -myo-IP 3 (1,4,5)-hexakis(acetoxymethyl)ester (IP 3 -AM, 20 μM) resulted in a peak of 20.31 ± 6.74%. These FRET changes imply an increase in cAMP. Prior application of IP 3 receptor (IP 3 R) inhibitors 2-aminoethyl diphenylborinate (2-APB, 2.5 μM) or Xestospongin-C (0.3 μM) significantly inhibited the change in FRET in NRAMs in response to PE. Xestospongin-C (0.3 μM) significantly inhibited the change in FRET in NRAMs in response to IP 3 -AM. The FRET change in response to PE in NRVMs was not inhibited by 2-APB or Xestospongin-C. Finally, the localization of cAMP signals was tested by expressing the FRET-based cAMP sensor, AKAP79-CUTie, which targets the intracellular surface of the plasmalemma. We found in NRAMs that PE led to FRET change corresponding to an increase in cAMP that was inhibited by 2-APB and Xestospongin-C. These data support further investigation of the proarrhythmic nature and components of IP 3 -induced cAMP signaling to identify potential pharmacological targets. NEW & NOTEWORTHY This study shows that indirect activation of the IP 3 pathway in atrial myocytes using phenylephrine and direct activation using IP 3 -AM leads to an increase in cAMP and is in part localized to the cell membrane. These changes can be pharmacologically inhibited using IP 3 R inhibitors. However, the cAMP rise in ventricular myocytes is independent of IP 3 R calcium release. Our data support further investigation into the proarrhythmic nature of IP 3 -induced cAMP signaling.

Site-independent ratings derived from audio-digital recordings of site-based interviews are often used for quality assurance monitoring to affirm ratings reliability in CNS clinical trials. The present study of subjects with schizophrenia and persistent negative symptoms used video instead of audio recordings of site-based interviews and thereby facilitated visual observation of the subject by the remote rater. "Paired" site-independent scores of the Positive and Negative Syndrome Scale (PANSS) and Brief Negative Symptom Scale (BNSS) were obtained from video-recordings of site-based interviews. The intraclass correlation between site-based and paired site-independent ratings was r = 0.839 for the total PANSS scores (n = 1006) and r = 0.871 for the total BNSS scores (n = 892); <5 % of paired scores deviated outside the acceptable confidence intervals. Ratings "outliers" were identified and remediated. We examined the pattern of paired scoring deviations for the BNSS, total PANSS, PANSS symptom subscales, and the Marder negative symptom factor. Each metric revealed a bidirectional pattern of scoring deviations such that mean site-based ratings were higher than site-independent ratings when symptom severity was high but lower than site-independent ratings when symptom severity was low. The pattern of bidirectional paired scoring deviations observed in this analysis has previously been noted in paired ratings analyses of subjects experiencing an acute exacerbation of psychosis in schizophrenia and major depressive disorder as well. The bidirectional pattern may reflect inherent differences between live ratings and remotely scored recorded ratings. This analysis affirms the utility of video-recordings of site-based ratings for surveillance in trials with subjects with schizophrenia and persistent negative symptoms., Competing Interests: Declaration of competing interest Steven D. Targum was an employee of Signant Health at the time this study was conducted. He has received vendor grants and/or has received consulting fees from Actinogen Medical Ltd., Acadia Pharmaceuticals Inc., AZ Therapies, BioXcel Therapeutics Inc., CSA Medical Inc., Deerfield Discovery and Development, LLC, EMA Wellness LLC, Frequency Therapeutics, Functional Neuromodulation, Johnson and Johnson PRD, Karuna Therapeutics, Maplight Therapeutics, Merck Inc., Methylation Sciences Inc., Neurocrine Bioscience, Supernus-Navitor Pharmaceuticals Inc., and PAX Neuroscience Inc. during the past 3 years. Petra Reksoprodjo is an employee of Signant Health. Tingting Ge and Jaz Singh are employees of Neurocrine Bioscience Inc., and own stock options in that company. Mahnaz Asgharnejad and Venkatesha Murthy are employees of Takeda Pharmaceuticals Ltd. And own stock or stock options., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Subjective surgeon interpretation of near-infrared perfusion video is limited by low inter-observer agreement and poor correlation to clinical outcomes. In contrast, quantification of indocyanine green fluorescence video (Q-ICG) correlates with histologic level of perfusion as well as clinical outcomes. Measuring dye volume over time, however, has limitations, such as it is not on-demand, has poor spatial resolution, and is not easily repeatable. Laser speckle contrast imaging quantification (Q-LSCI) is a real-time, dye-free alternative, but further validation is needed. We hypothesize that Q-LSCI will distinguish ischemic tissue and correlate over a range of perfusion levels equivalent to Q-ICG., Methods: Nine sections of intestine in three swine were devascularized. Pairs of indocyanine green fluorescence imaging and laser speckle contrast imaging video were quantified within perfused, watershed, and ischemic regions. Q-ICG used normalized peak inflow slope. Q-LSCI methods were laser speckle perfusion units (LSPU), the base unit of laser speckle imaging, relative perfusion units (RPU), a previously described methodology which utilizes an internal control, and zero-lag normalized cross-correlation (X-Corr), to investigate if the signal deviations convey accurate perfusion information. We determine the ability to distinguish ischemic regions and correlation to Q-ICG over a perfusion gradient., Results: All modalities distinguished ischemic from perfused regions of interest; Q-ICG values of 0.028 and 0.155 (p < 0.001); RPU values of 0.15 and 0.68 (p < 0.001); and X-corr values of 0.73 and 0.24 (p < 0.001). Over a range of perfusion levels, RPU had the best correlation with Q-ICG (r = 0.79, p < 0.001) compared with LSPU (r = 0.74, p < 0.001) and X-Corr (r = 0.46, p < 0.001)., Conclusion: These results demonstrate that Q-LSCI discriminates ischemic from perfused tissue and represents similar perfusion information over a broad range of perfusion levels comparable to clinically validated Q-ICG. This suggests that Q-LSCI might offer clinically predictive real-time dye-free quantification of tissue perfusion. Further work should include validation in histologic studies and human clinical trials., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: We sought to develop a risk prediction model for predischarge major mitral valve (MV) residual lesions or unplanned MV reinterventions following congenital MV repair., Methods: Patients who underwent congenital MV repair (excluding primary repair, but including secondary repair, of canal-type defects) at a single institution from January 2000 to December 2020 and survived to discharge were retrospectively reviewed. The primary outcome was major MV residua (mean gradient >6 mm Hg or moderate or greater regurgitation on the discharge echocardiogram) or predischarge unplanned MV reintervention. Risk factors of interest included age, single-ventricle physiology, preoperative and intraoperative postrepair MV stenosis and regurgitation severity, MV annular diameter z score, systemic ventricle ejection fraction, unfavorable anatomy, concomitant left-heart procedure, and various technique-related categories. Logistic regression was used to develop a weighted risk score for the primary outcome. Internal validation using bootstrap-resampling was performed., Results: Of 866 patients who underwent congenital MV repair at a median age of 2.7 years (interquartile range, 0.7-9.1 years), 202 (23.3%) patients developed the primary outcome. The final risk prediction model had a C-statistic of 0.82 (95% confidence interval, 0.78-0.85). A weighted risk score was formulated per the variables in this model. The median risk score was 8 (interquartile range, 6-11) points. Patients were categorized as low (score 0-5), medium (score 6-10), high (score 11-15), or very high (score ≥16) risk. The probability of the primary outcome was 5.0 ± 1.7%, 15.2 ± 6.7%, 45.9 ± 12.6%, and 76.7 ± 8.8% for low-, medium-, high-, and very-high-risk patients, respectively., Conclusions: Our risk prediction model may guide prognostication of patients following congenital MV repair., Competing Interests: Conflict of Interest Statement The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: The majority of recent estimates on the direct medical cost attributable to hospital-onset infections (HOIs) has focused on device- or procedure-associated HOIs. The attributable costs of HOIs that are not associated with device use or procedures have not been extensively studied., Objective: We developed simulation models of attributable cost for 16 HOIs and estimated the total direct medical cost, including nondevice-related HOIs in the USA for 2011 and 2015., Data and Methods: We used total discharge costs associated with HOI-related hospitalization from the National Inpatient Sample and applied an analogy costing methodology to develop simulation models of the costs attributable to HOIs. The mean attributable cost estimate from the simulation analysis was then multiplied by previously published estimates of the number of HOIs for 2011 and 2015 to generate national estimates of direct medical costs., Results: After adjusting all estimates to 2017 US dollars, attributable cost estimates for select nondevice-related infections attributable cost estimates ranged from $7661 for ear, eye, nose, throat, and mouth (EENTM) infections to $27,709 for cardiovascular system infections in 2011; and from $8394 for EENTM to $26,445 for central nervous system infections in 2016 (based on 2015 incidence data). The national direct medical costs for all HOIs were $14.6 billion in 2011 and $12.1 billion in 2016. Nondevice- and nonprocedure-associated HOIs comprise approximately 26-28% of total HOI costs., Conclusion: Results suggest that nondevice- and nonprocedure-related HOIs result in considerable costs to the healthcare system., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

While several functions of the endogenous prion protein have been studied, the homeostatic function of prion protein is still debated. Notably, prion protein is highly expressed on mast cells, granular immune cells that regulate inflammation. When activated, mast cells shed prion protein, although the mechanism and consequences of this are not yet understood. First, we tested several mast cell lines and found that, while prion protein was almost always present, the total amount differed greatly. Activation of mast cells induced a cleavage of the N-terminal region of prion protein, and this was reduced by protease inhibitors. Exogenous mast cell proteases caused a similar loss of the prion protein N-terminus. Additionally, mast cells shed prion protein in an ADAM10-dependent fashion, even in the absence of activation. Our results suggest that prion protein is cleaved from resting mast cells by ADAM10 and from activated mast cells by mast cell proteases. Prion protein also appears to affect mast cell function, as Prnp-/- bone marrow-derived mast cells showed lower levels of degranulation and cytokine release, as well as lower levels of both FcεRI and CD117. Finally, we sought to provide clinical relevance by measuring the levels of prion protein in bodily fluids of asthmatic patients, a disease that involves the activation of mast cells. We found an N-terminal fragment of prion protein could be detected in human sputum and serum, and the amount of this prion protein fragment was decreased in the serum of patients with asthma., Competing Interests: Conflict of interest statement. None declared., (Published by Oxford University Press on behalf of Society for Leukocyte Biology 2024.)

Background: This umbrella review aimed to summarize the findings and conclusions of published systematic reviews on the prophylactic role of mesh against parastomal hernias in colorectal surgery., Methods: PRISMA-compliant umbrella overview of systematic reviews on the role of mesh in prevention of parastomal hernias was conducted. PubMed and Scopus were searched through November 2023. Main outcomes were efficacy and safety of mesh. Efficacy was assessed by the rates of clinically and radiologically detected hernias and the need for surgical repair, while safety was assessed by the rates of overall complications., Results: 19 systematic reviews were assessed; 7 included only patients with end colostomy and 12 included patients with either ileostomy or colostomy. The use of mesh significantly reduced the risk of clinically detected parastomal hernias in all reviews except one. Seven reviews reported a significantly lower risk of radiologically detected parastomal hernias with the use of mesh. The pooled hazards ratio of clinically detected and radiologically detected parastomal hernias was 0.33 (95%CI: 0.26-0.41) and 0.55 (95%CI: 0.45-0.68), respectively. Six reviews reported a significant reduction in the need for surgical repair when a mesh was used whereas six reviews found a similar need for hernia repair. The pooled hazards ratio for surgical hernia repair was 0.46 (95%CI: 0.35-0.62). Eight reviews reported similar complications in the two groups. The pooled hazard ratio of complications was 0.81 (95%CI: 0.66-1)., Conclusions: The use of surgical mesh is likely effective and safe in the prevention of parastomal hernias without an increased risk of overall complications., (© 2024. The Author(s).)

Aims: The majority of dermatofibrosarcoma protuberans (DFSP) harbour PDGFB or PDGFD rearrangements. We encountered ALK expression/rearrangement in a PDGFB/D-negative CD34-positive spindle cell neoplasm with features similar to DFSP, prompting evaluation of ALK-rearrangements in DFSP and plaque-like CD34-positive dermal fibroma (P-LDF)., Methods and Results: We searched the archives of academic institutions for cases previously coded as DFSP and P-LDF. NGS-naïve or PDGFB-negative DFSP were screened for ALK (clone D5F3) expression by immunohistochemistry. NGS or ALK FISH was performed on ALK-positive cases. Methylome profiling studies were performed and compared with conventional DFSP. One case of "DFSP" and two "P-LDF" with ALK expression were identified from the archives, while four cases were detected prospectively. These seven cases (6F:1M; 8 months to 76 years) arose in the dermis of the arm (two), scalp, eyelid, thigh, abdomen, and shoulder and ranged from 0.4 to 4.2 cm. Tumours were composed of spindled cells and displayed a storiform growth pattern. Cytologic atypia was absent, and mitotic figures were scarce (0-2/10 HPFs, high power fields). The lesional cells were diffusely positive for CD34 and ALK and negative for S100 protein. By NGS (n = 5), ALK fusion partners included DCTN1 (2), PLEKHH2, and CLIP2 in DFSP-like cases and FLNA in P-LDF-like lesions. ALK FISH was positive in one (of two) cases previously labelled P-LDF. Methylome profiling of two (of three) ALK-rearranged DFSP-like tumours showed clustering with conventional DFSP in the UMAP dimension reduction plot. To date, no tumour has recurred (n = 2; 26, 27 months)., Conclusion: We describe a cohort of novel ALK-rearranged tumours with morphologic features similar to DFSP., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

Aims: The MicraVR™ transcatheter pacing system (TPS) has been implemented into clinical routine for several years. The primary recipients are patients in need for VVI pacing due to bradycardia in the setting of atrial fibrillation (AF). Implantation safety and acute success have been proven in controlled studies and registries. So far only few long-term real-life data on TPS exist. We report indication, procedure and outcome data from two high-volume implanting German centers., Methods: Between 2016 and 2019, 188 (of 303) patients were included. During follow-up (FU), TPS interrogation was performed after 4 weeks and thereafter every 6 months., Results: Indication for TPS implantation in 159/188 (85%) patients was permanent or intermittent AV block III° in the setting of atrial fibrillation. The mean procedure duration was 50 min [35.0-70.0]. The average acute values after system release were: thresholds: 0.5V [0.38-0.74]/0.24ms; R-wave sensing: 10.0mV [8.1-13.5]; impedance: 650 Ohm [550-783]; RV-pacing demand: 16.9% [0.9-75.9]; and battery status: 3.15 V [3.12-3.16]. During FU of 723.4 ± 597.9 days, neither pacemaker failure nor infections were reported. Long-term FU revealed: thresholds: 0.5V [0.38-0.63]/0.24 ms; sensing: 12.3mV [8.9-17.2]; impedance: 570 Ohm [488-633]; RV-pacing demand: 87.1% [29.5-98.6]; and battery status 3.02 V [3.0-3.1]. Forty-three patients died from not-device-related causes., Conclusion: This to date largest German long-term dataset for MicraVR™ TPS implantation revealed stable device parameter. Foremost, battery longevity seems to fulfill predicted values despite a significant increase in RV-pacing demand over time and even in patients with consecutive AV-node ablation. Of note, no infections or system failure were observed., (© 2023. The Author(s).)

Background: This study aimed to assess concordance between clinical and pathologic assessment of colon cancer., Patients and Methods: A retrospective cohort analysis of patients with stage I-III colon cancer in the National Cancer Database (2010-2019) was conducted. Concordance between clinical and pathologic assessment of colon cancer was calculated using Kappa coefficients and 95% confidence intervals (CIs)., Results: A total of 125,473 patients (51.2% female; mean age 68.2 years) were included. There was moderate concordance between clinical and pathologic T stage (Kappa = 0.606, 95%CI: 0.602-0.609) and between clinical and pathologic N stage (Kappa = 0.506, 95%CI: 0.501-0.511). For right-sided colon cancer, there was moderate agreement between clinical and pathologic T stage (Kappa = 0.594, 95%CI: 0.589-0.599) and N stage (Kappa = 0.530, 95%CI: 0.523-0.537). For left-sided colon cancer, there was substantial agreement between clinical and pathologic T stage (Kappa = 0.624, 95%CI: 0.619-0.630) and moderate agreement between N stage (Kappa 0.472, 95%CI: 0.463-0.480). Sensitivity of clinical assessment of T and N stage ranged from 64.3% to 77.2% and 41.6% to 54.5%, respectively. Specificity ranged from 96.7% to 97.7% for T stage and 95.7% to 97.3% for N stage., Conclusions: Clinical assessment of T and N stages of colon cancer had good diagnostic accuracy with moderate concordance with the final pathologic stage. While clinical assessment was highly specific with < 3% of patients being over-staged, it had modest sensitivity, especially for detection of nodal involvement. Diagnostic accuracy of clinical assessment of right and left colon cancers was similar, except for higher sensitivity and accuracy of assessment of nodal involvement in right than left colon cancers., (© 2024. The Author(s).)

Children from diverse ethnic groups are at significantly increased risk for dental caries. In particular, American Indian (AI) children have the highest incidence of detal caries of any ethnic group. The COVID-19 pandemic dramatically restricted health care access, including preventive oral health care. Given this context, it is unclear whether or not preventive oral health care for AI children has resumed since lockdown. To address this question, we surveyed adult AI caregivers (N = 152) of children aged 0-5 years, assessing recent (12-month) and pre-COVID (for caregivers of children aged 3-5 years) preventive oral and medical health services. We also examined medical health care access and utilization among caregivers. Among children aged 3-5 years old, both pre-pandemic and past year medical care utilization were generally high (80 and 90%, respectively) as was any oral health care utilization (64 & 78%, respectively). Oral health check-ups were more common over the last year (62%) compared to pre-COVID (44%). Recent health care utilization among children 1-5 years old in this sample were generally comparable to national estimates, except for higher reported preventive medical care (99% vs. 87.6%, respectively) and higher preventive oral care (96% vs. 59.6%, respectively). More caregivers reported delaying or foregoing needed health care due to COVID (28-38%) versus due to cost (8-17%). In this survey of AI caregivers, recent child preventive health care utilization was high, and changes in utilization following the lockdown phases of the pandemic were comparable for oral and medical health care., (© 2024. The Author(s).)

Study Design: Retrospective cross-sectional., Objectives: To determine associations between Hounsfield units (HU) within a region of interest on computed tomography (CT) scans and dual energy X-ray absorptiometry (DEXA) measurements in children and adolescents., Summary of Background Data: HU on CT scans as a proxy for bone mineral density (BMD) is widely used in adults. However, the utility of CT as a proxy for BMD have not been evaluated in children and adolescents., Materials and Methods: Patients younger than 18 years with a lumbar spine CT scan and a DEXA within 6 months of each other were identified. A region of interest was used to measure the HU at each lumbar vertebral body on midaxial cuts. Charts were reviewed for demographics, medical comorbidities, and DEXA reports. Correlation coefficients were calculated between the mean DEXA Z -score and the HU value. Patients were also stratified by Z -score (≥ -1.0, between -1.0 and -2.0, and ≤-2.0) and matched by age, sex and body mass index (BMI) to a cohort of healthy children and compared., Results: A moderate correlation between mean DEXA Z -score and mean HU on CT was found ( r2 =0.42, P <0.001). After matching for age, sex and BMI, 21 patients in each group between the ages of 4 and 17 years were analyzed. The mean HU value of the control group was 231.69. When stratified by Z -score (≥ -1.0, between -1.0 and -2.0, and ≤-2.0), the mean HU values were 244.59, 216.50, and 176.54, respectively. Patients with a Z -score of ≤-2.0 had a significantly lower mean HU than matched controls., Conclusions: HU on lumbar CT in children and adolescents with DEXA Z -scores <-2.0, were lower when compared with healthy matched controls. This study suggests that HU on opportunistic CT scans of the spine may be used as a reasonable proxy for BMD in the pediatric population., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: Reduction of atrial fibrillation (AF) burden is the preferred outcome measure over categorical AF rhythm recurrence after AF ablation. In this sub-analysis of the TeleCheck-AF project we tested the feasibility of smartphone app-based approximation of time spent with AF and/or symptoms., Methods: Patients scheduled for at least one teleconsultation during the 12-month follow-up after AF ablation were instructed to use a smartphone photoplethysmography (PPG)-based application for simultaneous symptom and rhythm monitoring 3-times daily for 1 week. Proxies of time spent with AF and/or symptoms (%-recordings, load, %-days), temporal aggregation of AF and/or symptoms (density), and symptom-rhythm correlation (SRC) were assessed., Results: In total 484 patients (60% male, 62±9.9 years) were included. Adherence, motivation and patient satisfaction were high. %AF-recordings, AF load and %AF-days (rs= 0.88-0.95) and %symptom-recordings, symptom load, %symptom-days (rs= 0.95-0.98) showed positive correlations. The SRC correlated negatively with time spent with symptoms (rs=-0.65--0.90) and with time spent with AF (rs=-0.31--0.34). In patients with paroxysmal AF before ablation and AF during the monitoring period, 87% (n=39/44) had a low-density score <50% ("paroxysmal AF pattern") while 5% (n=2/44) had a high-density score >90% ("persistent AF pattern"). Corresponding numbers for patients with persistent AF before ablation were 48% (n=11/23) and 43% (n=10/23), respectively., Conclusions: On-demand, app-based simultaneous rhythm and symptom assessment provides objective proxies of time spent with AF and/or symptoms and symptom-rhythm correlation, which may assist in assessing AF and symptom outcomes after AF ablation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: To characterize state laws targeting patient brokering and deceptive marketing of substance use disorder (SUD) treatment., Background: Patient brokering and deceptive marketing of SUD treatment leads to poor outcomes for individuals with SUD, including relapse- or overdose-related hospitalizations, ED visits, or death. In response, several states within the United States have passed laws targeting unethical practices of SUD treatment in recent years. The context in which these laws were passed has not been previously described. The extent to which states engaged in recovery residence regulation that also pass patient brokering and deceptive marketing laws is unknown., Methods: We conducted a descriptive study and identified state laws relating to patient brokering and deceptive marketing that were enacted and effective as of December 31, 2022. Using a model state law for addressing unethical SUD treatment practices as a guide, we developed a taxonomy to describe the laws' elements, including covered entities, prohibited activities, and penalties. We used descriptive statistics to characterize variation across current laws., Results: All patient brokering laws explicitly mention referrals to SUD treatment facilities, and most specify that both individuals and facilities are prohibited from paying, receiving, or soliciting referrals in exchange for fees or commissions. All deceptive marketing laws prohibit making false or misleading statements about the nature of services provided. Beyond these common features, there is wide variability in the degree to which states specifically prohibit other patient brokering and deceptive marketing activities (e.g., indirect offerings, lead generation, or kickback schemes involving laboratories)., Conclusions: State policies targeting patient brokering and deceptive marketing may be useful for preventing instances of unethical SUD treatment practices. We constructed a taxonomy to characterize elements of patient brokering and deceptive marketing laws and facilitate future evaluations of their effectiveness., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government.

Background: The Manufacturer and User Facility Device Experience (MAUDE) database houses medical device reports of adverse events involving medical devices marketed in the United States submitted to the U.S. Food and Drug Administration (FDA) by mandatory and voluntary reporters. The MAUDE database is frequently used in clinical studies to report on device-related complications. Data about its efficacy are scarce., Objective: To compare the mandatory MAUDE database (MAUDE group) with the invitation-based POTTER-AF Study (POTTER-AF 1 group) regarding data quality, procedural characteristics, diagnosis, treatment, and survival., Methods: The reports of esophageal fistula esophageal fistula following atrial fibrillation (AF) ablation in the MAUDE database were compared to those in the POTTER-AF Study between 01/08/2009 and 31/08/2019., Results: Esophageal fistula was reported in 47 patients in the MAUDE group and in 81 in the POTTER-AF 1 group. Procedures were performed with radiofrequency, cryoenergy or laser energy in 66.0%, 31.9% and 2.1% (MAUDE group) and in 96.3%, 2.5% and 1.2% (POTTER-AF 1 group). The median time to symptoms was 21 (14, 32.5) days (MAUDE group) and 18.0 (6.8, 22.3) days (POTTER-AF 1 group; p=0.031). The diagnostic method was reported in 38.3% of patients in the MAUDE group and in 98.8% in the POTTER-AF 1 group, the treatment in 57.4% and 100% and the outcome in all patients. In the MAUDE group, treatment was surgical (51.9%), endoscopic (37.0%), combined (3.7%) or conservative (7.4%), compared to 43.2%, 19.8%, 7.4% and 29.6% in the POTTER-AF 1 group. Overall mortality was 76.6% in the MAUDE group and 61.7% in the POTTER-AF 1 group (p=0.118)., Conclusion: In the mandatory MAUDE database, less esophageal fistula cases were reported as compared to an invitation-based study. The data quality in the MAUDE database was significantly poorer., (Copyright © 2024. Published by Elsevier Inc.)

The objective of study was to characterize HPV in vaginal samples from women being seen at the Center for Reproductive Medicine and Infertility at Weill Cornell Medicine before and following ovarian stimulation. A total of 29 women made samples available for analysis by viral metagenomics. Eighteen women were HPV-positive, six (33.3%) at their initial visit and 15 (83.3%) following hormone stimulation (p = 0.0059). Pairwise comparison of nucleotide sequences and phylogenetic analysis showed the classification sequences into two genera: Alphapapillomavirus and Gammapapillomavirus. Sequences were from 8 HPV types: HPV 51 (n = 2), HPV 68 (n = 1), HPV 83 (n = 9), HPV 84 (n = 2), HPV 121 (n = 6), HPV 175 (n = 1) and HPV 190 (n = 1). Additionally, C16b and C30 likely represent new types. In summary, multiple HPV types are present in the vagina of reproductive age women and are induced by hormone used to stimulate ovulation., (© 2024. The Author(s).)

Aim: Ulcerative colitis (UC) affects over 3 million (1.3%) US adults, approximately 20% of whom will require surgery. Since it was first described in 1978, restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has become the gold standard for patients requiring surgery, as well as for patients with familial adenomatous polyposis (FAP). In 1991 the laparoscopic approach to IPAA was introduced. The aim of this study was to evaluate the advances made in IPAA as minimally invasive surgery (MIS) has become more prevalent., Method: The American College of Surgeons NSQIP database from 2005 to 2019 was used. Laparoscopic (MIS) and open cases of IPAA construction for UC or FAP were used. These patients were subdivided into three time point cohorts: early (2005-2009), middle (2010-2014) and recent (2015-2019). Univariable and multivariable analyses were performed to evaluate morbidity, mortality and hospital length of stay., Results: A total of 6184 patients were analysed, and 2555 underwent MIS while 3629 underwent open surgery. After multivariable analysis, the MIS approach was associated with a lower risk of morbidity compared with open procedures [relative risk (RR) = 0.86, p < 0.0001, 95% CI 0.78-0.94], both in the early and recent periods [early period = RR = 0.66 (p < 0.0001), recent period RR = 0.78 (p = 0.0029)]. Superficial surgical site infection (SSI) was consistently lower in the MIS cohort across all three time periods. After multivariable analysis, the overall RR of superficial SSI in the MIS cohort was 0.41 (p < 0.0001) [early period RR = 0.35 (p < 0.0001), middle period RR = 0.55 (p = 0.0007), recent period RR = 0.31 (p < 0.0001)]. The RR of deep space SSI was decreased overall (RR = 0.58, p = 0.013, 95% CI 0.62-0.93), with the most significant effect occurring during the early period (RR = 0.30, p = 0.0260, 95% CI 0.105-0.868). Sepsis related to any infective aetiology was also decreased in the MIS cohort (RR = 0.76, p = 0.0093, 95% CI 0.62-0.93), especially in the recent time period (RR = 0.63, p = 0.0344, 95% CI 0.41-0.97). Furthermore, hospital length of stay was decreased in the MIS cohort (-0.287 days, p = 0.0170), with a greater difference occurring in the more recent cohort (-0.375 days, p = 0.0418)., Conclusion: With increasing utilization of minimally invasive techniques in IPAA creation there have been significant decreases in the rates of morbidity including decreasing rates of superficial and deep space SSI, as well as decreased hospital length of stay., (© 2024 The Author(s). Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Background: Advanced ablation strategies are needed to treat ventricular tachycardia (VT) and premature ventricular contractions (PVC) refractory to standard unipolar radiofrequency ablation (Uni-RFA). Bipolar radiofrequency catheter ablation (Bi-RFA) has emerged as a treatment option for refractory VT, PVC. Multicenter registry data on the use of Bi-RFA in the setting of refractory VT and PVC are lacking., Purpose: The aim of this Bi-RFA registry is to determine its real-world safety, feasibility, and efficacy in patients with refractory VT/PVC., Methods: Consecutive patients undergoing Bi-RFA at sixteen European centers for recurring VT/PVC after at least one standard Uni-RFA were included. Second ablation catheter was used instead of a dispersive patch and was positioned at the opposite site of the ablation target., Results: Between March 2021 and August 2024, ninety-one patients underwent 94 Bi-RFA procedures (74 males, age 62±13, prior Uni-RFA range 1-8). Indications were recurrence of PVC (n=56), VT (n=20), electrical storm (n=13), or PVC-triggered ventricular fibrillation (n=2). Procedural time was 160±73min, Bi-RFA time 426±286s, mean Uni-RFA time 819±697s. Elimination of clinical VT/PVC was achieved in 67 (74%) patients, suppression of VT/PVC in a further 10 (11%) patients. In the remaining 14 patients (15%) no effect on VT/PVC was observed. Three major complications occurred: coronary artery occlusion, AV block and arteriovenous fistula. Follow-up lasted 7±8 months. Nineteen (61%) remained VT-free. ≥80% PVC burden reduction was achieved in 45 (78%)., Conclusions: This real-world registry data indicates that Bi-RFA appears safe, is feasible, and effective in the majority of patients with VT/PVC., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: To achieve and maintain adequate weight, people with cystic fibrosis (CF) May often consume energy-dense, nutrient-poor foods high in added sugars and refined carbohydrates; however, little is known about the glycemic and metabolic effects of dietary composition in this patient population. The objective of this pilot study was to investigate the safety and tolerability of a low glycemic load (LGL) diet in adults with CF and abnormal glucose tolerance (AGT)., Methods: Ten adults with CF and AGT completed this prospective, open-label pilot study. Mean age was 27.0 ± 2.1 years, 64% were female, and all had pancreatic insufficiency. Each participant followed his/her typical diet for 2 weeks, then transitioned to a LGL diet via meal delivery service for 8 weeks. The primary outcome was change in weight from baseline to study completion, with safety established if no significant decline was noted. Other key safety outcomes included change in hypoglycemia measured by patient report and continuous glucose monitoring (CGM). Exploratory outcomes included changes in other CGM measures, body composition by dual energy X-ray absorptiometry (DXA), and patient reported outcomes., Results: There were no significant changes in weight or in subjectively-reported or objectively-measured hypoglycemia. Favorable non-significant changes were noted in CGM measures of hyperglycemia and glycemic variability, DXA measures of fat mass, and gastrointestinal symptom surveys., Discussion: A LGL dietary intervention was safe and well tolerated in adults with CF and AGT. These results lay the groundwork for future trials investigating the impact of low-glycemic dietary interventions on metabolic outcomes in the CF population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Scully, Truex, Brennan, Fowler, Sawicki, Uluer, Ludwig, Ebbeling, Langlais, Dziok, Freedman and Putman.)

The study was conducted to inform risk assessments concerning microbial exposure to quaternary ammonium biocides (QUATs) by investigating their effects on 10 microbial strains of hygiene relevance. Biocides were divided into three categories: simple aqueous solutions, biocide mixtures, and formulated biocides. Organisms were grown in the presence of biocides for 10 generations and then subsequently for another 10 generations in biocide-free media. Control organisms were passaged 20 times in biocide-free media. Strains were then assessed for biocide and antibiotic susceptibility, changes in growth dynamics, and single nucleotide polymorphisms (SNPs). Biocide mixtures demonstrated greater antimicrobial potency than singular and formulated biocides. Susceptibility changes of under twofold were observed for all biocides tested. Susceptibility decreased significantly for organisms passaged with singular biocides (1.29- to 4.35-fold) and biocide mixtures (1.4- to 1.5-fold), but not for formulated biocides (1.3- to 1.84-fold) compared to controls. Antibiotic susceptibility both increased and decreased in passaged organisms, with heightened susceptibility occurring more frequently in the singular biocide group. Changes in susceptibility and growth dynamics were similar in the passaged and unexposed controls for fitness measures of adapted bacteria; there were no significant differences between biocide groups, but significantly lower generation and doubling times in organisms exposed to singular biocides. Similar frequencies in SNPs occurred for the three biocide groups and unexposed controls. While some adaptations occurred, particularly with singular biocides, the impact on antibiotic resistance and genomic mutations was limited. These findings suggest that the use of formulated QUATs may pose a comparatively lower risk for antimicrobial resistance.IMPORTANCEBiocides are used globally to control microbial growth and effective assessment of the risks and benefits of their use is therefore a high priority. Much of the data used to assess risk has been based on sub-lethal exposure of bacteria to singular biocides in simple aqueous solutions. This work builds on limited prior realism-based studies to demonstrate enhanced potency in biocidal mixtures; the mitigation of resistance selection by formulations and inconsistent cross-resistance effects with both increases and decreases in susceptibility for a wide range of antibiotics. These data can be used to better inform risk assessments of biocide deployment.

Wilms tumors are commonly associated with predisposition syndromes many, but not all, of which include overgrowth. Several of these syndromes also include a risk of other embryonal malignancies - particularly hepatoblastoma. Guidelines for surveillance in this population were published in 2017 and recently members of the AACR Pediatric Cancer Working Group met to update those guidelines with a review of more recently published evidence and risk estimates. This perspective serves to update pediatric oncologists, geneticists, radiologists, counselors and other healthcare professionals on revised diagnostic criteria, review previously published surveillance guidelines and harmonize updated surveillance recommendations in the North American and Australian context for patients with overgrowth syndromes and other syndromes associated with Wilms tumor predisposition.

Myelodysplastic neoplasms/syndromes (MDS) are a heterogeneous group of biologically distinct entities characterized by variable degrees of ineffective hematopoiesis. Recently, two classification systems (the 5th edition of the WHO Classification and the International Consensus Classification) further sub-characterized MDS into morphologic and genetically defined groups. Accurate diagnosis and subclassification of MDS require a multistep systemic approach. The International Consortium for MDS (icMDS) summarizes a contemporary, practical, and multimodal approach to MDS diagnosis and classification., (Copyright © 2024. Published by Elsevier Inc.)

Dragonflies are poikilothermic animals with limited thermoregulation; therefore, their entire bodies, including the brain, experience a range of temperatures during their daily activities. 1 , 2 These flying insects exhibit hunting prowess, pursuing prey or conspecifics whether in direct sunlight or under the cover of cloud. 3 , 4 Likely to underlie these aerobatic feats are the small target motion detector (STMD) neurons. 5 These visual neurons are sensitive to target contrast and tuned to the target's size and velocity, with some neurons exhibiting complex predictive and selective properties, well suited for prey interception and feeding amid swarms. 3 , 4 , 6 , 7 , 8 , 9 Increased temperature can modulate the biochemical processes underlying neuronal processing, increasing sensitivity and quickening the responsiveness of insect photoreceptors and downstream optic flow neurons, 10 , 11 , 12 while in other neuronal pathways, compensatory processes have been shown to account for temperature changes. 13 , 14 We determined the ethological range of temperatures experienced by the dragonfly, Hemicordulia tau, in its natural environment. Across this behaviorally relevant range, we showed increased temperatures having a large 8.7-fold increase in the contrast sensitivity of STMD neurons. However, suppression of responses to larger targets was unaltered. STMD tuning for target velocities was changed remarkably, not only increasing the optimum but extending the fastest velocities encoded by an order of magnitude. These results caution against interpreting functionality underlying spike rates at constrained, experimental temperatures. Moreover, they raise intriguing new questions about how information is represented within the brain of these flying insects, given the relationship between visual stimulus parameters and neuronal activity varies so dramatically depending on current environmental conditions., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Some visual neurons in the dragonfly ( Hemicordulia tau ) optic lobe respond to small, moving targets, likely underlying their fast pursuit of prey and conspecifics. In response to repetitive targets presented at short intervals, the spiking activity of these "small target motion detector" (STMD) neurons diminishes over time. Previous experiments limited this adaptation by including intertrial rest periods of varying durations. However, the characteristics of this effect have never been quantified. Here, using extracellular recording techniques lasting for several hours, we quantified both the spatial and temporal properties of STMD adaptation. We found that the time course of adaptation was variable across STMD units. In any one STMD, a repeated series led to more rapid adaptation, a minor accumulative effect more akin to habituation. Following an adapting stimulus, responses recovered quickly, though the rate of recovery decreased nonlinearly over time. We found that the region of adaptation is highly localized, with targets displaced by ∼2.5° eliciting a naive response. Higher frequencies of target stimulation converged to lower levels of sustained response activity. We determined that adaptation itself is a target-tuned property, not elicited by moving bars or luminance flicker. As STMD adaptation is a localized phenomenon, dependent on recent history, it is likely to play an important role in closed-loop behavior where a target is foveated in a localized region for extended periods of the pursuit duration ., Competing Interests: The authors declare no competing financial interests, (Copyright © 2024 Schwarz et al.)

Heart Rhythm management is a continuously evolving sub-speciality of cardiology. Every year, many physicians and allied professionals start and complete their training in Cardiac Implantable Electronic Devices (CIED) or Electrophysiology (EP) across the EHRA member countries. While this training ideally ends with an EHRA certification, the description of the learning pathway (what, how, when and where) through an EHRA Core Curriculum is also a prerequisite for a successful training. The first EHRA core curriculum for physicians was published in 2009. Due to the huge developments in the field of electrophysiology and device therapy, this document needed updating. In addition, a certification process for allied professionals has been introduced, as well as a recertification process and accreditation of EHRA recognised training centres. Learning pathways are more individualised now, with Objective Structured Assessment of Technical Skills (OSATS) to monitor learning progression of trainees. The 2024 Updated EHRA Core Curriculum for physicians and allied professionals describes, for both CIED and EP, the syllabus, OSATS, training program and certification and recertification for physicians and allied professionals and stresses the importance of continued medical education after certification. In addition, requirements for accreditation of training centres and trainers are given. Finally, suggested reading lists for CIED and EP are attached as online supplements., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: While REIMS technology has successfully been demonstrated for the histological identification of ex-vivo breast tumor tissues, questions regarding the robustness of the approach and the possibility of tumor molecular diagnostics still remain unanswered. In the current study, we set out to determine whether it is possible to acquire cross-comparable REIMS datasets at multiple sites for the identification of breast tumors and subtypes., Methods: A consortium of four sites with three of them having access to fresh surgical tissue samples performed tissue analysis using identical REIMS setups and protocols. Overall, 21 breast cancer specimens containing pathology-validated tumor and adipose tissues were analyzed and results were compared using uni- and multivariate statistics on normal, WT and PIK3CA mutant ductal carcinomas., Results: Statistical analysis of data from standards showed significant differences between sites and individual users. However, the multivariate classification models created from breast cancer data elicited 97.1% and 98.6% correct classification for leave-one-site-out and leave-one-patient-out cross validation. Molecular subtypes represented by PIK3CA mutation gave consistent results across sites., Conclusions: The results clearly demonstrate the feasibility of creating and using global classification models for a REIMS-based margin assessment tool, supporting the clinical translatability of the approach., (© 2024. Waters Technologies Corporation and The Author(s).)

The powerstroke of human cardiac β-myosin is an important stage of the cross-bridge cycle that generates force for muscle contraction. However, the starting structure of this process has never been resolved, and the relative timing of the powerstroke and inorganic phosphate (Pi) release is still controversial. In this study, we generated an atomistic model of myosin on the thin filament and utilized metadynamics simulations to predict the absent starting structure of the powerstroke. We demonstrated that the displacement of Pi from the active site during the powerstroke is likely necessary, reducing the energy barrier of the conformation change. The effects of the presence of the thin filament, the hypertrophic cardiomyopathy mutation R712L, and the binding of mavacamten on the powerstroke process were also investigated., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Biophysical Society. Published by Elsevier Inc. All rights reserved.)