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Smoking, a major behavioral health burden, causes preventable and premature deaths globally. Nicotine, the addictive component present in tobacco products and Electronic cigarettes (E-cigarettes, vape), can bind to nicotinic acetylcholine receptors in the brain to trigger a dopamine release that reinforces smoking. Despite the widespread usage of nicotine, its mechanisms of toxicity, particularly in e-cigarettes, are poorly understood. Using Drosophila melanogaster as a model organism, this study aims to investigate the mechanism of the toxicity of nicotine and vape. Behavioral parameters, oxidative stress indicators, mRNA expression levels of Dopamine 1- receptor 1 (Dop1R1), Acetyl-coenzyme A synthetase (AcCoAs), and apoptotic proteins were assessed in the flies after a 5-day exposure to varying concentrations of nicotine (0.15, 0.25, and 0.35 mg/mL diet) and vape (0.06, 0.08, and 0.12 mg/mL diet). Furthermore, Gas Chromatography-Mass Spectrometry (GC/MS) and Gas Chromatography-Flame Ionization Detection (GC/FID) analyzes were conducted to gain more insight on the composition of the vape used in study. Findings indicate that both nicotine and vape exposure significantly reduced lifespan, impaired locomotor activity, and disrupted sleep patterns. Notably, nicotine exposure stimulated Dop1R1 transcription and altered Acetyl-CoA gene expression, impacting the viability and behavior of the flies. Elevated levels of reactive oxygen biomarkers were observed, contributing to cellular damage through oxidative stress and apoptotic mechanisms mediated by the Reaper and DIAP1 proteins. Additionally, the composition analysis of vape liquid revealed the presence of propylene glycol, nicotine, methyl esters, and an unidentified compound. This study highlights the complex interplay between nicotine, gene expression, and physiological responses in Drosophila., (© 2024 Wiley Periodicals LLC.)

Background: Bacillus Calmette-Guérin (BCG) injected during the COVID-19 convalescence period was safe and enhanced recovery from anosmia and dysgeusia in the acute phase., Objectives: To report the long-term results of the BATTLE trial, BCG vaccine in adults with mild COVID-19., Methods: Design: Double-blind, placebo-controlled, randomized (1:1) clinical trial., Intervention: BCG intradermal vaccine and placebo., Patients: A total of 157 BCG and 142 placebo recipients participated in the 6-month follow-up, and 97 BCG and 95 placebo recipients participated in the 12-month follow-up., Measurements: Long COVID symptoms and mechanistic analyses., Results: BCG reduced hearing problems at 6 months (odds ratio [OR] = 0.26) and sleeping, concentration, memory, and vision problems at 12 months (OR = 0.45, 0.36, 0.38, and 0.36, respectively). Sensitivity analyses confirmed that long COVID-19 symptoms were reduced at the 6- and 12-month follow-ups (p = 0.010 and 0.031, respectively). BCG's crossover interaction paradoxically increased hair loss in women and decreased it in men at 6 months (p = 0.032). BCG immunomodulation is likely mediated through inhibition of Fas ligand expression in the blood and increased induction of IL6, IL10, interferon-induced transmembrane protein 3, and angiotensin-converting enzyme 2 in cultured human macrophages., Conclusion: Long-term follow-up of the BATTLE trial participants revealed that BCG protects against long COVID development if administered within the COVID-19 convalescence period. The response to BCG was subject-specific, including a paradoxical crossover interaction based on sex., Limitations: Not tested for previous mycobacterial exposure; loss to follow-up, particularly at 12 months., (© 2024 The Association for the Publication of the Journal of Internal Medicine.)

Background: For patients with aortic root dilatation and a structurally normal aortic valve (AV) undergoing composite aortic valve-graft (Bentall-De Bono) versus valve-sparing aortic root replacement (VSARR) procedures there are conflicting data regarding early and long-term benefits. We undertook a study-level meta-analysis to compare the results of both procedures., Methods: Three databases were assessed, and both randomized trials and observational studies were considered eligible. Kaplan-Meier curves of long-term survival and reoperation risk were reconstructed and compared with Cox linear regression and incidence rate ratios (IRR) with 95 % confidence intervals (CI). Landmark analysis and time-varying hazard ratio (HR) were analyzed. Odds ratios (OR) were calculated for early mortality, postoperative stroke, and re-exploration for postoperative bleeding. A random effects model was used. Sensitivity analyses included leave-one-out-analysis, meta-regression and subgroups analysis., Results: 1456 articles were identified, including 39 observational studies, totaling 14,651 patients (Bentall-De Bono = 9557 and VSARR = 5094). Twelve studies were adjusted. The mean weighted follow-up was 5.05 ± 3.7 years. VSARR was associated with significantly greater survival (HR = 0.50; 95 % CI, 0.45-0.57; p < 0.0001) at 15-year follow-up. The reoperation risk was higher following VSARR (HR = 1.30; 95 % CI, 1.03-1.63; p = 0.02.), although time-varying HR model and landmark analysis reported an increased risk of reoperation within 5 years after VSARR (HR = 1.57; 95 % CI, 1.23-2.01; p < 0.001), after which the difference disappeared. Subgroups analysis of studies excluding aortic dissection showed a comparable rate of late reoperation., Conclusions: VSARR is associated with improved long-term survival compared to Bentall-De Bono. The risk of late reoperation is higher within 5 years following VSARR, after which the two procedures are comparable., Competing Interests: Declaration of competing interest Non declared., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: While standard clinical assessments provide great value for people with multiple sclerosis (PwMS), they are limited in their ability to characterize patient perspectives and individual-level symptom heterogeneity., Objectives: To identify PwMS subgroups based on patient-reported outcomes (PROs) of physical, cognitive, and emotional symptoms. We also sought to connect PRO-based subgroups with demographic variables, functional impairment, hypertension and smoking status, traditional qualitative multiple sclerosis (MS) symptom groupings, and neuroperformance measurements., Methods: Using a cross-sectional design, we applied latent profile analysis (LPA) to a large database of PROs; analytic sample N = 6619)., Results: We identified nine distinct MS subtypes based on PRO patterns. The subtypes were primarily categorized into low, moderate, and high mobility impairment clusters. Approximately 70% of participants were classified in a low mobility impairment group, 10% in a moderate mobility impairment group, and 20% in a high mobility impairment group. Within these subgroups, several unexpected patterns were observed, such as high mobility impairment clusters reporting low non-mobility impairment., Conclusions: The present study highlights an opportunity to advance precision medicine approaches in MS. Combining PROs with data-driven methodology allows for a cost-effective and personalized characterization of symptom presentations. that can inform clinical practice and future research designs., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Variants in rhodopsin (RHO) have been linked to autosomal dominant congenital stationary night blindness (adCSNB), which affects the ability to see in dim light, and the pathogenetic mechanism is still not well understood. In this study we report two novel RHO variants found in adCSNB families, p.W265R and p.A269V, that map in the sixth transmembrane domain of RHO protein. We applied in silico molecular simulation and in vitro biochemical and molecular studies to characterize the two new variants and compare the molecular determinants to two previously characterized adCSNB variants, p.G90D and p.T94I, that map in the second transmembrane domain of the RHO protein. We demonstrate that W265R and A269V cause constitutive activation of RHO with light-independent G protein coupling and impaired binding to arrestin. Differently, G90D and T94I are characterized by slow kinetics of RHO activation and deactivation. This study provides new evidence on the differential contribution of transmembrane α-helixes two and six to the interaction with intracellular transducers of RHO and mutations in these helixes result in a similar phenotype in patients but with distinct molecular effects., Competing Interests: Declaration of competing interest Authors A.B., S.DA., A.F., C.Z., B.B., F.F., L.C., V.K., I.M. and G.M. declare they have no competing financial interests. Author V.M. is shareholder of the company Mireca Medicines., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: A growing body of research has emerged to characterize differences in posttraumatic stress disorder (PTSD) symptom presentations in individuals from diverse racial and ethnic groups. However, less research has examined if these observed differences can be attributed to bias within PTSD assessments. Knowledge about potential bias in PTSD assessment is essential for interpreting group differences. If PTSD assessments do not perform similarly across diverse demographic groups, then observed differences may be artificial products of inaccurate measurement, new assessments could be required for individuals from different demographic groups, and we would be unable to accurately detect PTSD treatment effects in patients from diverse groups., Method: We evaluated PTSD assessment bias through tests of measurement invariance for the semistructured, clinician-administered AUDADIS-5 diagnostic assessment of participants in the National Epidemiologic Survey on Alcohol and Related Conditions-III. Participants included those who reported having experienced at least one potentially traumatic event in their lifetime ( N = 23,936). Measurement invariance was assessed for participants who identified from several demographic groups (Asian, Native Hawaiian, or Pacific Islander; Hispanic; American Indian/Alaskan Native; and Black) compared to participants who identified as White (non-Hispanic)., Results: Overall, PTSD assessment was largely invariant across groups, while small amounts of measurement invariance were detected that can inform future research and clinical adaptations., Conclusions: This work validates prior research that relies on a common conceptualization of PTSD, and it provides several paths for future improvement in research and clinical practice. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is linked to high mortality, primarily through an intense inflammatory response. Diacerein has emerged as a potential therapy for COVID-19 due to its potential impact in decreasing the inflammasome activation and coronavirus replication. This study aims to explore diacerein's influence in inhibiting both viral replication and the inflammatory response after SARS-CoV-2 infection., Methods: Human peripheral blood mononuclear cells (PBMCs) were obtained from healthy volunteers and infected in vitro with SARS-CoV-2. Additionally, we carried out a pilot randomized, double-blind, placebo-controlled study with 14 participants allocated to diacerein (n = 7) or placebo (n = 7) therapies every 12 h for 10 days. The primary endpoint was change in plasma markers of inflammasome activation (NLRP3, caspase-1, and gasdermin-D)., Results: In vitro protocols have shown that rhein, diacerein's primary metabolite, decreased IL-1β secretion caused by SARS-CoV-2 infection in human PBMCs ( p < 0.05), and suppressed viral replication when administered either before or after the virus incubation ( p < 0.05). This later effect was, at least partially, attributed to its inhibitory effect on 3-chymotrypsin-like protease (SARS-CoV-2 3CL pro ) and papain-like protease in the SARS-CoV-2 (SARS-CoV-2 PL pro ) virus and in the phosphorylation of proteins related cytoskeleton network ( p < 0.05). Diacerein-treated COVID-19 patients presented a smaller area under the curve for NLRP3, caspase-1 and GSDM-D measured on days 2, 5, and 10 after hospitalization compared to those receiving a placebo ( p < 0.05)., Conclusion: The indicated mechanisms of action of diacerein/rhein can reduce viral replication and mitigate the inflammatory response related to SARS-CoV-2. These findings are preliminary and require confirmation in clinical trials., Competing Interests: DB discloses the following relationships - Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Stasys; Board of Directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock); Consultant: Broadview Ventures, GlaxoSmithKline, Hims, SFJ, Youngene; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hô pitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and United States national co-leader, funded by Bayer), WebMD (CME steering committees), (steering committee); Other: Clinical Cardiology (Deputy Editor); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women' s Hospital who assigned to Lexicon; neither I nor Brigham and Women' s Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo. AS discloses the following relationships - Research Funding: Amgen, AstraZeneca, National Council for Scientific and Technological Development (CNPq) and Fundaç and#227; o de Apoio and#224; Pesquisa do Estado de Sã o Paulo (FAPESP). Dr. Pedro Gonç alves de Oliveira is responsible for R&D activities at TRB Pharma Indú stria Quí mica e Farmace utica Ltda, SP, Brazil. TRB Pharma is the owner of the product ARTRODAR® a diacerein-based product for osteoarthritis treatment. The remaining 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 Carmo, Castillo, Bonilha, Gomes, Barreto, Moura, Davanzo, de Brito Monteiro, Muraro, Fabiano de Souza, Morari, Galdino, Brunetti, Reis-de-Oliveira, Carregari, Nadruz, Martins-de-Souza, Farias, Velloso, Proenca-Modena, Mori, Loh, Bhatt, Yellon, Davidson, De Oliveira, Moraes-Vieira and Sposito.)

Study Objective: Although cystectomy remains the gold standard for the surgical treatments of endometriomas, concerns about the negative effect on ovarian reserve are rising. Laser-CO 2 vaporization of endometriomas has shown encouraging data on ovarian reserve preservation, postoperative pregnancy rates, and recurrence. The aim of this study was to assess postoperative recurrence rate and pregnancy rate in patients with endometriomas managed by CO 2 fiber laser vaporization after at least 5 years following surgery., Design: Retrospective study., Setting: Italian tertiary center from October 2023 to February 2024., Patients: We included women aged >18 years who underwent laparoscopic CO 2 fiber laser vaporization for endometriomas. Age ≥40 years, previous ovarian surgery, previous salpingectomy or hysterectomy, negative histologic finding for endometriosis, or any findings of malignancy at histology were exclusion criteria., Intervention: Ovarian endometriomas were vaporized through laparoscopic CO 2 fiber laser. After surgery, patients were included in a surveillance program with periodic clinical follow-ups., Measurements and Main Results: Seventy-eight patients were included. The mean age was 33.2 ± 4.6 years, the basal anti-Müllerian hormone was 2.7 ± 1.9 ng/mL, and the median diameter of the endometriomas was 4 (3-5) cm. The median duration of follow-up was 72.5 months (67-84.5). After surgery, 65.5% (n = 36) of women with reproductive desire achieved a pregnancy, 55.6% spontaneously, and 44.4% through Assisted Reproduction Techniques, with a mean time to pregnancy of 17.7 ± 18.1 months. A Kaplan-Meier curve for the 7 patients who experienced an ipsilateral recurrence showed that the median time to recurrence was 26 months and the estimated rate of disease-free patients was 91.03% at 100 months (95% confidence interval 82.10%-95.62%)., Conclusion: CO 2 fiber laser vaporization is an effective and safe surgical treatment of ovarian endometriomas, combining the advantage of being an ovarian tissue-sparing technique with long-term postoperative recurrence rate comparable with that described in literature for the cystectomy., (Copyright © 2024 AAGL. Published by Elsevier Inc. All rights reserved.)

Background: Loss of mobility is common in persons with multiple sclerosis (PwMS), but little is known about this impairment from the patient's perspective., Objective: The aim is to model longitudinal variation in a mobility patient-reported outcome (PRO) and compare trajectories to those observed for Timed 25-Foot Walk (T25FW) in a retrospective cohort., Methods: Latent-class growth analysis was applied to 47,508 measures of Performance Scales© Mobility PRO (PS-Mobility) over ~4 years for 8524 PwMS. For 7347 PwMS, there were 41,988 T25FW measures during this period. Repeated measures correlation and concordance of trajectory assignment were evaluated., Results: At the group level, PS-Mobility and T25FW linearly worsened and repeated-measures correlation was moderate. Eight latent classes with varying shapes that worsened described PS-Mobility variation, compared to six latent classes for T25FW that differed by intercept. The agreement between PS-Mobility and T25FW cluster assignment was modest. A higher proportion of individuals who were Black/African American, older, Medicaid beneficiaries, living in deprived neighborhoods, had longer disease duration, had progressive disease, and ever smokers were assigned to more impaired clusters., Discussion: Cross-sectionally, PS-Mobility and T25FW were highly correlated, but longitudinally correlation was modest to moderate, underscoring the importance of considering both objective and subjective perspectives in evaluating mobility changes in PwMS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Drought is a major challenge for the cultivation of durum wheat, a crucial crop for global food security. Plants respond to drought by adjusting their mineral nutrient profiles to cope with water scarcity, showing the importance of nutrient plasticity for plant acclimation and adaptation to diverse environments. Therefore, it is essential to understand the genetic basis of mineral nutrient profile plasticity in durum wheat under drought stress to select drought-tolerant varieties. The research study investigated the responses of different durum wheat genotypes to severe drought stress at the seedling stage. The study employed an ionomic, molecular, biochemical and physiological approach to shed light on distinct behaviors among different genotypes. The drought tolerance of SVEMS16, SVEVO, and BULEL was related to their capacity of maintaining or increasing nutrient's accumulation, while the limited nutrient acquisition capability of CRESO and S.CAP likely resulted in their susceptibility to drought. The study highlighted the importance of macronutrients such as SO 4 2- , NO 3 - , PO 4 3- , and K + in stress resilience and identified variant-containing genes potentially influencing nutritional variations under drought. These findings provide valuable insights for further field studies to assess the drought tolerance of durum wheat genotypes across various growth stages, ultimately ensuring food security and sustainable production in the face of changing environmental conditions., 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 Masson SAS.. All rights reserved.)

Background: Many conditions we now call body-focused repetitive behaviors (BFRBs) have been subject to research for several decades, most notably trichotillomania and skin picking. However, the American Psychiatric Association did not combine these conditions into a single category, body-focused repetitive behavior disorders (BFRBDs), until the fifth edition of the DSM (2013). Several aspects of the disorder remain uncertain and controversial. For example, ongoing debate surrounds which specific conditions fall under this diagnostic category and how to best differentiate BFRBs from conditions such as nonsuicidal self-injury (NSSI). The current article presents results from a survey of experts' opinions on diagnostic criteria, with the goal of refining the diagnostic criteria., Method: We contacted experts on BFRB via various sources and invited them to complete an online survey on the phenomenology, classification, and differential diagnosis of BFRB. We also inquired about possible alternative syndrome labels (e.g., body-focused habit)., Results: Data from the final sample of 50 experts demonstrates that most experts agree with the present classification of BFRB/BFRBD as an obsessive-compulsive and related disorder and recommend retaining the labels BFRB or BFRBD. The experts considered the following conditions BFRB, with an agreement of over 60%: trichotillomania, skin picking, dermatophagia, nail biting, and lip-cheek biting. Mixed results emerged for awake bruxism and thumb sucking in adults. Only a minority regarded night bruxism and knuckle cracking as BFRB. To differentiate BFRB from NSSI, the experts noted that the motive behind the urge (self-harm/injury versus release of tension) should be considered. Analyses of a sub-sample of experts with at least six years of clinical and/or research experience yielded results compatible with those of the entire sample., Discussion: The survey supports the usefulness of the BFRBD diagnostic entity. However, some criteria require further refinement. Future editions of the DSM should more explicitly delineate which conditions qualify as BFRB. Furthermore, it is important to give more attention to the primary motivation behind BFRB to distinguish it from NSSI and potentially from stereotypic movement behavior., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to investigate the effects of moderate combined training (CT) on both the gene expression of pro- and anti-inflammatory markers and senescence in the immune system in peripheral blood mononuclear cells (PBMCs) and subcutaneous adipose tissue (SAT) of obese middle-aged individuals with type 2 diabetes (T2D). Methods: Thirty obese individuals (50.2 ± 9.4 years; body mass index: 31.8 ± 2.3 kg/m²) with T2D underwent 16 weeks of a CT group [CT; aerobic (50-60% of VO2 max ) plus resistance (50-75% of 1RM) training; 3 times/week, 70 min/session; n = 16)] or a control group (CG, n = 14). Nutritional patterns, muscle strength (1RM), cardiorespiratory fitness (VO2 max ), waist circumference (WC), body composition (Air Displacement Plethysmograph) and blood collections for biochemical (serum leptin, IL-2, IL-4, IL-6, IL-10, TNF-α and anti-CMV) and molecular (gene expression of leptin, IL-2, IL-4, IL-6, IL-10, TNF-α, PD-1, P16 ink4a , CCR7, CD28 and CD27 in PBMCs and SAT) analyses were assessed before (Pre) and after (Post) the 16 weeks of the experimental period. Results: Significant decreases were observed in WC and IL4, TNF-α, PD-1 and CD27 expression in PBMCs for CT. Furthermore, significant increases were observed in 1RM and VO2max for CT after the experimental period. Conclusion: Moderate CT contributed to a reduction in the gene expression of markers associated to chronic inflammation and immunosenescence in PBMCs of obese middle-aged individuals with T2D.

Obsessive-compulsive disorder (OCD) is phenomenologically heterogeneous. While predominant models suggest fear and harm prevention drive compulsions, many patients also experience uncomfortable sensory-based urges ("sensory phenomena") that may be associated with heightened interoceptive sensitivity. Using an urge-to-blink eyeblink suppression paradigm to model sensory-based urges, we previously found that OCD patients as a group had more eyeblink suppression failures and greater activation of sensorimotor-interoceptive regions than controls. However, conventional approaches assuming OCD homogeneity may obscure important within-group variability, impeding precision treatment development. This study investigated the heterogeneity of urge suppression failure in OCD and examined relationships with clinical characteristics and neural activation. Eighty-two patients with OCD and 38 controls underwent an fMRI task presenting 60-s blocks of eyeblink suppression alternating with free-blinking blocks. Latent profile analysis identified OCD subgroups based on number of erroneous blinks during suppression. Subgroups were compared on behavior, clinical characteristics, and brain activation during task. Three patient subgroups were identified. Despite similar overall OCD severity, the subgroup with the most erroneous eyeblinks had the highest sensory phenomena severity, interoceptive sensitivity, and subjective urge intensity. Compared to other subgroups, this subgroup exhibited more neural activity in somatosensory and interoceptive regions during the early phase (first 30 s) of blink suppression and reduced activity in the middle frontal gyrus during the late phase (second 30 s) as the suppression period elapsed. Heterogeneity of urge suppression in OCD was associated with clinical characteristics and brain function. Our results reveal potential treatment targets that could inform personalized medicine., Competing Interests: Declaration of competing interest Dr. K.A. Collins has consulted for MedAvante-ProPhase, and A. Stein- Regulatory Affairs Consulting, Ltd. in the past, and currently serves as a consultant to Cronos Clinical Consulting Services, Inc. and Relmada Therapeutics, Inc. Dr. R.H. Tobe has received research support (through Nathan Kline Institute) from NIH, Roche Pharmaceuticals, Janssen Pharmaceuticals, Axial Therapeutics, and Maplight Pharmaceuticals; and participated in advisory boards for Roche Pharmaceuticals/Genentech - Nathan Kline Institute has received all honoraria for Dr. Tobe's consulting with Roche Pharmaceuticals/Genentech. All other authors report no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The systemic inflammatory syndrome called "cytokine storm" has been described in COVID-19 pathogenesis, contributing to disease severity. The analysis of cytokine and chemokine levels in the blood of 21 SARS-CoV-2 positive patients throughout the phases of the pandemic has been studied to understand immune response dysregulation and identify potential disease biomarkers for new treatments. The present work reports the cytokine and chemokine levels in sera from a small cohort of individuals primarily infected with SARS-CoV-2 during the first wave of the COVID-19 pandemic in Milan (Italy)., Results: Among the 27 cytokines and chemokines investigated, a significant higher expression of Interleukin-9 (IL-9), IP-10 (CXCL10), MCP-1 (CCL2) and RANTES (CCL-5) in infected patients compared to uninfected subjects was observed. When the change in cytokine/chemokine levels was monitored over time, from the hospitalization day to discharge, only IL-6 and IP-10 showed a significant decrease. Consistent with these findings, a significant negative correlation was observed between IP-10 and anti-Spike IgG antibodies in infected individuals. In contrast, IL-17 was positively correlated with the production of IgG against SARS-CoV-2., Conclusions: The cytokine storm and the modulation of cytokine levels by SARS-CoV-2 infection are hallmarks of COVID-19. The current global immunity profile largely stems from widespread vaccination campaigns and previous infection exposures. Consequently, the immunological features and dynamic cytokine profiles of non-vaccinated and primarily-infected subjects reported here provide novel insights into the inflammatory immune landscape in the context of SARS-CoV-2 infection, and offer valuable knowledge for addressing future viral infections and the development of novel treatments., (© 2024. The Author(s).)

The aim of this study is to identify the factors associated with mortality in patients with COVID-19 undergoing invasive mechanical ventilation at a university hospital in Northeastern Brazil. This is a retrospective cohort from April to August 2020 through an analysis of medical records, considering the demographic profile, comorbidities, complications, supports, respiratory and laboratory parameters. A total of 65 patients required invasive mechanical ventilation, of which 64.6% died in the ICU. They were older, had more comorbidities, shorter length of stay in the intensive care unit, received more support such as palliative care and two vasopressors simultaneously, showed lower levels of pH, hemoglobin and calcium, and higher levels of bicarbonate, lactate, prothrombin time, international normalized ratio, troponin and ferritin at the start of invasive mechanical ventilation. Furthermore, the time course of pH, arterial oxygen partial pressure to fractional inspired oxygen ratio, arterial carbon dioxide partial pressure, lactate, hemoglobin, platelets, lymphocytes, neutrophil-to-lymphocyte ratio, coagulation parameters, calcium, urea, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, ferritin, static compliance, airway resistance, tidal volume, and noradrenaline doses showed association with mortality. There was a high mortality rate in invasively mechanically ventilated COVID-19 patients, with some associated factors identified at the start of invasive mechanical ventilation and others identified over time.

In response to the spread of artemisinin (ART) resistance, ART-based hybrid drugs were developed, and their activity profile was characterized against drug-sensitive and drug-resistant Plasmodium falciparum parasites. Two hybrids were found to display parasite growth reduction, stage-specificity, speed of activity, additivity of activity in drug combinations, and stability in hepatic microsomes of similar levels to those displayed by dihydroartemisinin (DHA). Conversely, the rate of chemical homolysis of the peroxide bonds is slower in hybrids than in DHA. From a mechanistic perspective, heme plays a central role in the chemical homolysis of peroxide, inhibiting heme detoxification and disrupting parasite heme redox homeostasis. The hybrid exhibiting slow homolysis of peroxide bonds was more potent in reducing the viability of ART-resistant parasites in a ring-stage survival assay than the hybrid exhibiting fast homolysis. However, both hybrids showed limited activity against ART-induced quiescent parasites in the quiescent-stage survival assay. Our findings are consistent with previous results showing that slow homolysis of peroxide-containing drugs may retain activity against proliferating ART-resistant parasites. However, our data suggest that this property does not overcome the limited activity of peroxides in killing non-proliferating parasites in a quiescent state., Competing Interests: The authors declare no conflict of interest.

Endometriosis and adenomyosis are complex gynecological conditions characterized by diverse clinical presentations, including superficial peritoneal endometriosis (SPE), ovarian endometrioma (OMA), and deep infiltrating endometriosis (DIE). The hallmark features of these pathologies involve the manifestation of pain symptoms and infertility, and approximately 30% of patients are asymptomatic. Despite ongoing research, definitive treatments for these conditions remain elusive, and clinical management primarily revolves around medical or surgical interventions. Recent advancements in our understanding of the efficacy of various treatment modalities, including medical therapy and surgical interventions, have provided clinicians with valuable insights into pain relief and fertility preservation. This review aims to provide an updated overview of the latest literature on clinical outcomes, treatment options, and management strategies for different types of endometriosis. By synthesizing the newest available data, this review seeks to inform clinicians and guide decision making based on factors such as patients' symptom severity, childbearing desire, and overall health.

Background and Aim: The ideal surgical intervention for secondary mitral regurgitation (SMR), a disease of the left ventricle not the mitral valve itself, is still debated. We performed an updated systematic review and study-level meta-analysis investigating mitral valve repair (MVr) versus mitral valve replacement (MVR) for adult patients with SMR, with or without coronary artery disease (CAD)., Methods: PubMed, CENTRAL and EMBASE were searched for studies comparing MVr versus MVR. Randomized trial or observational studies were considered eligible. Primary endpoint was long-term mortality for any cause. Kaplan-Meier survival curves were reconstructed and compared with Cox linear regression. Landmark analysis and time-varying hazard ratio (HR) were analyzed. Sensitivity analyses included meta-regression and separate sub-analysis. A random effects model was used., Results: Twenty-three studies (MVr=3,727 and MVR=2,839) were included. One study was a randomized trial, and 19 studies were adjusted. The mean weighted follow-up was 3.7±2.8 years. MVR was associated with significative greater late mortality (HR=1.26; 95 % CI, 1.14-1.39; P<0.0001) at 10-year follow-up. There was a time-varying trend showing an increased risk of mortality in the first 2 years after MVR (HR=1.38; 95 % CI, 1.21-1.56; P<0.0001), after which this difference dissipated (HR=0.94; 95 % CI, 0.81-1.09; P=0.41). Separate sub-analyses showed comparable long-term mortality in patients with concomitant coronary surgery ≥90 %, left ventricle ejection fraction ≤40 %, and sub-valvular apparatus preservation rate of 100 %., Conclusions: Compared to repair, MVR is associated with higher probability of mortality in the first 2 years following surgery, after which the two procedures showed comparable late mortality rate., 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 Author(s). Published by Elsevier Inc. All rights reserved.)

Chloroplasts are the powerhouse of the plant cell, and their activity must be matched to plant growth to avoid photooxidative damage. We have identified a posttranslational mechanism linking the eukaryotic target of rapamycin (TOR) kinase that promotes growth and the guanosine tetraphosphate (ppGpp) signaling pathway of prokaryotic origins that regulates chloroplast activity and photosynthesis in particular. We find that RelA SpoT homolog 3 (RSH3), a nuclear-encoded enzyme responsible for ppGpp biosynthesis, interacts directly with the TOR complex via a plant-specific amino-terminal region which is phosphorylated in a TOR-dependent manner. Down-regulating TOR activity causes a rapid increase in ppGpp synthesis in RSH3 overexpressors and reduces photosynthetic capacity in an RSH-dependent manner in wild-type plants. The TOR-RSH3 signaling axis therefore regulates the equilibrium between chloroplast activity and plant growth, setting a precedent for the regulation of organellar function by TOR.

Background: The viral main protease (M pro ) of SARS-CoV-2 has been recently proposed as a key target to inhibit virus replication in the host. Therefore, molecules that can bind the catalytic site of M pro could be considered as potential drug candidates in the treatment of SARS-CoV-2 infections. Here we proposed the application of a state-of-the-art analytical platform which combines metabolomics and protein structure analysis to fish-out potential active compounds deriving from a natural matrix, i.e., a blueberry extract., Methods: The experiments focus on finding MS covalent inhibitors of M pro that contain in their structure a catechol/pyrogallol moiety capable of binding to the nucleophilic amino acids of the enzyme's catalytic site., Results: Among the potential candidates identified, the delphinidin-3-glucoside showed the most promising results. Its antiviral activity has been confirmed in vitro on Vero E6 cells infected with SARS-CoV-2, showing a dose-dependent inhibitory effect almost comparable to the known M pro inhibitor baicalin. The interaction of delphinidin-3-glucoside with the M pro pocket observed was also evaluated by computational studies., Conclusions: The HRMS analytical platform described proved to be effective in identifying compounds that covalently bind M pro and are active in the inhibition of SARS-CoV-2 replication, such as delphinidin-3-glucoside.

Infectious diseases are a significant cause of death, and recent studies estimate that common bacterial infectious diseases were responsible for 13.6% of all global deaths in 2019. Among the most significant bacterial pathogens is Staphylococcus aureus, accounting for more than 1.1 million deaths worldwide in 2019. Vitamin biosynthesis has been proposed as a promising target for antibacterial therapy. Here, we investigated the biochemical, structural, and dynamic properties of the enzyme complex responsible for vitamin B6 (pyridoxal 5-phosphate, PLP) biosynthesis in S. aureus, which comprises enzymes SaPdx1 and SaPdx2. The crystal structure of the 24-mer complex of SaPdx1-SaPdx2 enzymes indicated that the S. aureus PLP synthase complex forms a highly dynamic assembly with transient interaction between the enzymes. Solution scattering data indicated that SaPdx2 typically binds to SaPdx1 at a substoichiometric ratio. We propose a structure-based view of the PLP synthesis mechanism initiated with the assembly of SaPLP synthase complex that proceeds in a highly dynamic interaction between Pdx1 and Pdx2. This interface interaction can be further explored as a potentially druggable site for the design of new antibiotics., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Recurrence in glioblastoma lacks a standardized treatment, prompting an exploration of re-irradiation's efficacy., Methods: A comprehensive systematic review from January 2005 to May 2023 assessed the role of MRI sequences in recurrent glioblastoma re-irradiation. The search criteria, employing MeSH terms, targeted English-language, peer-reviewed articles. The inclusion criteria comprised both retrospective and prospective studies, excluding certain types and populations for specificity. The PICO methodology guided data extraction, and the statistical analysis employed Chi-squared tests via MedCalc v22.009., Results: Out of the 355 identified studies, 81 met the criteria, involving 3280 patients across 65 retrospective and 16 prospective studies. The key findings indicate diverse treatment modalities, with linac-based photons predominating. The median age at re-irradiation was 54 years, and the median time interval between radiation courses was 15.5 months. Contrast-enhanced T1-weighted sequences were favored for target delineation, with PET-imaging used in fewer studies. Re-irradiation was generally well tolerated (median G3 adverse events: 3.5%). The clinical outcomes varied, with a median 1-year local control rate of 61% and a median overall survival of 11 months. No significant differences were noted in the G3 toxicity and clinical outcomes based on the MRI sequence preference or PET-based delineation., Conclusions: In the setting of recurrent glioblastoma, contrast-enhanced T1-weighted sequences were preferred for target delineation, allowing clinicians to deliver a safe and effective therapeutic option; amino acid PET imaging may represent a useful device to discriminate radionecrosis from recurrent disease. Future investigations, including the ongoing GLIAA, NOA-10, ARO 2013/1 trial, will aim to refine approaches and standardize methodologies for improved outcomes in recurrent glioblastoma re-irradiation.

Background: There are no robust population-based Australian data on prevalence and attributed burden of migraine and medication-overuse headache (MOH) data. In this pilot cross-sectional study, we aimed to capture the participation rate, preferred response method, and acceptability of self-report questionnaires to inform the conduct of a future nationwide migraine/MOH epidemiological study., Methods: We developed a self-report questionnaire, available in hard-copy and online, including modules from the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire, the Eq. 5D (quality of life), and enquiry into treatment gaps. Study invitations were mailed to 20,000 randomly selected households across Australia's two most populous states. The household member who most recently had a birthday and was aged ≥ 18 years was invited to participate, and could do so by returning a hard-copy questionnaire via reply-paid mail, or by entering responses directly into an online platform., Results: The participation rate was 5.0% (N = 1,000). Participants' median age was 60 years (IQR 44-71 years), and 64.7% (n = 647) were female. Significantly more responses were received from areas with relatively older populations and middle-level socioeconomic status. Hard copy was the more commonly chosen response method (n = 736). Females and younger respondents were significantly more likely to respond online than via hard-copy., Conclusions: This pilot study indicates that alternative methodology is needed to achieve satisfactory engagement in a future nationwide migraine/MOH epidemiological study, for example through inclusion of migraine screening questions in well-resourced, interview-based national health surveys that are conducted regularly by government agencies. Meanwhile, additional future research directions include defining and addressing treatment gaps to improve migraine awareness, and minimise under-diagnosis and under-treatment., (© 2024. The Author(s).)

Dimethyl fumarate (DMF, Tecfidera) is an oral drug utilized to treat relapsing-remitting multiple sclerosis (MS). DMF treatment reduces disease activity in MS. Gastrointestinal discomfort is a common adverse effect of the treatment with DMF. This study aimed to investigate the effect of DMF administration in the gut draining lymph nodes cells of C57BL6/J female mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We have demonstrated that the treatment with DMF (7.5 mg/kg) significantly reduces the severity of EAE. This reduction of the severity is accompanied by the increase of both proinflammatory and anti-inflammatory mechanisms at the beginning of the treatment. As the treatment progressed, we observed an increasing number of regulatory Foxp3 negative CD4 T cells (Tr1), and anti-inflammatory cytokines such as IL-27, as well as the reduction of PGE2 level in the mesenteric lymph nodes of mice with EAE. We provide evidence that DMF induces a gradual anti-inflammatory response in the gut draining lymph nodes, which might contribute to the reduction of both intestinal discomfort and the inflammatory response of EAE. These findings indicate that the gut is the first microenvironment of action of DMF, which may contribute to its effects of reducing disease severity in MS patients., Competing Interests: LS received a Biogen-Idec research grant. The remaining 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 Lima, Ferrari, Pradella, Carvalho, Rivero, Quintiliano, Souza, Brunetti, Marques, Santos, Farias, Oliveira and Santos.)

Background: Cognitive-behavioral therapy (CBT) and serotonin reuptake inhibitors (SRIs) are recommended treatments for pediatric obsessive-compulsive disorder (OCD), but their relative efficacy and acceptability have not been comprehensively examined. Further, it remains unclear whether the efficacy of in-person CBT is conserved when delivered in other formats, such as over telephone/webcam or as Internet-delivered CBT (ICBT)., Methods: PubMed, PsycINFO, trial registries, and previous systematic reviews were searched for randomized controlled trials (RCTs) comparing CBT (in-person, webcam/telephone-delivered, or ICBT) or SRIs with control conditions or each other. Network meta-analyses were conducted to examine efficacy (post-treatment Children's Yale-Brown Obsessive Compulsive Scale) and acceptability (treatment discontinuation). Confidence in effect estimates was evaluated with CINeMA (Confidence in Network Meta-Analysis)., Results: Thirty eligible RCTs and 35 contrasts comprising 2,057 youth with OCD were identified. In-person CBT was significantly more efficacious than ICBT, waitlist, relaxation training, and pill placebo (MD range: 3.95-11.10; CINeMA estimate of confidence: moderate) but did not differ significantly from CBT delivered via webcam/telephone (MD: 0.85 [-2.51, 4.21]; moderate), SRIs (MD: 3.07 [-0.07, 6.20]; low), or the combination of in-person CBT and SRIs (MD: -1.20 [-5.29, 2.91]; low). SRIs were significantly more efficacious than pill placebo (MD: 4.59 [2.70, 6.48]; low) and waitlist (MD: 8.03 [4.24, 11.82]; moderate). No significant differences for acceptability emerged, but confidence in estimates was low., Conclusions: In-person CBT and SRIs produce clear benefits compared to waitlist and pill placebo and should be integral parts of the clinical management of pediatric OCD, with in-person CBT overall having a stronger evidence base. The combination of in-person CBT and SRIs may be most efficacious, but few studies hinder firm conclusions. The efficacy of CBT appears conserved when delivered via webcam/telephone, while more trials evaluating ICBT are needed., (© 2024 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

The interventricular septum (IVS) is a core myocardial structure involved in biventricular coupling and performance. Physiologically, during systole, it moves symmetrically toward the center of the left ventricle (LV) and opposite during diastole. Several pathological conditions produce a reversal or paradoxical septal motion, such as after uncomplicated cardiac surgery (CS). The postoperative paradoxical septum (POPS) was observed in a high rate of cases, representing a unicum in the panorama of paradoxical septa as it does not induce significant ventricular morpho-functional alterations nor negative clinical impact. Although it was previously considered a postoperative event, evidence suggests that it might also appear during surgery and gradually resolve over time. The mechanism behind this phenomenon is still debated. In this article, we will provide a comprehensive review of the various theories generated over the past fifty years to explain its pathological basis. Finally, we will attempt to give a heuristic interpretation of the biventricular postoperative motion pattern based on the switch of the ventricular anchor points.

The engineering of new 3D bioprinting approaches has shown great promise in the field of tissue engineering and disease modelling. However, the high cost of commercial 3D bioprinters has limited their accessibility, especially to those laboratories in resource-limited settings. Moreover, the need for a 3D bioprinting system capable of dispensing multiple materials is growing apace. Therefore, the development of a Microfluidic-assisted Open Source 3D bioprinting System (MOS3S) for the engineering of hierarchical tissues is needed to progress in fabricating functional tissues, but with a technology accessible to a wider range of researchers. The MOS3S platform is designed to allow the deposition of biomaterial inks using microfluidic printheads or coaxial nozzles for the in-situ crosslinking and scaffolds fabrication. The coupling of 3D printed syringe pumps with the motion control system is used for driving the tunable extrusion of inks for the fabrication of centimeter scale hierarchical lattice constructs for tissue engineering purposes. MOS3S performance have been validated to fabricate high-resolution structures with coaxial microfluidic technology, opening to new frontiers for seminal studies in pre-clinical disease modelling and tissue regeneration., Competing Interests: 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., (© 2024 The Authors.)

Introduction: In Brazil, the plant group popularly known as "pedra-ume-caá" is used in folk medicine for the treatment of diabetes, and its raw material is commonly sold., Objective: The aim of the study was to apply a method for chemical identification of extracts of dry pedra-ume-caá leaves using HPLC-high-resolution mass spectrometry (HRMS) and NMR and develop a multivariate model with NMR data to authenticate commercial samples. In addition, to evaluate the biological activities of the extracts., Materials and Methods: Dry extracts of Myrcia multiflora, Myrcia amazonica, Myrcia guianensis, Myrcia sylvatica, Eugenia punicifolia leaves, and 15 commercial samples (sold in Manaus and Belém, Brazil) were prepared by infusion. All the extracts were analysed using HPLC-high-resolution mass spectrometry (HRMS), NMR, principal component analysis (PCA), and hierarchical cluster analysis (HCA). The antidiabetic effect of extracts was evaluated according to enzymatic inhibition. Their content of total phenols, cell viability, and antioxidant and antiglycation activities were also determined., Results: HPLC-HRMS and NMR analysis of these extracts permitted the identification of 17 compounds. 1 H NMR data combined with multivariate analyses allowed us to conclude that catechin, myricitrin, quercitrin, and gallic and quinic acids are the main chemical markers of pedra-ume-caá species. These markers were identified in 15 commercial samples of pedra-ume-caá. Additionally, only the extracts of M. multiflora and E. punicifolia inhibited α-glucosidase. All the extracts inhibited the formation of advanced glycation end products (AGEs) and showed free-radical-scavenging activity. These extracts did not present cytotoxicity., Conclusion: This study revealed the chemical markers of matrices, and it was possible to differentiate the materials marketed as pedra-ume-caá. Moreover, this study corroborates the potential of these species for treating diabetes., (© 2024 John Wiley & Sons, Ltd.)

The COVID-19 pandemic was initiated by the rapid spread of a SARS-CoV-2 strain. Though mainly classified as a respiratory disease, SARS-CoV-2 infects multiple tissues throughout the human body, leading to a wide range of symptoms in patients. To better understand how SARS-CoV-2 affects the proteome from cells with different ontologies, this work generated an infectome atlas of 9 cell models, including cells from brain, blood, digestive system, and adipocyte tissue. Our data shows that SARS-CoV-2 infection mainly trigger dysregulations on proteins related to cellular structure and energy metabolism. Despite these pivotal processes, heterogeneity of infection was also observed, highlighting many proteins and pathways uniquely dysregulated in one cell type or ontological group. These data have been made searchable online via a tool that will permit future submissions of proteomic data ( https://reisdeoliveira.shinyapps.io/Infectome&#95;App/ ) to enrich and expand this knowledgebase., (© 2024. The Author(s).)

Retinitis pigmentosa (RP) is a form of retinal degeneration characterized by primary degeneration of rod photoreceptors followed by a secondary cone loss that leads to vision impairment and finally blindness. This is a rare disease with mutations in several genes and high genetic heterogeneity. A challenging effort has been the characterization of the molecular mechanisms underlying photoreceptor cell death during the progression of the disease. Some of the cell death pathways have been identified and comprise stress events found in several neurodegenerative diseases such as oxidative stress, inflammation, calcium imbalance and endoplasmic reticulum stress. Other cell death mechanisms appear more relevant to photoreceptor cells, such as high levels of cGMP and metabolic changes. Here we review some of the cell death pathways characterized in the RP mutant retina and discuss preclinical studies of therapeutic approaches targeting the molecular outcomes that lead to photoreceptor cell demise., Competing Interests: VM was shareholder of the company Mireca Medicines. The remaining 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 Bighinati, Adani, Stanzani, D’Alessandro and Marigo.)

Objective: To determine whether somatostatin (SST) could be a cortico-brainstem neurotransmitter involved in producing the headache of migraine., Background: There is evidence to support the idea that a cortico-brainstem-trigeminal nucleus neuraxis might be responsible for producing migraine headache; we have suggested that SST may be one of the neurotransmitters involved., Methods: Rats were anesthetised and prepared for recording neurons in either the periaqueductal gray matter (PAG) or nucleus raphe magnus (NRM), as well as the trigeminal nucleus caudalis (TNC). The dura mater and facial skin were stimulated electrically or mechanically. SST, the SST agonist L054264 and the SST antagonist CYN54806 were injected intravenously, by microinjection, or by iontophoresis into the PAG or NRM. Cortical neuronal activity was provoked by cortical spreading depression (CSD) or light flash (LF) and was monitored by recording cortical blood flow (CBF)., Results: Intravenous injection of SST: (a) selectively decreased the responses of TNC neurons to stimulation of the dura, but not skin, for up to 5 h; (b) decreased the ongoing discharge rate of TNC neurons while simultaneously increasing the discharge rate of neurons in either brainstem nucleus and; (c) prevented, or reversed, the effect of CSD and LF on brainstem and trigeminal neuron discharge rates. CSD and LF decreased the discharge rate of neurons in both brainstem nuclei and increased the discharge rate of TNC neurons. These effects were reversed by L054264 and mimicked by CYN54806. Injections of L054264 into the PAG or NRM reduced the response of TNC neurons to dural stimulation and skin stimulation differentially, depending on the nucleus injected. Injections of CYN54806 into either brainstem nucleus potentiated the responses of TNC neurons to dural and skin stimulation, but without a marked differential effect., Conclusions: These results imply that SST could be a neurotransmitter in a pathway responsible for migraine pain., Competing Interests: Declaration of Competing Interest Dr. Zagami reports that he is a past member of the Advisory Boards of Eli Lilly and TEVA; past chair of the Advisory Board of Novartis Australia. Dr. Lambert declares he has no conflicting interests., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

Introduction: The thymus is the primary lymphoid organ responsible for normal T-cell development. Yet, in abnormal metabolic conditions as well as an acute infection, the organ exhibits morphological and cellular alterations. It is well established that the immune system is in a tidy connection and dependent on the central nervous system (CNS), which regulates thymic function by means of innervation and neurotransmitters. Sympathetic innervation leaves the CNS and spreads through thymic tissue, where nerve endings interact directly or indirectly with thymic cells contributing to their maintenance and development., Methods: Herein, we hypothesized that brain damage due to an inflammatory process might elicit alterations upon the thymic-CNS neuroimmune axis, altering not just the sympathetic innervation and neurotransmitter release, but also modifying the thymus microenvironment and T-cell development. We used the well-established multiple sclerosis model of experimental autoimmune encephalomyelitis (EAE), to study putative changes in the thymic neural, lymphoid, and microenvironmental compartments., Results: We showed that along with EAE clinical development, thymus morphology, and cellular compartments are affected, altering the peripheric T-cell population and modifying the retrograde thymic communication toward the CNS., Conclusion: Altogether, our data suggest that the thymic-CNS neuroimmune bidirectional axis is compromised in EAE. This imbalance may contribute to an increased and uncontrolled auto-immune reaction., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

The benefits of single (SITA) and bilateral internal thoracic arteries (BITA) in diabetics undergoing coronary bypass grafting (CABG) are conflicting. We undertook a study-level meta-analysis to compare early and long-term outcomes of both CABG configurations. PubMed, CENTRAL, and EMBASE were searched for studies comparing BITA versus SITA for isolated CABG surgery in diabetics. Randomized trials or observational studies were considered eligible for the analysis. Kaplan-Meier curves of long-term survival were reconstructed and compared with Cox linear regression; incidence rate ratios (IRR) with 95% confidence intervals (CI) for long-term survival were calculated. Landmark analysis and time-varying hazard ratio (HR) were analyzed. Odds ratios (OR) were extracted for early mortality, postoperative stroke, deep sternal wound infection (DSWI), and myocardial infarction (MI). A random effects meta-analysis was performed. Sensitivity analyses included leave-one-out-analyses and meta-regression. Thirteen studies (7332 patients) were included. Overall, at 20-year follow-up, BITA was associated with higher survival (HR = 0.77; 95% CI, 0.71-0.84; P < 0.0001). Time-varying HR and landmark analysis reported BITA was associated with a higher rate of 10-year survival (HR = 0.75, 95% CI 0.68-0.82, P < 0.0001), while from 10 to 20-year follow-up no difference was revealed (HR = 0.99, 95% CI 0.82-1.19, P = 0.93). There was no increase in early mortality, postoperative MI, stroke, or DSWI between the groups. At meta-regression, the higher the age, the higher the long-term overall survival in patients with BITA. In diabetics, the BITA approach is associated with improved 10-year survival with no increase in early mortality, MI, stroke, or DSWI. In the 10-20-year timeframe, BITA and SITA showed comparable survival., 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 © 2023 Elsevier Inc. All rights reserved.)

Accumulation of ectopic pericardial adipose tissue has been associated with cardiovascular complications which, in part, may relate to adipose-derived factors that regulate vascular responses and angiogenesis. We sought to characterize adipose tissue microvascular angiogenic capacity in subjects who underwent elective cardiac surgeries including aortic, valvular, and coronary artery bypass grafting. Pericardial adipose tissue was collected intraoperatively and examined for angiogenic capacity. Capillary sprouting was significantly blunted (twofold, p <0.001) in subjects with coronary artery disease (CAD) (age 60 ± 9 years, body mass index [BMI] 32 ± 4 kg/m 2 , low-density lipoprotein cholesterol [LDL-C] 95 ± 46 mg/100 ml, n = 29) compared with age-, BMI-, and LDL-C matched subjects without angiographic obstructive CAD (age 59 ± 10 y, BMI 35 ± 9 kg/m 2 , LDL-C 101 ± 40 mg/100 ml, n = 12). For potential mechanistic insight, we performed mRNA expression analyses using quantitative real-time polymerase chain reaction and observed no significant differences in pericardial fat gene expression of proangiogenic mediators vascular endothelial growth factor-A (VEGF-A), fibroblast growth factor-2 (FGF-2), and angiopoietin-1 (angpt1), or anti-angiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and endostatin. In contrast, mRNA expression of anti-angiogenic thrombospondin-1 (TSP-1) was significantly upregulated (twofold, p = 0.008) in CAD compared with non-CAD subjects, which was confirmed by protein western-immunoblot analysis. TSP-1 gene knockdown using short hairpin RNA lentiviral delivery significantly improved angiogenic deficiency in CAD (p <0.05). In conclusion, pericardial fat in subjects with CAD may be associated with an antiangiogenic profile linked to functional defects in vascularization capacity. Local paracrine actions of TSP-1 in adipose depots surrounding the heart may play a role in mechanisms of ischemic heart disease., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Objectives: Reasons for compulsive hair pulling are heterogeneous and not fully understood. Given that many people who experience compulsive hair pulling do not respond to treatment, identifying subgroups can inform potential mechanisms and treatment design., Methods: We sought to identify empirical subgroups among participants in an online treatment program for trichotillomania (N = 1728). A latent class analysis was used to identify patterns of emotions associated with compulsive hair-pulling episodes., Results: Six classes of participants were found which reflected three predominant themes. One theme reflected expected patterns, where emotional changes were seen following pulling. Two other themes were more surprising, where one reflected high overall emotional activation that did not show consistent change in response to pulling, and another showed low emotional activation overall. These results suggest that there are multiple types of hair-pulling and a sizeable group of people may benefit from treatment adjustments., Limitations: Participants did not receive semi-structured diagnostic assessment. A majority of participants were Caucasian, and future research would benefit from increased participant diversity. Emotions associated with compulsive hair-pulling were measured across an entire treatment program, but the relationship between specific intervention components and change in specific emotions was not systematically collected., Conclusions: While previous research has addressed overall phenomenology and comorbidity, the present study is the first to identify empirical subgroups of people who experience compulsive hair-pulling at the level of individual pulling episodes. Identified participant classes had distinguishing features that can aid in personalizing treatment to individual symptom presentations., Competing Interests: Declaration of competing interest Dr. Mouton-Odum is the owner of PsycTech, LLC, which implemented the intervention and online platform used in data collection for the present study. No funding was obtained for this study., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background and Purpose: The main aim of this study has been the psychometric validation of an Italian translation of the Nurse Professional Competence Scale-Short Form (I-NPCS-SF), testing its validity and reliability. Methods: A multiphase design was used for the I-NPCS-SF translation and psychometric validation: (a) cultural and linguistic validation, (b) content and face validity, and (c) construct validity. Results: The I-NPCS-SF showed adequate linguistic translation, cultural adaptation, and content validity. Confirmatory factor analysis supported a four-factor structure of the I-NPCS-SF, in explaining data obtained from nurses and nursing students. Conclusions: The I-NPCS-SF demonstrated evidence of validity and reliability in measuring four professional competencies. Having an appropriate tool to be applied in the Italian context for professional competence self-assessment constitutes an essential step in measuring professional competencies., (© 2023 Springer Publishing Company, LLC.)

New regulatory functions in plant development and environmental stress responses have recently emerged for a number of apocarotenoids produced by enzymatic or nonenzymatic oxidation of carotenoids. β-Cyclocitric acid (β-CCA) is one such compound derived from β-carotene, which triggers defense mechanisms leading to a marked enhancement of plant tolerance to drought stress. We show here that this response is associated with an inhibition of root growth affecting both root cell elongation and division. Remarkably, β-CCA selectively induced cell cycle inhibitors of the SIAMESE-RELATED (SMR) family, especially SMR5, in root tip cells. Overexpression of the SMR5 gene in Arabidopsis induced molecular and physiological changes that mimicked in large part the effects of β-CCA. In particular, the SMR5 overexpressors exhibited an inhibition of root development and a marked increase in drought tolerance which is not related to stomatal closure. SMR5 up-regulation induced changes in gene expression that strongly overlapped with the β-CCA-induced transcriptomic changes. Both β-CCA and SMR5 led to a down-regulation of many cell cycle activators (cyclins, cyclin-dependent kinases) and a concomitant up-regulation of genes related to water deprivation, cellular detoxification, and biosynthesis of lipid biopolymers such as suberin and lignin. This was correlated with an accumulation of suberin lipid polyesters in the roots and a decrease in nonstomatal leaf transpiration. Taken together, our results identify the β-CCA-inducible and drought-inducible SMR5 gene as a key component of a stress-signaling pathway that reorients root metabolism from growth to multiple defense mechanisms leading to drought tolerance., (© The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences.)

Malaria is the one of the deadliest infectious diseases worldwide. Chemically, quinolines are excellent ligands for metal coordination and are deployed as drugs for malaria treatment. There is a growing body of evidence indicating that metal complexes can be conjugated with antimalarial quinolines to be used as chemical tools to overcome the disadvantages of quinolines, improving their bioactive speciation, cellular distribution, and subsequently broadening the spectrum of activity to multiple stages of the complex Plasmodium life cycle. In this study, four novel complexes of ruthenium(II)- and gold(I)-containing amodiaquine (AQ) were synthesized, and a careful chemical characterization revealed the precise coordination site of AQ to the metals. Their speciation in solution was investigated, demonstrating the stability of the quinoline-metal bond. Ru II - and Au I -AQ complexes were demonstrated to be potent and efficacious in inhibiting parasite growth in multiple stages of the Plasmodium life cycle as assayed in vitro and in vivo. These properties could be attributed to the ability of the metal-AQ complexes to reproduce the suppression of heme detoxification induced by AQ, while also inhibiting other processes in the parasite life cycle; this can be attributed to the action of the metallic species. Altogether, these findings indicate that metal coordination with antimalarial quinolines is a potential chemical tool for drug design and discovery in malaria and other infectious diseases susceptible to quinoline treatment., (© 2023 Wiley-VCH GmbH.)

Objective: Dopaminergic dysfunction, iron reduction and variations in the PTPRD gene (protein tyrosine phosphatase receptor type delta) may be associated with restless leg syndrome (RLS). Here, we evaluate the effect of pramipexole (PPX) and exercise on genes and proteins associated with RLS and on sleep patterns in spontaneously hypertensive rats (SHR)., Methods: Animals were distributed into 4 groups: 1) Control (CTRL); 2) Exercise (EX); 3) Exercise and pramipexole (EX + PPX); and 4) Pramipexole (PPX). PPX treatment was performed daily (0.125 mg/kg), while exercise was conducted over 5 sessions per week, both for 4 weeks., Results: EX + PPX increased the protein levels of PTPRD, reduced the protein levels of the enzyme tyrosine hydroxylase (TH) and improved sleep parameters in both cycles; on the other hand, the use of PPX reduced mRNA and protein levels of PTPRD and TH but improved the sleep pattern in the light cycle. However, in the dark cycle, pramipexole caused the worsening of symptoms., Conclusions: We suggest that the improvement in sleep pattern by EX + PPX may be associated with the increased protein levels of PTPRD and that EX + PPX can reverse the negative effects of PPX., 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 © 2023 Elsevier B.V. All rights reserved.)

Ethiprole, a phenylpyrazole insecticide, has been increasingly used in the Neotropical region to control stink bug pests in soybean and maize fields. However, such abrupt increases in use may have unintended effects on non-target organisms, including those inhabiting freshwater ecosystems. Here, we evaluated the effects of acute (96 h) sublethal exposure to ethiprole (up to 180 μg/L, which is equivalent to 0.013% of the recommended field dose) on biomarkers of stress in the gills, liver, and muscle of the Neotropical fish Astyanax altiparanae. We further recorded potential ethiprole-induced effects on the structural histology of A. altiparanae gills and liver. Our results showed that ethiprole exposure increased glucose and cortisol levels in a concentration-dependent manner. Ethiprole-exposed fish also exhibited higher levels of malondialdehyde and greater activity of antioxidant enzymes, such as glutathione-S-transferase and catalase, in both gills and liver. Furthermore, ethiprole exposure led to increased catalase activity and carbonylated protein levels in muscle. Morphometric and pathological analyses of the gills revealed that increasing ethiprole concentration resulted in hyperemia and loss of integrity of the secondary lamellae. Similarly, histopathological analysis of the liver demonstrated higher prevalence of necrosis and inflammatory infiltrates with increasing ethiprole concentration. Altogether, our findings demonstrated that sublethal exposure to ethiprole can trigger a stress response in non-target fish species, which may lead to potential ecological and economic imbalances in Neotropical freshwater systems., 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 © 2023 Elsevier Ltd. All rights reserved.)

Background: The optimal timing to perform percutaneous coronary interventions (PCI) in transcatheter aortic valve implantation (TAVI) patients remains unknown., Aims: We sought to compare different PCI timing strategies in TAVI patients., Methods: The REVASC-TAVI registry is an international registry including patients undergoing TAVI with significant, stable coronary artery disease (CAD) at preprocedural workup. In this analysis, patients scheduled to undergo PCI before, after or concomitantly with TAVI were included. The main endpoints were all-cause death and a composite of all-cause death, stroke, myocardial infarction (MI) or rehospitalisation for congestive heart failure (CHF) at 2 years. Outcomes were adjusted using the inverse probability treatment weighting (IPTW) method., Results: A total of 1,603 patients were included. PCI was performed before, after or concomitantly with TAVI in 65.6% (n=1,052), 9.8% (n=157) or 24.6% (n=394), respectively. At 2 years, all-cause death was significantly lower in patients undergoing PCI after TAVI as compared with PCI before or concomitantly with TAVI (6.8% vs 20.1% vs 20.6%; p<0.001). Likewise, the composite endpoint was significantly lower in patients undergoing PCI after TAVI as compared with PCI before or concomitantly with TAVI (17.4% vs 30.4% vs 30.0%; p=0.003). Results were confirmed at landmark analyses considering events from 0 to 30 days and from 31 to 720 days., Conclusions: In patients with severe aortic stenosis and stable coronary artery disease scheduled for TAVI, performance of PCI after TAVI seems to be associated with improved 2-year clinical outcomes compared with other revascularisation timing strategies. These results need to be confirmed in randomised clinical trials.

Parasitic nematodes infect and cause morbidity in over one billion people worldwide, with current anthelmintic drugs decreasing in efficacy. To date, nematodes produce more types of neuropeptides than any other animal. We are interested in the role of neuropeptide signaling systems as a possible target for new anthelmintic drugs. Although FMRFamide-related peptides are found throughout the animal kingdom, the number of these peptides in nematodes greatly exceeds that of any other phylum. We are using Caenorhabditis elegans as a model for examining FMRFamide-like peptides, all of which share a C-terminal Arg-Phe-amide and which are known as FLPs in nematodes. Our previous work indicated interactions between the daf-10 , tax-4 , and flp-1 signaling pathways. In this paper, we further explore these interactions with chemotaxis and dispersal assays., Competing Interests: The authors declare that there are no conflicts of interest present., (Copyright: © 2023 by the authors.)

Background: Ambulatory impairment is a common and complex manifestation of multiple sclerosis (MS), and longitudinal patterns are not well understood., Objective: To characterize longitudinal walking speed trajectories in a general MS patient population and in those with early disease (⩽ 5 years from onset), identify subgroups with similar patterns, and examine associations with individual attributes., Methods: Using a retrospective cohort study design, latent class growth analysis was applied to longitudinal timed 25-foot walk (T25-FW) data from 7683 MS patients, to determine T25-FW trajectories. Associations were evaluated between trajectory assignment and individual attributes. Analyses were repeated for 2591 patients with early disease., Results: In the general patient population, six trajectories were discerned, ranging from very minimal to very high impairment at baseline, with variability in impairment accrual. The clusters with moderate to very high walking impairment were associated with being female, older and Black American, longer symptom duration, progressive course, and depressive symptoms. In the early disease subset, eight trajectories were discerned that included two subgroups that rapidly accrued impairment., Conclusion: We identified novel subgroups of MS patients will distinct long-term T25-FW trajectories. These results underscore that socially disadvantaged and economically marginalized MS patients are the most vulnerable for severe ambulatory impairment.

Background: Post-acute myocardial infarction papillary muscle rupture (post-AMI PMR) may present variable clinical scenarios and degree of emergency due to result of cardiogenic shock. Veno-arterial extracorporeal life support (V-A ECLS) has been proposed to improve extremely poor pre- or postoperative conditions. Information in this respect is scarce., Methods: From the CAUTION (meChanical complicAtion of acUte myocardial infarcTion: an InternatiOnal multiceNter cohort study) database (16 different Centers, data from 2001 to 2018), we extracted adult patients who were surgically treated for post-AMI PMR and underwent pre- or/and postoperative V-A ECLS support. The end-points of this study were in-hospital survival and ECLS complications., Results: From a total of 214 post-AMI PMR patients submitted to surgery, V-A ECLS was instituted in 23 (11%) patients. The median age was 61.7 years (range 46-81 years). Preoperatively, ECLS was commenced in 10 patients (43.5%), whereas intra/postoperative in the remaining 13. The most common V-A ECLS indication was post-cardiotomy shock, followed by preoperative cardiogenic shock and cardiac arrest. The median duration of V-A ECLS was 4 days. V-A ECLS complications occurred in more than half of the patients. Overall, in-hospital mortality was 39.2% (9/23), compared to 22% (42/219) for the non-ECLS group., Conclusions: In post-AMI PMR patients, V-A ECLS was used in almost 10% of the patients either to promote bridge to surgery or as postoperative support. Further investigations are required to better evaluate a potential for increased use and its effects of V-A ECLS in such a context based on the still high perioperative mortality., (© 2023 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global outbreak of respiratory tract disease known as Coronavirus Disease 2019 (COVID-19). SARS-CoV-2 infects mainly lungs and may cause several immune-related complications, such as lymphocytopenia and cytokine storm, which are associated with the severity of the disease and predict mortality. The mechanism by which SARS-CoV-2 infection may result in immune system dysfunction is still not fully understood. Here, we show that SARS-CoV-2 infects human CD4 + T helper cells, but not CD8 + T cells, and is present in blood and bronchoalveolar lavage T helper cells of severe COVID-19 patients. We demonstrated that SARS-CoV-2 spike glycoprotein (S) directly binds to the CD4 molecule, which in turn mediates the entry of SARS- CoV-2 in T helper cells. This leads to impaired CD4 T cell function and may cause cell death. SARS-CoV-2-infected T helper cells express higher levels of IL-10, which is associated with viral persistence and disease severity. Thus, CD4-mediated SARS-CoV-2 infection of T helper cells may contribute to a poor immune response in COVID-19 patients., Competing Interests: NB, GD, Dd, AF, GS, SM, TK, VB, LM, JV, GP, NW, LN, VC, AD, FV, LT, JF, IC, LS, AP, EM, RU, AB, TN, LR, MA, MM, LB, FC, RL, JG, NM, AM, RS, MA, DT, PP, MM, KB, CS, FG, VS, Ed, VF, MC, BC, AP, LC, MD, PR, AG, FP, LS, LB, SS, MP, SW, AS, RC, AV, MV, AD, LV, AF, Ld, TC, HN, HM, RM, DM, MS, JP, PM, MM, AF No competing interests declared, (© 2023, Brunetti, Davanzo, de Moraes et al.)

Among the mucosal melanomas, vaginal melanomas are very rare tumors, accounting for less than 20% of melanomas arising from the female genital tract. They occur most frequently in women in post-menopausal age, but younger patients may also experience this neoplasm, mainly located in the lower third of the vagina or the anterior wall. The optimal management of this tumor remains controversial, with surgery reported as the most frequently adopted approach. However, a clear benefit of surgical treatment in terms of survival has not yet been demonstrated. Conversely, radiotherapy may represent an attractive non-invasive alternative, and there are several favorable reports of the role of radiation therapy, either delivered with photons, brachytherapy, or hadrontherapy. A wide range of techniques and fractionation regimens are reported with substantially good tolerance to the treatment, and acute G3 or higher toxicities are reported only in the case of concurrent immunotherapy. Of note, due to the rarity of the disease, there is a lack of high-level evidence for the optimal therapeutic option. In this scenario, recent studies theorize the possibility of developing combinatorial approaches of radiotherapy with immunotherapy based on cutaneous melanomas reports. In this review, we aim to summarize the evidence available in the literature supporting the role of definitive radiotherapy for vaginal melanomas, with a focus on the combination of RT with immunotherapy, in terms of optimal timing and biological rationale.

The sequence-dependent statistical mechanics of double-stranded nucleic acid, or dsNA, is believed to be essential in its biological functions. In turn, the equilibrium statistical mechanics behaviour of dsNA depends strongly both on sequence-dependent perturbations in its ground state shape away from an idealised, uniform, double-helical configuration, and on its fluctuations as governed by its sequence-dependent stiffness. We here describe the cgNA+web browser-based interactive tool for visualising the sequence-dependent ground states of dsNA fragments of arbitrary sequences, as predicted by the underlying cgNA+ coarse-grain model. Parameter sets are provided to model dsDNA, including the possibility of epigenetically modified CpG dinucleotide steps, dsRNA, and DNA:RNA Hybrid double helical fragments. The cgNA+web interface is specifically designed to compare ground state shapes of different sequences of the same dsNA, or analogous sequences of different dsNAs. The cgNA+web server is freely available at cgDNAweb.epfl.ch without any login requirement., 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 © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The present study reports on the outcomes of our mono-institutional experience of Helical Tomotherapy (HT)-based SRT for brain metastases. The use of this linac is less frequently reported for this kind of treatment. Methods: This retrospective study displays a series of patients treated with HT-SRT. The eligibility of using SRT for brain metastases was defined by a Karnofsky performance status of >70, a life expectancy of >6 months, and controlled extra-cranial disease; no SRT was allowed in the case of a number of brain metastases larger than 10. All the cases were discussed by a multidisciplinary board. Toxicity assessments were performed based on CTCAE v5.0. Survival endpoints were assessed using the Kaplan-Meier method, and univariate and multivariate analyses were carried out to identify any potential predictive factor for an improved outcome. Results: Sixty-four lesions in 37 patients were treated using HT-SRT with a median total dose of 30 Gy in five fractions. The median follow-up was 7 months, and the 1- and 2-year LC rates were both 92.5%. The IPFS rates were and 56.75% and 51.35%. The OS rates were 54% and 40%. The UA showed better IPFS rates significantly related to male sex ( p = 0.049), a BED 12 of ≥42 Gy ( p = 0.006), and controlled extracranial disease ( p = 0.03); in the MA, a favorable trend towards LC ( p = 0.11) and higher BED ( p = 0.11) schedules maintained a correlation with improved IPFS rates, although statistical significance was not reached. Conclusions: HT-based SRT for brain metastases showed safety and efficacy in our monoinstiutional experience. Higher RT doses showed statistical significance for improved outcomes of LC and OS.

Septins possess a conserved guanine nucleotide-binding (G) domain that participates in the stabilization of organized hetero-oligomeric complexes which assemble into filaments, rings and network-like structures. The fruit fly, Drosophila melanogaster, has five such septin genes encoding Sep1, Sep2, Sep4, Sep5 and Pnut. Here, we report the crystal structure of the heterodimer formed between the G-domains of Sep1 and Sep2, the first from an insect to be described to date. A G-interface stabilizes the dimer (in agreement with the expected arrangement for the Drosophila hexameric particle) and this bears significant resemblance to its human counterparts, even down to the level of individual amino acid interactions. On the other hand, a model for the G-interface formed between the two copies of Pnut which occupy the centre of the hexamer, shows important structural differences, including the loss of a highly favourable bifurcated salt-bridge network. Whereas wild-type Pnut purifies as a monomer, the reintroduction of the salt-bridge network results in stabilizing the dimeric interface in solution as shown by size exclusion chromatography and thermal stability measurements. Adaptive steered molecular dynamics reveals an unzipping mechanism for dimer dissociation which initiates at a point of electrostatic repulsion within the switch II region. Overall, the data contribute to a better understanding of the molecular interactions involved in septin assembly/disassembly., (© 2022 Wiley Periodicals LLC.)