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Background: The COVID-19 pandemic compelled changes to the structure and organization of many occupational sectors that may impact workers' well-being and work-related symptoms., Objective: Evaluate the effects of working modifications related to the COVID-19 pandemic on occupational health outcomes and work ability (WA) among a large group of Italian banking employees., Methods: 2,859 employees visited during health surveillance in 2021 were divided into two job groups: front-office (FO) and back-office workers (BO). Data on conditions associated with office work, psychological distress, WA, and fitness-to-work judgment were analyzed and compared with available data from the pre-pandemic period (2018-2019)., Results: The prevalence of analyzed outcomes was lower than in pre- and post-COVID evaluation literature. After COVID-19, a 28% increase in asthenopin was found in BO, while musculoskeletal symptoms increased about 22% in BO and 9% in FO. Post-COVID showed a 28% rise in stress-related symptoms and a 17% increase in psychotropic drug consumption in both groups. After the lockdown, the prevalence of moderate/poor scores decreased by 13% in each group. Fitness-to-work judgment without limitations prevalence was unchanged., Conclusion: The slight worsening in all examined outcomes at post-lockdown evaluation and the outcomes' prevalence consistently lower than the literature data could be linked to the measures the Institute took to support employees during the COVID-19 pandemic. In this context, a comprehensive integration between occupational safety and health promotion practices is recommended to ensure the highest level of safeguarding for workers' well-being.

The evaluation of estimated GFR (eGFR) is a pivotal staging step in patients with chronic kidney disease (CKD), and renal ultrasound plays an important role in diagnosis, prognosis and progression of CKD. The interaction between histopathological diagnosis and ultrasound parameters in eGFR determination has not been fully investigated yet. The study examined the results of native kidney biopsies performed in 48 Italian centers between 2012 and 2020. The primary goal was if and how the histopathological diagnosis influences the relationship between ultrasound parameters and eGFR. After exclusion of children, patients with acute kidney injury and patients without measure of kidney length or parenchymal thickness, 2795 patients have been selected for analysis. The median values were 52 years for patient age, 11 cm for bipolar kidney diameter, 16 mm for parenchymal thickness, 2.5 g/day for proteinuria and 70 ml/min/1.73 m 2 for eGFR. The bipolar kidney diameter and the parenchymal thickness were directly related with eGFR values (R square 0.064). Diabetes and proteinuria were associated with a consistent reduction of eGFR, improving the adjusted R square up to 0.100. Addition of histopathological diagnosis in the model increased the adjusted R square to 0.216. There is a significant interaction between histopathological diagnosis and longitudinal kidney diameter (P 0.006). Renal bipolar length and parenchymal thickness are directly related with eGFR. The magnitude of proteinuria and histopathological kidney diagnosis are associated with eGFR. The relationship between kidney length and the level of eGFR depends on the nature of the kidney disease., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest. The results presented in this paper have not been published previously in whole or part, except in abstract format. Informed consent: Informed consent was obtained from all the enrolled patients or their parents/legal guardians., (© 2024. The Author(s).)

Background: A series of interesting literature reports acknowledges the notable loss of essential and non-essential amino acids (EAAs and NEAAs) during hemodialysis sessions. These losses may exceed 800 g/year, thus contributing towards accelerating the onset of malnutrition in hemodialysis patients (HD)., Objective: A novel tailored amino acid formula for oral administration was developed to replace total amounts of each individual amino acid lost during dialysis diffusive/convective HD strategies, monitoring the effects produced on nutritional and hematological status., Methods: A three-month randomized double-blind study was conducted on 30 subjects over the age of 70 years extrapolated from a total population of 86 hemodialysis patients. The 30 patients were randomly assigned to two groups: a treatment group of 15 HD patients (TG) to whom a novel mixture containing 5.4 g of AAs was administered solely on interdialytic days, and a control group of 15 HD patients (CG) who received no amino acid supplementation. The AAs mixture was administered post-dialysis at an extended interval from the end of solute and compartmental rebound to replace AA losses and optimize their role in protein anabolism., Results: The results obtained highlighted a significant improvement in protein intake g/kg/day (Protein Catabolic Rate, p = 0.014), and increased IgG (p = 0.008) and C3 serum levels (p = 0.003) in the TG group alone. Fat mass losses were initially confirmed by means of bioelectrical impedance analysis (BIA) (p = 0.011) and plicometry (p < 0.001) in the CG group alone, although the main objective was to preserve nutritional status and, particularly, muscle mass. The study was extended to investigate the effects produced on anemia, yielding evidence of continued positive effects three months after the end of the study in the TG group alone based on an increase in Hb levels from 11.2 ± 0.6 to 12.1 ± 0.6 (p = 0.004) associated with a reduced demand for erythropoietin i.v. from 12928 ± 9033 to 9286 ± 5398 U.I/week (p = 0.012) and iron i.v. from 75.9 ± 55 to 71.4 ± 33.4 mg/week (p = 0.045)., Conclusions: The results obtained following oral administration of this novel tailored AA replacement mixture aimed at reinstating the high AA losses produced during hemodialysis suggest the mixture should be prescribed as a standard procedure to all HD patients., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Ziftomenib (KO-539) is an oral selective menin inhibitor with known preclinical activity in menin-dependent acute myeloid leukaemia models. The primary objective of this study was to determine the recommended phase 2 dose in patients with relapsed or refractory acute myeloid leukaemia based on safety, pharmacokinetics, pharmacodynamics, and preliminary activity., Methods: KOMET-001 is a multicentre, open-label, multi-cohort, phase 1/2 clinical trial of ziftomenib in adults with relapsed or refractory acute myeloid leukaemia. Results of the phase 1 study, conducted at 22 hospitals in France, Italy, Spain, and the USA, are presented here and comprise the dose-escalation (phase 1a) and dose-validation and expansion (phase 1b) phases. Eligible patients were aged 18 years or older, had relapsed or refractory acute myeloid leukaemia, and had an Eastern Cooperative Oncology Group performance status of 2 or less. For phase 1a, patients (all molecular subtypes) received ziftomenib (50-1000 mg) orally once daily in 28-day cycles. For phase 1b, patients with NPM1 mutations or with KMT2A rearrangements were randomly assigned (1:1) using third-party interactive response technology to two parallel dose cohorts (200 mg and 600 mg ziftomenib). Primary endpoints were maximum tolerated dose or recommended phase 2 dose in phase 1a, and safety, remission rates, and pharmacokinetics supporting recommended phase 2 dose determination in phase 1b. Analyses were performed in all patients who received at least one dose of ziftomenib (modified intention-to-treat population). Phase 1a/1b is complete. This trial is registered with ClinicalTrials.gov, NCT04067336, and the EU Clinical Trials register, EudraCT 2019-001545-41., Findings: From Sept 12, 2019, to Aug 19, 2022, 83 patients received 50-1000 mg ziftomenib (39 [47%] were male and 44 [53%] were female). Median follow-up was 22·3 months (IQR 15·4-30·2). Of 83 patients, the most common grade 3 or worse treatment-emergent adverse events were anaemia (20 [24%]), febrile neutropenia (18 [22%]), pneumonia (16 [19%]), differentiation syndrome (12 [15%]), thrombocytopenia (11 [13%]), and sepsis (ten [12%]). Overall, 68 of 83 patients had serious adverse events, with two reported treatment-related deaths (one differentiation syndrome and one cardiac arrest). Differentiation syndrome rate and severity influenced the decision to halt enrolment of patients with KMT2A rearrangements. In Phase 1b, no responses were reported in patients treated at the 200 mg dose level. At the recommended phase 2 dose of 600 mg, nine (25%) of 36 patients with KMT2A rearrangement or NPM1 mutation had complete remission or complete remission with partial haematologic recovery. Seven (35%) of 20 patients with NPM1 mutation treated at the recommended phase 2 dose had a complete remission., Interpretation: Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukaemia. Phase 2 assessment of ziftomenib combination therapy in the upfront and relapsed or refractory setting is ongoing., Funding: Kura Oncology., Competing Interests: Declaration of interests ESW declares honoraria for educational talks from Aptitude, Astellas, Bioascend, CEA, CCO, Curio Sciences, Dava Oncology, Medscape, MD Education, OncLive, PER, Peerview, RTP, and Pfizer; participation on Data Safety Monitoring Committees and research grant committees for AbbVie and Gilead; advisory board participation for Abbvie, Astellas, Blueprint, Bristol Myers Squibb, Daiichi Sankyo, Gilead, GlaxoSmithKline, Immunogen, Janssen, Jazz, Kite, Novartis, NuProbe, PharmaEssentia, Pfizer, Qiagen, Rigel, Schrodinger, Sumitomo, Syndax, and Takeda; other financial and non-financial interests with UptoDate; and medical writing support for this work from Kura Oncology. GCI declares research funding to their institution from Astex, Cullinan Oncology, Kura Oncology, Merck, Novartis, and Syndax Pharmaceuticals; consultancy fees from AbbVie, Kura Oncology, Novartis, and Syndax Pharmaceuticals; support for attending meetings and travel from Kura Oncology; steering committee role with Kura Oncology and Novartis; receipt of material for sample analysis from NuProbe; and medical writing support for this work from Kura Oncology. HPE declares a leadership role with AbbVie (Chair, Independent Review Committee for VIALE A and VIALE C), Bristol Myers Squibb (Chair, AML Registry Steering Committee), and Glycomimetics (Scientific Steering Committee); speakers bureau for AbbVie, Bristol Myers Squibb, Incyte, Jazz, Novartis, and Servier; contracted research from AbbVie, ALX Oncology, Amgen, Aptose, Ascentage, Daiichi Sankyo, Forma, Gilead, Glycomimetics, Immunogen, Jazz, Kura Oncology, MacroGenics, Novartis, PTC, and Sumitomo Pharma; consultancy fees from AbbVie, Astellas, Bristol Myers Squibb, Daiichi Sankyo, Glycomimetics, Incyte, Jazz, Kura Oncology, Novartis, Pfizer, Servier, Stemline, and Sumitomo Pharma; and medical writing support for this work from Kura Oncology. JKA declares a leadership role with the American Society of Hematology (guidelines panel), National Comprehensive Cancer Network (acute myeloid leukaemia panel vice-chair), and National Cancer Institute (co-chair on Leukemia Steering Committee); honoraria from Astellas, HMP Education, MD Education, and VJ HemOnc; advisory board role with AbbVie, Aptitude Health, Astellas, BlueBird Bio, Curio, Daiichi Sankyo, Dark Blue Therapeutics, Gilead, Kura Oncology, Kymera, Rigel, Stemline Therapeutics, Syros, and Treadwell Therapeutics; meeting attendance and travel expenses from Astellas, Daiichi Sankyo, HMP Education, MD Education, and VJ HemOnc; medical writing support for this work from Kura Oncology; and participation on a Data Safety Committee for Glycomimetics. PM declares consultancy fees from Kura Oncology and Syndax Pharmaceuticals and medical writing support for this work from Kura Oncology. SDB declares honoraria from Astellas, Bristol Myers Squibb, Menarini, and Servier; consultancy fees from AbbVie, Bristol Myers Squibb, Forma, Remix, Rigel, and Servier; travel expenses from Janssen, Pfizer, Rigel, and Servier; and medical writing support for this work from Kura Oncology. RBW declares clinical trial support from Kura Oncology and medical writing support for this work from Kura Oncology. KP declares honoraria from Merck (investigator meeting lecture); advisory board role with AbbVie, Incyte, PharmaEssentia, Protagonist, and Sobi; and medical writing support for this work from Kura Oncology. MRS declares research funding to institution from ALX Oncology, Astex, Incyte, Takeda, and TG Therapeutics; consultancy fees from AbbVie, Bristol Myers Squibb, CTI BioPharma, Forma, Geron, GlaxoSmithKline, Karyopharm, Rigel, Ryvu, Taiho, and Treadwell; stock or stock options in Empath Bioscience, Karyopharm, and Ryvu; and medical writing support for this work from Kura Oncology. MVS declares research grant to their institution from AbbVie, Astellas, Celgene, Kura Oncology, and MRKR Therapeutics; travel expenses from Dava Oncology; and medical writing support for this work from Kura Oncology. MK declares consultancy fees from AbbVie, CTI Biopharma, Incyte, and Protagonist; advisory board role with CTI BioPharma, Incyte, Kura Oncology, and Morphosys; travel expenses from Protagonist; and medical writing support for this work from Kura Oncology. MRB declares research funding to their institution from AbbVie, Ascentage, Astellas, Gilead, Kura Oncology, and Takeda and medical writing support for this work from Kura Oncology. JMF declares leadership role with National Cancer Institute Leukemia Steering Committee and the National Heart, Lung, and Blood Institute national Myelodysplastic Syndrome Study Steering Committee; stock or stock options with Aurinia; honoraria from AmerisourceBergen/IntrinsiQ Specialty Solutions, Aptitude Health, and MJH LifeSciences; consultancy fees from Autolus, Bristol Myers Squibb, Remix, and Syndax; grants to institution for clinical trial support from Actinium, Astellas, Celgene, Chordia, Kura Oncology, Novartis, Pfizer, Roivant, Sellas, and Servier; and medical writing support for this work from Kura Oncology. GS declares contracts through their institution from AbbVie, Actinium, Actuate, Agios, Arog, Astellas, AlloVir, Amgen, Aptevo, AltruBio, AVM Bio, Bristol Myers Squibb/Celgene; BioMea, Biopath, Biosight, Cellularity, Celator, Constellation, Cogent, Cellectis, Cullinan, Daiichi Sankyo, Deciphera, Delta-Fly, Fate, Forma, FujiFilm, Gamida, Genentech-Roche, Rigel Glycomimetics, Geron, Gilead, Incyte, Janssen, Jazz, Karyopharm, Kite/Gilead, Kronos Bio, Kura Oncology, Immunogene, ImmuneOnc, Loxo, Marker, Mateon, Novartis, Onconova, Ono-UK, Orca, Pfizer, PrECOG, Regimmune, Samus, Sangamo, Sellas, Stemline, Syros, Takeda, Tolero, and Trovagene; consultancy fees from Bristol Myers Squibb, Curios, Daiichi, and Novartis; speakers bureau role for AbbVie, Agios, Amgen, Astellas, Blueprint Medicine, Bristol Myers Squibb, Celgene, Karyopharm, GlaxoSmithKline, Kite (Gilead), Jazz, Rigel, Seattle genetics, and Stemline; board or advisory committee membership for Agios, Autolus, AVM Biotech, Bristol Myers Squibb, Gamida, Gilead, GlaxoSmithKline, Incyte, Novartis, Orca, Rigel, and Stemline; board of trustees membership for Leukemia Lymphoma Society Los Angeles; secretary or treasurer membership for the American Society of Hematology Research Collaborative Board of Directors; and holds stock with Amgen, Bristol Myers Squibb, and Janssen/Johnson & Johnson. LA declares research funding to institution from AbbVie, Bristol Myers Squibb, Jazz Pharmaceuticals, and Novartis; consultancy fees from AbbVie, Jazz Pharmaceuticals, and Novartis; and medical writing support for this work from Kura Oncology. ER declares consulting fees from Astellas and Laboratories Delbert; honoraria from AbbVie, Astellas, Eurocept, and Jazz Pharmaceuticals; support for attending meetings and travel from AbbVie, Gilead, and Jazz Pharmaceuticals; and medical writing support for this work from Kura Oncology. MMP declares research funding to institution from Epigenetix, Kura Oncology, Polaris, Solutherapeutics, and Stem Line Pharma; medical writing support for this work from Kura Oncology; and Data Safety Monitoring Boards with CTI Biopharma. CP declares honoraria from AbbVie, Amgen, Astellas, Blueprint, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Incyte, Janssen, Jazz Pharmaceuticals, Laboratories Delbert, Menarini-Stemline, Novartis, Paladin Labs, Pfizer, and Servier; travel expenses from AbbVie, Amgen and Pfizer; medical writing support for this work from Kura Oncology; and Data Safety Monitoring Board or advisory board membership for AbbVie, Amgen, Astellas, Blueprint, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Incyte, Janssen, Jazz Pharmaceuticals, Laboratories Delbert, Paladin Labs, and Pfizer. JG declares research support to institution, consultancy fees, royalties, patents, and stock with Kura Oncology, and medical writing support for this work from Kura Oncology. TC declares research support to institution and royalties from, and patents and owns stock with Kura Oncology; and medical writing support for this work from Kura Oncology. BC, JR, BML, MH, PP, and OS declare medical writing support for this work from Kura Oncology. KN declares employment with Kura Oncology; received stock options from Kura Oncology; and medical writing support for this work from Kura Oncology. AM declares employment with Kura Oncology; owns stock with Kura Oncology; patents and patent applications with Kura Oncology; and medical writing support for this work from Kura Oncology. JMA declares employment and stock or stock options with and travel expenses from Kura Oncology, and medical writing support for this work from Kura Oncology. MT declares employment with Kura Oncology; stock and restricted stock units with Kura Oncology; reimbursement for conference fees, hotels and travel expenses from Kura Oncology; and medical writing support for this work from Kura Oncology. HSS declares employment, patents and patent applications, and owns stock with, Kura Oncology, and medical writing support for this work from Kura Oncology. DC declares employment with Kura Oncology; stock or stock options with Kura Oncology; and medical writing support for this work from Kura Oncology. ML declares employment, patents and patent applications, stock or stock options, support for attending meetings and travel, and other financial or non-financial interests with Kura Oncology; and medical writing support for this work from Kura Oncology. SD declares employment, patents and patent applications, stock or stock options, and other financial or non-financial interests with Kura Oncology; and medical writing support for this work from Kura Oncology. ATF declares consultancy fees from AbbVie, Amgen, Astellas, AstraZeneca, Autolus, Bristol Myers Squibb/Celgene, Daiichi Sankyo, EnClear, Forma, Genentech, Gilead, Immunogen, Ipsen, Kite, Mablytics, Menarini, Novartis, Orum, Pfizer, PureTech, Remix, Rigel, Servier, and Takeda; clinical trial support from AbbVie, Bristol Myers Squibb, and Servier; and medical writing support for this work from Kura Oncology. CB declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Abstract: A phase 2, international, open-label, nonrandomized, single-arm trial was conducted to evaluate the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, as monotherapy for relapsed/refractory peripheral T-cell lymphoma (PTCL) and to evaluate tumor mutation profile as a biomarker of response. Adults with relapsed/refractory PTCL received tipifarnib 300 mg orally twice daily for 21 days in a 28-day cycle. The primary end point was objective response rate (ORR); secondary end points included ORR, progression-free survival (PFS), duration of response (DOR), and adverse events (AEs) in specific subtypes. Sixty-five patients with PTCL were enrolled: n = 38 angioimmunoblastic T-cell lymphoma (AITL), n = 25 PTCL not otherwise specified, and n = 2 other T-cell lymphomas. The ORR was 39.7% (95% confidence interval [CI], 28.1-52.5) in all patients and 56.3% (95% CI, 39.3-71.8) for AITL. Median PFS was 3.5 months overall (954% CI, 2.1-4.4), and 3.6 months (95% CI, 1.9-8.3) for AITL. Median DOR was 3.7 months (95% CI, 2.0-15.3), and greatest in patients with AITL (7.8 months; 95% CI, 2.0-16.3). The median overall survival was 32.8 months (95% CI, 14.4 to not applicable). Tipifarnib-related hematologic AEs were manageable and included neutropenia (43.1%), thrombocytopenia (36.9%), and anemia (30.8%); other tipifarnib-related AEs included nausea (29.2%) and diarrhea (27.7%). One treatment-related death occurred. Mutations in RhoA, DNMT3A, and IDH2 were seen in 60%, 33%, and 27%, respectively, in the AITL tipifarnib responder group vs 36%, 9%, and 9% in the nonresponder group. Tipifarnib monotherapy demonstrated encouraging clinical activity in heavily pretreated relapsed/refractory PTCL, especially in AITL, with a manageable safety profile. This trial was registered at www.ClinicalTrials.gov as #NCT02464228., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Scuba diving is a recreational activity usually considered at low impact on cardiovascular system. However, when diving, increased ambient pressure exerts several effects on the cardiovascular and pulmonary systems, mainly due to redistribution of peripheral blood into the central circulation. This phenomenon, also known as blood shift, may produce a significant overload on a non-healthy heart., Case Summary: We present the case of a female patient who experienced sudden cardiac death during scuba diving: post-mortem cardiac magnetic resonance and autopsy revealed that the patient was affected by previously unknown hypertrophic cardiomyopathy., Discussion: Diving exposes the body to significant physiological changes that may overstress a diseased heart. This case suggests the need for some cardiovascular exams, such as an echocardiogram or, at least, an electrocardiogram, for screening cardiovascular abnormalities in subjects who wish to practice scuba diving., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Multiple sclerosis (MS) is a prevalent immune-mediated inflammatory disease of the central nervous system inducing a widespread degradation of myelin and resulting in neurological deficits. Recent advances in molecular and atomic imaging provide the means to probe the microenvironment in affected brain tissues at an unprecedented level of detail and may provide new insights. This study showcases state-of-the-art spectroscopic and mass spectrometric techniques to compare distributions of molecular and atomic entities in MS lesions and surrounding brain tissues. MS brains underwent post-mortem magnetic resonance imaging (MRI) to locate and subsequently dissect MS lesions and surrounding white matter. Digests of lesions and unaffected white matter were analysed via ICP-MS/MS revealing significant differences in concentrations of Li, Mg, P, K, Mn, V, Rb, Ag, Gd and Bi. Micro x-ray fluorescence spectroscopy (μXRF) and laser ablation - inductively coupled plasma - time of flight - mass spectrometry (LA-ICP-ToF-MS) were used as micro-analytical imaging techniques to study distributions of both endogenous and xenobiotic elements. The essential trace elements Fe, Cu and Zn were subsequently calibrated using in-house manufactured gelatine standards. Lipid distributions were studied using IR-micro spectroscopy and matrix assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI). MALDI-MSI was complemented with high-resolution tandem mass spectrometry and trapped ion mobility spectroscopy for the annotation of specified phospho- and sphingolipids, revealing specific lipid species decreased in MS lesions compared to surrounding white matter. This explorative study demonstrated that modern molecular and atomic mapping techniques provide high-resolution imaging for relevant bio-indicative entities which may complement our current understanding of the underlying pathophysiological processes., Competing Interests: Declaration of competing interest Marten Seeba works for Bruker Corporation., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Very preterm (VPT; < 33 weeks' gestation) toddlers screening positively for autism spectrum conditions (ASC) may display heterogenous neurodevelopmental trajectories. Here we studied neonatal brain volumes and childhood ASC traits evaluated with the Social Responsiveness Scale (SRS-2) in VPT-born toddlers (N = 371; median age 20.17 months) sub-divided into three groups based on their Modified-Checklist for Autism in Toddlers scores. These were: those screening positively failing at least 2 critical items (critical-positive); failing any 3 items, but less than 2 critical items (non-critical-positive); and screening negatively. Critical-positive scorers had smaller neonatal cerebellar volumes compared to non-critical-positive and negative scorers. However, both positive screening groups exhibited higher childhood ASC traits compared to the negative screening group, suggesting distinct aetiological trajectories associated with ASC outcomes., (© 2022. The Author(s).)

Currently, available therapeutics for the treatment of Parkinson's disease (PD) fail to provide sustained and predictable relief from motor symptoms without significant risk of adverse events (AEs). While dopaminergic agents, particularly levodopa, may initially provide strong motor control, this efficacy can vary with disease progression. Patients may suffer from motor fluctuations, including sudden and unpredictable drop-offs in efficacy. Dopamine agonists (DAs) are often prescribed during early-stage PD with the expectation they will delay the development of levodopa-associated complications, but currently available DAs are less effective than levodopa for the treatment of motor symptoms. Furthermore, both levodopa and DAs are associated with a significant risk of AEs, many of which can be linked to strong, repeated stimulation of D2/D3 dopamine receptors. Targeting D1/D5 dopamine receptors has been hypothesized to produce strong motor benefits with a reduced risk of D2/D3-related AEs, but the development of D1-selective agonists has been previously hindered by intolerable cardiovascular AEs and poor pharmacokinetic properties. There is therefore an unmet need in PD treatment for therapeutics that provide sustained and predictable efficacy, with strong relief from motor symptoms and reduced risk of AEs. Partial agonism at D1/D5 has shown promise for providing relief from motor symptoms, potentially without the AEs associated with D2/D3-selective DAs and full D1/D5-selective DAs. Tavapadon is a novel oral partial agonist that is highly selective at D1/D5 receptors and could meet these criteria. This review summarizes currently available evidence of tavapadon's therapeutic potential for the treatment of early through advanced PD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

People with autism and intellectual disabilities, much like individuals with typical development, share a fundamental right and aspiration to realise their own life projects. However, this natural pursuit is uniquely challenging for individuals with autism and intellectual disabilities due to their communication and adaptive hurdles. This growing need has prompted the development of a specific procedure for crafting life projects geared toward enhancing their quality of life. In the present work, we will describe the six key steps and the corresponding assessment, support, and verification tools essential for establishing and actualising the life project for individuals with disabilities, as conceptualised by the Italian Society of Neurodevelopmental Disorders (SIDIN). We will start by delineating diverse preference and value assessment procedures, showcasing an array of tools tailored to accommodate the distinct characteristics of adaptive and communicative functioning in individuals with disabilities. Following this, we will provide a succinct overview of support needs assessment tools. Subsequently, we will introduce the Ecological Life Balance, which serves as an integrative tool for harmonising various assessment systems. We will propose methods for defining existential goals that prioritise quality of life and suggest strategies for implementing support plans. Lastly, we will delve into the methodologies for monitoring and verifying outcomes in the final section.

Purpose: Since glioma therapy is currently still limited until today, new treatment options for this heterogeneous group of tumours are of great interest. Eukaryotic initiation factors (eIFs) are altered in various cancer entities, including gliomas. The purpose of our study was to evaluate the potential of eIFs as novel targets in glioma treatment., Methods: We evaluated eIF protein expression and regulation in 22 glioblastoma patient-derived xenografts (GBM PDX) after treatment with established cytostatics and with regards to mutation profile analyses of GBM PDX., Results: We observed decreased expression of several eIFs upon temozolomide (TMZ) treatment independent from the phosphatidylinositol 3-kinase (PI3K)/ AKT/ mammalian target of the rapamycin (mTOR) signalling pathway. These effects of TMZ treatment were not present in TMZ-resistant PDX. Combination therapy of regorafenib and TMZ re- established the eIF/AKT/mTOR axis., Conclusion: Our study provides novel insights into chemotherapeutic effects on eIF regulation in gliomas and suggests that eIFs are interesting candidates for future research to improve glioma therapy., (© 2023. The Author(s).)

Background: Autistic people experience higher rates of most mental health conditions and report more difficulties with change than nonautistic people. As such, the periods of national stay-at-home orders (known in the United Kingdom as a "lockdown") endured since the beginning of the COVID-19 (coronavirus disease 2019) pandemic in March 2020 may have been particularly challenging for autistic people., Aim: This study explored autistic adults' experience of quality of life and well-being during the start of the COVID-19 pandemic (specifically March to August 2020) using open-text responses from an online survey., Methods: In total, 79 autistic adults from the United Kingdom (aged 21-75 years) took part. Participants completed an online survey, including open-text questions on how various factors influencing quality of life, such as social interactions, general health, well-being, and sensory experiences, were impacted by the COVID-19 pandemic and the first set of national lockdowns that occurred between March and August 2020., Results: Thematic analysis created four key themes, each illustrated by several subthemes. These four themes explore (1) health, (2) social changes, (3) support provisions, and (4) adopting new routines. Many participants discussed the impact that the COVID-19 pandemic and the first set of national lockdowns had on their health and expressed concerns regarding the transition out of periods of lockdown, including readjusting to new rules, going back to in-person interactions, and reacclimatizing to high-stimulation sensory environments. However, several participants reported positive experiences of the periods of lockdown, such as reduced commuting, more control over sensory environments, and more time to pursue personal interests and self-care., Conclusions: These findings highlight the importance of giving autistic individuals the support they need to transition back to "normality" as COVID-19 becomes endemic., Competing Interests: No competing financial interests exist., (Copyright 2023, Mary Ann Liebert, Inc., publishers.)

Autoimmune heart disease is a non-random condition characterised by immune system-mediated aggression against cardiac tissue. Cardiac changes often exhibit nonspecific features and, if unrecognised, can result in fatal outcomes even among seemingly healthy young individuals. In the absence of reliable medical history, the primary challenge lies in differentiating between the various cardiopathies. Numerous immunohistochemical and genetic studies have endeavoured to characterise distinct types of cardiopathies, facilitating their differentiation during autopsy examinations. However, the presence of a standardised protocol that forensic pathologists can employ to guide their investigations would be beneficial. Hence, this summary aims to present the spectrum of autoimmune cardiopathies, including emerging insights such as SARS-CoV-2-induced cardiopathies, and proposes the utilisation of practical tools, such as blood markers, to aid forensic pathologists in their routine practice.

Objective. Thermal cellular injury follows complex dynamics and subcellular processes can heal the inflicted damage if insufficient heat is administered during the procedure. This work aims to the identification of irreversible cardiac tissue damage for predicting the success of thermal treatments. Approach. Several approaches exist in the literature, but they are unable to capture the healing process and the variable energy absorption rate that several cells display. Moreover, none of the existing models is calibrated for cardiomyocytes. We consider a three-state cell death model capable of capturing the reversible damage of a cell, we modify it to include a variable energy absorption rate and we calibrate it for cardiac myocytes. Main results. We show how the thermal damage predicted by the model response is in accordance with available data in the literature on myocytes for different temperature distributions. When coupled with a computational model of radiofrequency catheter ablation, the model predicts lesions in agreement with experimental measurements. We also present additional experiments (repeated ablations and catheter movement) to further illustrate the potential of the model. Significance. We calibrated a three-state cell death model to provide physiological results for cardiac myocytes. The model can be coupled with ablation models and reliably predict lesion sizes comparable to experimental measurements. Such approach is robust for repeated ablations and dynamic catheter-cardiac wall interaction, and allows for tissue remodelling in the predicted damaged area, leading to more accurate in-silico predictions of ablation outcomes., (Creative Commons Attribution license.)

Introduction: The COVID-19 pandemic has caused a global mental health crisis, especially for those individuals who are vulnerable to stress and anxiety due to pre-existing mental health problems. This study aimed to understand the emotional impact of the COVID-19 lockdown on children who were born very preterm (VPT, <32 weeks' gestation), as they are vulnerable to mental health difficulties and are at increased risk of developing psychiatric problems during childhood compared to their full-term-born counterparts., Methods: The parents of 32 VPT children (mean age = 8.7) and 29 term-born controls (mean age = 8.8), who had previously taken part in a study of brain development and psychopathology following VPT birth, completed an online modified version of the Coronavirus Health and Impact Survey (CRISIS). The emotional impact of the COVID-19 lockdown on the child and the parent, measured by the CRISIS, was studied in relation to pre-existing mental health, assessed with the parent-rated Strengths and Difficulties Questionnaire (SDQ), evaluated before the CRISIS completion (mean time gap 15 months). Linear regression model comparisons were conducted to study the effects of COVID-19-related stressors on children's and parents' behavior, relationships and mental health., Results: There were no significant group differences in pre-existing SDQ internalizing/externalizing symptoms, child's emotions or parent's emotions during the COVID-19 lockdown. However, higher pre-existing internalizing symptoms in VPT children were associated with greater lockdown-related emotional problems and worries (simple slope = 1.95, p  < 0.001), whereas this was not observed in term-born children., Conclusion: Our results suggest that VPT children with pre-existing internalizing problems may be more vulnerable to the negative impact of certain societal and familial stressors, such as social restrictions during the national COVID-19 lockdown periods. Further rigorous studies are therefore needed to assess the severity of increased risks for this particularly vulnerable group in the context of potentially stressful life changes and adjustments., 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., (© 2023 Sun, Hadaya, Leoni, Dazzan, Simonoff, Counsell, Edwards, Nosarti and Vanes.)

Corrosion poses safety and operational challenges in the oil and gas field, particularly in a sour environment. Corrosion inhibitors (CIs) are thus employed to protect the integrity of industrial assets. However, CIs have the potential to dramatically impair the effectiveness of other co-additives, such as kinetic hydrate inhibitors (KHIs). Here, we propose an acryloyl-based copolymer, previously used as a KHI, as an effective CI. The copolymer formulation provided a corrosion inhibition efficiency of up to 90% in a gas production environment, implying that it can reduce or even eliminate the need for an additional dedicated CI in the system. It also demonstrated a corrosion inhibition efficiency of up to 60% under field-simulated conditions for a wet sour crude processing environment. Molecular modeling suggests that the enhanced corrosion protection is imparted by the favorable interaction of the heteroatoms of the copolymer with the steel surface, potentially displacing adhered water molecules. All in all, we show that an acryloyl-based copolymer with dual functionalities can potentially overcome issues caused by incompatibilities in a sour environment, resulting in significant cost savings and operational ease., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Introduction: Compared to full-term (FT) born peers, children who were born very preterm (VPT; <32 weeks' gestation) are likely to display more cognitive and behavioral difficulties, including inattention, anxiety and socio-communication problems. In the published literature, such difficulties tend to be studied independently, thus failing to account for how different aspects of child development interact. The current study aimed to investigate children's cognitive and behavioral outcomes as interconnected, dynamically related facets of development that influence one another., Methods: Participants were 93 VPT and 55 FT children (median age 8.79 years). IQ was evaluated with the Wechsler Intelligence Scale for Children-4 th edition (WISC-IV), autism spectrum condition (ASC) traits with the social responsiveness scale-2 nd edition (SRS-2), behavioral and emotional problems with the strengths and difficulties questionnaire (SDQ), temperament with the temperament in middle childhood questionnaire (TMCQ) and executive function with the behavior rating inventory of executive functioning (BRIEF-2). Outcome measures were studied in VPT and FT children using Network Analysis, a method that graphically represents partial correlations between variables and yields information on each variable's propensity to form a bridge between other variables., Results: VPT and FT children exhibited marked topological differences. Bridges (i.e., the variables most connected to others) in the VPT group network were: conduct problems and difficulties with organizing and ordering their environment. In the FT group network, the most important bridges were: difficulties with initiating a task or activity and prosocial behaviors, and greater emotional problems, such as lower mood., Discussion: These findings highlight the importance of targeting different aspects of development to support VPT and FT children in person-based interventions., 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 © 2023 Leoni, Vanes, Hadaya, Kanel, Dazzan, Simonoff, Counsell, Happé, Edwards and Nosarti.)

Background: There is an urgent need to better understand the mechanisms underlying acute and long-term neurological symptoms after COVID-19. Neuropathological studies can contribute to a better understanding of some of these mechanisms., Methods: We conducted a detailed postmortem neuropathological analysis of 32 patients who died due to COVID-19 during 2020 and 2021 in Austria., Results: All cases showed diffuse white matter damage with a diffuse microglial activation of a variable severity, including one case of hemorrhagic leukoencephalopathy. Some cases revealed mild inflammatory changes, including olfactory neuritis (25%), nodular brainstem encephalitis (31%), and cranial nerve neuritis (6%), which were similar to those observed in non-COVID-19 severely ill patients. One previously immunosuppressed patient developed acute herpes simplex encephalitis. Acute vascular pathologies (acute infarcts 22%, vascular thrombosis 12%, diffuse hypoxic-ischemic brain damage 40%) and pre-existing small vessel diseases (34%) were frequent findings. Moreover, silent neurodegenerative pathologies in elderly persons were common (AD neuropathologic changes 32%, age-related neuronal and glial tau pathologies 22%, Lewy bodies 9%, argyrophilic grain disease 12.5%, TDP43 pathology 6%)., Conclusions: Our results support some previous neuropathological findings of apparently multifactorial and most likely indirect brain damage in the context of SARS-CoV-2 infection rather than virus-specific damage, and they are in line with the recent experimental data on SARS-CoV-2-related diffuse white matter damage, microglial activation, and cytokine release.

Purpose: In head and neck squamous cell carcinoma (HNSCC), HRAS mutation is a new actionable oncogene driver. We aimed to evaluate HRAS mutational variants, comutation profile, and survival outcomes of this molecularly defined population., Methods: We leveraged four deidentified patient data sets with HRAS -mutant HNSCC, MD Anderson Cancer Center, Kura Oncology, Inc trial, Foundation Medicine, and American Association for Cancer Research GENIE v.12. Patient demographic information and clinical courses were extracted, when available, in addition to HRAS mutation type and co-occurring mutations. Survival outcomes were analyzed (Kaplan-Meier method)., Results: Two hundred forty-nine patients with HRAS -mutant HNSCC were identified from the four data sets. Median age ranged from 55 to 65 years, with a higher frequency in male patients (64%); the majority of HRAS -mutant HNSCC occurred in human papillomavirus-negative HNSCC. HRAS mutation patterns were similar across data sets; G12S was the most common (29%). Treatment responses to tipifarnib were not codon-specific. Compared with wild-type, significantly co-occurring mutations with HRAS were Casp8 (Fisher's exact test, P < .00013), TERT ( P < .0085), and NOTCH1 ( P < .00013). Analysis of clinical courses from the MD Anderson Cancer Center and Kura Oncology, Inc data sets demonstrated poor clinical outcomes with a high rate of recurrence following primary definitive treatment (50%-67% relapse < 6 months) and short disease-free survival (4.0 months; 95% CI, 1.0 to 36.0) and overall survival (OS; 15.0 months; 95% CI, 6.0 to 52.0). Use of tipifarnib in this data set demonstrated improved OS (25.5 months; 95% CI, 18.0 to 48.0)., Conclusion: Oncogenic mutations in HRAS occur in 3%-4% of HNSCC, with G12S being the most frequent. Without targeted therapy, patients with HRAS -mutant HNSCC had poor clinic outcomes; observable trend toward improvement in OS has been noted in cohorts receiving treatments such as tipifarnib. The comutation pattern of HRAS -mutant in HNSCC is distinct, which may provide insight to future therapeutic combination strategies.

Lay Abstract: Eye Movement Desensitisation and Reprocessing (EMDR) is a psychological therapy that can help people process memories and distress about past events, so they have less impact on their daily lives. EMDR can be effective for treating symptoms of post-traumatic stress disorder, including nightmares and anxiety. Psychological therapies usually require adaptation so they are more accessible and effective for autistic people, but minimal research has focused on how best EMDR can be adapted. In this online survey study, we asked 103 EMDR therapists about barriers they think autistic people face when trying to have EMDR and what adaptations they use in their everyday practice. Four barriers were highlighted: client-related characteristics, therapist-related characteristics, differences in the therapeutic relationship and broader issues. Therapists identified a range of adaptations that can potentially be useful for autistic people, relating to being flexible, communicating clearly and having an awareness of individual differences. Many therapists emphasised the importance of not making assumptions about a person based on their autism diagnosis. Overall, the study findings suggest adaptations to EMDR are likely to be useful, but how relevant they are depends on each person.

Background: Emraclidine is a novel, brain-penetrant, highly selective M4 receptor positive allosteric modulator in development for the treatment of schizophrenia. We aimed to evaluate the safety and tolerability of multiple ascending doses of emraclidine in patients with schizophrenia., Methods: We conducted a two-part, randomised, phase 1b trial in the USA. Eligible participants were aged 18-50 years (part A) or 18-55 years (part B) with a primary diagnosis of schizophrenia per the Diagnostic and Statistical Manual of Mental Disorders 5th edition, as confirmed by the Mini International Neuropsychiatric Interview, and extrapyramidal symptom assessments indicating normal to mild symptoms at screening. Part A evaluated the safety and tolerability of emraclidine in five cohorts of participants with stable schizophrenia who received ascending oral doses of emraclidine 5-40 mg (40 mg was administered as 20 mg twice daily) or placebo at a single US site. Part B was a double-blind, randomised, placebo-controlled study that enrolled adults with acute schizophrenia across five US sites; participants were randomly assigned (1:1:1) to receive emraclidine 30 mg once daily, emraclidine 20 mg twice daily, or placebo for 6 weeks (doses established in part A). The primary endpoint was safety and tolerability, assessed in the safety population (participants who received at least one dose of emraclidine or placebo). This trial is now complete and is registered with ClinicalTrials.gov, NCT04136873., Findings: Between Sept 23, 2019, and Sept 17, 2020, 118 patients were assessed for eligibility and 49 were randomly assigned across five cohorts in part A. 44 participants completed the study, with 36 participants receiving emraclidine and eight receiving placebo. The two highest doses tested were selected for part B. Between Oct 12, 2020, and May 7, 2021, 148 patients were assessed for eligibility and 81 were randomly assigned to emraclidine 30 mg once daily (n=27), emraclidine 20 mg twice daily (n=27), or placebo (n=27) in part B. Incidence of adverse events (14 [52%] of 27 participants in the emraclidine 30 mg once daily group, 15 [56%] of 27 in the emraclidine 20 mg twice daily group, and 14 [52%] of 27 in the placebo group), clinical assessments, and weight changes were similar across groups. The most common adverse event was headache (15 [28%] of 54 participants in the emraclidine groups, seven [26%] of 27 in the placebo group). Modest, transient increases in blood pressure and heart rate in emraclidine groups observed at treatment initiation diminished over time and were not considered clinically meaningful by week 6., Interpretation: These data support further investigation of emraclidine as a once-daily treatment for schizophrenia without need for titration and with a potentially favourable side-effect profile., Funding: Cerevel Therapeutics., Competing Interests: Declaration of interests JHK reports consulting agreements with Aptinyx, Atai Life Sciences, AstraZeneca, Biogen Idec, Biomedisyn Corporation, Bionomics, Boehringer Ingelheim International, Cadent Therapeutics, Clexio Bioscience, COMPASS Pathways, Concert Pharmaceuticals, Eisai, Epiodyne, EpiVario, Greenwich Biosciences, Heptares Therapeutics, Janssen Research & Development, Jazz Pharmaceuticals, Lohocla Research Corporation, Novartis, Otsuka America Pharmaceutical, Perception Neuroscience Holdings, PsychoGenics, RBNC Therapeutics, Spring Care, Sunovion Pharmaceuticals, Taisho Pharmaceutical Holdings, Takeda Industries, Tempero Bio, and Terran Biosciences; serves on the scientific advisory boards of Biohaven Pharmaceuticals, BioXcel Therapeutics (Clinical Advisory Board), Cadent Therapeutics (Clinical Advisory Board), and Cerevel Therapeutics; holds consulting agreements with EpiVario, Eisai, Jazz Pharmaceuticals, Lohocla Research Corporation, Novartis, PsychoGenics, RBNC Therapeutics, Tempero Bio, and Terran Biosciences; serves on the Board of Directors for Freedom Biosciences and holds stock or stock options in Biohaven Pharmaceuticals, Sage Pharmaceuticals, Spring Care, Biohaven Pharmaceuticals Medical Sciences, EpiVario, RBNC Therapeutics, Terran Biosciences, and Tempero Bio; has received research support from AstraZeneca, Novartis, and Cerevel Therapeutics; and serves as Editor of Biological Psychiatry and is a named inventor on a number of patents and patent applications—most recently, US Provisional Patent Application 63/125,181, filed on Dec 14, 2020. JMK has been a consultant or adviser to or has received honoraria from Acadia, Alkermes, Allergan, Cerevel Therapeutics, IntraCellular Therapies, Janssen or Johnson & Johnson, Karuna, LB Pharma, Lundbeck, Lyndra, Medscape, Merck, Neurocrine, Otsuka, Reviva, Roche, Sumitomo Dainippon, Saladex, Sunovion, Takeda, and Teva; has received grant support from Janssen, Lundbeck, Otsuka, and Sunovion; and is a shareholder of LB Pharma and a shareholder in Vanguard Research Group. CUC has been a consultant or adviser to or has received honoraria from AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Axsome Therapeutics, Cerevel Therapeutics, Compass, Damitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen or Johnson & Johnson, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Segirus, Servier, SK Life Science, Sumitomo Dainippon, Sunovion, Supernus, Takeda, Teva, and Viatris; has provided expert testimony for Janssen and Otsuka; has served on a Data Safety Monitoring Board for Lundbeck, Rovi, Supernus, and Teva; has received grant support from Janssen and Takeda; and has received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, and LB Pharma. DPW reports grants and research support from AbbVie, Acadia, Alkermes, Allergan, Avanir, Biogen, Boehringer Ingelheim, Cerevel, Indivior, IntraCellular, Janssen, Johnson & Johnson Research and Development, Lundbeck, Lupin, Lyndra, Novartis, Noven, Otsuka, Pfizer, Roche, Sunovion, and Takeda; has been a consultant for Biogen, Boehringer Ingelheim, Janssen, Lyndra, and Otsuka; and served as principal investigator on this trial. ML, SD, SP, IC, PI, LF, SV, PP, RS, and JR are employees of Cerevel Therapeutics and might hold stock or stock options in the company., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Despite being vital in treating intensive-care patients with lung failure, especially COVID-19 patients, Veno-Venous Extra-Corporeal Membrane Oxygenation does not exploit its full potential, leaving ample room for improvement. The objective of this study is to determine the effect of cannula positioning and blood flow on the efficacy of Veno-Venous Extra-Corporeal Membrane Oxygenation, in particular in relationship with blood recirculation. We performed 98 computer simulations of blood flow and oxygen diffusion in a computerized-tomography-segmented right atrium and venae cavae for different positions of the returning and draining cannulae and ECMO flows of 3 L/min and [Formula: see text]. For each configuration we measured how effective Veno-Venous Extra-Corporeal Membrane Oxygenation is at delivering oxygen to the right ventricle and thus to the systemic circulation. The main finding is that VV-ECMO efficacy is largely affected by the ECMO flow (global peak blood saturation: [Formula: see text]; average inter-group saturation gain: 9 percentage points) but only scarcely by the positioning of the cannulae (mean saturation ± standard deviation for the 3 L/min case: [Formula: see text]; for the [Formula: see text] case: [Formula: see text]). An important secondary outcome is that recirculation, more intense with a higher ECMO flow, is less detrimental to the procedure than previously thought. The efficacy of current ECMO procedures is intrinsically limited and fine-tuning the positions of the cannulae, risking infections, offers very little gain. Setting a higher ECMO flow offers the biggest benefit despite mildly increasing blood recirculation., (© 2022. The Author(s).)

This study was aimed at developing a clinical risk score for cardiovascular autonomic neuropathy (CAN) for type 1 and type 2 diabetes. In a retrospective cross-sectional one-centre study in an unselected population, 115 participants with type 1 diabetes (age 41.1 ± 12.2 years) and 161 with type 2 diabetes (age 63.1 ± 8.9 years), well-characterized for clinical variables, underwent standard cardiovascular reflex tests (CARTs). Strength of associations of confirmed CAN (based on 2 abnormal CARTs) with clinical variables was used to build a CAN risk score. CAN risk score was based on resting heart rate, HbA1c, retinopathy, nephropathy, cardiovascular disease in both type 1 and type 2 diabetes, and on HDL cholesterol, systolic blood pressure, and smoking in type 1 diabetes or insulin treatment and physical activity in type 2 diabetes (range 0-10). In type 1 diabetes, CAN risk score showed an area under the ROC curve (AUC) of 0.890 ± 0.034, and at cut-off of 4 sensitivity of 88%, specificity of 74.4%, and negative predictive value (NPV) of 95.7% for confirmed CAN. In type 2 diabetes, CAN risk score showed an AUC of 0.830 ± 0.051 and at the cut-off of 4 sensitivity and specificity of 78.6% and 73.5%, respectively, and NPV of 97.3% for confirmed CAN. These newly developed CAN risk scores are accessible in clinical practice and, if confirmed in a validation study, they might identify asymptomatic individuals with diabetes at greater risk of CAN to be referred to CARTs, thus limiting the burden of a universal screening., (© 2022 Peripheral Nerve Society.)

Background: COVID-19 can affect the persistence of symptoms and work ability (WA), hence the fitness to work of healthcare workers (HCW). We describe the effects of COVID-19 in hospitalized HCWs of a large Hospital in Lombardy and their implications on WA and fitness to work., Methods: Fifty-six HCWs of Fatebenefratelli-Sacco Hospital have been hospitalized for COVID-19 since March 2020. Clinical and fitness-to-work data were acquired from Occupational Health Surveillance Program. A structured questionnaire was administered to 53/56 HCWs 18 months after infection to investigate Long-COVID symptoms and WA., Results: Symptoms most reported at recovery (rhino-pharyngeal swab-NPS-negative) were exertional dyspnea (86.8%), asthenia (86.8%), arthro-myalgia (71.7%), sleep disorders (64.2%), resting dyspnea (62.3%), cough (56.6%). 69.6% underwent evaluation at out-patient clinics experienced in Long-COVID. Ten months after recovery, symptoms related to physical well-being decreased while memory and anxiety/depression were more persistent. At recovery, the WA score decreased from 10 to 8, and then an improvement from 8 to 9 was noted during the survey. At the return-to-work examination, fit-to-work judgements with restrictions increased from 31.4% to 58.7%; then, a slight decrease in the rate of judgements with restrictions was observed at the survey's time., Conclusion: Post-COVID-19 symptoms can persist for a long time and could impact WA and fitness-to-work of HCW. Adequate health surveillance protocols should guarantee the health protection of HCW with persistent disorders after COVID-19.

Background: The role of catheter tip shape on the safety and efficacy of radiofrequency (RF) ablation has been overlooked, although differences have been observed in clinical and research fields., Objective: The purpose of this study was to analyze the role of electrode tip shape in RF ablation using a computational model., Methods: We simulated 108 RF ablations through a realistic 3-dimensional computational model considering 2 clinically used, open-irrigated catheters (spherical and cylindrical tip), varying contact force (CF), blood flow, and irrigation. Lesions are defined by the 50°C isotherm contour and evaluated by means of width, depth, depth at maximum width, and volume. Ablations are deemed as safe, critical (tissue temperature >90°C), and pop (tissue temperature >100°C)., Results: Tissue-electrode contact is less for the spherical tip at low CF but the relationship is inverted at high CF. At low CF, the cylindrical tip generates deeper and wider lesions and a 4-fold larger volume. With increasing CF, the lesions generated by the spherical tip become comparable to those generated by the cylindrical tip. The 2 tips feature different safety profiles: CF and power are the main determinants of pops for the spherical tip; power is the main factor for the cylindrical tip; and CF has a marginal effect. The cylindrical tip is more prone to pop generation at higher powers. Saline irrigation and blood flow effect do not depend on tip shape., Conclusion: Tip shape determines the performance of ablation catheters and has a major impact on their safety profile. The cylindrical tip shows more predictable behavior in a wide range of CF values., (© 2022 Heart Rhythm Society. Published by Elsevier Inc.)

Directional cell locomotion requires symmetry breaking between the front and rear of the cell. In some cells, symmetry breaking manifests itself in a directional flow of actin from the front to the rear of the cell. Many cells, especially in physiological 3D matrices, do not show such coherent actin dynamics and present seemingly competing protrusion/retraction dynamics at their front and back. How symmetry breaking manifests itself for such cells is therefore elusive. We take inspiration from the scallop theorem proposed by Purcell for micro-swimmers in Newtonian fluids: self-propelled objects undergoing persistent motion at low Reynolds number must follow a cycle of shape changes that breaks temporal symmetry. We report similar observations for cells crawling in 3D. We quantified cell motion using a combination of 3D live cell imaging, visualization of the matrix displacement, and a minimal model with multipolar expansion. We show that our cells embedded in a 3D matrix form myosin-driven force dipoles at both sides of the nucleus, that locally and periodically pinch the matrix. The existence of a phase shift between the two dipoles is required for directed cell motion which manifests itself as cycles with finite area in the dipole-quadrupole diagram, a formal equivalence to the Purcell cycle. We confirm this mechanism by triggering local dipolar contractions with a laser. This leads to directed motion. Our study reveals that these cells control their motility by synchronizing dipolar forces distributed at front and back. This result opens new strategies to externally control cell motion as well as for the design of micro-crawlers., Competing Interests: AG, ML, JC, TG, ML, HD, AO, SH, DR No competing interests declared, PS Reviewing editor, eLife, (© 2022, Godeau, Leoni et al.)

Background: To date, the usage of Galaxy, an open-source bioinformatics platform, has been reported primarily in research. We report 5 years' experience (2015 to 2020) with Galaxy in our hospital, as part of the "Assistance Publique-Hôpitaux de Paris" (AP-HP), to demonstrate its suitability for high-throughput sequencing (HTS) data analysis in a clinical laboratory setting., Methods: Our Galaxy instance has been running since July 2015 and is used daily to study inherited diseases, cancer, and microbiology. For the molecular diagnosis of hereditary diseases, 6970 patients were analyzed with Galaxy (corresponding to a total of 7029 analyses)., Results: Using Galaxy, the time to process a batch of 23 samples-equivalent to a targeted DNA sequencing MiSeq run-from raw data to an annotated variant call file was generally less than 2 h for panels between 1 and 500 kb. Over 5 years, we only restarted the server twice for hardware maintenance and did not experience any significant troubles, demonstrating the robustness of our Galaxy installation in conjunction with HTCondor as a job scheduler and a PostgreSQL database. The quality of our targeted exome sequencing method was externally evaluated annually by the European Molecular Genetics Quality Network (EMQN). Sensitivity was mean (SD)% 99 (2)% for single nucleotide variants and 93 (9)% for small insertion-deletions., Conclusion: Our experience with Galaxy demonstrates it to be a suitable platform for HTS data analysis with vast potential to benefit patient care in a clinical laboratory setting., (© American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Medication regimens for Parkinson's disease (PD) may change as the disease progresses, symptoms fluctuate, or medication-related adverse events occur. This study evaluated treatment trends by observation year for patients initially receiving monotherapy with levodopa and a peripheral dopa decarboxylase inhibitor (PDDI)., Methods: In this retrospective chart review, therapy changes were evaluated for patients across the US diagnosed with PD on or before 6/30/2014 who initially received levodopa-PDDI monotherapy. Index date was the first clinic visit. Post-index was any time between the first 31 days after index and study end (6/30/2019). Index Hoehn-Yahr (H-Y) score and medication changes were also analyzed by index low (<400 mg/day) or high (≥400 mg/day) levodopa doses in the levodopa-PDDI combinations., Results: In the levodopa-PDDI cohort (n = 95), there were 0.39 dose escalations, 0.16 dose reductions, 0.12 discontinuations, 0.19 therapy switches, and 0.24 add-ons per patient per year during the study. Most dose escalations or add-ons occurred within the first 6 months post-index. Of those who ever stopped levodopa-PDDI (n = 34), 31 (91%) restarted within the study period. Most (83%) patients who restarted levodopa-PDDI did so in the same year as stopping treatment. Index low dose users were associated with lower H-Y scores, were more inclined to escalate their dose, and were less inclined to reduce their dose in the first 2 years of treatment than index high dose users., Conclusions: Prescribers and patients tend to experiment with levodopa-PDDI treatment. Although many patients appeared to stop levodopa-PDDI after an initial course of treatment, most subsequently restarted treatment., Competing Interests: P. Navaratnam and H. Friedman are employees of DataMed Solutions, LLC, which provides contracted services to Cerevel Therapeutics. S. Arcona, M. Leoni, and R. Sasane are employees of Cerevel Therapeutics., (© 2022 The Author(s).)

Background: Parkinson's disease (PD) management seeks to balance the benefits and harms of current medications and evolves as the disease progresses. The natural history of PD and associated patterns of treatment change were analyzed to identify unmet needs in treatment of PD symptoms., Methods: Medical charts of patients from clinics across the US diagnosed on or before June 30th, 2014 were retrospectively reviewed. Index date was the first clinic visit, and the post-index period was through study end (June 30th, 2019). Outcomes included the frequency of therapy changes in the post-index period, reasons for therapy change, and adverse events (AE)., Results: Patients (n = 203) at index were receiving levodopa-peripheral dopa decarboxylase inhibitor (PDDI) monotherapy (47%), dopaminergic agonist (DA) monotherapy (15%), monoamine oxidase B inhibitor (MAOBI) monotherapy (14%), or combination therapies. The percentage of patients in Hoehn-Yahr disease Stage 1-2 was 52% at index and 20% by the end of the study. Frequencies of motor, non-motor, and neuropsychiatric symptoms increased during the enrollment. Levodopa-PDDI monotherapy and levodopa-PDDI + MAOBI had the lowest rates of therapy changes. Symptom relapse was the most common reason for dose escalation, add-on, and dose reduction, whereas AEs were the most common reason for discontinuation and switching. Dose escalation, add-on, and forward switch were most likely to occur in the first 6 months of treatment., Conclusions: Therapy changes during the study period reflected the challenging and evolving management of PD as the disease progresses. New or add-on symptomatic treatments are needed that are well-tolerated and able to control PD symptoms., 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., (© 2021 Published by Elsevier Ltd.)

Background: High-power short-duration (HPSD) recently emerged as a new approach to radiofrequency (RF) catheter ablation. However, basic and clinical data supporting its effectiveness and safety is still scarce. Objective: We aim to characterize HPSD with an advanced virtual model, able to assess lesion dimensions and complications in multiple conditions and compare it to standard protocols. Methods: We evaluate, on both atrium and ventricle, three HPSD protocols (70 W/8 s, 80 W/6 s, and 90 W/4 s) through a realistic 3D computational model of power-controlled RF ablation, varying catheter tip design (spherical/cylindrical), contact force (CF), blood flow, and saline irrigation. Lesions are defined by the 50°C isotherm contour. Ablations are deemed safe or complicated by pop (tissue temperature >97°C) or charring (blood temperature >80°C). We compared HPSD with standards protocols (30-40 W/30 s). We analyzed the effect of a second HPSD application. Results: We simulated 432 applications. Most (79%) associated a complication, especially in the atrium. The three HPSD protocols performed similarly in the atrium, while 90 W/4 s appeared the safest in the ventricle. Low irrigation rate led frequently to charring (72%). High-power short-duration lesions were 40-60% shallower and smaller in volume compared to standards, although featuring similar width. A second HPSD application increased lesions to a size comparable to standards. Conclusion: High-power short-duration lesions are smaller in volume and more superficial than standards but comparable in width, which can be advantageous in the atrium. A second application can produce lesions similar to standards in a shorter time. Despite its narrow safety margin, HPSD seems a valuable new clinical approach., Competing Interests: JG served as consultant for Biosense Webster, Boston Scientific and Abbott, received speaker fees from Boston Scientific and Abbott, and received a research grant from Abbott. 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 © 2021 Petras, Moreno Weidmann, Leoni, Gerardo-Giorda and Guerra.)

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with a strong genetic basis. Recent studies have suggested that its aetiology is also influenced by environmental factors. Some of the most examined environmental factors are obstetric complications. However, the results are inconsistent., Methods: We aimed to explore the association between obstetric complications and autism in a population-based twin sample using the Obstetric Enquiry Scale (OES), a scale that measures the presence or absence of pre-, peri- and neonatal factors. Additionally, we report the meta-analytic results for obstetrical factors reported in previously published sibling studies., Results: Our study included 115 cases pairs and 62 controls pairs and showed that children with autism and their unaffected co-twins present significantly more obstetric complications than controls (ASD vs. controls β 1.26, CI 95% 1.11-1.40 p < .001; unaffected co-twin vs. controls β 1.20, 95% CI 1.07-1.36 p < .003). However, we did not find statistically significant differences between children with ASD and their unaffected co-twins (β .96, 95% CI 0.85-1.09, p 0.55). Meta-analysis demonstrated that maternal hypertension (RR 1.35, CI 95% 1.23-1.48), uterine bleeding (RR 1.20 CI 95% 1.01-1.42) and exposure to antibiotic during pregnancy (1.11 CI 95% 1.00-1.22) increase risk of ASD., Conclusions: This study confirms that children with ASD and their unaffected twins show more obstetric complications than controls. However, these complications do not distinguish between ASD twins and their unaffected co-twins. In addition, the meta-analysis showed little influence of birth factors on ASD which suggests a shared familial liability for both obstetric complications and autism, rather than a causal association., (© 2021 Association for Child and Adolescent Mental Health.)

Current therapies for recurrent and metastatic SCC are associated with poor outcomes, and options for later lines of treatment are limited. Insights into potential therapeutic targets, as well as mechanisms of resistance to available therapies, have begun to be elucidated, creating the basis for exploration of combination approaches to drive better patient outcomes. Tipifarnib, a farnesyl transferase inhibitor (FTI), is a small molecule drug that has demonstrated encouraging clinical activity in a genetically-defined subset of head and neck squamous cell carcinoma (HNSCC)-specifically, tumors that express a mutation in the HRAS protooncogene. More recently, bioinformatic analyses and results from patient-derived xenograft modeling indicate that HRAS pathway dependency may extend to a broader subpopulation of SCCs beyond HRAS mutants in the context of combination with agents such as cisplatin, cetuximab, or alpelisib. In addition, tipifarnib can also inactivate additional farnesylated proteins implicated in resistance to approved therapies, including immunotherapies, through a variety of distinct mechanisms, suggesting that tipifarnib could serve as an anchor for combination regimens in SCCs and other tumor types.

Introduction: Most Parkinson's disease (PD) medication adherence studies have focused on patients with commercial or Medicare health insurance coverage. However, less is known regarding medication treatment patterns within the Medicaid population., Methods: This retrospective cohort study utilized 2011-2019 administrative healthcare claims from 7 state Medicaid programs. We compared newly diagnosed patients with PD started on either levodopa or a dopamine agonist (DA). Baseline comorbidities were compared. Outcomes were assessed during a 12-month post-index observation period, and included total medication days, proportion of days covered (PDC), adherence status, persistence to initiating PD medication, and time to non-persistence of initiating PD medication., Results: Our study sample of 805 Medicaid patients had an average age of 54.1 years, with 52.0% being female. Levodopa was the predominant PD medication at initiation (75.4%). Roughly half of patients had a baseline depressive disorder and nearly 40% had an anxiety disorder. Levodopa patients had a significantly higher PDC compared to DA patients (0.621 vs. 0.546, p = 0.007). An adjusted logistic regression model showed no significant difference in the number of adherent patients between the two groups (p = 0.058). An adjusted Cox proportional hazards model controlling for demographic and baseline variables showed a 26% lower risk of non-persistence for levodopa patients versus DA patients (HR 0.740, CI 0.597-0.917, p = 0.006)., Conclusions: Adherence and persistence rates were suboptimal following initiation of either levodopa or DA medication for patients with PD in Medicaid programs, though rates were better for those initiated on levodopa., 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., (© 2021 The Authors.)

In sporadic Creutzfeldt-Jakob disease, molecular subtypes are neuropathologically well identified by the lesioning profile and the immunohistochemical PrP d deposition pattern in the grey matter (histotypes). While astrocytic PrP pathology has been reported in variant CJD and some less frequent histotypes (e.g., MV2K), oligodendroglial pathology has been rarely addressed. We assessed a series of sCJD cases with the aim to identify particular histotypes that could be more prone to harbor oligodendroglial PrP d . Particularly, the MM2C phenotype, in both its more "pure" and its mixed MM1+2C or MV2K+2C forms, showed more frequent oligodendroglial PrP pathology in the underlying white matter than the more common MM1/MV1 and VV2 histotypes, and was more abundant in patients with a longer disease duration. We concluded that the MM2C strain was particularly prone to accumulate PrP d in white matter oligodendrocytes.

Arachnoiditis ossificans is a rare disease, characterized by intradural ossifications, representing the end stage of chronic adhesive arachnoiditis. We describe the case of a 55-year-old patient who developed symptoms of a cauda equina syndrome after an open microdiscectomy at the L5 to S1 segment. A subsequent exploratory surgery revealed an intradural concentric bony structure with partly incorporated and partly adherent nerve roots. A partial removal of the intradural calcifications was performed. Postoperatively, the patient showed neurological improvement. The removed intradural calcifications were submitted for histological analysis and proved to be normal bone tissue, notably containing yellow bone marrow. To our knowledge, the presence of yellow bone marrow within bony cavities of arachnoiditis ossificans has not previously been reported., Competing Interests: Conflict of Interest All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or nonfinancial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

To date, metformin remains the first-line oral glucose-lowering drug used for the treatment of type 2 diabetes thanks to its well-established long-term safety and efficacy profile. Indeed, metformin is the most widely used oral insulin-sensitizing agent, being prescribed to more than 100 million people worldwide, including patients with prediabetes, insulin resistance, and polycystic ovary syndrome. However, over the last decades several observational studies and meta-analyses have reported a significant association between long-term metformin therapy and an increased prevalence of vitamin B12 deficiency. Of note, evidence suggests that long-term and high-dose metformin therapy impairs vitamin B12 status. Vitamin B12 (also referred to as cobalamin) is a water-soluble vitamin that is mainly obtained from animal-sourced foods. At the cellular level, vitamin B12 acts as a cofactor for enzymes that play a critical role in DNA synthesis and neuroprotection. Thus, vitamin B12 deficiency can lead to a number of clinical consequences that include hematologic abnormalities ( e.g. , megaloblastic anemia and formation of hypersegmented neutrophils), progressive axonal demyelination and peripheral neuropathy. Nevertheless, no definite guidelines are currently available for vitamin B12 deficiency screening in patients on metformin therapy, and vitamin B12 deficiency remains frequently unrecognized in such individuals. Therefore, in this "field of vision" article we propose a list of criteria for a cost-effective vitamin B12 deficiency screening in metformin-treated patients, which could serve as a practical guide for identifying individuals at high risk for this condition. Moreover, we discuss additional relevant topics related to this field, including: (1) The lack of consensus about the exact definition of vitamin B12 deficiency; (2) The definition of reliable biomarkers of vitamin B12 status; (3) Causes of vitamin B12 deficiency other than metformin therapy that should be identified promptly in metformin-treated patients for a proper differential diagnosis; and (4) Potential pathophysiological mechanisms underlying metformin-induced vitamin B12 deficiency. Finally, we briefly review basic concepts related to vitamin B12 supplementation for the treatment of vitamin B12 deficiency, particularly when this condition is induced by metformin., Competing Interests: Conflict-of-interest statement: The authors declare that they have no competing interests., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Purpose: Mutations in the HRAS (m HRAS ) proto-oncogene occur in 4%-8% of patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Tipifarnib is a farnesyltransferase inhibitor that disrupts HRAS function. We evaluated the efficacy of tipifarnib in patients with R/M m HRAS HNSCC., Methods: We enrolled 30 patients with R/M HNSCC in a single-arm, open-label phase II trial of tipifarnib for m HRAS malignancies; one additional patient was treated on an expanded access program. After an ad hoc analysis of the first 16 patients with HNSCC with m HRAS variant allele frequency (VAF) data, enrollment was limited to those with a m HRAS VAF of ≥ 20% (high VAF). The primary end point was objective response rate. Secondary end points included assessing safety and tolerability. Patients received tipifarnib 600 or 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles., Results: Of the 22 patients with HNSCC with high VAF, 20 were evaluable for response at the time of data cutoff. Objective response rate for evaluable patients with high-VAF HNSCC was 55% (95% CI, 31.5 to 76.9). Median progression-free survival on tipifarnib was 5.6 months (95% CI, 3.6 to 16.4) versus 3.6 months (95% CI, 1.3 to 5.2) on last prior therapy. Median overall survival was 15.4 months (95% CI, 7.0 to 29.7). The most frequent treatment-emergent adverse events among the 30 patients with HNSCC were anemia (37%) and lymphopenia (13%)., Conclusion: Tipifarnib demonstrated encouraging efficacy in patients with R/M HNSCC with HRAS mutations for whom limited therapeutic options exist (NCT02383927)., Competing Interests: Alan L. HoConsulting or Advisory Role: Bristol-Myers Squibb, Eisai, Genzyme, Merck, Novartis, Sun Pharma, Regeneron, TRM Oncology, Ayala Pharmaceuticals, AstraZeneca, Sanofi, CureVac, Prelude Therapeutics, Kura Oncology, McGivney Global Advisors, Rgenta, Exelixis, Genentech/Roche, AffyimmuneSpeakers' Bureau: Medscape, Omniprex America, NovartisResearch Funding: Lilly, Genentech/Roche, AstraZeneca, Bayer, Kura Oncology, Kolltan Pharmaceuticals, Eisai, Bristol-Myers Squibb, Astellas Pharma, Novartis, Merck, Pfizer, Ayala Pharmaceuticals, Allos Therapeutics, Daiichi Sankyo, Elevar TherapeuticsTravel, Accommodations, Expenses: Janssen Oncology, Merck, Kura Oncology, Ignyta, Ayala Pharmaceuticals, Klus Pharma Irene BranaConsulting or Advisory Role: Merck Sharp and Dohme, Rakuten Medical, Sanofi, Achilles Therapeutics, eTheRNA Immunotherapies, Cancer Expert NowSpeakers' Bureau: Bristol-Myers Squibb, Merck Serono, RocheResearch Funding: AstraZeneca, Bristol-Myers Squibb, Celgene, Gliknik, GlaxoSmithKline, Janssen Oncology, Kura Oncology, Merck Sharp and Dohme, Novartis, Orion Pharma GmbH, Pfizer, Roche, Shattuck Labs, Nanobiotix, Seattle GeneticsTravel, Accommodations, Expenses: AstraZeneca Spain, Merck Serono Robert HaddadEmployment: Dana-Farber Cancer InstituteLeadership: NCCNConsulting or Advisory Role: Celgene, Merck, Eisai, Bristol-Myers Squibb, AstraZeneca, Pfizer, Loxo, Genentech, Immunomic Therapeutics, GlaxoSmithKline, Gilead Sciences, Vaccinex, EMD Serono, BioNTech AG, Achilles TherapeuticsResearch Funding: Boehringer Ingelheim, Merck, Bristol-Myers Squibb, Celgene, AstraZeneca, VentiRx, Genentech, Pfizer, Kura OncologyPatents, Royalties, Other Intellectual Property: UpToDateOther Relationship: Nanobiotix, ISA Pharmaceuticals Jessica BaumanConsulting or Advisory Role: Pfizer, Bayer, AstraZeneca, Kura OncologyResearch Funding: Bristol-Myers SquibbTravel, Accommodations, Expenses: Trident Pharmaceuticals Sjoukje OostingResearch Funding: Celldex Deborah J. WongConsulting or Advisory Role: Bristol-Myers Squibb, Genentech/Roche, Sanofi/Aventis, Blueprint MedicinesResearch Funding: BioMed Valley Discoveries, Merck Serono, Merck Sharp and Dohme, ARMO BioSciences, AstraZeneca/MedImmune, Kura Oncology, Regeneron, Genentech/Roche, Bristol-Myers Squibb, FSTAR, Pfizer, Astellas Pharma, Enzychem Lifesciences, Lilly, Elevar Therapeutics Myung-Ju AhnHonoraria: AstraZeneca, Lilly, MSD, TAKEDAConsulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Lilly, MSD, TAKEDA, Alpha pharmaceutical Caroline EvenConsulting or Advisory Role: Innate Pharma, Bristol-Myers Squibb, MSD Oncology, Merck Serono Jerome FayetteHonoraria: AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, Merck Serono, Innate Pharma, RocheConsulting or Advisory Role: AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, Merck Serono, Innate Pharma, RocheResearch Funding: Bristol-Myers SquibbTravel, Accommodations, Expenses: Bristol-Myers Squibb, AstraZeneca, Merck Sharp and Dohme Kevin HarringtonHonoraria: Merck Sharp and Dohme, Amgen, Merck Serono, AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Replimune, Oncolys BioPharma, MersanaConsulting or Advisory Role: Merck Sharp and Dohme, Merck Serono, AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, ReplimuneSpeakers' Bureau: Merck Sharp and Dohme, Merck Serono, Bristol-Myers SquibbResearch Funding: AstraZeneca, Merck Sharp and Dohme, Boehringer Ingelheim, Replimune Sung-Bae KimHonoraria: DAEHWA Pharmaceutical, ISU ABXISConsulting or Advisory Role: Lilly, AstraZeneca, DAEHWA Pharmaceutical, ISU AbxisResearch Funding: Novartis, Dongkook Pharma, Genzyme Lisa LicitraConsulting or Advisory Role: Eisai, Boehringer Ingelheim, AstraZeneca, SOBI, Novartis, Bayer, MSD, Merck Serono, Roche, Bristol-Myers Squibb, Incyte, Doxapharma, GlaxoSmithKline, Nanobiotix, Debiopharm Group, Amgen, IpsenResearch Funding: AstraZeneca, Novartis, Roche, MSD, Eisai, Merck Serono, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Exelixis, IRX Therapeutics, Medpace, Pfizer, Debiopharm Group, RocheTravel, Accommodations, Expenses: Merck Serono, Bayer, Bristol-Myers Squibb, MSD, Eisai, AstraZeneca Nabil F. SabaHonoraria: Merck, Lilly, Pfizer, Bristol-Myers Squibb, CUE Biopharma, GlaxoSmithKline, Aduro Biotech, Kura Oncology, Genentech/RocheConsulting or Advisory Role: Pfizer, Bristol-Myers Squibb, Merck, Lilly, Bluprint, BiontechResearch Funding: Bristol-Myers Squibb, ExelixisTravel, Accommodations, Expenses: Bristol-Myers Squibb, Merck, Pfizer, Lilly, GlaxoSmithKline, Genentech/Roche, Bluprint Francis WordenHonoraria: Merck Sharp & Dohme, Eisai, Bristol-Myers Squibb, Bayer, RegeneronConsulting or Advisory Role: Merck, Loxo, Bristol-Myers Squibb, Eisai, Bayer, CUE Biopharma, Rakuten Medical, RegeneronResearch Funding: Pfizer, Merck, Eisai, Bristol-Myers Squibb, Loxo, Oragenics, LillyTravel, Accommodations, Expenses: Merck Sharp & Dohme, Bayer Binaifer BalsaraEmployment: Kura OncologyStock and Other Ownership Interests: Kura Oncology Mollie LeoniEmployment: Kura Oncology, Kyowa Kirin InternationalStock and Other Ownership Interests: Kura OncologyTravel, Accommodations, Expenses: Kura Oncology, Kyowa Kirin International Catherine ScholzEmployment: Kura Oncology, H3 BiomedicineStock and Other Ownership Interests: Kura OncologyPatents, Royalties, Other Intellectual Property: Methods of Treating Cancer Patients With Farnesyltransferase Inhibitors (FTI treatment of H-Ras mutant cancers), co-Inventor (014168-0011-999), Methods of Treating Cancer With Farnesyltransferase Inhibitors (FTI treatment of a CXCL12-expressing cancer), co-Inventor (014168-0021-999), Methods of Treating Cancer Patients With Farnesyltransferase Inhibitors (FTI treatment of Casitas B cell lymphoma [CBL] mutant cancers), co-Inventor (014168-0024-228), Therapies For Squamous Cell Carcinomas (FTI treatment of SCC with high frequencies of H-Ras mutant allele frequency), co-Inventor (014168-0051-888)Travel, Accommodations, Expenses: Kura OncologyNo other potential conflicts of interest were reported.

Objectives: Describe cases of female genital mutilation (FGM) presenting to consultant paediatricians and sexual assault referral centres (SARCs), including demographics, medical symptoms, examination findings and outcome., Design: The well-established epidemiological surveillance study performed through the British Paediatric Surveillance Unit included FGM on the monthly returns., Setting: All consultant paediatricians and relevant SARC leads across the UK and Ireland., Patients: Under 16 years old with FGM., Interventions: Data on cases from November 2015 to November 2017 and 12 months later meeting the case definition of FGM., Main Outcome Measures: Returns included 146 cases, 103 (71%) had confirmed FGM and 43 (29%) did not meet the case definition. There were none from Northern Ireland., Results: The mean reported age was 3 years. Using the WHO classification of FGM, 58% (n=60) had either type 1 or type 2, 8% (n=8) had type 3 and 21% (n=22) had type 4. 13% (n=13) of the cases were not classified and none had piercings or labiaplasty. The majority, 70% had FGM performed in Africa with others from Europe, Middle East and South-East Asia. There were few physical and mental health symptoms. Only one case resulted in a successful prosecution., Conclusions: There were low numbers of children presenting with FGM and in the 2 years there was only one prosecution. The findings may be consistent with attitude changes in FGM practising communities and those at risk should be protected and supported by culturally competent national policies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Glioblastoma (GBM) is an utterly devastating cerebral neoplasm and current therapies only marginally improve patients' overall survival (OS). The PI3K/AKT/mTOR pathway participates in gliomagenesis through regulation of cell growth and proliferation. Since it is an upstream regulator of the rate-limiting translation initiation step of protein synthesis, controlled by eukaryotic initiation factors (eIFs), we aimed for a profound basic characterization of 17 eIFs to identify potential novel therapeutic targets for gliomas. Therefore, we retrospectively analyzed expressions of mTOR-related proteins and eIFs in human astrocytoma samples (WHO grades I-IV) and compared them to non-neoplastic cortical control brain tissue (CCBT) using immunoblot analyses and immunohistochemistry. We examined mRNA expression using qRT-PCR and additionally performed in silico analyses to observe the influence of eIFs on patients' survival. Protein and mRNA expressions of eIF3B, eIF3I, eIF4A1, eIF4H, eIF5 and eIF6 were significantly increased in high grade gliomas compared to CCBT and partially in low grade gliomas. However, short OS was only associated with high eIF3I gene expression in low grade gliomas, but not in GBM. In GBM, high eIF4H gene expression significantly correlated with shorter patient survival. In conclusion, we identified eIF3I and eIF4H as the most promising targets for future therapy for glioma patients.

Background: Sézary syndrome (SS) and mycosis fungoides (MF), 2 types of cutaneous T-cell lymphoma, cause significant morbidity and adversely affect patients' quality of life (QoL). The present study assessed the QoL measurement changes in patients receiving mogamulizumab versus vorinostat., Patients and Methods: A multicenter phase III trial was conducted of patients with stage IB-IV MF/SS with ≥ 1 failed systemic therapy. The QoL measures included Skindex-29 and the Functional Assessment of Cancer Therapy-General. The symptoms, function, and QoL subdomains were longitudinally modeled using mixed models with prespecified covariates. Meaningful change thresholds (MCTs) were defined using distribution-based methods. The categorical changes by group over time and the time to clinically meaningful worsening were analyzed., Results: Of the 372 randomized patients, mogamulizumab demonstrated improvement in Skindex-29 symptoms (cycles 3, 5, and 7; P < .05) and functional (cycles 3 and 5; P < .05) scales. A significantly greater proportion of mogamulizumab-treated patients improved by MCTs or more from baseline in the Skindex-29 symptoms domain (cycles 3, 5, 7, and 11) and functioning domain (cycle 5). Significant differences in the Functional Assessment of Cancer Therapy-General physical well-being (cycles 1, 3, and 5; P < .05) were observed in favor of mogamulizumab and a greater proportion of patients had declined by MCTs or more at cycles 1, 3, 5, and 7 with vorinostat treatment. The median time to symptom worsening using Skindex-29 was 27.4 months for mogamulizumab versus 6.6 months for vorinostat. In the patients with SS, the time to worsening favored mogamulizumab (P < .005) for all Skindex-29 domains. The time to worsening was similar for the 2 MF treatment arms., Conclusion: The symptoms, function, and overall QoL of patients with MF/SS favored mogamulizumab over vorinostat across all time points. Patients with the greatest symptom burden and functional impairment derived the most QoL benefit from mogamulizumab., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The origin of diamonds in ureilite meteorites is a timely topic in planetary geology as recent studies have proposed their formation at static pressures >20 GPa in a large planetary body, like diamonds formed deep within Earth's mantle. We investigated fragments of three diamond-bearing ureilites (two from the Almahata Sitta polymict ureilite and one from the NWA 7983 main group ureilite). In NWA 7983 we found an intimate association of large monocrystalline diamonds (up to at least 100 µm), nanodiamonds, nanographite, and nanometric grains of metallic iron, cohenite, troilite, and likely schreibersite. The diamonds show a striking texture pseudomorphing inferred original graphite laths. The silicates in NWA 7983 record a high degree of shock metamorphism. The coexistence of large monocrystalline diamonds and nanodiamonds in a highly shocked ureilite can be explained by catalyzed transformation from graphite during an impact shock event characterized by peak pressures possibly as low as 15 GPa for relatively long duration (on the order of 4 to 5 s). The formation of "large" (as opposed to nano) diamond crystals could have been enhanced by the catalytic effect of metallic Fe-Ni-C liquid coexisting with graphite during this shock event. We found no evidence that formation of micrometer(s)-sized diamonds or associated Fe-S-P phases in ureilites require high static pressures and long growth times, which makes it unlikely that any of the diamonds in ureilites formed in bodies as large as Mars or Mercury., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

We examine the interplay of motility and information exchange in a model of run-and-tumble active particles where the particle's motility is encoded as a bit of information that can be exchanged upon contact according to the rules of AND and OR logic gates in a circuit. Motile AND particles become non-motile upon contact with a non-motile particle. Conversely, motile OR particles remain motile upon collision with their non-motile counterparts. AND particles that have become non-motile additionally "reawaken", i.e., recover their motility, at a fixed rate μ, as in the SIS (susceptible, infected, susceptible) model of epidemic spreading, where an infected agent can become healthy again, but keeps no memory of the recent infection, hence it is susceptible to a renewed infection. For μ = 0, both AND and OR particles relax irreversibly to absorbing states of all non-motile or all motile particles, respectively. The relaxation kinetics is, however, faster for OR particles that remain active throughout the process. At finite μ, the AND dynamics is controlled by the interplay between reawakening and collision rates. The system evolves to a state of all motile particles (an absorbing state in the language of absorbing phase transitions) for μ > μc and to a mixed state with coexisting motile and non-motile particles (an active state in the language of absorbing phase transitions) for μ < μc. The final state exhibits a rich structure controlled by motility-induced aggregation. Our work can be relevant to biochemical signaling in motile bacteria, the spreading of epidemics and of social consensus, as well as light-controlled organization of active colloids.

This article summarizes the literature on prevalence and establishment of severe problem behavior in individuals with intellectual and developmental disabilities, empirical support for applied behavior analysis, and evidence-based behavioral assessment and treatment procedures. Early intervention and prevention approaches and the role of the pediatrician with regard to surveillance, early intervention, and coordination of care are discussed., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The UK national incidence of nutritional rickets is unknown. We aimed to describe the incidence, presentation and clinical management of children under 16 years with nutritional rickets in the UK presenting to secondary care., Methods: Prospective data were collected monthly between March 2015 and March 2017 from 3500 consultant paediatricians using British Paediatric Surveillance Unit methodology. Clinicians completed online clinical questionnaires for cases fitting the surveillance case definition., Results: 125 cases met the case definition, an annual incidence of 0.48 (95% CI 0.37 to 0.62) per 100 000 children under 16 years. 116 children were under 5 years (annual incidence of 1.39 (95% CI 1.05 to 1.81) per 100 000. Boys (70%) were significantly more affected than girls (30%) (OR 2.17, 95% CI 1.25 to 3.78). The majority were of Black (43%) or South Asian (38%) ethnicity. 77.6% of children were not taking vitamin D supplements despite being eligible. Complications included delayed gross motor development (26.4%), fractures (9.6%), hypocalcaemic seizures (8%) and dilated cardiomyopathy (3%). Two children died (1.6%). In eight cases, rickets was confirmed radiologically and biochemically [raised serum alkaline phosphatase (ALP) and parathyroid hormone (PTH) levels ] but were excluded from the incidence analysis for not meeting the case definition of 25-hydroxyvitamin D of <25 nmol/L., Conclusion: The incidence of nutritional rickets in the UK is lower than expected. Serious complications and unexpected deaths, particularly in Black and South Asian children under 5 years, occurred. Both vitamin D deficiency and dietary calcium deficiency are role players in pathogenesis. Uptake of vitamin D supplementation remains low., Competing Interests: Competing interests: MB receives funding from the National Institute for Health Research under the Collaborations for Leadership in Applied Health Research and Care programme for North West London. ZM has received honoraria from Internis Pharmaceuticals Ltd., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

For some years, the term "project of life" has become widely used in the field of neurodevelopmental disorders, and, at the same time, it has begun to make its way in many social and health planning documents. However, beyond its relatively widespread use, this term does not yet possess an adequate and shared frame of the main underlying decision-making processes. In particular, there is a need to identify the crucial questions for orienting the choice of goals within the adolescent transition, which represents the complex hinge between childhood and adulthood. Moreover, adulthood, which is often completely devoid of culturally and socially shared references, is still critical precisely because of the lack of future direction prompts usually represented by the stages of development. In this case, the themes of quality of life functioning as a guiding compass appear pertinent and much more relevant. The present contribution is, therefore, an attempt to present, in a unitary manner, the decision-making processes and questions at the basis of a construct of "project of life" shared within the scientific and associative communities.

Supporting individuals with NDD is extremely demanding, with significant exposure to critical contexts and events, and painful ongoing experiences. Stress and burnout condition is a main concern with growing interest in research, despite the lack of consensus on theoretical explanatory models and modification standards.The paper provides an up-to-date review of risk factors and involved processes, and presents evidence-based procedures and protocols to implement effective preventive actions addressing both organizational and individual factors. The aim is to offer a global understanding of the subject and offer examples of practical plans to increase the impact on the quality of life of clients and staff members.