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Many studies have demonstrated the impact of intestinal microbiota on normal brain development. Moreover, the gut microbiota (GM) is impacted by multiple endogenous and environmental factors that may promote gut dysbiosis (GD). An increasing number of studies are investigating the possible role of the GD in the development of neurological and behavioral disorders. For autism spectrum disorders (ASD), specific intestinal bacterial signatures have been identified, knowing that gastrointestinal symptoms are frequently found in ASD. In this review, the peri and post-natal factors modulating the GM are described and the specific gut bacterial signature of ASD children is detailed. Through bidirectional communication between the GM and the brain, several mechanisms are involved in the development of ASD, such as cytokine-mediated neuroinflammation and decreased production of neuroprotective factors such as short-chain fatty acids by the GM. Imbalance of certain neurotransmitters such as serotonin or gamma-aminobutyric acid could also play a role in these gut-brain interactions. Some studies show that this GD in ASD is partly reversible by treatment with pre- and probiotics, or fecal microbiota transplantation with promising results. However, certain limitations have been raised, in particular concerning the short duration of treatment, the small sample sizes and the diversity of protocols. The development of standardized therapeutics acting on GD in large cohort could rescue the gastrointestinal symptoms and behavioral impairments, as well as patient management.

Many enveloped viruses bud from the plasma membrane that is tightly associated with a dense and thick actin cortex. This actin network represents a significant challenge for membrane deformation and scission, and how it is remodeled during the late steps of the viral cycle is largely unknown. Using superresolution microscopy, we show that HIV-1 buds in areas of the plasma membrane with low cortical F-actin levels. We find that the cellular oxidoreductase MICAL1 locally depolymerizes actin at budding sites to promote HIV-1 budding and release. Upon MICAL1 depletion, F-actin abnormally remains at viral budding sites, incompletely budded viruses accumulate at the plasma membrane and viral release is impaired. Remarkably, normal viral release can be restored in MICAL1-depleted cells by inhibiting Arp2/3-dependent branched actin networks. Mechanistically, we find that MICAL1 directly disassembles branched-actin networks and controls the timely recruitment of the Endosomal Sorting Complexes Required for Transport scission machinery during viral budding. In addition, the MICAL1 activator Rab35 is recruited at budding sites, functions in the same pathway as MICAL1, and is also required for viral release. This work reveals a role for oxidoreduction in triggering local actin depolymerization to control HIV-1 budding, a mechanism that may be widely used by other viruses. The debranching activity of MICAL1 could be involved beyond viral budding in various other cellular functions requiring local plasma membrane deformation., Competing Interests: Competing interests statement:The authors declare no competing interest.

Avian influenza active surveillance was conducted in Bangladesh from January 2022 to November 2023 in live-poultry markets (LPMs) and Tanguar Haor wetlands. The predominant viruses circulating in LPMs were low pathogenic avian influenza (LPAI) A(H9N2) and clade 2.3.2.1a highly pathogenic avian influenza (HPAI) A(H5N1) viruses. Non-H9N2 LPAIs were found at Tanguar Haor and at a lower prevalence in LPMs. Starting from June 2023, we detected novel genotypes of clade 2.3.4.4b A(H5N1) viruses from ducks in LPMs. The HA, NA, and M genes of these viruses are related to those of 2020 European clade 2.3.4.4b H5N1 viruses such as A/Eurasian wigeon/Netherlands/1/2020 (Netherlands/1). However, analyses of the other five gene segments' sequences identified three distinct genotypes (BD-G2, BD-G3, and BD-G4). BD-G2 viruses were closely related to the clade 2.3.4.4b H5N1 viruses that have been detected in Japan and nearby regions since November 2022. BD-G3 viruses were reassortants, with gene segments from other Eurasian LPAI viruses. BD-G4 viruses were similar to BD-G2 viruses, but their NS gene was accrued from contemporary Bangladeshi clade 2.3.2.1a A(H5N1) viruses. The ability of any of the clade 2.3.4.4b viruses to displace the long-entrenched 2.3.2.1a A(H5N1) viruses in Bangladesh is unknown.

Engineering on the nanoscale often involves optimizing performance by designing and creating new types of nanostructured materials. Multifunctional nanoparticles can be formed by combining elements that carry fundamentally different properties. The elements can be chosen based on the desired functionality, and by combining, e.g. , magnetic, and catalytic elements, it is possible to self-assemble nanoparticles into catalytically active magnetic nanochains. However, mixing and assembling nanoparticles in a controlled way is challenging, and it is not obvious how the intermixing of the elements influences the properties of the individual nanoparticles. In this work, we synthesize and assemble intermixed magnetic and catalytic Cobalt-Palladium (Co-Pd) nanoparticles into multifunctional nanochains. The magnetic behavior is explored by studying the magnetic field-directed self-assembly of the nanoparticles into elongated nanochains. The catalytic properties are determined by measuring CO oxidation at elevated temperatures. Our results confirm that the magnetic and catalytic functionalities of the individual elements are retained when intermixed, which implies the potential to create nanochains with dual functionality that can be assembled in a controlled way.

Clinical guidelines for infant feeding among people with HIV in the U.S. were updated in 2023 to encourage providers to utilize a shared decision-making approach that includes breastfeeding/chestfeeding (B/CF) when appropriate. Despite this historic shift in policy to support B/CF as an infant feeding choice for people living with HIV, birthing people living with HIV who desire B/CF face many barriers, and there is currently a gap in research identifying best practices for facilitating safe and satisfying B/CF in this population. Lactation support specialists have been identified as a positive factor in successful B/CF and a key resource for supporting B/CF for people with HIV. Recent research has shown that telelactation, the provision of care from a qualified lactation consultant or counselor using telehealth, can increase access to quality lactation support in underserved areas and can effectively improve outcomes, such as increased rates of exclusive breastfeeding and decreased early breastfeeding cessation while maintaining high levels of patient satisfaction. Telelactation is an innovative approach to improving access to B/CF among birthing people living with HIV, but little is currently known about what kind of support lactation support specialists and other perinatal HIV care providers may need to meet the clinical and psychosocial needs of B/CF people living with HIV and their infants. More research is needed to identify possible gaps in knowledge and other needs within the lactation support community so that infant feeding specialists are adequately equipped with evidence-based strategies to support the unique needs of parents living with HIV.

This study reports that the well-known Co(III) precursor Co(η 5 -Cp*)I 2 (CO) ( 1 ) is an effective precatalyst for dehydrocoupling reactions of phosphines. Reaction monitoring by NMR, complemented by ESI-MS and EPR, suggests that Co(III) complexes containing secondary and primary phosphine ligands play an important role in this catalysis but that redox chemistry is also facile for these complexes, resulting in paramagnetic species. Representative examples of the mono(phosphine) complexes Co(η 5 -Cp*)I 2 (PR 2 H) ( 2 ) and Co(η 5 -Cp*)I 2 (PRH 2 ) ( 4 ) and bis(phosphine) complexes [Co(η 5 -Cp*)I(PR 2 H) 2 ] I ( 3 ) have been prepared. The characterization of these complexes through structural, computational, spectroscopic, and electrochemical analysis is reported and serves as a foundation for considering their mechanistic significance in the observed catalytic dehydrocoupling chemistry.

Background: Ganglioneuroblastoma intermixed (GNBi) and ganglioneuroma (GN) represent benign variants of peripheral neuroblastic tumours. While historically surgical resection was recommended, watchful active observation has become the accepted management for a subset of patients., Objectives: To review clinical features, biology, natural history and management of a retrospective UK CCLG study cohort of GN and GNBi, and compare outcomes of patients treated with surgical resection or watchful active observation., Methods: Retrospective review of histologically confirmed non-metastatic GN and GNBi diagnosed between 1990 and 2020., Results: A total of 259 patients were identified (163 GN, 93 GNBi, median age 62 months). In all 201 (78%) had initial surgery and 58 (22%) were observed. Overall survival was 98%. Twenty-one of 58 observed (36%) required subsequent surgery due to progressive tumour growth (52%). Gross total resection (GTR) was achieved in 79% of patients with a 19% complication rate. GTR was obtained in a similar proportion of patients having initial surgery (65%) and delayed surgery (76%). Patients obtaining GTR were more likely to have complete symptom(s) control (43% vs. 24%). In 45 cases (39%), surgical pathology was different from pathology at biopsy, and in 14 (12%) the pathology changed from GN/GNBi to neuroblastoma/GNB nodular., Conclusion: Watchful active observation can be a safe approach, with surgical resection reserved for symptomatic patients. However, a small proportion of patients in the observation group had their diagnosis revised to malignant at surgery. Careful assessment of surgical risk and expected benefits, after considering an initial period of observation, will allow clinicians to make optimal decisions for patients and their families., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: Group consultations (GCs) in healthcare have been shown to improve clinical outcomes with greater efficiency. This project aimed to develop a more efficient musculoskeletal (MSK) physiotherapy-led GC approach for common lower limb problems. This was to help manage an anticipated increase in demand while maintaining high patient satisfaction and ensuring clinical effectiveness., Methods: Three 'Plan-Do-Study-Act' (PDSA) cycles were undertaken to test out the new approach of virtual group consultations (VGCs) and face-to-face GCs with MSK patients. These two approaches were tested and refined on four common lower limb conditions: patellofemoral pain syndrome, Achilles tendinopathy, plantar fasciopathy and knee osteoarthritis. We measured the number of patients seen, staff time, patients' experience and patient outcome scores., Results: Each patient used 45 min of physiotherapy time via the traditional one-to-one physiotherapy consultation approach, this was reduced to 22 min in the VGCs and 12 min for the face-to-face GCs. We found a significant increase in EQ-5D scores (PDSA 1: +0.19, p=0.004 and PDSA 2: +0.17, p=0.002) and the Visual Analogue Score for Pain (PDSA 1: -1.95, p=0.001 and PDSA 2: -2.6, p=0.007) from the first to the second virtual GC sessions., Conclusion: GCs were shown to be an efficient way of providing physiotherapy to patients with lower limb conditions. Feedback from patients attending GCs has shown a good level of effectiveness and patient satisfaction. This alternative way to review and treat patients has yielded a reduction in physiotherapist contact time per patient, improving the efficiency of our MSK service. We did not compare these groups to the one-to-one face-to-face consultations, therefore whether they are better, is unknown., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Viral infection triggers a rapid and effective cellular response primarily mediated by interferon β (IFNβ), which induces an antiviral state through complex signaling cascades. To maintain a robust antiviral response while preventing excessive activation, the induction of IFNβ and downstream signaling are tightly regulated. Members of the tripartite-motif (TRIM) family of E3 ubiquitin (Ub) ligases play crucial roles in modulating these processes. In this study, we demonstrate that TRIM65 interacts with interferon regulatory factor 3 (IRF3), a key transcription factor downstream of multiple innate immune signaling pathways, to regulate type-I IFN production. Specifically, TRIM65 activation enables interaction of TRIM65 BBCC domain with the IAD domain of IRF3. This interaction increases K6-linked ubiquitination of IRF3, enhancing IRF3 recruitment to chromatin and subsequent binding to the IFNβ promoter. This process boosts the expression of IFNβ and interferon-stimulated genes (ISGs), thereby strengthening the control of viral infection., Competing Interests: Declaration of interests The A.G.-S. laboratory has received research support from GSK, Pfizer, Senhwa Biosciences, Kenall Manufacturing, Blade Therapeutics, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, Applied Biological Laboratories, and Merck, outside of the reported work. A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Castlevax, Amovir, Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Pagoda, Accurius, Esperovax, Applied Biological Laboratories, Pharmamar, CureLab Oncology, CureLab Veterinary, Synairgen, Paratus, Pfizer, and Prosetta, outside of the reported work. A.G.-S. has been an invited speaker in meeting events organized by Seqirus, Janssen, Abbott, and Astrazeneca. A.G.-S. is inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer, owned by the Icahn School of Medicine at Mount Sinai, New York, outside of the reported work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The significance of thyroid hormones (THs) in beige adipocyte thermogenesis remains incompletely understood. We previously reported that THs directly regulate the expression of zinc-finger protein 423 (ZFP423), an anti-thermogenic factor, in adipose tissue. This study investigates the interaction between THs and adrenergic signaling in regulating thermogenic capacity and activation of beige adipocytes formed in response to Zfp423 deletion. We demonstrate that THs are indispensable for uncoupling protein 1 (UCP1)-dependent thermogenesis, leading to increased energy expenditure in mice with adipocyte-specific Zfp423 knockout. Targeted activation of the thyroid receptor isoform TRβ, which plays a central role in the inguinal depot, is sufficient to enhance energy expenditure in hypothyroid Zfp423iAKO mice. Mechanistically, THs and ZFP423 pathways cooperate to regulate early B cell factor 2 (EBF2)-mediated activation of the Ucp1 gene. RNA sequencing (RNA-seq) analysis of human adipose tissue samples supports the relevance of this regulatory network for human adipose tissue plasticity., Competing Interests: Declaration of interests M.B. received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Lilly, Novo Nordisk, Novartis, and Sanofi, which had no role in the conducting of this study., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The acute and chronic pancreatitis (CP) can lead to severe complications like walled-off necrosis, large symptomatic pseudocyst or multiorgan failure. The treatment of these complications is multivariate and can differ from conservative, symptomatic treatment or minimal-invasive, endoscopic transgastral stenting to transgastral necrosectomy., Objectives: This study aims to analyse the clinical course for patients that develop local complications of severe pancreatitis., Design: This is a retrospective observational single-centre study on 46 patients with severe pancreatitis., Methods: In this retrospective single-centre study, 46 out of 474 inpatients from January 2014 to December 2020, who were treated because of an acute or CP, developed acute pancreatitis complications and could be included. We analysed and compared the clinical course of different treatments (lumen apposing metal stents, transgastral double pigtail stent, endoscopic retrograde cholangiopancreatography, operation, conservative treatment) and different complications (walled-off necrosis (WON), pancreatic pseudocyst (PPC))., Results: Forty-six patients developed an acute complication due to severe pancreatitis. Twenty-seven patients developed a WON, while 19 patients suffered from PPC. 48% of the whole cohort had an alcoholic aetiology of pancreatitis. 78% were treated with antibiotics, 48% suffered from infected pancreatitis and 22% needed intensive care treatment. WON patients more often had a longer hospitalization of more than 21 days. PPC patients were correlated with an alcoholic aetiology, whereas WON patients were inversely correlated with an alcoholic aetiology. Increased lactate dehydrogenase, lipase, and C-reactive protein levels as well as leucocyte count could be associated with a higher probability to exhibit a WON instead of another local complication. The mortality rate was low with 7% in our study., Conclusion: WON and PPC differ in certain patients and laboratory characteristics such as aetiology, elevated laboratory values, antibiotic treatment or the duration of hospitalization. Invasive treatment is not required in all severe pancreatitis cases., (© The Author(s), 2024.)

Background: Immune tolerance induction (ITI) is the gold standard for inhibitor eradication to restore the clinical efficacy of factor replacement therapy in haemophilia. However, as ITI often requires frequent administration over extended periods, it can be considered burdensome for patients and healthcare resources. Therefore, there is a need to optimise ITI treatment, particularly in patients who failed previous ITI attempts., Objectives: The ReITIrate study aimed to prospectively evaluate rescue ITI with efmoroctocog alfa, an extended half-life recombinant FVIII Fc fusion protein (herein rFVIIIFc), within a limited 60-week timeframe in patients with severe haemophilia A and inhibitors who failed previous ITI attempts., Design: ReITIrate was a phase IV, open-label, single-arm, interventional, multicentre study., Methods: Primary endpoint was ITI success (negative titre, <0.6 BU/mL; incremental recovery >66%; elimination half-life ⩾7 hours) within 60 weeks. Exploratory immunophenotype analyses were performed to characterise anti-drug antibodies (ADA) and cellular immune responses., Results: Nine of 16 enrolled subjects completed the ITI period during ReITIrate, of which one subject attained all 3 ITI success criteria after 46 weeks with no relapse. Two subjects achieved partial success (one subject met 2/3 success criteria; one met all criteria, but not simultaneously, with inhibitor recurrence). One additional subject (ITI failure) achieved negative inhibitor titre. Across these four subjects, median (range) time to negative titre was 19 (11-60) weeks. No new safety concerns were identified. IgG4 was the major contributor to the ADA IgG response. Subjects with partial/complete ITI success had fewer IgG subclasses involved than those who failed/withdrew. Immunophenotyping indicated an increase in regulatory T-cells (CD4 + CD25 + CD127 low ), supporting the ability to perform sensitive blood sampling to identify immune tolerance markers., Conclusion: This study demonstrates that ITI with rFVIIIFc given within a limited timeframe has potential benefit in a difficult-to-treat inhibitor haemophilia population who failed previous ITI attempts., Trial Registration: NCT03103542., (© The Author(s), 2024.)

The tire-rubber-derived ozonation product of N -(1,3-dimethylbutyl)- N '-phenyl- p -phenylenediamine (6PPD), N -(1,3-dimethylbutyl)- N '-phenyl- p -phenylenediamine-quinone (6PPD-Q), was recently discovered to cause acute mortality in coho salmon ( Oncorhynchus kisutch ). para -Phenylenediamines (PPDs) with variable side chains distinct from 6PPD have been identified as potential replacement antioxidants, but their toxicities remain unclear under environmentally relevant ozone conditions. We herein tested the multiphase gas-surface ozone reactivity of four select PPDs [6PPD, N -isopropyl- N '-phenyl- p -phenylenediamine (IPPD), N , N '-diphenyl- p -phenylenediamine (DPPD), and N -phenyl- N '-cyclohexyl- p -phenylenediamine (CPPD)] and evaluated the toxicity of their reaction mixtures in coho salmon, rainbow trout ( Oncorhynchus mykiss ), and fathead minnow ( Pimephales promelas ). 6PPD and IPPD were found to rapidly react with ozone, while no significant multiphase ozone reactivity was observed for DPPD or CPPD. The viability of coho salmon CSE-119 cells was strongly affected by the ozonolysis products of 6PPD but not by those of the other three PPDs. Acute mortality was only observed in juvenile rainbow trout that were exposed to oxidized 6PPD, suggesting a common mechanism of toxic action in the two salmonid fish species. This study reports the structurally selective ozone reactivity of PPDs and the unique toxicity of 6PPD ozonolysis mixtures, which demonstrates that other PPDs are potential alternative antioxidants.

The human MRGPRD protein is a member of the Mas-related G protein-coupled receptors (MRGPRs) that is involved in the sensing of pain, itch, and other inflammatory stimuli. As with other MRGPRs, MRGPRD is a relatively understudied receptor with few known agonists. The most potent small-molecule agonist of MRGPRD reported so far is β-alanine, with an affinity in the micromole range, which largely restricts its functional study. Here, we report two MRGPRD agonists, EP-2825 and EP-3945, that are approximately 100-fold more potent than β-alanine and determine the structures of MRGPRD-Gq in complex with EP-2825 and EP-3945, respectively. The structures reveal distinct agonist binding modes of MRGPRD and large conformational plasticity of the orthosteric pocket. Collectively, the discovery of high-affinity MRGPRD agonists and their distinct binding modes will facilitate the functional study and the structure-based design of ligands targeting this understudied receptor., Competing Interests: Declaration of interests A pending patent application has been filed by Escient Pharmaceuticals that includes compounds EP-2825 and EP-3945. B.L.R. is on the scientific advisory board of Escient Pharmaceuticals., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Hormones are known to be involved in life-history trade-offs as systemic signals that establish functional links among traits and regulate key behavioural and physiological transitions between states in organisms. Although major functions of many steroid hormones such as testosterone are conserved among vertebrates, circulating concentrations vary widely both within and across species, and the degree to which observed hormone concentrations mediate life-history responses to environmental variation is less understood. In this study, we investigated how faecal testosterone metabolite (FTM) concentrations varied with extrinsic and intrinsic factors. To do so, we took advantage of a 6-year period of longitudinal sampling of FTM, indicators of stress and oxidative status in a semi-captive population of Asian elephants ( n  = 3163 samples from 173 individuals) in Myanmar. We determined how the variation in FTM is associated with age, sex, origin (captive-born or wild-caught), seasonality of the environment, individual stress level [measured by faecal glucocorticoid metabolite (FGM) and heterophil to lymphocyte ratio (H/L)] and oxidative status (reactive oxygen metabolite concentrations and superoxide dismutase activity). We reported that FTM increased with age from juvenile to adulthood for both sexes, with higher FTM concentrations in males than females. Moreover, elephants showed significantly higher FTM concentrations during the hot season and monsoon than in the cold season. However, for the physiological indicators, we found contrasting results. While FTM concentrations were strongly positively correlated with FGM concentrations, FTM concentrations were not related to H/L ratios. Finally, we found no relationship between FTM and the oxidative status of individuals. Our study provides new insights on the factors associated with variation in testosterone concentrations-a key hormone for reproduction and fitness of individuals-in Asian elephants living in their natural environment, which has relevance for effective conservation measures of this endangered species., Competing Interests: The authors have no conflicts of interest to declare., (© The Author(s) 2024. Published by Oxford University Press and the Society for Experimental Biology.)

BRAF p.V600E exon 15 hotspot mutation can identify a molecular subgroup of metastatic colorectal cancer (mCRC) patients exhibiting poor prognosis under the conventional chemotherapy regimen. Recently, the chemotherapy-free combination of encorafenib and cetuximab has been approved as the standard of care for previously treated BRAF p.V600E mCRC patients, and genomic testing for BRAF mutations at the time of mCRC diagnosis is currently recommended. In clinical practice, BRAF mutation testing strategies are dramatically impacted by a lack of harmonization and standardization, both in the pre-analytical and analytical phases, which can result in BRAF-mutated patients not receiving the most appropriate therapy at recurrence. This paper proposes nine statements providing practical and concise advice on BRAF mutation testing in CRC, derived from collegial discussion and analysis of a multidisciplinary team of experts, including referral Italian oncologists and pathologists. The statements overview pivotal aspects implied in the detection, treatment and management of BRAF-mutated patients and have been drafted to represent a valuable tool for healthcare professionals committed to mCRC patient management. In addition, they represent a platform for implementing diagnostic-therapeutic workflows that can adapt to the variability of local resources while respecting the high-quality standards required by modern precision oncology., Competing Interests: Declaration of Competing Interest FB received personal honoraria as invited speaker from Eli-Lilly, MSD, EISAI, Bristol Myers Squibb, AstraZeneca, Pierre Fabre; participation in advisory board for Servier, AAA Novartis. CC reported the following: advisory board or consultant role with Astra Zeneca, Merck Serono, MSD, Nordic Pharma, Roche, Pierre Fabre, Takeda, Tempus; invited speaker with compensation for Amgen, Bayer, Merck Serono, MSD, Pierre Fabre Servier, Takeda; Research grants by Amgen, Merck, Pierre Fabre, Roche, Seagen (Pfizer), Servier, Tempus. MF reported the following: advisory board or consultant role with Amgen, Astellas, Astra Zeneca, BMS, Sanofi, Diapath, Eli Lilly, GSK, Incyte, IQvia, Janssen Pharma, MSD, Novartis, Pierre Fabre, Roche; Research Funding (To Institution): Astellas, Diaceutics, Roche. FG reported the following: ADVISORY BOARDS: - MSD; GSK; Beigene; LECTURE FEES: Pierre Fabre; MSD; GSK; AAA; Novartis; Servier; Astellas; Incyte; BMS; AstraZeneca; BeiGene; Daiichi-Sankyo. EGR, outside the submitted work, has received advisory fees, honoraria, travel accommodation/expenses, grants and/or non-financial support from AstraZeneca, Exact Sciences, GSK, Illumina, MSD, Novartis, Roche, Sophia Genetics and Thermo Fisher Scientific; receipt of honoraria or consultation fees for speaker, consultancy or advisory roles: Amgen, Bayer, Eisai, Merck Serono, Pierre Fabre, Roche, Servier, Incyte, ESMO, MSD, Takeda; travel grant: AstraZeneca, Pierre Fabre,Bayer. RI reports consulting or advisory role for Pierre-Fabre and Bayer. TPL state no conflict of interest and have received no payment in the preparation of this manuscript. TPL reports receipt of honoraria or consultation fees for speaker, consultancy or advisory roles: Bayer, Pierre Fabre, Servier, Takeda. SL reports: consulting or Advisory Role from Amgen, Astellas, Astra Zeneca, Bayer Bristol-Myers Squibb, Daiichi-Sankyo, GSK, Incyte, Lilly, Merck Serono, MSD, Servier, Takeda, Rottapharm, Beigene; speakers' Bureau: Amgen, Astra Zeneca, Bristol-Myers Squibb, Incyte, GSK, Lilly, Merck Serono, MSD, Pierre-Fabre, Roche, Servier; Research Funding (To Institution): Amgen, Astellas, Astra Zeneca, Bayer, Bristol-Myers Squibb, Daichii Sankyo, Hutchinson, Incyte, Merck Serono, Mirati, MSD, Pfizer, Roche, Servier. UM has served as consultant and/or speaker bureau for Boehringer Ingelheim, Roche, MSD, Amgen, Thermo Fisher Scientifics, Eli Lilly, Diatech, GSK, Merck, AstraZeneca, Menarini Steamline, outside the current work. EM reported receiving honoraria or consultation fees for speaker, consultancy or advisory roles from Amgen, Bayer, Eisai, Merck Serono, Pierre Fabre, Roche, Servier, Incyte, ESMO, MSD, Takeda; travel grant: AstraZeneca, Pierre Fabre, Bayer. NN reports: Personal financial interests (speaker’s fee and/or advisory boards): MSD, Bayer, Biocartis, Illumina, Incyte, Roche, BMS, MERCK, Thermofisher, Astrazeneca, Eli Lilly, Novartis, Servier; Institutional financial interests (financial support to research projects): MERCK, Thermofisher, QIAGEN, Roche, Astrazeneca, Biocartis, Illumina; Non-financial interests: President, International Quality Network for Pathology (IQN Path); Past President, Italian Cancer Society (SIC); Scientific Director, IRST “Dino Amadori”, Forlì. PP received personal fees from MSD, Pierre-Fabre, Servier, Astellas, Incyte, AstraZeneca, GSK, Pharmacogenetics, BeiGene, Bristol-Myers Squibb, Lilly. AP reported consulting or advisory role for Daiichi, Beigene, Pierre-Fabre, Merck, Amgen, Bayer, Servier. FP reported receiving institutional research grants from BMS, Incyte, Agenus, Amgen, Lilly and AstraZeneca, and personal fees from BMS, MSD, Amgen, Merck-Serono, Pierre-Fabre, Servier, Bayer, Takeda, Astellas, Johnson&Johnson, Rottapharm, Ipsen, AstraZeneca, GSK, Daiichi-Sankyo, Seagen/Pfizer, Beigene. LS is currently supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) under My First Grant (MFAG) No. MFAG27367. LS reports consulting or advisory role for Pierre-Fabre, AstraZeneca, Bayer, SERVIER, Merck, Amgen, GSK, Incyte, Leopharma, MSD, Takeda. VA, FP reports no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Frailty is characterized by reduced physiologic reserve and vulnerability to adverse events in the presence of a stressor such as surgery. We prospectively implemented a preoperative frailty screening and optimization pathway for vascular surgery patients and assessed its impact on postoperative outcomes., Methods: As part of an ongoing quality improvement initiative, surgical frailty was assessed prospectively in all patients undergoing inpatient surgery using the Risk Analysis Index (RAI). Baseline data were collected from May to July 2022. Frail patients (RAI score ≥ 37) were referred to an anesthesia optimization clinic, nutrition consultation, and case management evaluation in the intervention phase (August 2022 to July 2023). Primary outcomes were postoperative hospital length of stay, 30-day readmission, and 30-day mortality. Secondary outcomes included ICU admission, ICU length of stay, discharge disposition, and non-home discharge. Two-way analyses compared frail vs non-frail patients and pre- vs post-intervention groups using Student t-test or Wilcoxon rank sum test for continuous variables and chi-squared or Fisher's exact test for categorical outcomes., Results: Of all patients scheduled for elective inpatient vascular surgery procedures at a single institution (N=225), 216 completed frailty screening [mean age 72 years, 68.5% male, 54.6% white, mean RAI 28.9, 18.5% frail]. Of these, 15 had surgeries cancelled, and 201 ultimately underwent surgery with 36 (17.9%) identified as frail. Overall, frail patients had significantly longer ICU (median [IQR] 4.0 [2.5, 13.5] vs 2.0 [1, 4] days, P=.001) and hospital length of stay (2.45 [1.51, 5.67] vs 1.23 [1.0, 2.10] days, P=.001), higher non-home discharge (30.6% vs 4.2%, P<.0001), and higher 30-day readmission (22.2% vs 6.7%, P=.009) compared to non-frail patients. Comparing pre- and post-intervention groups, 30-day readmission for the overall cohort declined significantly (22.2% to 7.5%, P=.03). Amongst frail patients, there was a trend to reduced hospital length of stay (4.73 to 2.14 days), non-home discharge (57.1% vs 24.1%), and 30-day readmission (42.9% to 17.2%); however, these did not reach statistical significance. Overall, 30-day mortality was 1.5% with all 3 deaths (2 frail, 1 non-frail) occurring post-intervention (0% pre vs 1.7% post, P=1.0)., Conclusions: Successful implementation of a preoperative frailty screening and optimization pathway for patients undergoing elective vascular surgery led to a significant decrease in overall 30-day readmission and a trend toward reduced hospital length of stay, non-home discharge, and 30-day readmission for frail patients. Further expansion to all surgical clinics has the potential to improve quality metrics for the healthcare system., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: Spinal cord stimulation (SCS) and dorsal root ganglion stimulation (DRGS) have individually shown efficacy in relieving pain in patients with persistent spinal pain syndrome after spinal surgery (PSPS-T2). Combining SCS and DRGS simultaneously, along with Burst stimulation programming, may enhance the responder rate of patients with PSPS-T2., Material and Methods: This study aimed to compare the pain relief (≥50%) responder rates in SCS, DRGS, and SCS+DGRS (DUAL) through a three-month randomized cross-over trial in patients with PSPS-T2. After the cross-over period, stimulation programming was switched to Burst. Secondary objectives included evaluating the clinical efficacy at three-, four-, six-, and 12-month follow-ups, assessing pain intensity, area of pain, area of paresthesia coverage, quality of life, functional disability, psychologic distress, medication intake, and the Multidimensional Clinical Response Index (MCRI)., Results: The responder rate of pain relief was similar in SCS, DRGS, and DUAL (60%, p = 0.84) at the end of the cross-over period, increasing to 80% with the ability to switch between stimulation possibilities. Burst programming did not provide additional pain relief at the four-month follow-up (p = 0.99). Clinical outcomes significantly improved until 12-month follow-up compared with baseline. Considering a clinically significant increase of 1.05 of the MCRI, all patients were responders at three-, four-, and six- month follow-up, and 80% were responders at 12 months compared with baseline., Conclusions: The full option to stimulate different neural structures, separately or simultaneously, led to improved responder rates, allowing patients to personalize treatment. A multidimensional assessment is essential to reveal the full potential benefits of neuromodulation in patients with chronic pain., Competing Interests: Conflict of Interest Philippe Rigoard reports financial support provided by Quantel Medical and grants and speaker fees from Quantel Medical, Medtronic, Abbott, and Boston Scientific. Maarten Moens reports speaker fees from Medtronic and Nevro. Sam Eldabe reports consulting agreements with Mainstay Medical and Medtronic, institutional research grants from Medtronic, and other from Abbott. The remaining authors reported no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background of Study: Crack cocaine use in Ireland began to emerge as a significant problem in the early 2000s, with prevalence increasing from 2016 onwards. Services such as harm reduction, treatment/rehabilitation, primary healthcare and social services are available to crack cocaine users in Ireland. However, research addressing specific barriers to accessing these services remains limited. Internationally, while research on healthcare access barriers for crack cocaine users exists, it predominantly focuses on user perspectives. This paper uses a dual-perspective approach to investigate access challenges from both service user and service provider viewpoints, promoting a more patient-centred, holistic approach to service provision., Methodology: The study is qualitative and used semi-structured interviews and a focus group to obtain study data. Levesque's conceptual framework for healthcare access underpins this study. Data were analysed using thematic analysis., Results: The study highlighted barriers to healthcare access such as the inadequacy of services to support those with dual diagnosis. However, an advancement has been made through the establishment of specialised dual diagnosis teams and community dual diagnosis services in Ireland. Stigma from health care providers further hindered people from seeking help, highlighting the significance of ongoing efforts in Ireland to address stigma. Systemic factors such as distrust in services, stringent requirements and insufficient knowledge of user needs hamper timely access to care, underlining the need for more adaptive responses., Conclusion: The study underlines the need for a tailored approach to enhancing access to health care for crack cocaine users in Ireland. Facilitating collaboration among health care providers, fostering partnerships with educational institutions/communities, and implementing policy changes are essential in creating a supportive environment that promotes help-seeking in Ireland., Competing Interests: Declarations. Ethics approval and consent to participate: Ethical approval was obtained from the University of Limerick Hospital group ethics committee and all methods were carried out under relevant guidelines and regulations. Also, informed consent was obtained from all subjects and/or their legal guardian(s). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Competing Interests: Competing interests: The authors declare no competing interests.

Thromboembolic complication is common in severe coronavirus disease (COVID-19), leading to an investigation into the presence of prothrombotic antibodies akin to those found in heparin-induced thrombocytopenia (HIT). In a study of samples from 130 hospitalized patients collected 3.6 days after COVID-19 diagnosis, 80% had IgG antibodies recognizing complexes of heparin and platelet factor 4 (PF4/H), and 41% had antibodies inducing PF4-dependent P-selectin expression in CpG-treated normal platelets. Unlike HIT, both PF4/H-reactive and platelet-activating antibodies were found in COVID-19 patients regardless of recent heparin exposure. Notably, PF4/H-reactive IgG antibodies correlated with those targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Moreover, introducing exogenous RBD to or removing RBD-reactive IgG from COVID-19 plasma or IgG purified from COVID-19 plasma significantly reduced their ability to activate platelets. RBD-specific antibodies capable of platelet activation were cloned from peripheral blood B cells of COVID-19 patients. These antibodies possessed sequence motifs in the heavy-chain complementarity-determining region 3 (HCDR3) resembling those identified in pathogenic HIT antibodies. Furthermore, IgG+ B cells having these HCDR3 signatures were markedly expanded in severe COVID-19 patients. Importantly, platelet-activating antibodies present in COVID-19 patients were associated with a specific elevation of platelet α-granule proteins in the plasma and showed a positive correlation with markers for inflammation and tissue damage, suggesting functionality of these antibodies in patients. The demonstration of functional and structural similarities between certain RBD-specific antibodies in COVID-19 patients and pathogenic antibodies typical of HIT suggests a novel mechanism whereby RBD-specific antibodies might contribute to thrombosis in COVID-19., (Copyright © 2024 American Society of Hematology.)

Pregnancy may be associated with risk of developing tuberculosis (TB) in those infected with Mycobacterium tuberculosis (Mtb). The perinatal period could provide opportunities for targeted screening and treatment. This study aims to synthesise published literature on Mtb infection in pregnancy, relating to prevalence, natural history, test performance, cascade of care, and treatment. We searched Ovid MEDLINE, Embase+Embase Classic, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) on October 3, 2023, and 47 studies met the inclusion criteria. The prevalence of Mtb infection was as high as 57.0% in some populations, with rates increasing with maternal age and in women from high TB-incidence settings. Five studies quantified perinatal progression from Mtb infection to active TB disease, with two demonstrating increased risk compared to non-pregnant populations (IRR 1.3-1.4 during pregnancy and IRR 1.9-2 postpartum). Concordance between Tuberculin Skin Test (TST) and Interferon Gamma-Release Assay (IGRA) ranged from 49.4%-96.3%, with k-values of 0.19-0.56. High screening adherence was reported, with 62.0-100.0% completing antenatal TST and 81.0-100.0% of those positive having chest radiograph. Four studies of TB preventative treatment (TPT) did not find a significant association with serious adverse events. The antenatal period could provide opportunities for contextualised Mtb infection screening and treatment. As women with increased age and from high TB-incidence settings demonstrate higher prevalence and risk of disease, this cohort should be prioritised. TPT appears safe and feasible; however, further studies are needed to optimise algorithms, ensuring pregnant and postpartum women can make evidence-informed decisions for effective TB prevention., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Morton et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Buprenorphine has demonstrated benefit for acute and chronic pain and various psychiatric disorders. However, many studies evaluating buprenorphine's effect on psychiatric conditions are not specific to the chronic pain population. This retrospective study was conducted to assess the impact of buprenorphine on depressive symptoms in patients with chronic pain at a Veterans Affairs healthcare facility. Adults with chronic pain started on any formulation of buprenorphine or traditional opioid (non-buprenorphine opioid) with at least two depression screenings between May 1, 2016 and November 1, 2021 were included. The primary outcome was change in depressive symptoms, measured by Patient Health Questionnaire-9 (PHQ-9), from baseline to 6-18 months after starting therapy. Secondary outcomes included changes in Columbia-Suicide Severity Rating Scale and mental health services utilization. Twenty-one patients were included. Median baseline PHQ-9 in the buprenorphine and traditional opioid groups were 14 and 13, respectively. Median change in PHQ-9 was -5 in the buprenorphine group and -1.5 in the traditional opioid group. Compared to traditional opioids, buprenorphine was associated with a greater reduction in depressive symptoms among Veterans with chronic pain. Although this reduction met the threshold for clinically significant improvement, further investigation is needed to evaluate the clinical relevance of these findings.

Background: As food insecurity and healthcare costs are linked, healthcare entities (i.e., providers, healthcare systems, insurers) are increasingly interested in identifying and providing solutions to address food insecurity among their patients. Home-delivered meals are one long-standing solution to address food insecurity among homebound older adults. However, there is limited evidence about what mode of delivery is most effective in promoting community independence, reducing healthcare utilization, and improving quality of life as well as how these outcomes may vary as a function of people's preferences for how meals are delivered to them., Methods: With extensive stakeholder input, we designed and implemented a pragmatic randomized comparative effectiveness study in which we will enroll 2300 older adults on waiting lists at home-delivered meals programs across the country and randomize them to receive for 6 months, either (1) weekday lunchtime meals delivered by a local volunteer or driver who also provides socialization and wellness checks or (2) biweekly delivery of 10 frozen meals to participants' homes. Participant data will be combined with Centers for Medicare and Medicaid Services (CMS) data to calculate post-randomization institutional vs. community days. Baseline and 3-month surveys will evaluate secondary outcomes (e.g., food insecurity, loneliness, quality of life) and exploratory outcomes (e.g., nutritional risk). To examine heterogeneity of treatment effects, we will test for interactions between the two types of meal delivery and participants' preferred mode of meal delivery as well as participants' living arrangements., Discussion: This research will be the first to prospectively evaluate the comparative effectiveness of the two predominant meal delivery options. The knowledge generated from this research will be of value to healthcare providers, health systems, payers, community-based organizations, older adults, and their families, because it will identify the mode of meal delivery that best meets homebound older adults' needs and promotes community independence. In addition, the experience of working closely with stakeholders in designing and conducting this trial will be useful to researchers seeking to engage with stakeholders in the development and evaluation of complex social service interventions while balancing regulatory, resource, and human subjects research considerations., Trial Registration: ClinicalTrials.gov.  NCT05357261 . Registered on May 02, 2022., Competing Interests: Declarations. Ethics approval and consent to participate: Advara Institutional Review Board approved this protocol (#Pro00060759). This study received a waiver of written consent. Verbal consent to participate will be obtained from all participants. Consent for publication: N/A. There are no details/images/videos that could compromise a participant’s identity included in this protocol. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Purpose: To prospectively evaluate the effect of a preventive jaw-training intervention program on the development of temporomandibular disorders (TMD) in patients treated for head and neck cancer (HNC)., Methods: We randomized 58 consecutive patients with squamous cell carcinoma in the head and neck area into two groups before initiation of a curatively intended oncologic treatment: training with a jaw mobilizer once a day or a control group without active exercise. A comprehensive examination according to diagnostic criteria for temporomandibular disorders (DC/TMD) was conducted at baseline (before oncologic treatment) 6 and 12 months after completed radiation therapy (RT). The patients recorded training frequency in a diary., Results: There were significant differences in the changes of maximal incisal opening (MIO) between the intervention and control groups at 6 and 12 months compared to baseline (p = 0.010 and p = 0.012, respectively) with more deterioration in the control group. The control group had a higher prevalence of TMD diagnosis at the 6-month follow-up (p = 0.010) and a close to significant level at the 12-month follow-up (p = 0.055)., Conclusion: This unique study, which evaluates the effect of a preventive jaw-training program for prevention of TMD in patients with HNC undergoing high dose RT, found that the preventive jaw-training program could prevent the deterioration of MIO and development of TMD., Implications for Cancer Survivors: This preventive exercise program could prevent the deterioration in MIO and the development of TMD in HNC patients, leading to less pain and better jaw function., Competing Interests: Declarations. Ethics approval: The study was approved by the Swedish Ethical Review Authority, reference numbers 1151–18 and 2019- 00752. Consent to participation: All study participants provided oral and written informed consent. Competing interests: The authors declare no competing interests. Conflict of interest: The authors declare no conflicts of interest., (© 2024. The Author(s).)

Background: Post-Therapy-Pneumonitis (PTP) is a critical side effect of both, thoracic radio(chemo)therapy (R(C)T) and immune checkpoint inhibition (ICI). However, disease characteristics and patient-specific risk factors of PTP after combined R(C)T + ICI are less understood. Given that RT-triggered PTP is strongly dependent on the volume and dose of RT [1], driven by inflammatory mechanisms, we hypothesize that combination therapy of R(C)T with ICI influences the dose-volume-effect correlation for PTP. This study focuses on the development of a method for evaluation of alterations of dosimetric parameters for PTP after R(C)T with and without ICI., Methods and Materials: PTP volumes were delineated on the follow-up diagnostic Computed Tomography (CT) and deformably matched to the planning CT for patients with PTP after thoracic R(C)T + ICI or R(C)T. Dose data was converted to 2-Gy equivalent doses (EQD2) and dosimetrically analyzed. Dosimetric and volumetric parameters of the segmented PTP volumes were analyzed. The method was exemplarily tested on an internal patient cohort including 90 patients having received thoracic R(C)T + ICI (39) and R(C)T (51). Thirtytwo patients with PTP were identified for further analysis. Additional data on previous chemotherapy, RT, smoking status and pulmonary co-morbidity were conducted. A matched pair analysis with regard to planning target volumes (PTV) was conducted for curative intended (definitive) and palliative patient cohorts individually., Results: The presented method was able to quantify and compare the dosimetric parameters of PTP for the different therapies. For our study group, no significant differences between R(C)T + ICI and R(C)T only was observed. However, the dosimetric analysis revealed large volumetric fractions (55%) of the PTP volumes to be located outside of high dose (EQD2 < 40 Gy) regions for R(C)T + ICI. There was a non-significant trend towards increased area under the curve of the dose volume histogram (AUC) values for R(C)T + ICI compared to R(C)T only (3743.6 Gy∙% vs. 2848.8 Gy∙%; p-value = 0.171). In contrast to the data for the palliative intended treatment group, for definitive R(C)T + ICI, data tended towards increased volumes with higher doses., Conclusions: The proposed method was capable to quantify dosimetric differences in the dose-volume-effect relationship of PTP for patients with R(C)T + ICI and patients with R(C)T only. In this exploratory analysis, no significant dosimetric differences within PTP volumes for the different groups could be observed. However, our observations suggest, that for safe application of thoracic R(C)T + ICI, further careful investigation of dosimetric prescription and analysis concepts with larger and conformer study groups is recommendable., Competing Interests: Declarations. Ethical approval: The studies involving human participants were reviewed and approved by the Institutional Review Board with the ethical vote number 149/21 S-SR. Informed consent: Informed consent about radiotherapy was obtained from all subjects involved in the study. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Understanding the structural reconfiguration of a biomolecular receptor remains a topic of particular interest to the biosensing community. This is because conformationally changing receptors are commonly employed in biosensors to harness their capability to bind specifically to their target. Often, such receptors are attached to surfaces so that binding can be transduced into a measurable response. Doing so, however, can impose constraints on the possible configurations they can adopt. Such constraints can ultimately influence, for example, their receptor-target binding models or their affinity, which is essential to provide the desired analytical performances in biosensors. Motivated by the idea of gaining further insights into the impact of surface attachment on conformationally switching receptors attached to surfaces, we explore here the various surface-based techniques capable of monitoring structural changes. We decided to narrow our survey to techniques that have been applied to the investigation of nucleic acids to provide an overview of their key features. We envision that this will bring a broader perspective of the field and the challenges ahead with the hopes of "finding the switch" in surface-attached biomolecular receptors.

Background: To investigate the feasibility of using the Stopping Elderly Accidents, Deaths and Injuries (STEADI) Falls Risk Tool Kit during community-based eye health screenings to assess falls risk of participants enrolled in the Manhattan Vision Screening and Follow-Up Study (NYC-SIGHT)., Methods: Cross-sectional analysis of data from a 5-year prospective, cluster-randomised clinical trial conducted in affordable housing developments in New York City in adults age 40 years and older. Prescreening questions determined whether participants were at risk of falling. STEADI tests classified participants at low, moderate or high risk of falling. Multivariate logistic regression determined odds of falls risk of all enrolled participants., Results: 708 participants completed the eye health screening; 351 (49.6%) performed STEADI tests; mean age: 71.0 years (SD±11.3); 72.1% female; 53.6% Black, non-Hispanic, 37.6% Hispanic/Latino. Level of falls risk: 32 (9.1%) low, 188 (53.6%) moderate and 131 (37.3%) high. Individuals age >80 (OR 5.921, 95% CI (2.383 to 14.708), p=0.000), had blurry vision (OR 1.978, 95% CI (1.186 to 3.300), p=0.009), high blood pressure (OR 2.131, 95% CI (1.252 to 3.628), p=0.005), arthritis (OR 2.29876, 95% CI (1.362 to 3.875), p=0.002) or foot problems (OR 5.239, 95% CI (2.947 to 9.314), p=0.000) had significantly higher odds of falling, emergency department visits or hospitalisation due to falling., Conclusion: This study detected a significant amount of falls risk in an underserved population. The STEADI Falls Risk screening questions were easy for eye care providers to ask, were highly predictive of falls risk and may be adequate for referral to occupational health and/or physical therapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To review the oral prosthetic rehabilitation of patients with epidermolysis bullosa hereditaria (EBH) and study the level of evidence and quality of the presented available articles and establish clinical recommendations for the prosthetic management of these patients., Materials and Methods: An electronic search was done in July 2022 in five databases following PICOTS elements. The quality of the reports was established using the modified Pierson, Bradford Hills, and Ottawa Newcastle scale., Results: Data extracted from 19 case reports for protocolized analysis corresponded to 64 patients and 80 dental prostheses, with almost 9 out of 10 patients being completely edentulous. The distribution of EBH types was 84% dystrophic, 10.5% junctional, and 5.5% simplex. The difficulties encountered by the authors synthesized in this review characteristically reflected those most likely encountered in dental practice. Most rehabilitations were implant-supported prostheses (85%), followed by removable dentures (10%) and dental-supported rehabilitations (5%). Fixed full-arch implant-supported prostheses represented 76.4% of implant-supported prostheses, and this prosthetic solution reflected the highest scientific quality., Conclusions: For an individualized approach to treatment, we recommend that in cases of total edentulism, fixed full-arch implant-supported prostheses are the most appropriate because they allow the best computer-aided planning, design, manufacture, and fitting of the prosthesis in such a complex clinical context.

Reliable, validated diagnostic tests are critical for rabies control in animals and prevention in people. We present a performance assessment and updates to the LN34 real-time RT-PCR assay for rabies diagnosis in postmortem animal brain samples. In two U.S. laboratories during 2017 to 2022, routine used of the LN34 assay produced excellent diagnostic sensitivity (99.72% to 100%) and specificity (99.99% to 100%) compared to the direct fluorescence antibody test (DFA). Almost all (>90%) DFA indeterminate results caused by non-specific or atypical fluorescence were negative by LN34 testing, representing up to 111 cases where unnecessary post-exposure prophylaxis could be avoided. LN34 assay original primer sequences showed low sensitivity for some rare lyssaviruses. Increased primer concentration combined with new primer formulation showed improved performance for impacted lyssaviruses with no loss in performance across diverse rabies virus variants from clinical samples. The updated LN34 and internal control assays were combined into a single-well LN34 multiplexed (LN34M) format, run at half reagent volumes. The LN34M assay showed similar detection of rabies virus to the singleplexed assay with simplified assay set-up, lower cost, and improved quality controls., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Herein, we present an economical method for highly enantioselective and diastereoselective Cu-BINAP-catalysed reductive coupling of alkoxyallenes with a range of electronically and structurally diverse ketones to afford 1,2- syn-tert , sec -diols, using PMHS as the hydride source. This reductive coupling has also been efficiently employed in the enantioselective desymmetrization of prochiral cyclic ketones harboring quaternary centres, in high yields with exclusive diastereoselectivity. Density Functional Theory (DFT) calculations are used to elucidate that the reaction is facilitated by a kinetically favourable "open" Z -enolate copper-alkoxyallene conformer, occurring at a lower Gibbs free energy barrier (by 3.9 kcal mol -1 ) than its E -enolate counterpart, dictating the stereoselectivity. Subsequently, this Z -enolate conformer synchronizes with appropriate nucleophilic faces to achieve the targeted syn -diastereoselectivity in the product through six-membered chair-like transition states during ketone addition., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Groundwater level (GWL) can vary over a wide range of timescales. Previous studies highlighted that low-frequency variability (interannual (2-8 years) to decadal (>10 years)) originating from large-scale climate variability, represents a significant part of GWL variance. It remains an open question, however, how GWL, including extremes, may respond to changes in large-scale climate forcing, affecting precipitation variability. Focusing on the Seine River basin, this study therefore aims to assess how GWLs respond to changes in interannual to decadal climate variability. We implemented an empirical numerical approach, which enables an assessment of the GWL sensitivity to changes in precipitation variability over a range of timescales (up to decadal), using the Seine hydrosystem as a case study. The approach consists in: i) identifying and modifying the spectral content of precipitation in the low-frequency range; ii) using these perturbed precipitation fields as input in the physically-based hydrological/hydrogeological CaWaQS model for the Seine River basin to simulate the corresponding GWL response; iii) comparing the spectral content, mean, variance and extremes of perturbed GWLs with reference (i.e. unperturbed) GWLs. Two interannual (2-4 yr and 5-8 yr) and one decadal (15 yr) timescales were modified individually by either increasing or decreasing their amplitude by 50 %. This led to six scenarios of perturbed low-frequency precipitation variability, which were subsequently used as CaWaQS inputs to assess the GWL response. Results indicated increased (decreased) GWL up to 5 m when low-frequency precipitation variability increased (decreased) by 50 %. This led to an increased occurrence of groundwater floods (droughts) with increased severity and decreased occurrence of groundwater droughts (floods) with decreased severity, respectively. These results indicate: i) how using biased climate data, in terms of low-frequency variability, leads to large deviations in the GWL simulation, ii) to what extent potential changes in low-frequency climate variability may affect future GWL, and particularly drought and flood occurrence and severity., (Copyright © 2024. Published by Elsevier B.V.)

Background: The increasing incidence of proximal humeral fractures (PHF) poses complex challenges in determining the optimal therapeutic strategies due to the diverse fracture patterns and individual patient characteristics. Traumatologists and orthopedic surgeons face significant decisions, as potential consequences such as pain, functional limitations, and complications may significantly affect patients' quality of life. Given the varying viewpoints on appropriate treatment modalities, a thorough examination of current care practices is crucial., Methods: An adaptive online survey was conducted to present realistic case scenarios, aimed at elucidating decision-making processes in the management of proximal humeral fractures. This survey encompassed relevant patient and fracture-related variables, employing a dynamic querying algorithm that featured up to 48 conceivable case scenarios., Results: Analysis of 7012 case scenarios unveiled significant differences in treatment preferences across distinct patient age groups. Plate osteosynthesis emerged as the preferred modality for individuals under 50 years of age with complex fracture patterns. On the other hand, a balanced consideration between plate osteosynthesis and reverse shoulder arthroplasty was observed in the 50-70 age cohort. Notably, respondents favored reverse shoulder arthroplasty as the treatment modality of choice for individuals over 70 years of age. A treatment algorithm was developed to outline decision pathways concisely, considering these patient age groups and the option of reverse shoulder arthroplasty., Discussion and Conclusion: This study provides clinically relevant insights into therapeutic decision-making processes in the management of proximal humeral fractures. The illustration of treatment preferences through a visualized algorithm serves as a crucial tool for evidence-based clinical decision-making, offering potential in enhancing the individualized care spectrum for patients with PHF., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The world has experienced devastating extreme weather events, alongside slow-onset processes including increasing temperature means, that scientists agree are manifestations of human-induced climate change. Even with radical action to reduce greenhouse gas emissions, effects of climate change will become increasingly severe., Objectives: The aim of this review was to classify impacts of climate change for people who use alcohol and other drugs (AoD), as reflected in peer reviewed literature., Method: A scoping review was conducted to achieve this. Included studies involved a human population, a climate change related exposure, and an AoD outcome. Studies were published in English between 1998 and November 2023. Exposure events of interest included extreme heat, fires, storms, floods, droughts, and longer-term environmental changes. 8,204 studies were screened, with 82 included for data extraction and narrative analysis., Results: Most papers describe increased AoD use, with smaller numbers showing decreased or unchanged substance use. Some studies identify unplanned withdrawal, changed drug markets, disrupted service access, specific physiological vulnerabilities of AoD users to extreme heat, and compounding effects on mental health. We note the relative absence of peer reviewed studies investigating impacts of climate change on AoD use in low-and middle-income countries. Further, few studies consider impacts that occur because of long-term or gradual climatic shifts such as environmental changes that are detrimental to livelihoods., Conclusion: It is crucial to document effects of a changing climate on people who use AoD so that policy and services can meet future needs. We call for research to remedy gaps identified in this review., Competing Interests: Declaration of competing interest The authors have no interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Migrants living in large urban areas are disproportionately impacted by health crises such as pandemics. This policy brief explores how urban areas mitigate and/or exacerbate the impact of COVID-19 on migrant groups and provides policy recommendations. We conducted a policy review to focus on the effects of COVID-19 on migrants living in cities with > 500,000 residents. We found that structural inequity, lack of migrants' inclusion in as relief programs, and residential segregation exacerbated COVID-19 impacts. Engagement of Civil Society Organizations (CSOs) and e-governance showed promising effects mitigating the impact of COVID-19 on these groups; yet the use of technology introduced additional barriers such as access to devices and internet connection. We recommend increasing policy attention to systemic social inequities faced by migrant groups in urban areas and supporting innovative and inclusive implementation of public health policies, urban design, and greater engagement of CSOs in the delivery of services to migrants., Competing Interests: Declarations. Conflict of interest: The authors declare no conflicts of interest., (© 2024. The Author(s).)

This study aimed to analyze Optical Coherence Tomography (OCT) parameters and Macular Pigment Optical Density (MPOD) changes in patients affected by Retinitis pigmentosa (RP). Eighteen eyes of 18 patients suffering from early-stage RP were enrolled in our observational study. 18 eyes of 18 patients age and gender matched were enrolled as controls. Patients were analyzed at baseline by undergoing complete baseline ophthalmologic examination, Spectral-domain Optical Coherence Tomography (OCT), Electroretinogram (ERG) and Heterochromatic Flicker Photometry (HFP). Main outcome measures were Macular Pigment Optical Density (MPOD), Central macular thickness (CMT), Central Choroidal Thickness (CCT) and Choroidal Vascularity Index (CVI). Lower CCT (p = 0.006), CVI (p < 0.001) and MPOD levels (p = 0.038) were found in affected patients, whereas higher CMT was detected in cases compared to healthy controls. Correlation analysis revealed the presence of a negative correlation between BCVA and Age and CMT and BCVA and a positive correlation between CCT and MPOD and CVI and CCT. Retinal and choroidal variations occur in patients affected by early-stage RP regarding functional and anatomical changes., Competing Interests: Declarations. Ethics approval and consent to participate: The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of the University “G. d’Annunzio”of Chieti- Pescara. Informed consent was obtained from all subjects involved in the study. Consent for publication: Consent was obtained from all subjects involved in the study. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

This technical report describes use of a novel, conformable receive-only radiofrequency coil for 3T magnetic resonance (MR) neurography in a cohort of patients with occipital neuralgia. Applying a sub-millimeter, isotropic three-dimensional double-echo steady-state sequence, detailed visualization of the occipital nerves and associated pathologies could be achieved.ABBREVIATIONS: ABC＝ definition; XYZ＝ definition. FACE＝ Flexible Array coil for Cervical and Extraspinal; DESS＝ double-echo steady-state; C1, C2, C3＝ First, second, and third cervical vertebrae respectively., (© 2024 by American Journal of Neuroradiology.)

Purpose: We explored intervention fidelity, participant satisfaction, and the goals and reminder strategies participants chose to reduce sitting., Approach: Mixed methods approach leveraging data collected during study coaching and fidelity monitoring., Setting: A successful 6-month randomized controlled trial of a sedentary behavior (SB) intervention for adults ≥60 years in Washington, USA., Participants: N = 283 (140 intervention, 143 attention control); mean age 69, 66% women, 69% Non-Hispanic White., Intervention: Theory-based SB reduction intervention structured around phone-based health coaching and goal setting. Attention control received equal coaching on non-SB health topics., Method: Coaches tracked all participant goals, and 8% of visits were randomly observed and fidelity coded using a structured template. Participants completed a satisfaction questionnaire at study end. Goals data were qualitatively grouped by reminder strategy and topic. Fidelity and satisfaction data were summarized and compared by study arm using two-sided paired t-tests., Results: Both participants' satisfaction (>90% satisfied, between-group P = .195) and coach fidelity to intervention content and techniques were high (96% sessions set SMART goals, P = .343) across both arms. Intervention participants primarily set goals leveraging outward (e.g., fitness band prompts) and habit (e.g., adding standing to a daily meal) reminder strategies highly tailored to individual preferences and lifestyle., Conclusion: Participants' SB-related goals varied widely, suggesting tailored intervention approaches are important to change sitting behavior, particularly for older adults with chronic conditions., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This strategic plan summarizes the major accomplishments achieved in the last quinquennial by the soybean [Glycine max (L.) Merr.] genetics and genomics research community and outlines key priorities for the next 5 years (2024-2028). This work is the result of deliberations among over 50 soybean researchers during a 2-day workshop in St Louis, MO, USA, at the end of 2022. The plan is divided into seven traditional areas/disciplines: Breeding, Biotic Interactions, Physiology and Abiotic Stress, Functional Genomics, Biotechnology, Genomic Resources and Datasets, and Computational Resources. One additional section was added, Training the Next Generation of Soybean Researchers, when it was identified as a pressing issue during the workshop. This installment of the soybean genomics strategic plan provides a snapshot of recent progress while looking at future goals that will improve resources and enable innovation among the community of basic and applied soybean researchers. We hope that this work will inform our community and increase support for soybean research., (© 2024 The Author(s). The Plant Genome published by Wiley Periodicals LLC on behalf of Crop Science Society of America.)

Liquid biopsies have the potential to revolutionize cancer care through non-invasive early detection of tumors. Developing a robust liquid biopsy test requires collecting high-dimensional data from a large number of blood samples across heterogeneous groups of patients. We propose that the generative capability of variational auto-encoders enables learning a robust and generalizable signature of blood-based biomarkers. In this study, we analyze orphan non-coding RNAs (oncRNAs) from serum samples of 1050 individuals diagnosed with non-small cell lung cancer (NSCLC) at various stages, as well as sex-, age-, and BMI-matched controls. We demonstrate that our multi-task generative AI model, Orion, surpasses commonly used methods in both overall performance and generalizability to held-out datasets. Orion achieves an overall sensitivity of 94% (95% CI: 87%-98%) at 87% (95% CI: 81%-93%) specificity for cancer detection across all stages, outperforming the sensitivity of other methods on held-out validation datasets by more than  ~ 30%., Competing Interests: Competing interests: The authors are either employees, shareholders, or stock option holders of Exai Bio, Inc. B.A., H.G., F.H., and M.K. have a pending patent application (U.S. Patent “Systems and Methods for Early-Stage Cancer Detection and Subtyping” Application Serial No. 18/636,128 and International Application No. PCT/US24/24682) related to this work., (© 2024. The Author(s).)

Background: Genomic sequencing technology allows for identification of reproductive couples with an increased chance, as compared with that in the general population, of having a child with an autosomal recessive or X-linked genetic condition., Methods: We investigated the feasibility, acceptability, and outcomes of a nationwide, couple-based genetic carrier screening program in Australia as part of the Mackenzie's Mission project. Health care providers offered screening to persons before pregnancy or early in pregnancy. The results obtained from testing at least 1281 genes were provided to the reproductive couples. We aimed to ascertain the psychosocial effects on participants, the acceptability of screening to all participants, and the reproductive choices of persons identified as having an increased chance of having a child with a condition for which we screened., Results: Among 10,038 reproductive couples enrolled in the study, 9107 (90.7%) completed screening, and 175 (1.9%) were newly identified as having an increased chance of having a child with a genetic condition for which we screened. These conditions involved pathogenic variants in 90 different genes; 74.3% of the conditions were autosomal recessive. Three months after receiving the results, 76.6% of the couples with a newly identified increased chance had used or planned to use reproductive interventions to avoid having an affected child. Those newly identified as having an increased chance had greater anxiety than those with a low chance. The median level of decisional regret was low in all result groups, and 98.9% of participants perceived screening to be acceptable., Conclusions: Couple-based reproductive genetic carrier screening was largely acceptable to participants and was used to inform reproductive decision making. The delivery of screening to a diverse and geographically dispersed population was feasible. (Funded by the Medical Research Future Fund of the Australian government; ClinicalTrials.gov number, NCT04157595.)., (Copyright © 2024 Massachusetts Medical Society.)

Aim: To map the existing evidence and identify research gaps regarding the self-management of prediabetes or type 2 diabetes among first-generation immigrants ≥ 18 years., Design: A scoping review followed the JBI guidelines and was in accordance with the PRISMA extension for Scoping Reviews., Methods: A systematic search of CINAHL, Cochrane, EMBASE, MEDLINE, PsycINFO, ProQuest, SCOPUS and the Web of Science was conducted. Grey literature and reference lists of included studies were searched for additional citations. Articles published in English from the database inception to February 2023 were included., Results: We included 96 studies, of which 28.1% were published within the last 5 years. Most studies (71.9%) were conducted in the United States. Study participants were recruited mainly from community settings and English was their second language. The most common study methodologies used were cross-sectional surveys and phenomenological interviews. Only two studies specifically focussed on individuals with prediabetes. Multiple factors, such as age, gender, country of origin and other societal, linguistic, cultural and resource barriers or facilitators, as well as patient's cultural unique experiences, were of particular significance for self-management behaviours. Although several studies reported that culturally tailored interventions were feasible and acceptable among first-generation immigrants living with type 2 diabetes but not prediabetes, the duration and intensity of these interventions varied., Conclusion: Health professionals should consider various demographic, societal, linguistic and cultural factors, such as participants' low English language proficiency, and provide appropriate support for this group to ensure better self-management behaviours. Tailoring interventions to individual and cultural preferences in collaboration with key stakeholders is crucial for adult immigrants with prediabetes and type 2 diabetes across diverse cultural and ethnic groups., Impact: Developing and applying culturally tailored self-management interventions for the targeted population, particularly those with prediabetes, should be an important direction for future research. No Patient or Public Contribution., (© 2024 John Wiley & Sons Ltd.)

Objectives: To compare the safety and efficacy of ketamine and etomidate as induction agents to facilitate emergent endotracheal intubation., Data Sources: We searched MEDLINE, Embase, Cochrane Clinical Trials Register, and ClinicalTrials.gov from inception to April 3, 2024., Study Selection: We included randomized controlled trials (RCTs) that compared ketamine to etomidate to facilitate emergent endotracheal intubation in adults., Data Extraction: Reviewers screened abstracts, full texts, and extracted data independently and in duplicate. We pooled data using a random-effects model, assessed risk of bias using the modified Cochrane tool and certainty of evidence using the Grading Recommendations Assessment, Development, and Evaluation approach. We pre-registered the protocol on PROSPERO (CRD42023472450)., Data Synthesis: We included seven RCTs (n = 2384 patients). Based on pooled analysis, compared with etomidate, ketamine probably increases hemodynamic instability in the peri-intubation period (relative risk [RR], 1.29; 95% CI, 1.07-1.57; moderate certainty) but probably decreases the need for initiation of continuous infusion vasopressors (RR, 0.75; 95% CI, 0.57-1.00; moderate certainty) and results in less adrenal suppression (RR, 0.54; 95% CI, 0.45-0.66; moderate certainty). Ketamine probably has no effect on successful intubation on the first attempt (RR, 1.01; 95% CI, 0.97-1.05; moderate certainty) or organ dysfunction measured as the maximum Sequential Organ Failure Assessment (SOFA) score during the first 3 days in ICU (mean difference, 0.55 SOFA points lower; 95% CI, 1.12 lower to 0.03 higher; moderate certainty) and may have no effect on mortality (RR, 1.00; 95% CI, 0.83-1.21; low certainty) when compared with etomidate., Conclusions: Compared with etomidate, ketamine probably results in more hemodynamic instability during the peri-intubation period and appears to have no effect on successful intubation on the first attempt or mortality. However, ketamine results in decreased need for the initiation of vasopressor use and decreases adrenal suppression compared with etomidate., Competing Interests: Dr. Semler received support for article research from the National Institutes of Health. Dr. Sharif received funding from the McMaster University Department of Medicine Internal Career Research Award. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Aim: Current literature favours individualised decision making, an approach that requires understanding patients within their context and tailoring treatment and recommendations to their unique needs. In neonatology, family context becomes synonymous with patient context. In the neonatal intensive care unit (NICU), the team may be challenged to understand the intricacies of the family context, paramount for both families and clinicians. However, a significant gap exists between the intent to share information about the family context and the process of doing so. The transformational goal of this project was to embed an understanding of the family context into all interactions that occur in the NICU between clinicians and families, and between clinicians when discussing patients., Methods: We designed and implemented the Family Snapshot (FS), an innovation to bridge the gap between the intent and the process to share the family context., Results: Two groups of process measures have been collected to understand workflow integration: (1) whether the forms are being used and (2) how the forms are being used. Overall, completion of at least some part of the FS was >90%., Conclusion: This manuscript describes our process, its feasibility and impact and presents two tools, the FS antenatal consultations and the FS tab., (© 2024 The Author(s). Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)