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Bipolar disorder is a leading contributor to the global burden of disease 1 . Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown 2 . We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings 3 , and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder 4 , highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder., Competing Interests: Competing interests: T.E.T., H. Stefansson and K.S. are employed by deCODE Genetics/Amgen. E.A.S. is an employee of Regeneron Genetics Center and owns stocks of Regeneron Pharmaceutical. K.-H.L. and X.W. are employed by 23andMe. Multiple additional authors work for pharmaceutical or biotechnology companies in a manner directly analogous to academic co-authors and collaborators. A.H.Y. has given paid lectures and served on advisory boards relating to drugs used in affective and related disorders for several companies (AstraZeneca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allergan, Bionomics and Sumitomo Dainippon Pharma), was Lead Investigator for the Embolden study (AstraZeneca), BCI Neuroplasticity study and Aripiprazole Mania study, and is an investigator for Janssen, Lundbeck, Livanova and Compass. J.I.N. is an investigator for Janssen. P.F.S. is on the advisory committee and a shareholder of Neumora Therapeutics. G.B. reports consultancy and speaker fees from Eli Lilly and Illumina, and grant funding from Eli Lilly. M. Landén has received speaker fees from Lundbeck. O.A.A. has served as a speaker for Janssen, Lundbeck and Sunovion, and as a consultant for Cortechs.ai. A.M.D. is a founder of and holds equity interest in CorTechs Labs and serves on its scientific advisory board; is a member of the scientific advisory board of Human Longevity and the Mohn Medical Imaging and Visualization Center; and has received research funding from General Electric Healthcare. E.V. has received grants and served as a consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, AstraZeneca, Bristol Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, GlaxoSmithKline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, SAGE, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Catalan Government (AGAUR and PERIS), the Spanish Ministry of Science, Innovation, and Universities (AES and CIBERSAM), the Seventh European Framework Programme and Horizon 2020 and the Stanley Medical Research Institute. S.K.-S. received author’s, speaker’s and consultant honoraria from Janssen, Medice Arzneimittel Pütter GmbH and Takeda outside of the current work. A. Serretti is or has been a consultant and/or speaker for: Abbott, AbbVie, Angelini, AstraZeneca, Clinical Data, Boheringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi and Servier. J.R.D. has served as an unpaid consultant to Myriad-Neuroscience (formerly Assurex Health) in 2017 and 2019, and owns stock in CVS Health. B.M.N. is a member of the scientific advisory board at Deep Genomics, and consultant for Camp4 Therapeutics, Takeda Pharmaceutical and Biogen. B.-C.L., J.-W.K., Y.K.L., J.H.K., M. J. Cheon and D.J.K. are employed by Genoplan. I.B.H. is the Co-Director of Health and Policy at the Brain and Mind Centre (BMC) University of Sydney. The BMC operates an early-intervention youth services at Camperdown under contract to Headspace. I.B.H. is also the Chief Scientific Advisor to, and a 3.2% equity shareholder in, InnoWell. InnoWell was formed by the University of Sydney (45% equity) and PwC (Australia; 45% equity) to deliver the $30 M (AUD) Australian Government-funded Project Synergy (2017–2020; a 3-year program for the transformation of mental health services) and to lead transformation of mental health services internationally through the use of innovative technologies. M.J.O. and M.C.O. have received funding from Takeda Pharmaceuticals and Akrivia Health outside the scope of the current work. P. B. Mitchell. has received remuneration from Janssen (Australia) and Sanofi (Hangzhou) for lectures or advisory board membership. J.A.R.-Q. was on the speakers’ bureau and/or acted as consultant for Biogen, Idorsia, Casen-Recordati, Janssen-Cilag, Novartis, Takeda, Bial, Sincrolab, Neuraxpharm, Novartis, BMS, Medice, Rubió, Uriach, Technofarma and Raffo in the past 3 years; has also received travel awards (airplane tickets and hotel) for taking part in psychiatric meetings from Idorsia, Janssen-Cilag, Rubió, Takeda, Bial and Medice; and the Department of Psychiatry chaired by J.A.R.-Q. received unrestricted educational and research support from the following companies in the past 3 years: Exeltis, Idorsia, Janssen-Cilag, Neuraxpharm, Oryzon, Roche, Probitas and Rubió. All other authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature Limited.)

Diffuse coronary artery disease (CAD) impacts the immediate hemodynamic and clinical outcomes of percutaneous coronary intervention (PCI). We evaluated whether the diffuse pattern of CAD derived from angiographic Quantitative flow ratio (QFR) impacts the immediate hemodynamic outcome post-PCI and the medium term predicted vessel-oriented composite endpoint (VOCE). Paired pre-procedure QFRs were assessed in 503 patients and 1022 vessels in the Multivessel TALENT (MVT) trial. The pathophysiological pattern of CAD was defined as "predominantly diffuse" or "focal" according to a virtual QFR pullback pressure gradient (PPG) index < 0.78 and ≥ 0.78, respectively. Physiological "focal severity" was assessed using the QFR gradient per mm (dQFR/ds), with a value ≥ 0.025/mm the threshold for a "major gradient". A post-PCI QFR ≥ 0.91 was considered optimal. Median pre-PCI PPG index was 0.70 (IQR 0.59-0.80). The prevalence of "predominantly diffuse" CAD and "major gradient" were 68.6% and 85.8%, respectively. A "Predominantly diffuse" pattern with a major gradient had a higher risk of a post-PCI QFR < 0.91 (OR 1.52,95%CI 1.47-1.58). In multivariable analysis, low QFR PPG index (diffuse disease) was an independent determinant of a post-PCI QFR < 0.91 (per 0.1 decrease of QFR PPG index, OR:9.8, 95% CI 3.0-32.2, p < 0.001). Based on post-PCI QFR the predicted 2-year VOCE, a powered endpoint in the MVT trial, was 6.1% and 4.2% in diffuse and focal lesions, respectively. A pre-procedure physiological pattern of diffuse CAD is an independent determinant of an unfavourable immediate hemodynamic outcome post-PCI, and detrimentally affects the predicted 2-year VOCE.Clinical Trial Registration URL: https://www.clinicaltrials.gov/ct2/show/NCT04390672 Unique Identifier: NCT04390672 (registration date 15/05/2020)., Competing Interests: Declarations. Competing interests: Dr Serruys reports institutional grants from Philips/Volcano, SMT, Novartis, Xeltis, Merillife, outside the submitted work. Dr Tu reports research grants and consultancy from Pulse Medical. Dr Sabaté has received consultant fees from Abbott Vascular and Ivascular outside the submitted work. Dr Möllmann reports speaker honoraria from Abbott, Boston Scientific, and SMT. All other authors have no conflict of interest to declare., (© 2025. The Author(s).)

Prescribing errors are a source of preventable harm in healthcare, which may be mitigated using Electronic Prescribing (EP) systems. Anyone who routinely prescribes medication could benefit from digitally assisted automated checks to identify whether a prescription should potentially not be allowed (e.g. drug allergy). National Health Service (NHS) Trusts have implemented a range of EP systems; however, their performance has not hitherto been evaluated. We developed the web-based Electronic Prescribing Risk and Safety Evaluation (ePRaSE) tool, which comprises a bank of prescribing scenarios to evaluate the performance of EP systems. We solicited ePRaSE testing: 68 pharmacists from across 45 English NHS Trusts, utilising 13 different EP systems volunteered for the study. We found considerable variability in mitigation performance (systems correctly identifying risk of error when prescribing) across both NHS Trusts and EP systems. Moreover, we found that mitigation performance varied considerably across NHS Trusts using the same EP system, strongly suggesting there are opportunities to optimise performance within systems. The ePRaSE tool is effective in identifying variability in risk management between NHS Trusts and EP systems. Wider use of this tool may facilitate improvements in EP system configurations, thus minimising potential harm from prescribing errors., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval: The study was approved by Newcastle University Ethics Committee [Ref: 13114/2018]., (© 2025. The Author(s).)

SARS-CoV-2 is the viral pathogen responsible for COVID-19. Although morbidity and mortality frequently occur as a result of lung disease, the gastrointestinal (GI) tract is recognized as a primary location for SARS-CoV-2. Connections and interactions between the microbiome of the gut and respiratory system have been linked with viral infections via what has been referred to as the 'gut-lung axis' with potential aerodigestive communication in health and disease. This research explored the relationship between the microbiomes of the upper respiratory and GI tracts in patients with COVID-19 and examined Extraesophageal reflux (EOR), a mechanism which could contribute to dysregulated communication between the GI and respiratory tract (as identified in COVID-19). 97 patients with a laboratory diagnosis of COVID-19 infection, and 50 age-matched controls were recruited and stool, saliva and sputum were obtained from each participant. ELISA Pepsin tests and Reflux Symptom Index scores (RSI) were conducted for EOR assessment. DNA sequencing of the V4 region of the 16 S rRNA gene was performed for microbiome analysis. No differences were observed between the fecal microbiome's alpha and Shannon diversity indices; however, a distinct microbial composition was observed in COVID-19 patients (when compared to the controls). The respiratory microbiota from individuals with COVID-19 demonstrated a statistically significant reduction in Shannon diversity and bacterial richness alongside an overall reduction in the prevalence of organisms from a typical healthy respiratory microbiome. Furthermore, the bacterial richness of the stool and sputum samples was significantly lower among COVID-19 patients admitted to ICU. A significantly higher RSI score and salivary pepsin level were detected among those with COVID-19. The data indicates that COVID-19 is associated with a dysregulation of both the gut and lung microbiome with a more marked perturbation in the lung, particularly among COVID-19 patients who had been admitted to the ICU. The presence of increased RSI scores, combined with elevated levels of Pepsin, suggests that increased micro-aspiration may occur, which is consistent with of under-recognized interactions between the GI and lung microbiomes in COVID-19 patients and requires additional study. Such studies would benefit from the insights provided by biological samples which reflect the continuum of the aerodigestive tract., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Optimizing vaccine uptake is a public health challenge that requires the implementation of effective strategies. The asymmetric dominance (or decoy) effect describes the increasing likelihood of selecting an option when a clearly inferior alternative is offered. Therefore, we aimed to test the impact of offering decoy alternatives-less convenient vaccination appointments-on vaccination intentions. Participants aged 18-33 years, residing in England, and initially not intending to get vaccinated, completed three online experiments. Participants were randomly assigned to either a control or an experimental condition in each experiment. The asymmetrically dominated options were: an appointment in two weeks at a distant location (experiment 1); a later time at the participant's local GP, pharmacy, or community centre (experiment 2); and a later time at a distant location (experiment 3). The primary outcome was vaccination intention, while secondary outcomes included an active interest in reading additional information about the vaccination procedure, perceived difficulty and cognitive effort. Initial analysis revealed no evidence of an asymmetric dominance effect. However, further subgroup analysis, supported by formative research, indicated that ensuring decoy alternatives are clearly perceived as inferior could enhance the effectiveness of this approach for certain individuals., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: This research was approved by HSSREC (number 117/20–21) at the University of Warwick, and all methods were performed in accordance with the relevant guidelines and regulations. The study participants provided informed consent for their data to be used and published as part of this research project., (© 2024. The Author(s).)

Facioscapulohumeral dystrophy type 1 (FSHD1) displays prominent intra- and interfamilial variability, which complicates the phenotype-genotype correlation. In this retrospective study, we investigated FSHD1 patients classified as category D according to the Comprehensive Clinical Evaluation Form (CCEF), a category defined by FSHD patients showing uncommon clinical features, to identify genetic causes explaining these uncommon phenotypes. Demographics, clinical data and clinical scales of FSHD1 patients were retrospectively evaluated. Patients were divided into four CCEF categories, and comparisons between groups were performed. In category D, when uncommon features suggested the presence of an unrelated genetic disease, a more extensive collection of data was performed. 157 FSHD1 patients were included in the study (82 males, 75 females) with mean age of 52.1 ± 13.5 years at the time of the study. D4Z4 repeat sizes ranged between 2 and 10 RU. According to the CCEF, 114 patients were classified into category A, 8 into category B and C each, and 27 into category D. In category D, 9 patients presented uncommon features related to commonly acquired comorbidities, whereas in the remaining 18 patients, all but two with upper-sized FSHD1 D4Z4 repeats (7-10 RU), we suspected an unrelated genetic neurological disease based on clinical phenotype. In 14/18 patients, we identified FSHD-unrelated genetic causes, most often unrelated repeat expansion disorders. This emphasizes the need of careful clinical and genetic work-up to avoid confusion between FSHD-intrinsic clinical variability and clinical features unrelated to the disease., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: This retrospective study was approved by local ethics committee. All the patients signed non-opposition to the use of their data., (© 2025. The Author(s).)

Aims: This study aimed to assess the effectiveness of a novel antimicrobial gel, containing copper and silver nanoparticles, for use in root canal disinfection., Methods: Copper and silver-based gels were created in-house, using a support network of biocompatible polymers, including polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), and polyethylene glycol (PEG). Six experimental groups were created, three containing silver ions and three copper ions, where the PVA, PVP and PEG ratios were also adjusted in each group to test the gel's physical state. One control contained no metal nanoparticles. The gels surface characteristics, roughness, mechanical properties, and flowability, were characterised using a combination of atomic force microscopy, scanning electron microscopy, transmission electron microscopy and Rheometery. Further biological testing measured the gels cytotoxicity levels, using human periodontal ligament cells, and the anti-microbial effects against E. Faecalis and a multi-species bacteria biofilm., Results: Each gel demonstrated high levels of viscosity, which was lowered in gels containing a reduced PVA concentration. The overall antimicrobial properties of the gels increased in those with a higher dissolution, lower porosity, and reduced surface roughness. Copper nanoparticles were shown to be significantly more effective against E. Faecalis, compared with silver. Gels containing higher PVA levels, and silver nanoparticles, had greater toxicity levels against human cells, however, testing was not possible for most experimental groups as the gels dissolved before measurements took place. The antimicrobial properties of all gel formulations were significantly less effective than sodium hypochlorite (after 1 h), but a similar outcome was detected in comparison with calcium hydroxide (after 7 days)., Conclusions: Developing an antimicrobial gel is highly dependent upon numerous compositional factors, where development is still at the early stages. The use of copper nanoparticles appeared to be more appropriate for use in canal disinfection, compared with silver that also had higher levels of human cell toxicity. The ratios selected for the biocompatible polymers had a critical impact on the physical state, antimicrobial, and toxicity levels. At present, antimicrobial gels are not as effective as sodium hypochlorite., Competing Interests: Competing interests: The author declares no competing interests., (© 2025. The Author(s).)

Fatigue is prevalent in immune-mediated inflammatory and neurodegenerative diseases, yet its assessment relies largely on patient-reported outcomes, which capture perception but not fluctuations over time. Wearable sensors, like inertial measurement units (IMUs), offer a way to monitor daily activities and evaluate functional capacity. This study investigates the relationship between sit-to-stand and stand-to-sit transitions and self-reported physical and mental fatigue in participants with Parkinson's, Huntington's, rheumatoid arthritis, systemic lupus erythematosus, primary Sjögren's syndrome and inflammatory bowel disease. Over 4 weeks, participants wore an IMU and reported fatigue levels four times daily. Using mixed-effects models, associations were identified between fatigue and specific kinematic features, such as 5th and 95th percentiles of sit-to-stand performance, suggesting that fatigue alters the control and effort of movement. These kinematic features show promise as indicators for fatigue in these patient populations., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

The cellular concentrations of splicing factors (SFs) are critical for controlling alternative splicing. Most serine and arginine-enriched (SR) protein SFs regulate their own concentration via a homeostatic feedback mechanism that involves regulation of inclusion of non-coding 'poison exons' (PEs) that target transcripts for nonsense-mediated decay. The importance of SR protein PE splicing during animal development is largely unknown despite PE ultra-conservation across animal genomes. To address this, we used mouse genetics to disrupt an ultra-conserved PE in the Tra2b gene encoding the SR protein Tra2β. Focussing on germ cell development, we found that Tra2b PE deletion causes azoospermia due to catastrophic cell death during meiotic prophase. Failure to proceed through meiosis was associated with increased Tra2b expression sufficient to drive aberrant Tra2β protein hyper-responsive splice patterns. Although critical for meiotic prophase, Tra2b PE deletion spared earlier mitotically active germ cells, even though these still required Tra2b gene function. Our data indicate that PE splicing control prevents the accumulation of toxic levels of Tra2β protein that are incompatible with meiotic prophase. This unexpected connection with male fertility helps explain Tra2b PE ultra-conservation and indicates the importance of evaluating PE function in animal models., Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests and approve the current version of the manuscript., (© 2025. The Author(s).)

Double C-2 Like Domain Beta (DOC2B) located at 17q13.3 prevents metastasis by senescence induction and epithelial to mesenchymal transition inhibition in cervical cancer (CC). The extracellular vesicle (EV) mediated trafficking of DOC2B and its impact on tumor suppressive activity are not investigated in CC. Using a retroviral method, we first ectopically expressed DOC2B in SiHa, which do not normally express DOC2B. DOC2B-SiHa and vector-SiHa EVs were co-incubated separately with recipient cell and subjected to various cellular and biochemical experiments. For the first time, we demonstrated that DOC2B localizes to EVs, and its transfer to EV may require intracellular calcium. Co-culture of SiHa and HeLa cells with DOC2B-SiHa derived EVs induced morphological changes and suppressed their growth and migration, possibly by induction of G0/G1 to S phase arrest and anoikis. DOC2B-SiHa EVs elevated intracellular reactive oxygen species (ROS) and calcium levels and promoted lipid droplet accumulation and lipid peroxidation rate in recipient cells. DOC2B-SiHa EVs reduced active AKT1 and ERK1/2 levels and EMT marker expression and enhanced cellular senescence and cytotoxic effects of cisplatin. Re-expression of DOC2B significantly altered the global metabolite profile of EVs.  Finally, we demonstrated that intracellular calcium chelation significantly reduces DOC2B localization to EVs and impacts its tumor-suppressive properties. Altogether, EV-mediated DOC2B transfer may reduce the aggressive behavior of CC cells., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Claims of industrially induced seismicity vary from indisputable to unpersuasive and yet the veracity of industrial induction is vital for regulatory and operational practice. Assessment schemes have been developed in response to this need. We report here an initial assessment of the reliability of all globally known cases of proposed human-induced earthquakes and invite specialists on particular cases to refine these results. 1235 cases were assessed, requiring over 1000 h of work. From the 881 cases for which scorable evidence is available, we class 87% as 'Confidently Induced', 10% as 'Probably Induced', 2% as 'Equivocal' and < 1% as 'Confidently Natural'. The most seismogenic activities are fracking, research, geothermal, water reservoir impoundment, conventional oil and gas. Least seismogenic activities are construction, deep penetrating bombs, coal bed methane. 354 cases (29%) lack enough information to be assessable. Future work could include applying data mining techniques including natural language processing and AI to uncover new evidence. Future best practice for rapid assessment of cases would ideally involve an independent panel of scientists who rapidly apply a questionnaire scheme, reach consensus, and inform a response., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Oblique lumbar interbody fusion (OLIF) is a minimally invasive lateral lumbar fusion technique and patients are discharged 1-2 days after surgery. Because OLIF utilizes a retroperitoneal approach close to the superior hypogastric plexus, postoperative urinary retention (POUR) may not be an uncommon problem. The purpose of this study was to present the incidence and outcomes of POUR with a systematic care protocol. The records of 102 consecutive patients (M:F = 34:68; mean age, 68.0 ± 8.4 years) were retrospectively reviewed. After OLIF, the indwelling urinary catheter was immediately removed, and every patient was encouraged to void within 6 h. The POUR care protocol, following a clinical pathway, was based on residual urine (RU), which was monitored with an ultrasound bladder scan after each voiding or every 6 h for 48 h. The incidence rate of POUR was 44% (45/102) at 24 h, 17% (17/102) at 48 h, and 2% (2/102) at 1 month. Preoperative urological symptoms (odds ratio [OR] 3.2) and violation of the protocol (OR 28.3) were risk factors at 24 h. At 48 h, violation of the protocol was the only risk factor (OR 9.6). Identifying risk factors and a preemptive care protocol may reduce permanent POUR., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Constitutional mismatch repair deficiency (CMMRD), first described 25 years ago, confers an extremely high and lifelong cancer risk, including haematologic, brain, and gastrointestinal tract malignancies, and is associated with several non-neoplastic features. Our understanding of this condition has improved and novel assays to assist CMMRD diagnosis have been developed. Surveillance protocols need adjustment taking into account recent observational prospective studies assessing their effectiveness. Response to immune checkpoint inhibitors and the effectiveness and toxicity of other treatments have been described. An update and merging of the different guidelines on diagnosis and clinical management of CMMRD into one comprehensive guideline was needed. Seventy-two expert members of the European Reference Network GENTURIS and/or the European care for CMMRD consortium and one patient representative developed recommendations for CMMRD diagnosis, genetic counselling, surveillance, quality of life, and clinical management based on a systematic literature search and comprehensive literature review and a modified Delphi process. Recommendations for the diagnosis of CMMRD provide testing criteria, propose strategies for CMMRD testing, and define CMMRD diagnostic criteria. Recommendations for surveillance cover each CMMRD-associated tumour type and contain information on starting age, frequency, and surveillance modality. Recommendations for clinical management cover cancer treatment, management of benign tumours or non-neoplastic features, and chemoprevention. Recommendations also address genetic counselling and quality of life. Based on existing guidelines and currently available data, we present 82 recommendations to improve and standardise the care of CMMRD patients in Europe. These recommendations are not meant to be prescriptive and may be adjusted based on individual decisions., Competing Interests: Competing interests: All members of the ERN GENTURIS CMMRD Guideline Group, including the Core Working Group, have provided disclosure statements on all relationships that they have that might be perceived to be a potential conflict of interest. Amedeo Azizi reports receipt of honoraria or consultation fees from Alexion, AstraZeneca and Novartis. Kevin Beccaria reports previous employment with Carthera SAS. Laurence Brugières reports receipts of honoraria or consultation fees from ESAI and TAKEDA. Chrystelle Colas reports receipt of honoraria or consultation fees from AstraZeneca. Volodia Dangouloff-Ros reports receipt of grants/research support from GE Healthcare. Richard Gallon reports receipt of grants/research support from Cancer Research UK Catalyst and UK National Health Service. Christian Kratz reports support from BMBF ADDRess (01GM1909A) and Deutsche Kinderkrebsstiftung (DKS2021.25). Magali Svrcek reports receipt of grants/research support from Bayer and Roche, and receipt of honoraria or consultation fees from Astellas, MSD and Sanofi. All participants of the ERN GENTURIS CMMRD Delphi survey have provided disclosure statements on all relationships that they have that might be perceived to be a potential source of a competing interests. Andishe Attarbaschi reports receipt of honoraria or consultation fees from Amgen, Novartis, Jazz, Gilead and MSD. Patrick Benusiglio reports receipt of honoraria or consultation fees from AstraZeneca, BMS and MSD. Christof Kramm reports receipt of grants/research support from Deutsche Kinderkrebsstiftung (non-commercial), research collaboration with Bayer to develop NTRK-inhibitors, being a member of the advisory board for Boehringer Ingelheim, and participation in Blueprint Medicines ROVER trial NCT04773782. Eric Legius reports receipt of honoraria or consultation fees from Alexion and AstraZeneca. Rianne Oostenbrink reports receipt of grants/research support from EU Patient-centric clinical trial platform (EU-PEARL), which includes support from the European Union’s Horizon 2020 research and innovation program, EFPIA, Children’s Tumor Foundation, Global Alliance for TB Drug Development non-profit organization and Springworks Therapeutics Inc., receipt of honoraria or consultation fees from AstraZeneca, and participation in a speaker’s bureau sponsored by Alexion. Enrico Opocher reports receipt of honoraria or consultation fees from Alexion (RareDisease). Markus G. Seidel reports receipt of grants/research support from Takeda, Amgen and Novartis, and receipt of honoraria or consultation fees from Jazz, Amgen and Novartis., (© 2024. The Author(s).)

Birt-Hogg-Dubé syndrome (BHD syndrome) is an autosomal dominant multisystem disorder with variable expression due to pathogenic constitutional variants in the FLCN gene. Patients with BHD syndrome are predisposed to benign cutaneous fibrofolliculomas/trichodischomas, pulmonary cysts with an associated risk of spontaneous pneumothorax, and renal cell carcinoma. A requirement for updated International consensus recommendations for the diagnosis and management of BHD syndrome was identified. Based on a comprehensive literature review and expert consensus within the fields of respiratory medicine, urology, radiology, dermatology, clinical oncology and clinical genetics, updated recommendations for diagnosis, surveillance and management in BHD syndrome were developed. With the widespread availability of FLCN genetic testing, clinical scenarios in which a diagnosis should be considered and criteria for genetic testing were defined. Following a clinical and/or molecular diagnosis of BHD syndrome, a multidisciplinary approach to disease management is required. Regular renal cancer surveillance is recommended in adulthood and life-long, but the evidence base for additional tumour surveillance is limited and further research warranted. Recommendations for the treatment of cutaneous, pulmonary and renal manifestations are provided. Awareness of BHD syndrome needs to be raised and better knowledge of the clinical settings in which the diagnosis should be considered should enable earlier diagnosis. Further details, including areas for future research topics are available at: https://www.genturis.eu/l=eng/Guidelines-and-pathways/Clinical-practice-guidelines.html ., Competing Interests: Competing interests: All members of the ERN GENTURIS BHD Guideline Group, including the Core Working Group, have provided disclosure statements on all relationships that they have that might be perceived to be a potential source of a conflict of interest. Core Working Group patient representatives KN and JH were employed by the Myrovlytis Trust. MGM reports receipt of honoraria or consultation fees from Ipsen. CMC reports receipt of research funding from Boehringer Ingelheim, honoraria or consultation fees from Savara Inc, Theravance, AI Therapeutics, Roche, Aerogen as well as grants from Health Research Board, LAM Foundation and Enterprise Ireland. NR reports participation in a company sponsored speaker’s bureau from Takeda UK. MTAW reports receipt of honoraria or consultation fees from Microsoft. All participants of the ERN GENTURIS BHD syndrome Delphi survey have provided disclosure statements on all relationships that they have that might be perceived to be a potential source of competing interests. Patrick Benusiglio reports receipt of honoraria or consultation fees from AstraZeneca, Bristol Myers Squibb and Merck Sharp & Dohme. Raphael Borie reports receipt of grants/research support from Roche and Boehringer Ingelheim, as well as receipt of honoraria or consultation fees from Roche, Boehringer Ingelheim and Sanofi. Jesper Rømhild Davidsen reports receipt of honoraria or consultation fees from Boehringer Ingelheim. Arndt Hartmann reports receipt of grants/research support from AstraZeneca, Biocartis, Biontech, Cepheid, Gilead, Illumina, Janssen, Nanostring, Novartis, Owkin, Qiagen, QUIP GmbH, Roche and Sanofi, as well as receipt of honoraria or consultation fees from Abbvie, AstraZeneca, Biocartis, Biontech, BMS, Boehringer Ingelheim, Cepheid, Diaceutics, Gilead, Illumina, Ipsen, Janssen, Lilly, MSD, Nanostring, Novartis, Qiagen, QUIP GmbH, Roche, Sanofi and 3DHistotech. Arjan C. Houweling reports receipt of a research grant from the Myrovlytis Trust. Stefan J. Marciniak reports receipt of grants/research support from the Myrovlytis Trust, Asthma+Lung UK, Alpha 1 Foundation, the Medical Research Council (MRC) UK, and the Engineering and Physical Sciences Research Council (EPSRC). Maria Molina-Molina reports receipt of grants/research support from Boehringer Ingelheim and Roche, as well as receipt of honoraria or consultation fees from Ferrer, Chiesi, Boehringer Ingelheim, Roche and Esteve-Teijin. Charles Van Praet reports receipt of honoraria or consultation fees from Astellas, IPSEN and Baxter. Robin de Putter reports receipt of honoraria or consultation fees from AstraZeneca. Lore van Riel reports receipt of a research grant from the Myrovlytis Trust. Jacobo Sellarés Torres reports receipt of grants/research support from Roche and Boehringer Ingelheim, receipt of honoraria or consultation fees from Boehringer Ingelheim, as well as participation in a speaker’s bureau sponsored by Boehringer Ingelheim. Grant D. Stewart reports receipt of grants/research support from AstraZeneca and Pfizer, receipt of honoraria or consultation fees from Pfizer, Merck, EUSA Pharma and Eisai, as well as participation in a speaker’s bureau sponsored by Eisai., (© 2024. The Author(s).)

Stride velocity 95th centile (SV95C) is a wearable-derived endpoint representing the 5% fastest strides taken during everyday living. In July 2023, SV95C received European Medicines Agency (EMA) qualification for use as a primary endpoint in trials of patients with Duchenne muscular dystrophy (DMD) aged ≥ 4 years-becoming the first digital endpoint to receive such qualification. We present the data supporting this qualification, providing insights into the evidentiary basis of qualification as a digital clinical outcome assessment. Clinical trials, natural history studies, and patient surveys (ages 5 - 14 years) showed that SV95C is accurate, valid, reliable, sensitive, and clinically meaningful. SV95C significantly correlated with traditional DMD assessments, increased rapidly after steroid initiation (0.090 m/s 3 months post-treatment), and declined steadily in patients on stable steroid regimens. Compared with traditional assessments, SV95C demonstrated earlier sensitivity to disease progression (3 vs 9 months) and greater sensitivity at 12 months. Distribution- and anchor-based approaches revealed a change of - 0.10 to - 0.20 m/s as clinically meaningful. The EMA qualification of SV95C illustrates the willingness of regulators to accept novel digital endpoints for drug approval, setting an important precedent for the evidentiary basis of regulatory digital endpoint qualification that could transform clinical development in disorders affecting movement., Competing Interests: Declarations. Competing interests: L.S. is a member of scientific advisory boards for Novartis Gene Therapies (formerly AveXis), Biogen, Biophytis, Cytokinetics, Dynacure, F. Hoffmann-La Roche Ltd, GeneTx Biotherapeutics, REGENXBIO, Santhera Pharmaceuticals, and Sarepta Therapeutics, Inc., has consulted for Pfizer and Affinia, conducts research funded by Novartis Gene Therapies (formerly AveXis), Biogen, and F. Hoffmann-La Roche Ltd, holds part of the patent WO2017129890A1 with no financial interest, and has provided consultancy services to SYSNAV. P.S. is an employee of and hold stocks in F. Hoffmann-La Roche Ltd. M.P. reports no disclosures relevant to the manuscript. A.M. reports no disclosures relevant to the manuscript. N.B. reports no disclosures relevant to the manuscript. V.A.S. provides intellectual consultancies and teaching activities for Biogen, F. Hoffmann-La Roche Ltd, Novartis, Lupin, Dyne Therapeutics, and PTC Therapeutics. C.V. reports participation in scientific advisory boards for Novartis Gene Therapies (formerly AveXis), Biogen, PTC Therapeutics, F. Hoffmann-La Roche Ltd, Italfarmaco, and Sarepta Therapeutics, Inc., and is involved in research funded by Novartis Gene Therapies (formerly AveXis), Biogen, Sarepta Therapeutics, Inc., and F. Hoffmann-La Roche Ltd. U.S.S. is a member of scientific advisory boards for Novartis Gene Therapies (formerly AveXis), Biogen, F. Hoffmann-La Roche Ltd, Pfizer, Santhera Pharmaceuticals, Sarepta Therapeutics, Inc., Italfarmaco, and PTC Therapeutics, and has received honoraria for invited talks or chair positions in scientific symposia from Novartis Gene Therapies (formerly AveXis), Biogen, F. Hoffmann-La Roche Ltd, Pfizer, Santhera Pharmaceuticals, Sarepta Therapeutics, Inc., Italfarmaco, and PTC Therapeutics. M.S. has provided consultancy services for and received honoraria (as a member of scientific advisory boards) from Biogen, F. Hoffmann-La Roche Ltd, and Novartis Gene Therapies (formerly AveXis). A.M.S. reports no disclosures relevant to the manuscript. S.C.P. reports participation in scientific advisory boards for EspeRare Foundation, Wave Life Sciences Ltd, Argenx, and Sarepta Therapeutics, Inc., and has provided consultancy service for Alia Therapeutics and LSC Lifesciences. M.T. has participated in scientific advisory boards for Biogen, PTC Therapeutics, F. Hoffmann-La Roche Ltd, and Sarepta Therapeutics, Inc., and has received honoraria for invited lectures from Biogen, Sarepta Therapeutics, Inc., and PTC Therapeutics. A.N. reports participation in scientific advisory boards for Novartis Gene Therapies (formerly AveXis), Biogen, PTC Therapeutics, F. Hoffmann-La Roche Ltd, Italfarmaco, Pfizer, Dyne Therapeutics, and Sarepta Therapeutics, Inc., and is involved in research funded by Novartis Gene Therapies (formerly AveXis) and Biogen. P.F. reports no disclosures relevant to the manuscript. T. S. is an employee of Sarepta Therapeutics, Inc. and has stock and stock options. R.D.D. is Head of Clinical Development at Solid Biosciences, was previously employed at F. Hoffmann-La Roche Ltd, Santhera Pharmaceuticals, and Novartis, and has stock in Solid Biosciences and F. Hoffmann-La Roche Ltd. N.G. reports activities as a Data and Safety Monitoring Board member for Pfizer, Antisense Therapeutics, Wave Life Sciences Ltd, and Genethon. E.M. has served on clinical steering committees and/or as a consultant and received compensation from Italfarmaco, PTC Therapeutics, Sarepta Therapeutics, Inc., Santhera Pharmaceuticals, Pfizer Inc., F. Hoffmann-La Roche Ltd, Wave Life Sciences, NS Pharma, and Dyne Therapeutics, and is involved in research funded by Novartis Gene Therapies (formerly AveXis), Biogen, Sarepta Therapeutics, Inc., and F. Hoffmann-La Roche Ltd. V.S. has served on scientific advisory boards for Astellas Gene Therapies, Biogen, Edgewise Therapeutics, Ipsen, Kate Therapeutics, ML Bio Solutions, Novartis Gene Therapies, PepGen, F. Hoffmann-La Roche Ltd, Sanofi, Sarepta Therapeutics, Inc., Vertex Pharmaceuticals, and Wave Therapeutics, has received speaker honoraria from Pfizer, F. Hoffmann-La Roche Ltd, Sanofi, and Sarepta Therapeutics, Inc., has received grants for clinical research from Sarepta Therapeutics, Inc. and Sanofi, and has received support from the NIHR Newcastle Biomedical Research Centre. M.G.O. is an employee of and hold stocks in F. Hoffmann-La Roche Ltd. J.B. is an employee of and hold stocks in F. Hoffmann-La Roche Ltd. F.M. reports participation in scientific advisory boards for Novartis Gene Therapies (formerly AveXis), Biogen, F. Hoffmann-La Roche Ltd, Italfarmaco, Pfizer, Dyne Therapeutics, and Sarepta Therapeutics, Inc., and is involved in research funded by Novartis Gene Therapies (formerly AveXis), Biogen, Sarepta Therapeutics, Inc., and F. Hoffmann-La Roche Ltd. A.T. has nothing to disclose other than his employment at SYSNAV, a company that collaborated with the Institute of Myology to create ActiMyo®. M.A. was an employee of SYSNAV at the time that this manuscript was developed. D.E. has nothing to disclose other than his employment at SYSNAV, a company that collaborated with the Institute of Myology to create ActiMyo®., (© 2024. The Author(s).)

Parkinson's Disease is a progressive neurodegenerative disorder afflicting almost 12 million people. Increased understanding of its complex and heterogenous disease pathology, etiology and symptom manifestations has resulted in the need to design, capture and interrogate substantial clinical datasets. Herein we advocate how advances in the deployment of artificial intelligence models for Federated Data Analysis and Federated Learning can help spearhead coordinated and sustainable approaches to address this grand challenge., Competing Interests: Competing interests: AK, LG and GJ are all employees of Novartis Pharmaceuticals and may hold common stock in the company. MD and JR are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may own stock and/or stock options. JA has received research support from the Michael J. Fox Foundation for Parkinson’s Research, NIH/NINDS, the Huntington Study Group, and PhotoPharmics; received compensation as a consultant/steering committee/advisory board member from the Huntington Study Group, the Parkinson Study Group, Sana Biotechnology, Biohaven, and the Michael J. Fox Foundation for Parkinson’s Research. CA is supported by the National Institute for Health Research Oxford Biomedical Research Centre and received research grant support from UCB Pharma, MSD, EPSRC and has been a consultant for UCB and J & J. BRB: No declaration. CC has been a consultant for AbbVie, Mission Therapeutics and Roche and received research funding from Parkinson’s UK, Edmond J Safra Foundation, National Institute of Health and Care Research and Cure Parkinson’s. JCe has been a consultant for VanquaBio, MiCure, Elsie Bio, has stock/options from Vanqua Bio, Micure, Immunobrain Checkpoint and has received grant funding from ASAP, the Marcus Foundation. JCo is an employee of AbbVie Pharmaceuticals. DTD: No declaration. JE is an employee of Biogen. EG is an employee of UCB Pharmaceuticals. DH has been a consultant for the Critical Path Institute, a share holder and employee of Panoramic Digital Health and received funding from the EPSRC, and France Relance. FH is employed part-time at Clario. ESI is an employee of Koneksa Health and may own company stock. TK is an employee of Takeda Pharmaceuticals. DK No declaration. CK No declaration. ML is a consultant to F. Hoffmann– La Roche Ltd via Inovigate. JM has consulted for and received funding from the Michael J Fox Foundation for Parkinson’s Research. KM No declaration. KMc No declaration. AM has been a consult for Koneksa and received grant funding from MJFF, JPND, US Department of Defense, and the EU IMI. MM No declaration. GP is an employee of F. Hoffmann La-Roche. MJP is an employee of Sanofi, and may hold shares and/or stock options in the company. LR has received honorarium from the MJ Fox Foundation and grant funding from EU, NIHR, MRC, EPSRC, Cure Parkinson’s Trust, PDUK, Dunhill Medical Trust. SS No declaration. AS has been a consultant to the following companies in the past year: Acadia, Boerhinger-Ingelheim, GE Healthcare, Wave Life Sciences, Inhibikase, Prevail, Mitzubishi and Alertity Therapeutics. He has served on DSMBs for the Huntington Study Group and The Healey ALS Consortium (Massachusetts General Hospital).He has received grant funding from the Michael J. Fox Foundation, NIA and NINDS. TS has served as a consultant for AskBio, Amneal, Blue Rock Therapeutics, Critical Path for Parkinson’s Consortium (CPP), Denali, General Electric, Kyowa, Neuroderm/ MTPA, Prevail/ Lilly, Roche, Sanofi, Sinopia, Takeda and Vanqua Bio. She has served on the ad board for AskBio, Amneal, Biohaven, Denali, GAIN, General Electric, Kyowa, MJFF, Neuron23, Parkinson Study Group, Prevail/ Lilly, and Roche. She has also served as a member of the scientific advisory board of Koneksa, Neuroderm/ MTPA, Sanofi and UCB. Dr. Simuni has received research funding from Amneal, Biogen, Neuroderm, Prevail, Roche, UCB and is an investigator for NINDS, MJFF, Parkinson’s Foundation. DS No declaration. CS-F No declaration. JAW is an employee of Koneksa Health and may own stock and/or stock options. No funding is associated with the production of this manuscript., (© 2024. The Author(s).)

Artificial intelligence (AI)-enabled decision aids can contribute to the shared decision-making process between patients and clinicians through personalised recommendations. This systematic review aims to understand users' perceptions on using AI-enabled decision aids to inform shared decision-making. Four databases were searched. The population, intervention, comparison, outcomes and study design tool was used to formulate eligibility criteria. Titles, abstracts and full texts were independently screened and PRISMA guidelines followed. A narrative synthesis was conducted. Twenty-six articles were included, with AI-enabled decision aids used for screening and prevention, prognosis, and treatment. Patients found the AI-enabled decision aids easy to understand and user-friendly, fostering a sense of ownership and promoting better adherence to recommended treatment. Clinicians expressed concerns about how up-to-date the information was and the potential for over- or under-treatment. Despite users' positive perceptions, they also acknowledged certain challenges relating to the usage and risk of bias that would need to be addressed.Registration: PROSPERO database: (CRD42020220320)., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Deep brain stimulation (DBS) can ameliorate motor symptoms in Parkinson's disease (PD), but its mechanism remains unclear. This work constructs a multi-scale brain model using the fMRI data from 27 PD patients with subthalamic DBS and 30 healthy controls. The model fits microscopic coupling parameters in the cortico-basal ganglia-thalamic neural loop to match individual connectivity, finding the "push-pull" effect of basal ganglia network. Specifically, increased GABAergic projection into the thalamus from basal ganglia worsens rigidity, while reduced GABAergic projection within the cortex exacerbates bradykinesia, suggesting that the dopamine deficiency induces the chain coupling variations to "push" the network to an abnormal state. Conversely, DBS can alleviate rigidity by enhancing GABAergic projections within the basal ganglia, and improve bradykinesia by reducing cortical projections to basal ganglia, exhibiting that DBS "pulls" the network to a healthy state. This work combines the microscopic and macroscopic neural information for understanding PD and its treatment., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The importance of accurate blood pressure (BP) measurement is well-established. However, there is little quantitative comparative data on the influence of different measurement conditions on BP or the stability of the oscillometric pulse waveform from which BP is calculated. This study investigates the effect of six different measurement conditions (Quiet, Reading, Speaking, Deep Breathing, Moving, and Tapping) on BP readings in 30 healthy normotensive subjects. We hypothesize that non-standard conditions will result in significant deviations in BP measurements compared to the Quiet condition. Additionally, the quality and stability of the oscillometric waveform were assessed by evaluating the smoothness of the oscillometric pulse waveform characteristics during cuff deflation. Compared with the Quiet condition, all others resulted in significantly higher blood pressures, except for the respiratory condition, which resulted in significantly lower BPs. Average subject systolic BP (SBP) rose from 117.4 ± 6.0 mmHg for the Quiet condition to 129.7 ± 7.2 mmHg for the light finger tapping condition, P < 0.00001. Overall, changes for diastolic BP (DBP) were not significant. For the quality Noise indicator, all conditions in comparison with the Quiet condition were significantly noisier, increasing from 0.144 ± 0.024 to 1.055 ± 0.308 mmHg, P < 0.00001. Changes in SBP were significantly correlated to changes in quality Noise (r = 0.965, P < 0.001). This study confirms the importance of following international BP measurement guidelines, providing quantitative data showing significant changes in BP when guidelines are not followed. A method for assessing the quality of the measurement is also demonstrated, and shows that BP changes are significantly related to changes in the quality indicator., Competing Interests: Competing interests: None declared. The patent for the technique is cited in the paper, but as yet there is no commercial agreement. Ethics Statement: The investigation conformed with the Declaration of Helsinki, and all subjects gave their written informed consent to participate in the study. Ethical approval was granted by the Independent Ethics Committee (IEC) for Clinical Research of Zhongda Hospital, affiliated with Southeast University, under approval number 2021ZDSYLL206-P01., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Stress hyperglycaemia is common in critical illness. We have previously observed that increasing severity of respiratory failure in patients with severe COVID-19 is associated with increased insulin demand. Given previously reported direct effects of hypoxia on insulin action, we reasoned that rapid improvements in oxygenation following prone positioning may improve insulin sensitivity and increase risk of hypoglycaemia. A retrospective multi-centre service evaluation comparing blood glucose and insulin administration in patients with COVID-19 pneumonitis receiving prone mechanical ventilation, comparing the 16 h pre-prone and 16 h post-prone time periods. 155 patients were included in this analysis. Oxygenation improved significantly following prone positioning (change in SpO 2 /FIO 2 per hour prone: 3.01 ± 0.14, P < 0.0001). Glycaemic control was similar during the supine and prone study periods, and there were no hypoglycaemic events in the prone study period. Prone positioning was associated with an unexpected modest but significant increase in insulin requirements (mean difference in total insulin dose (IU): 8.32 ± 2.14, P < 0.001) that was robust to several sensitivity analyses, and could not be explained by changes in carbohydrate intake. We did not observe an increased rate of hypoglycaemia during prone ventilation and the adequacy of glycaemic control was comparable during the supine and prone study periods. Unexpectedly, prone ventilation was associated with an increase in insulin requirements despite significant improvement in hypoxaemia. Our findings support the safety of prone ventilation with respect to glycaemic control and identify a novel relationship between ventilation position and insulin requirements in critical illness., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics approval and consent to participate This study was approved as a multisite service evaluation at the host institution (Cambridge University Hospitals Service development and Audit Department) and participation of additional centres was confirmed with their respective Audit Departments. The study was exempt from the need for NHS research ethics committee review according to UK Health Research Authority guidance, as it was deemed service evaluation using anonymised data. It was reviewed by the institutional review board (Cambridge University Hospitals) and deemed service evaluation using routinely collected data, with no data collected specifically for this study. All data was anonymised by the direct care team before being analysed centrally. The institutional review board confirmed a consent waiver. The study was registered as a multi-site service evaluation at Cambridge University Hospitals (ref number) and at each individual site., (© 2024. The Author(s).)

This untargeted metabolomics study investigated the synergistic antibacterial activity of polymyxin B and Leu 10 -teixobactin, a depsipeptide inhibitor of cell wall biosynthesis. Checkerboard microdilution assays revealed a significant synergy against polymyxin-susceptible and -resistant A. baumannii, excluding lipopolysaccharide-deficient variants. Time-kill assays confirmed bactericidal synergy, reducing bacterial burden by approximately 4-6-log 10 CFU/mL. The combination (2xMIC polymyxin B and 0.5xMIC Leu 10 -teixobactin) prevented bacterial regrowth after 24 h, indicating sustained efficacy against the emergence of resistant mutants. The analysis of A. baumannii ATCC™ 19606 metabolome demonstrated that the polymyxin B-Leu 10 -teixobactin combination produced more pronounced perturbation compared to the individual antibiotics across all time points (1, 3 and 6 h). Pathway analysis revealed that lipid metabolism, cell envelope biogenesis, and cellular respiration were predominantly impacted by the combination, and to a lesser extent by polymyxin B monotherapy. Leu 10 -teixobactin treatment alone had only a minor impact on the metabolome, primarily at the 6 h time point. Peptidoglycan assays confirmed the combination's concerted deleterious effects on bacterial cell envelope integrity. Electron microscopy further substantiated these findings, revealing pronounced cell envelope damage, membrane blebbing, and vacuole formation. These findings highlight the potential of the polymyxin B-Leu 10 -teixobactin combination as an effective treatment in preventing resistance in A. baumannii., (© 2024. The Author(s).)

Natural killer (NK) cells recognize and may kill malignant cells via their cell surface receptors. Killer cell immunoglobulin-like receptor (KIR) genotypes of donors have been reported to adjust the risk of relapse after allogeneic stem cell transplantation (HSCT), particularly in patients with acute myeloid leukemia. To test whether non-KIR NK cell receptors have a similar effect, we screened 1,638 genetic polymorphisms in 21 non-KIR NK cell receptor genes for their associations with relapse and graft-versus-host disease (GVHD) after HSCT in 1,491 HSCT donors (from Finland, the UK, Spain, and Poland), divided into a discovery and replication cohort. Eleven polymorphisms regulating or located in CD226, CD244, FCGR3A, KLRD1, NCR3, and PVRIG were associated with the risks for relapse and GVHD. These associations could not be confirmed in the replication cohort. Blood donor NK cells carrying alleles showing genetic protection for relapse had a higher in vitro NK cell killing activity than non-carriers whereas those with alleles genetically protective for GVHD had lower cytotoxicity, potentially indicating functional effects. Taken together, these results show no robust effects of genetic variation in the tested non-KIR NK cell receptors on the outcome of HSCT., (© 2024. The Author(s).)

Terrorism causes emotional reactions among public audiences, with downstream consequences for their well-being, attitudes and policy preferences. We utilise a novel approach which harnesses a unique dataset of Twitter activity from 324K users to precisely capture emotional responses to terrorism. Our results demonstrate that terrorist attacks induce dramatic spikes in various discrete emotions of a negative valence, which vary based on the characteristics of the attacks. Furthermore, we show that the terrorism-induced effects on emotions are accompanied by changes in feelings about immigration., (© 2024. The Author(s).)

Now extinct, the aurochs (Bos primigenius) was a keystone species in prehistoric Eurasian and North African ecosystems, and the progenitor of cattle (Bos taurus), domesticates that have provided people with food and labour for millennia 1 . Here we analysed 38 ancient genomes and found 4 distinct population ancestries in the aurochs-European, Southwest Asian, North Asian and South Asian-each of which has dynamic trajectories that have responded to changes in climate and human influence. Similarly to Homo heidelbergensis, aurochsen first entered Europe around 650 thousand years ago 2 , but early populations left only trace ancestry, with both North Asian and European B. primigenius genomes coalescing during the most recent glaciation. North Asian and European populations then appear separated until mixing after the climate amelioration of the early Holocene. European aurochsen endured the more severe bottleneck during the Last Glacial Maximum, retreating to southern refugia before recolonizing from Iberia. Domestication involved the capture of a small number of individuals from the Southwest Asian aurochs population, followed by early and pervasive male-mediated admixture involving each ancestral strain of aurochs after domestic stocks dispersed beyond their cradle of origin., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Human prenatal skin is populated by innate immune cells, including macrophages, but whether they act solely in immunity or have additional functions in morphogenesis is unclear. Here we assembled a comprehensive multi-omics reference atlas of prenatal human skin (7-17 post-conception weeks), combining single-cell and spatial transcriptomics data, to characterize the microanatomical tissue niches of the skin. This atlas revealed that crosstalk between non-immune and immune cells underpins the formation of hair follicles, is implicated in scarless wound healing and is crucial for skin angiogenesis. We systematically compared a hair-bearing skin organoid (SkO) model derived from human embryonic stem cells and induced pluripotent stem cells to prenatal and adult skin 1 . The SkO model closely recapitulated in vivo skin epidermal and dermal cell types during hair follicle development and expression of genes implicated in the pathogenesis of genetic hair and skin disorders. However, the SkO model lacked immune cells and had markedly reduced endothelial cell heterogeneity and quantity. Our in vivo prenatal skin cell atlas indicated that macrophages and macrophage-derived growth factors have a role in driving endothelial development. Indeed, vascular network remodelling was enhanced following transfer of autologous macrophages derived from induced pluripotent stem cells into SkO cultures. Innate immune cells are therefore key players in skin morphogenesis beyond their conventional role in immunity, a function they achieve through crosstalk with non-immune cells., Competing Interests: Competing interests: J.L. and K.R.K., with the Indiana University Research and Technology Corporation, have a patent relating to the methodology and composition of SkOs (PCT/US2016/058174). K.R.K. is a consultant for StemCell Technologies. All other authors declare no competing interests., (© 2024. The Author(s).)

Objective: The fragility index (FI) of a meta-analysis evaluates the extent that the statistical significance can be changed by modifying the event status of individuals from included trials. Understanding the FI improves the interpretation of the results of meta-analyses and can help to inform changes to clinical practice. This review determined the fragility of ophthalmology-related meta-analyses., Methods: Meta-analyses of randomized controlled trials with binary outcomes published in a journal classified as 'Ophthalmology' according to the Journal Citation Report or an Ophthalmology-related Cochrane Review were included. An iterative process determined the FI of each meta-analysis. Multivariable linear regression modeling evaluated the relationship between the FI and potential predictive factors in statistically significant and non-significant meta-analyses., Results: 175 meta-analyses were included. The median FI was 6 (Q1-Q3: 3-12). This meant that moving 6 outcomes from one group to another would reverse the study's findings. The FI was 1 for 18 (10.2%) of the included meta-analyses and was ≤5 for 75 (42.4%) of the included meta-analyses. The number of events (p < 0.001) and the p-value (p < 0.001) were the best predictors of the FI in both significant and non-significant meta-analyses., Conclusion: The statistical significance of meta-analyses in ophthalmology often hinges on the outcome of a few patients. The number of events and the p-value are the most important factors in determining the fragility of the evidence. The FI is an easily interpretable measure that can supplement the reader's understanding of the strength of the evidence being presented., Prospero Registration: CRD42022377589., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

T cells develop from circulating precursor cells, which enter the thymus and migrate through specialized subcompartments that support their maturation and selection 1 . In humans, this process starts in early fetal development and is highly active until thymic involution in adolescence. To map the microanatomical underpinnings of this process in pre- and early postnatal stages, we established a quantitative morphological framework for the thymus-the Cortico-Medullary Axis-and used it to perform a spatially resolved analysis. Here, by applying this framework to a curated multimodal single-cell atlas, spatial transcriptomics and high-resolution multiplex imaging data, we demonstrate establishment of the lobular cytokine network, canonical thymocyte trajectories and thymic epithelial cell distributions by the beginning of the the second trimester of fetal development. We pinpoint tissue niches of thymic epithelial cell progenitors and distinct subtypes associated with Hassall's corpuscles and identify divergence in the timing of medullary entry between CD4 and CD8 T cell lineages. These findings provide a basis for a detailed understanding of T lymphocyte development and are complemented with a holistic toolkit for cross-platform imaging data analysis, annotation and OrganAxis construction (TissueTag), which can be applied to any tissue., Competing Interests: Competing interests: J.C.M. has been an employee of Genentech since September 2022. S.A.T. is a scientific advisory board member of ForeSite Labs, OMass Therapeutics, Qiagen, a co-founder and equity holder of TransitionBio and EnsoCell Therapeutics, a non-executive director of 10x Genomics and a part-time employee of GlaxoSmithKline. The other authors declare no competing interests., (© 2024. The Author(s).)

Human embryonic bone and joint formation is determined by coordinated differentiation of progenitors in the nascent skeleton. The cell states, epigenetic processes and key regulatory factors that underlie lineage commitment of these cells remain elusive. Here we applied paired transcriptional and epigenetic profiling of approximately 336,000 nucleus droplets and spatial transcriptomics to establish a multi-omic atlas of human embryonic joint and cranium development between 5 and 11 weeks after conception. Using combined modelling of transcriptional and epigenetic data, we characterized regionally distinct limb and cranial osteoprogenitor trajectories across the embryonic skeleton and further described regulatory networks that govern intramembranous and endochondral ossification. Spatial localization of cell clusters in our in situ sequencing data using a new tool, ISS-Patcher, revealed mechanisms of progenitor zonation during bone and joint formation. Through trajectory analysis, we predicted potential non-canonical cellular origins for human chondrocytes from Schwann cells. We also introduce SNP2Cell, a tool to link cell-type-specific regulatory networks to polygenic traits such as osteoarthritis. Using osteolineage trajectories characterized here, we simulated in silico perturbations of genes that cause monogenic craniosynostosis and implicate potential cell states and disease mechanisms. This work forms a detailed and dynamic regulatory atlas of bone and cartilage maturation and advances our fundamental understanding of cell-fate determination in human skeletal development., Competing Interests: Competing interests: C.D.B. is a founder of Mestag Therapeutics. S.A.T. is a scientific advisory board member of ForeSite Labs, OMass Therapeutics, Qiagen, a co-founder and equity holder of TransitionBio and EnsoCell Therapeutics, a non-executive director of 10x Genomics and a part-time employee of GlaxoSmithKline. Sarah also holds equity in TransitionBio and options for equity in Element Biosciences, where she is a former SAB member.  All other authors declare no competing interests., (© 2024. The Author(s).)

The gastrointestinal tract is a multi-organ system crucial for efficient nutrient uptake and barrier immunity. Advances in genomics and a surge in gastrointestinal diseases 1,2 has fuelled efforts to catalogue cells constituting gastrointestinal tissues in health and disease 3 . Here we present systematic integration of 25 single-cell RNA sequencing datasets spanning the entire healthy gastrointestinal tract in development and in adulthood. We uniformly processed 385 samples from 189 healthy controls using a newly developed automated quality control approach (scAutoQC), leading to a healthy reference atlas with approximately 1.1 million cells and 136 fine-grained cell states. We anchor 12 gastrointestinal disease datasets spanning gastrointestinal cancers, coeliac disease, ulcerative colitis and Crohn's disease to this reference. Utilizing this 1.6 million cell resource (gutcellatlas.org), we discover epithelial cell metaplasia originating from stem cells in intestinal inflammatory diseases with transcriptional similarity to cells found in pyloric and Brunner's glands. Although previously linked to mucosal healing 4 , we now implicate pyloric gland metaplastic cells in inflammation through recruitment of immune cells including T cells and neutrophils. Overall, we describe inflammation-induced changes in stem cells that alter mucosal tissue architecture and promote further inflammation, a concept applicable to other tissues and diseases., Competing Interests: Competing interests: S.A.T. is a scientific advisory board member of ForeSite Labs, OMass Therapeutics, a co-founder and equity holder of TransitionBio and EnsoCell Therapeutics, a non-executive director of 10x Genomics and a part-time employee of GlaxoSmithKline. R.E. is an equity holder in EnsoCell. P.K. has consulted for AstraZeneca, UCB, Biomunex and Infinitopes. N.M.P reports consulting fees from Infinitopes. J.S.-R. reports funding from GSK, Pfizer and Sanofi and fees/honoraria from Travere Therapeutics, Stadapharm, Astex, Owkin, Pfizer, Moderna and Grunenthal. A.S. is the recipient of research grants from Roche-Genentech, Abbvie, GSK, Scipher Medicine, Pfizer, Alimentiv, Boehringer Ingelheim and Agomab and has received consulting fees from Genentech, GSK, Pfizer, HotSpot Therapeutics, Alimentiv, Agomab, Goodgut and Orikine. R.E. and S.A.T are inventors on the patent GB2412853.0 filed in the UK, some components of which are related to this work. All other authors declare no competing interests., (© 2024. The Author(s).)

Interest in how ageing affects attention is long-standing, although interactions between sensory and attentional processing in older age are not fully understood. Here, we examined interactions between peripheral hearing and selective attention in a spatialised cocktail party listening paradigm, in which three talkers spoke different sentences simultaneously and participants were asked to report the sentence spoken by a talker at a particular location. By comparing a sample of older (N = 61; age = 55-80 years) and younger (N = 58; age = 18-35 years) adults, we show that, as a group, older adults benefit as much as younger adults from preparatory spatial attention. Although, for older adults, this benefit significantly reduces with greater age-related hearing loss. These results demonstrate that older adults with excellent hearing retain the ability to direct spatial selective attention, but this ability deteriorates, in a graded manner, with age-related hearing loss. Thus, reductions in spatial selective attention likely contribute to difficulties communicating in social settings for older adults with age-related hearing loss. Overall, these findings demonstrate a relationship between mild perceptual decline and attention in older age., (© 2024. The Author(s).)

Aquatic species living in productive coastal habitats with abundant primary producers have evolved in highly dynamic diel and seasonally fluctuating environments in terms of, for example, water temperature and dissolved oxygen. However, how environmental fluctuations shape the thermal tolerance of marine species is still poorly understood. Here we hypothesize that the degree of predictability of the diel environmental fluctuations in the coastal area can explain the thermal response of marine species. To test this hypothesis, we measured the thermal tolerance of 17 species of marine ectotherm from tropical, warm temperate and cold temperate latitudes under two levels of oxygen (around saturation and at supersaturation), and relate the results to their site-specific temperature and oxygen fluctuation and their environmental predictability. We demonstrate that oxygen and temperature fluctuations at tropical latitudes have a higher predictability than those at warm and cold temperate latitudes. Further, we show that marine species that are adapted to high predictability have the potential to tune their thermal performance when exposed to oxygen supersaturation, despite being constrained within a narrow safety margin. We advocate that the predictability of the environmental fluctuation needs to be considered when measuring and forecasting the response of marine animals to global warming., (© 2024. The Author(s).)

Asthma is one of the most common chronic illnesses affecting children. Long-term asthma control medications (LTACMs) are an important aspect of asthma management, with under-prescription associated with poor asthma control and increased asthma deaths. This study aimed to document temporal trends in the prescribing of LTACMs for paediatric patients for asthma-related presentations to Australian general practice registrars (trainees). Longitudinal analyses of data from 2010 to 2022 from the Registrars Clinical Encounters in Training study were undertaken. Proportions of paediatric presentations where LTACMs were prescribed were calculated, and temporal trends analysed and graphed. There was no change over time in registrar prescribing of LTACMs for paediatric asthma, although temporal changes were seen in the types of LTACMs prescribed. The lack of temporal increase in overall LTACMs prescription, despite evidence showing their importance in preventing asthma morbidity and mortality, has significant educational, clinical, and policy implications., (© 2024. The Author(s).)

The colubrid snakes of the genera Gongylosoma Fitzinger, 1843 and Liopeltis Fitzinger, 1843 are distributed across south and southeast Asia with five and eight nominate species, respectively. Despite their wide distribution, members of these genera are among some of the least-known colubrids. The two genera were considered synonymous in the past only to be separated later, and are defined on rather nebulose characters with a lack of support from molecular data. To test the monophyly of the two genera, we generated molecular data for the type species of Gongylosoma and species representing the two genera, including samples of Liopeltis rappii (Günther, 1860) from the western Himalayas. Results recovered paraphyly of Liopeltis, especially with regard to the genus Gongylosoma. Morphological data supports recognizing the western and eastern populations of L. rappii as two distinct species. The findings from our integrative taxonomic approach advocate establishing a new genus to embody Liopeltis rappii and a new allied species from the central and western Himalayas. A rediagnosis and revised classification of the genera Gongylosoma and Liopeltis is presented. The results further hint at cryptic diversity across members of the two genera, warranting scrutiny of the most widespread members of the group., (© 2024. The Author(s).)

Normal pressure hydrocephalus (NPH) is associated with a reduction in cerebral blood flow and an ischemic metabolic state. Ischemia should exhaust the available autoregulation in an attempt to correct the metabolic imbalance. There is evidence of some retained autoregulation reserve in NPH. The aim of this study is to model the cerebral autoregulation in NPH to discover a solution to this apparent paradox. A lumped parameter model was developed utilizing the known limits of autoregulation in man. The model was tested by predicting the cerebral blood volume changes which would be brought about by changes in resistance. NPH and the post shunt state were then modeled using the known constraints provided from the literature. The model successfully predicted the cerebral blood volume changes brought about by altering the cerebral perfusion pressure to the limit of autoregulation. The model suggests that NPH is associated with a balanced increase in resistance within the arterial and venous outflow segments. The arterial resistance decreased after modelling shunt insertion. The model suggests that the cerebral blood flow is actively limited in NPH by arteriolar constriction. This may occur to minimize the rise in ICP by reducing the apparent CSF formation rate., (© 2024. Crown.)

Data Sources: PubMed, Scopus, Embase, Web of Science, Cochrane Library, and gray literature up to May 2023. Twelve studies were included for meta-analysis., Study Selection: Two authors screened databases to identify suitable studies, with a third investigator resolving disagreements. Inclusion criteria were randomized controlled trials (RCTs) involving individuals without systemic diseases, who underwent root canal treatment in a permanent tooth with or without apical patency. Outcomes included pain, number of patients with pain and analgesic use. Exclusion criteria included patients who had undergone tooth extraction, incomplete data reports and studies which were not RCTs. There were no limits on publication language. A search of PubMed, Scopus, Embase, Web of Science, Cochrane Library, and gray literature from Google Scholar, ProQuest, OpenAire, and BASE identified 92 articles until May 2023. After removing 42 duplicates, 50 article full texts were assessed. Ultimately, 12 studies were included, seven of which were new relative to previous systematic reviews., Data Extraction and Synthesis: Data were analysed using RevMan 5.4 software. Dichotomous categorical data were analysed through the Cochran-Mantel-Haenszel test, with the inverse variance method used for continuous data. Following assessment of heterogeneity with the χ 2 test, fixed- or random- effects modeling was used. Pain scores were reported within one week by ten studies, but three were excluded from meta-analysis due to methodological issues., Results: Studies involving participants aged 14-65 years, with pulp necrosis, apical periodontitis, or pulpitis, were included for analysis. Irrigation solutions varied from saline to sodium hypochlorite (2.25-5.25%), EDTA, citric acid, or chlorhexidine. Types of teeth treated included molars and anterior teeth. All studies used a 10# K-file for apical patency and various hand and nickel-titanium instruments for canal preparation. Generally, there was slightly reduced post-operative pain reported through the maintenance of patency. This was evident in the initial post-operative period of 24 h (OR = 1.69, P = 0.002), 1-day (MD = -1.69, P = 0.03) and 2-days (MD = -0.85, P = 0.04), but became non-significant over the remainder of the 7-day monitoring period. There was no significant difference in analgesic use between groups (OR = 0.82, P = 0.42). Studies were classified into three groups based on quality: four high quality with low risk of bias; three moderate quality with some concerns; and five low quality with high risk of bias. Evidence quality varied; pain scores on days 1 and 2 were of low quality, with very low quality for 12 h and days 3-6. High heterogeneity and imprecision were noted, especially in pain measurements and analgesic use., Conclusions: The meta-analysis indicates that during the initial post-operative period, apical patency significantly reduces postoperative pain. However, the findings should be interpreted cautiously due to high heterogeneity and variable evidence quality. Given that apical patency is seen as desirable for achieving the biological aims of endodontic treatment, the fact that it also appears to reduce post-operative pain helps to align patient reported outcome measures with traditional measures indicating success., (© 2024. Crown.)