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Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRDs) are broad-impact multifactorial neurodegenerative diseases. Their complexity presents unique challenges for developing effective therapies. This review highlights research presented at the 2024 Society for Neuroscience meeting which emphasized the gut microbiome's role in AD pathogenesis by influencing brain function and neurodegeneration through the microbiota–gut–brain axis. This emerging evidence underscores the potential for targeting the gut microbiota to treat AD/ADRD.

We applied reaction microscopy to elucidate fast non-adiabatic dissociation dynamics of deuterated water molecules after direct photo-double ionization at 61 eV with synchrotron radiation. For the very rare D+ + O+ + D breakup channel, the particle momenta, angular, and energy distributions of electrons and ions, measured in coincidence, reveal distinct electronic dication states and their dissociation pathways via spin-orbit coupling and charge transfer at crossings and seams on the potential energy surfaces. Notably, we could distinguish between direct and fast sequential dissociation scenarios. For the latter case, our measurements reveal the geometry and orientation of the deuterated water molecule with respect to the polarization vector that leads to this rare 3-body molecular breakup channel. Aided by multi-reference configuration-interaction calculations, the dissociation dynamics could be traced on the relevant potential energy surfaces and particularly their crossings and seams. This approach also unraveled the ultrafast time scales governing these processes.

IntroductionEmerging evidence links changes in the gut microbiome to late-onset Alzheimer's disease (LOAD), necessitating examination of AD mouse models with consideration of the microbiome.MethodsWe used shotgun metagenomics and untargeted metabolomics to study the human amyloid beta knock-in (hAβ-KI) murine model for LOAD compared to both wild-type (WT) mice and a model for early-onset AD (3xTg-AD).ResultsEighteen-month female (but not male) hAβ-KI microbiomes were distinct from WT microbiomes, with AD genotype accounting for 18% of the variance by permutational multivariate analysis of variance (PERMANOVA). Metabolomic diversity differences were observed in females, however no individual metabolites were differentially abundant. hAβ-KI mice microbiomes were distinguishable from 3xTg-AD animals (81% accuracy by random forest modeling), with separation primarily driven by Romboutsia ilealis and Turicibacter species. Microbiomes were highly cage specific, with cage assignment accounting for more than 40% of the PERMANOVA variance between the groups.DiscussionThese findings highlight a sex-dependent variation in the microbiomes of hAβ-KI mice and underscore the importance of considering the microbiome when designing studies that use murine models for AD.HighlightsMicrobial diversity and the abundance of several species differed in human amyloid beta knock-in (hAβ-KI) females but not males. Correlations to Alzheimer's disease (AD) genotype were stronger for the microbiome than the metabolome. Microbiomes from hAβ-KI mice were distinct from 3xTg-AD mice. Cage effects accounted for most of the variance in the microbiome and metabolome.

On December 5, 2022, an indirect drive fusion implosion on the National Ignition Facility (NIF) achieved a target gain G_{target} of 1.5. This is the first laboratory demonstration of exceeding "scientific breakeven" (or G_{target}>1) where 2.05 MJ of 351 nm laser light produced 3.1 MJ of total fusion yield, a result which significantly exceeds the Lawson criterion for fusion ignition as reported in a previous NIF implosion [H. Abu-Shawareb et al. (Indirect Drive ICF Collaboration), Phys. Rev. Lett. 129, 075001 (2022)PRLTAO0031-900710.1103/PhysRevLett.129.075001]. This achievement is the culmination of more than five decades of research and gives proof that laboratory fusion, based on fundamental physics principles, is possible. This Letter reports on the target, laser, design, and experimental advancements that led to this result.

Jolijn R van Leeuwen,1 Luca Quartuccio,2 Juliana Bordignon Draibe,3 Iva Gunnarson,4 Ben Sprangers,5 Y K Onno Teng1 1Center of Expertise for Lupus-, Vasculitis- and Complement-Mediated Systemic Diseases (Luvacs), Department of Internal Medicine - Nephrology Section, Leiden University Medical Center, Leiden, the Netherlands; 2Division of Rheumatology, Department of Medicine, University of Udine, Udine, Italy; 3Department of Nephrology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain; 4Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Karolinska University Hospital, Stockholm, Sweden; 5Department of Nephrology, Ziekenhuis Oost Limburg Genk, Genk, BelgiumCorrespondence: Y K Onno Teng, Department of Nephrology, Leiden University Medical Center (LUMC), P.O. Box 9600, Leiden, 2300 RC, the Netherlands, Tel +31-71-5262148, Fax +31-71-5266868, Email Y.K.O.Teng@lumc.nlAbstract: Recently, avacopan has been approved for the treatment of ANCA-associated vasculitis (AAV). Avacopan is an inhibitor of the C5a-receptor, which plays an important role in chemotaxis and the amplification loop of inflammation in AAV. In the most recent, international guidelines avacopan is recommended as steroid-sparing agents for the management of AAV. Here, we review the clinical trials that have led to demonstrate that avacopan is an effective treatment option in the management of AAV, where it can significantly reduce the cumulative dosage of glucocorticoids (GC). Despite the new guideline recommendations, clear guidance on how to employ avacopan in real-world clinical practice is lacking. We therefore also address in this review the data and clinical experience with avacopan obtained from real-world evidence. Combining preclinical studies, clinical trials, and real-world evidence helps to provide a better position of avacopan for the management of AAV in routine clinical practice, taking advantage of the GC-sparing effects of avacopan as a possible solution for the current challenge of reducing GC-toxicity in AAV patients. Furthermore, we delineate current knowledge gaps and future research areas that need to be addressed.Keywords: antineutrophil cytoplasmic antibody, ANCA, pauci-immune glomerulonephritis, complement, C5a inhibition, glucocorticoid toxicity

Grace Baldwin, John B Miller Retina Service, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USACorrespondence: John B Miller, Retina Service, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Harvard Retinal Imaging Lab, 243 Charles St, Boston, MA, 02114, USA, Tel +1 (617) 573-3750, Fax +1 (617) 573-3698, Email John_Miller@meei.harvard.eduPurpose of Review: Intimate partner violence (IPV) is a leading cause of death and disability across the world. We sought to investigate the prevalence and clinical presentation of ocular injuries in IPV.Recent Findings: Literature review revealed 16 published studies that evaluated ocular injuries in IPV, of which the study types included 9 retrospective studies, 2 prospective, 1 review, 1 invited commentary, 2 case reports, and 1 population-based cross-sectional survey. These studies suggest that 45% of IPV incidents involve ocular injury. Various injury types have been described including traumatic cataract, dislocated lens, retinal detachment, intraocular hemorrhage, orbital and zygomaticomaxillary complex fractures, optic nerve avulsion, and open globe injuries. Implementation of IPV screening programs in various clinical settings, including an emergency department evaluating ocular trauma, suggests a positive association with identification of IPV and improving access to resources.Summary: Within IPV, ocular injuries are a prevalent and important cause of vision loss. Various injuries have been reported affecting nearly every anatomical region of the eye. Routine screening for IPV among patients that present with ocular injuries and evaluating for visual complaints among patients experiencing IPV are both important. Future work focused on prospective studies and evaluation of screening techniques may be impactful.Keywords: intimate partner violence, ocular injuries, trauma

Søren Valgreen Knudsen,1,2 Inge Kristensen,3 Nanna Kure-Biegel,4 Mickael Bech,5 Hanne Agerbak,6 Camilla Plambeck Hansen,7 Christina Mohr-Jensen,1,8 Jan Brink Valentin,2 Michael Bang Petersen,9 Jan Mainz1,2,10,11 1Psychiatry, Aalborg University Hospital, Aalborg, Denmark; 2Danish Center for Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 3Danish Society for Patient Safety, Frederiksberg, Copenhagen, Denmark; 4Health and Care, Aarhus Municipality, Aarhus, Denmark; 5Department of Political Science and Public Management, University of Southern Denmark, Odense, Denmark; 6Local Government Denmark (KL), Copenhagen, Denmark; 7National Clinical Registries (RKKP), the Danish Clinical Quality Program, Aarhus, Denmark; 8Institute of Communication and Psychology, Aalborg University, Aalborg, Denmark; 9Department of Political Science, Aarhus University, Aarhus, Denmark; 10Department for Community Mental Health, Haifa University, Haifa, Israel; 11Department of Health Economics, University of Southern Denmark, Odense, DenmarkCorrespondence: Søren Valgreen Knudsen, Psychiatry, Aalborg University Hospital, Møllegade 10, 9000, Aalborg, Denmark, Tel +45 25215522, Email soeren.k@rn.dkIntroduction: The COVID-19 pandemic disrupted global economies, social structures, and public health systems. However, Denmark stood out as an exception, maintaining steady life expectancy during this period. This raises important questions about the factors that strengthened the Danish healthcare system and society against the pandemic’s challenges.Methods: The Danish healthcare system serves 5.8 million citizens with free care, advanced digital infrastructure, and comprehensive health registers. Under the auspices of the Danish Society for Patient Safety, insights from Denmark’s response to COVID-19 were collected from the onset of the pandemic. This paper builds on these collected experiences, covering crucial areas such as strategies to reduce transmission, digitalization, management of non-COVID diseases, tracking adverse events, workplace well-being, development and use of predictive models, and maintaining public trust. Patient-level data on contacts, contact types, and clinical procedures were obtained from health administrative systems and clinical quality registries. All results were reported as raw counts, with no statistical analyses applied.Results: During COVID-19, Denmark’s healthcare system demonstrated resilience by adapting swiftly, achieving a high vaccination rate, shifting to virtual care, enhancing response capacity through real-time adverse event tracking, and supporting healthcare workers through crisis teams minimizing prolonged sick leave. Predictive models accurately forecasted healthcare demands, while public health strategies focused on monitoring public behavior and trust in authorities.Discussion: A key lesson from Denmark’s handling of COVID-19 is that much of the observed resilience stemmed from pre-existing structures that could be reused, further developed, and expanded. This resilience was further enhanced by an unprecedented readiness for change, cross-sectoral and interdisciplinary collaboration, and the removal of typical barriers. These experiences aim to further improve the quality and resilience of healthcare in Denmark and inspire other countries’ healthcare systems. Moving forward, acknowledging chronic conflicts as the new normal, coupled with the reminder that “hope is not a strategy”, could serve as a pivotal approach.Keywords: health services research, crisis management, quality of care, patient safety, working wellbeing, adverse events

Kenneth Lado Sube,1 Joseph Daniel Wani Lako,2 Justin Bruno Tongun,3 Tatjana Gerber,4 Jurel Payii Mamur,4 Sekonjo Juliano Hamid Moto,4 Stephen Raimon Legge Jada,5 Joseph Nelson Siewe Fodjo,6 Adrian Dennis Hopkins,7 Charles D Mackenzie,8,9 Robert Colebunders6,10 1Department Ophthalmology, College of Medicine, University of Juba, Juba, South Sudan; 2Department of Biotechnology, College of Applied and Industrial Sciences, University of Juba, Juba, South Sudan; 3Department of Pediatrics and Child Health, College of Medicine, University of Juba, Juba, South Sudan; 4Catholic Diocese of Wau, Wau, Western Bahr El Ghazal State, South Sudan; 5Amref Health Africa, Juba, South Sudan; 6Global Health Institute, University of Antwerp, Antwerp, Belgium; 7Neglected and Disabling Diseases of Poverty Consultant, Gravesend, Kent DA11 OSL, UK; 8Cor-NTD, Task Force for Global Health, Atlanta, Georgia, USA; 9The END Fund, Neglected Tropical Diseases, New York, NY, USA; 10Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, UKCorrespondence: Robert Colebunders, Global Health Institute, University of Antwerp, Antwerp, Belgium, Email robert.colebunders@uantwerpen.beIntroduction: Raga County is an onchocerciasis-endemic area in the Western Bahr El Ghazal state of South Sudan, known to have a high prevalence of blindness. The objective of this study was to determine the causes of eye disease and blindness in Raga County as well as to assess the relationship of eye diseases with other prevalent conditions like onchocerciasis and epilepsy.Methods: We reviewed unpublished pre-community directed treatment with ivermectin (CDTI) data about eye disease and onchocerciasis in Western Bahr El Ghazal including Raga. In addition, a cross-sectional study was conducted from 21st March to 2nd April 2023 in 11 villages in Raga County. Participants were persons with blindness or other eye/vision problems, recruited via a community-based approach. Two senior ophthalmic clinical officers, supervised by an experienced ophthalmologist, performed the following assessments on participants: visual acuity measurement with Snellen Charts, anterior chamber examination with a loupe, and fundoscopy to assess the posterior segment with direct and indirect ophthalmoscopes.Results: Pre-CDTI data showed that the most severe vision problems in villages with a high prevalence of O. volvulus infection were caused by onchocerciasis eye disease. During the 2023 survey, in total, 1559 persons (3,118 eyes) were examined (mean age: 47 ± 19.2 years, 58.4% male). The most frequent eye diagnosis was allergic conjunctivitis, observed in 1453 (46.6%) eyes of the participants. The main causes of blindness were onchocerciasis-related blindness (22.6%, caused by onchocerciasis chorioretinitis (9.4%), sclerosing keratitis, punctate keratitis (5.6%), and onchocerciasis optic neuropathy (7.6%)), and cataract (9.3%). A significantly higher proportion of persons with epilepsy presented with clinical signs of onchocerciasis including blindness (53.2%), compared to persons without epilepsy (32.5%) (p = 0.0007).Conclusion: Despite years of CDTI, the main causes of blindness in Raga County remain onchocerciasis-related blindness observed in 22.6% and cataract observed in 9.3% of the study participants. The study confirmed an epidemiological association between onchocerciasis and epilepsy.Keywords: Onchocerciasis, ocular disease, blindness, epilepsy, nodding syndrome, ivermectin

Steven Mullane,1 Jacob B Hicks,2 Kazi Sharmin,1 Camden Harrell,1 Angie Rock,1 Crystal Miller1 1BIOTRONIK Inc., Lake Oswego, OR, 97035, USA; 2BIOTRONIK NRO INC., Lake Oswego, OR, 97035, USACorrespondence: Steven Mullane, BIOTRONIK, Inc., 6024 Jean Road, Lake Oswego, OR, 97070, USA, Tel +503-201-3892, Email steven.mullane@biotronik.comBackground: As part of Electrophysiology Predictable and Sustainable Implementation of National Registries (EP PASSION), a multi-stakeholder collaboration between the US Food and Drug Administration (FDA), academic and society partners, and cardiovascular implantable electronic device manufacturers, a 5-year bradycardia lead study transitioned from a traditional post-approval study (PAS) to a real-world data (RWD) approach using a novel method to evaluate chronic cardiac lead complications.Methods: Lead complications were identified using a combination of diagnosis and procedure codes from 2013 to 2020 fee-for-service Medicare claims data along with BIOTRONIK device registration and Medical Device Reporting data from patients implanted between 2013 and 2015 with a Solia S lead. A proof-of-concept analysis was performed using McNemar’s test to compare lead complications reported in the traditional PAS with lead complications identified in the RWD. Kaplan–Meier survival and incidence rates were evaluated to determine real-world long-term safety.Results: The proof-of-concept analysis of 896 patients found in both traditional PAS and RWD sources demonstrated a 99.7% proportion of overall agreement in identifying lead complications (p = 0.0833). Following this validation, 1841 study leads from 1015 Medicare patients were analyzed. A total of 33 lead complications (attributable or possibly attributable to the study lead) were identified for a rate of 0.005 complications per lead-year. The complication-free rate at 5-years post-implant was 97.2% (95% CI: 96.07%, 98.06%).Conclusion: These results led to the first FDA approval for transition of a cardiac lead PAS to long-term safety reporting using RWD, paving the way for future real-world cardiac lead and device surveillance studies.ClinicalTrials.gov Identifier: NCT01791127.Keywords: real-world data, real-world evidence, cardiac lead, pacemaker

Alexander Evans,1 Yasir Tarabichi,2 Wilson D Pace,3,4 Barry Make,5 Nicholas Bushell,6 Victoria Carter,7 Ku-Lang Chang,8 Chester Fox,9 MeiLan K Han,10 Alan Kaplan,11,12 Janwillem WH Kocks,13– 15 Chantal Le Lievre,6 Alexander Roussos,6 Neil Skolnik,10,16 Joan B Soriano,17 Barbara P Yawn,10 David Price1,6,7,18 1Observational and Pragmatic Research Institute, Singapore, Singapore; 2Center for Clinical Informatics Research and Education, MetroHealth, Cleveland, OH, USA; 3DARTNet Institute, Aurora, CO, USA; 4Department of Family Medicine, Anschutz Medical Campus University of Colorado, Aurora, CO, USA; 5Department of Medicine, National Jewish Hospital, Denver, CO, USA; 6Optimum Patient Care, Brisbane, Queensland, Australia; 7Optimum Patient Care, Oakington, Cambridge, UK; 8Lucas Research, a Centricity Research Company, Morehead City, NC, USA; 9University at Buffalo, Buffalo, NY, USA; 10University of Minnesota, Minneapolis, MN, USA; 11Family Physician Airways Group of Canada, Stouffville, Ontario, Canada; 12University of Toronto, Toronto, Canada; 13General Practitioners Research Institute, Groningen, the Netherlands; 14Groningen Research Institute Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 15Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 16Abington Jefferson Health, Jenkintown, PA, USA; 17School of Medicine, Universitat de les Illes Balears, Palma, Spain; 18Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UKCorrespondence: David Price, Observational and Pragmatic Research Institute, 22 Sin Ming Lane, &num;06-76, Midview City, Singapore, 573969, Singapore, Tel +65 3105 1489, Email dprice@opri.sgBackground: Preserved ratio impaired spirometry (PRISm) represents a population with spirometry results that do not meet standardized COPD obstruction criteria, yet present with high respiratory symptom burden and might benefit from respiratory management and treatment. We aimed to determine prevalence of PRISm in US primary care patients diagnosed with COPD, describe their demographic, clinical, and CT scan characteristics.Methods: An observational registry study utilizing the US APEX COPD registry, composed of patients diagnosed with COPD aged 35+ years. Demographic and clinical data were collected from EHRs and complemented by questionnaires. Multivariable logistic regression was performed to assess whether PRISm predicts lung function decline.Results: Prevalence of PRISm within a primary care population clinically diagnosed with COPD was 23.6% (678/2866, 95% CI 22.0– 25.1). Those with PRISm were more likely female (55.9% vs 46.9%), younger (66.3± 11.1 vs 69.2± 10.3 years), with a greater mean BMI (33.5± 9.2 vs 27.8± 7.2 kg/m2), more often African American or Hispanic (37.2% vs 26.3%), and with fewer current smokers (33.1% vs 36.8%) when compared to those meeting COPD spirometry criteria (all p< 0.05). Compared to COPD GOLD 0 patients, individuals with PRISm had greater BMI (33.5± 9.2 vs 30.6± 7.8), and were more likely current smokers (33.1% vs 23.4%), both p< 0.05. Patients with PRISm had similar respiratory symptoms (chronic bronchitis, CAT, and mMRC) to overall COPD patients, but more frequently than GOLD 0 COPD patients (p< 0.01). Emphysema was more commonly reported in CT scans from patients with PRISm 70.3% (260/369, 95% CI 65.8– 75.3) than those with GOLD 0 COPD 64.1% (218/340, 95% CI 58.8– 69.2) (p< 0.05). PRISm status was not predictive of lung function decline.Interpretation: One in four primary care patients with clinically diagnosed COPD in a large US registry fulfil the spirometric definition of PRISm rather than COPD, but suffers from emphysema in CT and significant respiratory symptoms.Keywords: APEX, COPD, PRISm, US primary care, COPD exacerbations, electronic health records, patient reported outcomes

Mohamed Mustaf Ahmed,1,2 Hassan Hakeem Kayode,3 Olalekan John Okesanya,4 Bonaventure Michael Ukoaka,5 Gilbert Eshun,6,7 Marina Ramzy Mourid,8 Olaniyi Abideen Adigun,9 Jerico Bautista Ogaya,10,11 Zeinab Omar Mohamed,1 Don Eliseo Lucero-Prisno III12– 14 1Faculty of Medicine and Health Sciences, SIMAD University, Mogadishu, Somalia; 2Institute for Global Health, SIMAD University, Mogadishu, Somalia; 3Department of Medical Laboratory Science, Oyo State Hospital Management Board, Oyo, Nigeria; 4Faculty of Medicine, Department of Public Health and Maritime Transport, University of Thessaly, Volos, Greece; 5Community and Clinical Research Division, First on-Call Initiative, Port Harcourt, Nigeria; 6Department of Medicine, Seventh Day Adventist Hospital, Asamang, Ghana; 7The Royal (Dick) School of Veterinary Studies and the Roslin Institute, University of Edinburgh, Midlothian, UK; 8Faculty of Medicine, Alexandria University, Alexandria, Egypt; 9Department of Medical Laboratory Science, Nigerian Defence Academy, Kaduna, Kaduna State, Nigeria; 10Department of Medical Technology, Institute of Health Sciences and Nursing, Far Eastern University, Manila, Philippines; 11Center for University Research, University of Makati, Makati City, Philippines; 12Department of Global Health and Development, London School of Hygiene and Tropical Medicine, London, UK; 13Research and Innovation Office, Southern Leyte State University, Sogod, Leyte, Philippines; 14Research and Development Office, Biliran Province State University, Naval, Biliran, PhilippinesCorrespondence: Mohamed Mustaf Ahmed, Email momustafahmed@simad.edu.soBackground: Antimicrobial resistance (AMR) is a critical global health concern that threatens the efficacy of existing antibiotics and poses significant challenges to public health and the economy worldwide. This review explores the potential of CRISPR-Cas systems as a novel approach to combating AMR and examines current applications, limitations, and prospects.Methods: A comprehensive literature search was conducted across multiple databases, including PubMed, Google Scholar, Scopus, and Web of Science, covering publications published from 2014 to August 2024. This review focuses on CRISPR-Cas technologies and their applications in AMR.Results: CRISPR-Cas systems have demonstrated efficacy in combating antimicrobial resistance by targeting and eliminating antibiotic-resistance genes. For example, studies have shown that CRISPR-Cas9 can effectively target and eliminate colistin resistance genes in MCR-1 plasmids, restoring susceptibility to carbapenems in bacteria such as E. coli and Klebsiella pneumoniae. Further molecular findings highlight the impact of CRISPR-Cas systems on various bacterial species, such as Enterococcus faecalis, in which CRISPR systems play a crucial role in preventing the acquisition of resistance genes. The effectiveness of CRISPR-Cas in targeting these genes varies due to differences in CRISPR locus formation among bacterial species. For instance, variations in CRISPR loci influence the targeting of resistance genes in E. faecalis, and CRISPR-Cas9 successfully reduces resistance by targeting genes such as tetM and ermB.Conclusion: CRISPR-Cas systems are promising for fighting AMR by targeting and eliminating antibiotic-resistant genes, as demonstrated by the effective targeting of colistin resistance genes on MCR-1 plasmids and their similar activities. However, the effectiveness of CRISPR-Cas is affected by variations in the CRISPR loci among bacterial species. Challenges persist, such as optimizing delivery methods and addressing off-target effects to ensure the safety and precision of CRISPR-Cas systems in clinical settings.Keywords: CRISPR-Cas systems, antimicrobial resistance, gene editing, bacteriophage delivery

Scovia Nalugo Mbalinda,1,&ast; Mark Kaddumukasa,2,&ast; Josephine Nambi Najjuma,3,&ast; Doreen R Birungi,2,&ast; Martin Ntambi Kaddumukasa,1,4,&ast; Jennifer B Levin,5,&ast; Carolyn Harmon Still,6,&ast; Christopher J Burant,7,&ast; Avani C Modi,8,&ast; Elly T Katabira,2,&ast; Martha Sajatovic5,&ast; 1Department of Nursing, College of Health Sciences, Makerere University, Kampala, Uganda; 2Department of Medicine, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda; 3Department of Nursing, Mbarara University of Science and Technology, Mbarara, Uganda; 4Department of Medicine, Mulago Hospital, Kampala, Uganda; 5Neurological and Behavioral Outcomes Center, University Hospitals Cleveland Medical Center & Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA; 6Louis Stokes VA Medical Center, Geriatric Research Education, and Clinical Center, Cleveland, OH, 44106, USA; 7Frances Payne Bolton School of Nursing, Case Western Reserve University, Cleveland, OH, 44106, USA; 8Cincinnati Children, S Hospital Medical Center, Cincinnati, Ohio, USA&ast;These authors contributed equally to this workCorrespondence: Scovia Nalugo Mbalinda, Email snmbalinda@gmail.comBackground: People of all ages are affected by epilepsy, a prevalent chronic brain illness that is primarily found in underdeveloped nations. It is very necessary to implement epilepsy self-management techniques to support individuals with epilepsy in order to impact outcomes related to epilepsy. The purpose of this 2-site randomised controlled experiment is to investigate this further, based on encouraging preliminary evidence.Methods: A total of 188 adult people with epilepsy (PWE) attending the neurology clinics at Mulago and Mbarara hospitals and consent to participate in the study will be recruited. They will be randomised into intervention versus enhanced treatment control (eTAU) study groups. The intervention group will receive 12-week “intensive” educational sessions and a 12-week remotely accessed telephone follow-up stage. The controls will continue in their usual care supplemented by written materials on epilepsy in their preferred language and tailored to the reading level of most patients at the clinic. SMART-U consists of 2 main components: a 12-week “intensive” group format stage and a 12-week remotely accessed telephone follow-up stage. SMART-U will be assessed for acceptability, fidelity, and efficacy compared to eTAU. The primary study outcome is the mean change in cumulative past 24-week seizure frequency (24 weeks prior to the study baseline compared to the 24-week follow-up). Seizure frequency will be via self-report with corroboration by family/support system informants whenever possible. Participants will self-report the seizure frequency (numeric count) that they experienced between baseline and 13 weeks and again between 13 and 24 weeks, and the mean change from baseline to 24 weeks in QOL.Discussion: The curriculum-guided Self-Management intervention for Reducing The epilepsy burden among Ugandans (SMART-U) program is anticipated to reduce the epilepsy burden seizure frequency and improve other health outcomes, including depression, functional status and health resource use.Trial Registration Number (TRN): NCT06139198.Date of registration: November142023.Keywords: self-management, epilepsy, targeted management, intervention

Schistosomiasis is a disease affecting >200 million people worldwide, but its treatment relies on a single agent, praziquantel. To investigate new avenues for schistosomiasis control, we have conducted the first systematic analysis of bromodomain-containing proteins (BCPs) in a causative species, Schistosoma mansoni. Having identified 29 putative bromodomains (BRDs) in 22 S. mansoni proteins, we selected SmBRD3, a tandem BRD-containing BCP that shows high similarity to the human bromodomain and extra terminal domain (BET) family, for further studies. Screening 697 small molecules identified the human BET BRD inhibitor I-BET726 as a ligand for SmBRD3. An X-ray crystal structure of I-BET726 bound to the second BRD of SmBRD3 [SmBRD3(2)] enabled rational design of a quinoline-based ligand (15) with an ITC Kd = 364 ± 26.3 nM for SmBRD3(2). The ethyl ester pro-drug of compound 15 (compound 22) shows substantial effects on sexually immature larval schistosomula, sexually mature adult worms, and snail-infective miracidia in ex vivo assays.

We have captured an 8.7 A conformational change that takes place in the cleavage site of the hammerhead ribozyme during self-cleavage, using X-ray crystallography combined with physical and chemical trapping techniques. This rearrangement brings the hammerhead ribozyme from the ground state into a conformation that is poised to form the transition state geometry required for hammerhead RNA self-cleavage. Use of a 5’-C-methylated ribose adjacent to the cleavage site permits this ordinarily transient conformational change to be kinetically trapped and observed crystallographically after initiating the hammerhead ribozyme reaction in the crystal. Cleavage of the corresponding unmodified hammerhead ribozyme in the crystal under otherwise identical conditions is faster than in solution, indicating that we have indeed trapped a catalytically relevant intermediate form of this RNA enzyme

BackgroundSchwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas.MethodsWe performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a fetal glial cell model following transduction with wildtype and tumor-derived mutant isoforms of SOX10.ResultsWe identified that nearly one-third of sporadic schwannomas lack alterations in known nerve sheath tumor genes and instead harbor novel recurrent in-frame insertion/deletion mutations in SOX10, which encodes a transcription factor responsible for controlling Schwann cell differentiation and myelination. SOX10 indel mutations were highly enriched in schwannomas arising from nonvestibular cranial nerves (eg facial, trigeminal, vagus) and were absent from vestibular nerve schwannomas driven by NF2 mutation. Functional studies revealed these SOX10 indel mutations have retained DNA binding capacity but impaired transactivation of glial differentiation and myelination gene programs.ConclusionsWe thus speculate that SOX10 indel mutations drive a unique subtype of schwannomas by impeding proper differentiation of immature Schwann cells.

Ya-Qing Lin,1 Na Li,2 Yan-Li Wu,1 Jin-Bao Ma,3 Hai-Nv Gao,1 Xuan Zhang4 1Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan (Hangzhou) Hospital Affiliated to Shulan International Medical College, Zhejiang Shuren University, Hangzhou, People’s Republic of China; 2Zhejiang Provincial General Hospital of the Chinese People’s Armed Police Force, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Drug-Resistance Tuberculosis, Xi’an Chest Hospital, Xi’an, People’s Republic of China; 4State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Xuan Zhang, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China, Tel/Fax +86-571-87236479, Email zhangxuanxz@zju.edu.cn Hai-Nv Gao, Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan (Hangzhou) Hospital Affiliated to Shulan International Medical College, Zhejiang Shuren University, Hangzhou, People’s Republic of China, Tel +86-571-56757279, Email hainv.gao@shulan.comPurpose: There is a lack of real-world data on the epidemiology, clinical manifestations, treatment effects, and prognosis of coronavirus disease 2019 (COVID-19) in patients with B-cell non-Hodgkin lymphoma (B-NHL). This study aimed to investigate the clinical features and prognostic factors of COVID-19 in patients with B-NHL.Patients and Methods: This study included individuals diagnosed with B-NHL who were also diagnosed with COVID-19 and hospitalized. A retrospective analysis was conducted, and univariate and multivariate logistic regression were used to identify independent factors affecting the duration of the positive-to-negative transition of COVID-19 nucleic acid test results and prognoses. Receiver operating characteristic curves were used to assess diagnostic accuracy and determine the optimal threshold.Results: Among 80 patients with COVID-19 and B-NHL, relapsed or refractory lymphoma and diffuse large B-cell lymphoma (DLBCL) accounted for 13.8% and 65% of cases, respectively. The mean age was 60.4 ± 13.0 years, and 50% of patients were women. The median duration of the positive-to-negative transition was 14 days (interquartile range [IQR], 17.2), and the median hospitalization duration was 12 days (IQR, 13). The rate of severe disease was 26.25%, and the 28-day mortality rate was 10.00%. Univariate and multivariate logistic regression analyses revealed that pathological classification of B-NHL, infection with COVID-19 within 3 months after the last dose of anti-CD20 monoclonal antibodies, and corticosteroid use were independent factors associated with a prolonged duration of the positive-to-negative transition. Compared with patients with DLBCL or FL and COVID-19, patients with B-NHL had longer nucleic acid test transition durations and higher rates of severe disease and mortality.Conclusion: In patients with B-NHL, infection with COVID-19 within 3 months after treatment with anti-CD20 monoclonal antibodies prolonged the positive-to-negative transition of nucleic acid test results and increased the risks of severe disease and 28-day mortality. Treatment with corticosteroids further prolonged this transition.Keywords: COVID-19 infection, B-cell non-Hodgkin lymphoma, clinical features, prognosis

Immaculate Mandera,1 Geoffrey Ayebazibwe,2 Alex Tumusiime,1 Topher Byamukama,3 Valence Mfitumukiza,1 John Bosco Tamu Munezero,1 Timothy Nduhukire,4 Everd B Maniple3 1Department of Nursing Sciences, Kabale University, Kampala, Uganda; 2Department of Pharmacology, Kabale University, Kampala, Uganda; 3Department of Community Health, Kabale University, Kampala, Uganda; 4Department of Pediatrics and Child health, Kabale University, Kampala, UgandaCorrespondence: Immaculate Mandera, Email imandera@kab.ac.ugBackground: Globally, > 1.1 million children had tuberculosis (TB) and > 214,000 died in 2022. The integration of pediatric TB screening should help in the identification and management of cases among children attending clinics at entry points. This study aimed to establish the extent of integrating pediatric TB screening into mainstream childcare activities and the factors affecting integration of TB screening among children.Methods: A cross-sectional design using both quantitative and qualitative methods. Simple random sampling was used to select and observe 40 participants for integration of TB screening in the routine assessment of children. Twenty key informants were interviewed and two focus group discussions conducted on the integration of pediatric TB screening.Results: Of the 302 children assessed, only 41.1% underwent pediatric TB screening integrated in their assessment. A binary logistic regression model using Wald chi-square showed that a cadre having worked at outpatient department (OPD) and young child clinic (YCC) significantly affected integration, with a p-value of 0.002 and 95% CI (1.040– 1.152) and a p-value of 0.002 and 95% CI (1.000– 1.519). Participants who had 3 to 5 years in service were 7.05 times more likely to integrate pediatric TB screening at the OPD and Cadres who had over 6 years in service were 6.32 times more likely at the YCC. Being a nurse or a midwife was associated with an increased likelihood of integrating pediatric tuberculosis screening. Knowledge, skills, and confidence gaps in screening and assessing for tuberculosis in children among staff and lack of necessary logistics were identified barriers.Conclusion: The integration of pediatric TB screening in routine assessments at the OPD/YCC was low. Focus more on HC IIIs to improve health workers’ involvement and capacity to integrate TB screening at entry points in health facilities and provide logistics.Keywords: Pediatric, tuberculosis, integration and screening

Joo Sung Shim,1 Youhyun Kim,1 Taeho Yuh,1 Jii Bum Lee,2 Hye Ryun Kim,2 Min Hee Hong,2 Byoung Chul Cho,2 Sun Min Lim2 1Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; 2Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of KoreaCorrespondence: Sun Min Lim, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea, Tel +82-2-2228-1946 ; +82-10-2520-3969, Email Limlove2008@yuhs.acPurpose: Small-cell lung cancer (SCLC) accounts for approximately 10– 15% of all lung cancers and is characterized by a high recurrence rate, early metastasis, and poor prognosis. Before the FDA approved lurbinectedin for SCLC that progressed on or after platinum-based chemotherapy in 2020, topotecan was the sole second-line option associated with hematological toxicities and modest efficacy. Lurbinectedin received conditional approval in Korea in September 2022 for metastatic SCLC progression, with the same indications. Real-world data on its efficacy remains scarce owing to its recent implementation.Patients and Methods: Patients with metastatic SCLC who progressed on or after first-line therapy (n = 51) at Yonsei Cancer Center, Seoul, received lurbinectedin at 3.2 mg/m². Efficacy data, including tumor response, progression, survival, and demographics, were recorded.Results: A total of fifty-one patients received lurbinectedin between April 2023 and March 2024, with thirty-four patients being eligible for the assessment. At diagnosis, approximately one-third of the patients were female, 3% had a poor performance status with an Eastern Cooperative Oncology Group Performance Score (ECOG PS ≥ 2), and the median age was 68. Most patients (80%) had extensive disease. Overall objective response rate (ORR) and disease control rate (DCR) were 20% and 47%, respectively. The median progression-free survival (PFS) was 2.8 months, and the median overall survival (OS) was 3.3 months. Never smokers showed prolonged OS compared with current/former smokers (Smokers; 3.0 vs 7.3 months). Common adverse effects were nausea (53%), loss of appetite (24%), general weakness (18%), anemia (29%), neutropenia (12%), dizziness (6%), alopecia (6%), thrombocytopenia (3%), and pneumonia (3%). Overall, 24% of the patients experienced grade ≥ 3 adverse events (AEs), with the most common being anemia (9%) and neutropenia (9%).Conclusion: Real-world data suggest that lurbinectedin is a viable option for patients with SCLC who have progressed on or after platinum-based chemotherapy.Keywords: SCLC, lurbinectedin, real-world evidence, second line

Pierre Louis Bernard,1 Xavier de la Tribonniere,2 Alessandra Pellecchia,2 Lucie Gamon,3 Fanchon Herman,3 Marie-Christine Picot,3 Nathalie J Raffort,4 Thierry Paillard,5 Jean-Baptiste Robiaud,6 Gregory Ninot,7 Jean Bousquet,8 Hubert Blain6 1Euromov Digital Health in Motion, Université de Montpellier, IMT Mines d’Ales, France; 2Transversal Patient Education Unit (UTEP), University Hospital of Montpellier, Montpellier, France; 3Centre d’Investigation Clinique 1411, University Hospital of Montpellier, Montpellier, France; 4Balaruc-les-bains balneotherapy centre, Balaruc-les-bains, France; 5Movement, Balance, Performance and Health Laboratory, University of Pau and Pays de l’Adour, Tarbes, France; 6Department of Geriatrics, University of Montpellier, Montpellier, France; 7Desbrest Institute of Epidemiology and Public Health UMR 1318 Inserm - University of Montpellier, Montpellier, France; 8Institute of Allergology, Charite - Universitätsmedizin Berlin, Berlin, GermanyCorrespondence: Hubert Blain, Email h-blain@chu-montpellier.frBackground: The effects on gait and posture of balneotherapy in fallers are unknown. We assessed the effects on physical functioning and fear of falling of a balneotherapy program alone or combined with a physical activity and educational program in older adult fallers.Methods: A multicenter randomized controlled trial enrolled patients aged 65 or older referred to a 3-week balneotherapy program, and screened for risk of falling (a history of falls in the last year and a timed up and go test or a five chair rising test > 12 sec or a 4-meter walk test > 4 sec). In addition to balneotherapy, patients had either no intervention (controls) or twelve 60-minute sessions of physical activity including 15 minutes of health education and three 90-minute sessions of an educational program (intervention).Results: There were 118 control and 105 intervention patients. The balneotherapy program alone had a clinically significant effect on (i) the grip strength, (ii) the five chair rising test, (iii) the 4-meter walk test, and (iv) the short physical performance battery (Cohen’s d 0.29– 0.46). It had no effect on (i) the maximum time stood on one foot, and (ii) the timed up and go test. Furthermore, it worsened the falls efficacy scale (d = 0.27). Adding a physical activity and educational program significantly improved (i) the time stood on one foot (Cohen’s d =− 0.34), and (ii) the timed up and go test (d=- 0.44), (iii) and reduced the concern about falling (Falls Efficacy scale, d=− 0.25), and (iv) the fear of falling (d=− 0.34).Conclusion: Older patients referred to a balneotherapy program and at high risk of falling when screened at the entrance of the center should be offered an additional physical and educational program to further improve the functional effects of balneotherapy on the timed up and go test, balance, and the fear of falling.Keywords: balneotherapy, falls, physical activity, educational program, fear of falling, physical performances

Dan-Dan Li,1,&ast; Xue Yang,1,&ast; Yang Yang,2,&ast; Li-Hua Zhao,1 Tian-Tian Zhang,3 Yi-Nan Wang,1 Jian-Bin Su,1 Li-Hua Wang,4 Hai-Yan Shi3 1Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China; 2Department of General Practice, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China; 3Department of Hepatobiliary Surgery, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China; 4Department of Nursing, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li-Hua Wang, Department of Nursing, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China, Email wlh512512@163.com Hai-Yan Shi, Department of Hepatobiliary Surgery, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, 226006, People’s Republic of China, Email 1198827119@qq.comBackground: Physical activity (PA) exerts an important influence on glycemic control in type 2 diabetes (T2D) patients. Alterations in body composition in patients with T2D may be involved in the overall pathophysiologic process, but PAs and alterations in body composition have been poorly studied.Methods: A total of 615 patients with T2D were selected by convenient sampling. The patients were investigated with the International Physical Activity Questionnaire (IPAQ-S). Moreover, biochemical indices were collected, and the progression of the body composition of the subjects was determined via dual-energy X-ray absorptiometry (DXA). The variables included lumbar bone mineral density (LSBMD), femoral neck bone mineral density (FNBMD), hip bone mineral density (HBMD), whole-body bone mineral density (TBMD), limb skeletal muscle mass index (ASMI), whole-body fat percentage (B-FAT) and trunk fat percentage (T-FAT). Moreover, the levels of physical activity (high level of physical activity [H-PA], medium level of physical activity [M-PA] and low level of physical activity [L-PA]) were divided into three groups to analyze the changes in patient body composition with changes in physical activity level.Results: One-way analysis of variance showed that β-CTX, TP1NP, HbA1c, B-FAT and T-FAT increased significantly (p< 0.05), while 25(OH)D, LSBMD, FNBMD, HBMD, TBMD and ASMI decreased significantly (p< 0.001) with the decrease of physical activity. However, there was no significant difference in serum lipids between lnHOMA-ir and lnHOMA-β (p> 0.05). Multiple linear regression model was established to gradually adjust for clinical confounding factors. It was found that physical activity level was independently positively correlated with LSBMD, FNBMD, HBMD, TBMD, and ASMI, and was independently negatively correlated with B-FAT and T-FAT in patients with type 2 diabetes.Conclusion: A lack of physical activity is an independent risk factor for decreased bone mineral density, decreased skeletal muscle content and increased fat content in patients with T2D.Keywords: type 2 diabetes, physical activity, body composition, correlation

Xiao-Dong Huang,1,&ast; Jia-Bao Chen,2,&ast; Xiao-Yun Dong,1 Wei-Long Wang,1 Jin Zhou,1 Zhen-Feng Zhou1 1Department of Anesthesiology, Hangzhou Women’s Hospital (Hangzhou Maternity and Child Health Care Hospital, Hangzhou First People’s Hospital Qianjiang New City Campus, Zhejiang Chinese Medical University), Hangzhou, People’s Republic of China; 2Department of Anesthesiology, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medicine College), Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhen-Feng Zhou, Department of Anesthesiology, Hangzhou Women’s Hospital (Hangzhou Maternity and Child Health Care Hospital, Hangzhou First People’s Hospital Qianjiang New City Campus, Zhejiang Chinese Medical University), Hangzhou, 310008, People’s Republic of China, Tel +86-571-56005077, Email zhenfeng9853@163.comPurpose: This study aimed to investigate the influence of fentanyl on the effective dose of remimazolam-induced sedation in elderly female patients undergoing general anesthesia.Patients and Methods: Sixty female patients aged 65– 80 years undergoing selective general anesthesia were randomized into two groups: Group R+F received an initial dose of remimazolam (7.5 mg) with fentanyl (1 μg/kg), while Group R received remimazolam alone. Dosing adjustments (± 2.5 mg) were made based on the response of the preceding patient using the up-and-down allocation technique. The ED50 and ED95 were calculated using a sequential formula and probit regression. Probit regression was also used to assess the relative potency of remimazolam between groups. Sedation levels were evaluated using the Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) scale.Results: The ED50 for remimazolam was significantly lower in Group R+F compared to Group R (p= 0.007). Probit regression estimated the ED50 and ED95 values for Group R+F at 4.878 mg (95% CI, 3.845– 5.859) and 8.184 mg (95% CI, 6.636– 13.546), respectively. In contrast, Group R demonstrated ED50 and ED95 values of 6.733 mg (95% CI, 5.533– 8.068) and 11.298 mg (95% CI, 9.101– 19.617), respectively.Conclusion: This study provides compelling evidence that the administration of 1 μg/kg of fentanyl significantly reduces the required sedative dose of remimazolam by approximately 30% during induction in elderly patients. Importantly, the concomitant use of 1 μg/kg of fentanyl does not increase the risk of adverse effects such as hypotension, respiratory depression.Keywords: remimazolam, fentanyl, effective dose, elderly

Human-driven environmental changes shape ecological communities from local to global scales. Within cities, landscape-scale patterns and processes and species characteristics generally drive local-scale wildlife diversity. However, cities differ in their structure, species pools, geographies and histories, calling into question the extent to which these drivers of wildlife diversity are predictive at continental scales. In partnership with the Urban Wildlife Information Network, we used occurrence data from 725 sites located across 20 North American cities and a multi-city, multi-species occupancy modelling approach to evaluate the effects of ecoregional characteristics and mammal species traits on the urbanization-diversity relationship. Among 37 native terrestrial mammal species, regional environmental characteristics and species traits influenced within-city effects of urbanization on species occupancy and community composition. Species occupancy and diversity were most negatively related to urbanization in the warmer, less vegetated cities. Additionally, larger-bodied species were most negatively impacted by urbanization across North America. Our results suggest that shifting climate conditions could worsen the effects of urbanization on native wildlife communities, such that conservation strategies should seek to mitigate the combined effects of a warming and urbanizing world.

We present an investigation of the relaxation dynamics of deuterated water molecules after direct photo-double ionization at 61 eV. We focus on the very rare D+ + O+ + D reaction channel in which the sequential fragmentation mechanisms were found to dominate the dynamics. Aided by theory, the state-selective formation and breakup of the transient OD+(a1Δ, b1Σ+) is traced, and the most likely dissociation path-OD+: a1Δ or b1Σ+ → A 3Π → X 3Σ- → B 3Σ--involving a combination of spin-orbit and non-adiabatic charge transfer transitions is determined. The multi-step transition probability of this complex transition sequence in the intermediate fragment ion is directly evaluated as a function of the energy of the transient OD+ above its lowest dissociation limit from the measured ratio of the D+ + O+ + D and competing D+ + D+ + O sequential fragmentation channels, which are measured simultaneously. Our coupled-channel time-dependent dynamics calculations reproduce the general trends of these multi-state relative transition rates toward the three-body fragmentation channels.

The radiation pattern within high energy quark- and gluon-initiated jets (jet substructure) is used extensively as a precision probe of the strong force as well as an environment for optimizing event generators with numerous applications in high energy particle and nuclear physics. Looking at electron-proton collisions is of particular interest as many of the complications present at hadron colliders are absent. A detailed study of modern jet substructure observables, jet angularities, in electron-proton collisions is presented using data recorded using the H1 detector at HERA. The measurement is unbinned and multi-dimensional, using machine learning to correct for detector effects. All of the available reconstructed object information of the respective jets is interpreted by a graph neural network, achieving superior precision on a selected set of jet angularities. Training these networks was enabled by the use of a large number of GPUs in the Perlmutter supercomputer at Berkeley Lab. The particle jets are reconstructed in the laboratory frame, using the kT jet clustering algorithm. Results are reported at high transverse momentum transfer Q2>150GeV2, and inelasticity 0.2

We present the relaxation dynamics of deuterated water molecules via autoionization, initiated by the absorption of a 61 eV photon, producing the very rare D+ + O+ + D breakup channel. We employ the COLd target recoil ion momentum spectroscopy method to measure the 3D momenta of the ionic fragments and emitted electrons from the dissociating molecule in coincidence. We interpret the results using the potential energy surfaces extracted from multi-reference configuration interaction calculations. The measured particle energy distributions can be related to a super-excited monocationic state located above the double ionization threshold of D2O. The autoionized electron energy shows a sharp distribution centered around 0.5 eV, which is a signature of the atomic oxygen autoionization occurring in the direct and sequential dissociation processes of D2O+* at a large internuclear distance. In this way, an O+ radical fragment and a low-energy electron are created, both of which can trigger secondary reactions in their environment.

Biological processes play important roles in determining how global changes manifest at local scales. Primary producers can absorb increased CO2 via daytime photosynthesis, modifying pH in aquatic ecosystems. Yet producers and consumers also increase CO2 via respiration. It is unclear whether biological modification of pH differs across the year, and, if so, what biotic and abiotic drivers underlie temporal differences. We addressed these questions using the intensive study of tide pool ecosystems in Alaska, USA, including quarterly surveys of 34 pools over 1 year and monthly surveys of five pools from spring to fall in a second year. We measured physical conditions, community composition, and changes in pH and dissolved oxygen during the day and night. We detected strong temporal patterns in pH dynamics. Our measurements indicate that pH modification varies spatially (between tide pools) and temporally (across months). This variation in pH dynamics mirrored changes in dissolved oxygen and was associated with community composition, including both relative abundance and diversity of benthic producers and consumers, whose role differed across the year, particularly at night. These results highlight the importance of the time of year when considering the ways that community composition influences pH conditions in aquatic ecosystems.

Continued methodological advances have enabled numerous statistical approaches for the analysis of summary statistics from genome-wide association studies. Genetic correlation analysis within specific regions enables a new strategy for identifying pleiotropy. Genomic regions with significant ‘local’ genetic correlations can be investigated further using state-of-the-art methodologies for statistical fine-mapping and variant colocalisation. We explored the utility of a genome-wide local genetic correlation analysis approach for identifying genetic overlaps between the candidate neuropsychiatric disorders, Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Parkinson’s disease, and schizophrenia. The correlation analysis identified several associations between traits, the majority of which were loci in the human leukocyte antigen region. Colocalisation analysis suggested that disease-implicated variants in these loci often differ between traits and, in one locus, indicated a shared causal variant between ALS and AD. Our study identified candidate loci that might play a role in multiple neuropsychiatric diseases and suggested the role of distinct mechanisms across diseases despite shared loci. The fine-mapping and colocalisation analysis protocol designed for this study has been implemented in a flexible analysis pipeline that produces HTML reports and is available at: https://github.com/ThomasPSpargo/COLOC-reporter.

Using the Planck Low Frequency Instrument (LFI) and WMAP data within the global Bayesian BEYONDPLANCK framework, we constrained the polarized foreground emission between 30 and 70 GHz. We combined, for the first time, full-resolution Planck LFI time-ordered data with low-resolution WMAP sky maps at 33, 40, and 61 GHz. The spectral parameters were fit with a likelihood defined at the native resolution of each frequency channel. This analysis represents the first implementation of true multi-resolution component separation applied to CMB observations for both amplitude and spectral energy distribution (SED) parameters. For the synchrotron emission, we approximated the SED as a power-law in frequency and we find that the low signal-to-noise ratio of the current data strongly limits the number of free parameters that can be robustly constrained. We partitioned the sky into four large disjoint regions (High Latitude; Galactic Spur; Galactic Plane; and Galactic Center), each associated with its own power-law index. We find that the High Latitude region is prior-dominated, while the Galactic Center region is contaminated by residual instrumental systematics. The two remaining regions appear to be signal-dominated, and for these we derive spectral indices of βsSpur=3.17±0.06 and βsPlane=3.03±0.07, which is in good agreement with previous results. For the thermal dust emission, we assumed a modified blackbody model and we fit a single power-law index across the full sky. We find βda =â 1.64±0.03, which is slightly steeper than the value reported in Planck HFI data, but still statistically consistent at the 2Ï confidence level.

We describe the computational infrastructure for end-to-end Bayesian cosmic microwave background (CMB) analysis implemented by the BeyondPlanck Collaboration. The code is called Commander3. It provides a statistically consistent framework for global analysis of CMB and microwave observations and may be useful for a wide range of legacy, current, and future experiments. The paper has three main goals. Firstly, we provide a high-level overview of the existing code base, aiming to guide readers who wish to extend and adapt the code according to their own needs or re-implement it from scratch in a different programming language. Secondly, we discuss some critical computational challenges that arise within any global CMB analysis framework, for instance in-memory compression of time-ordered data, fast Fourier transform optimization, and parallelization and load-balancing. Thirdly, we quantify the CPU and RAM requirements for the current BEYONDPLANCK analysis, finding that a total of 1.5 TB of RAM is required for efficient analysis and that the total cost of a full Gibbs sample for LFI is 170 CPU-hrs, including both low-level processing and high-level component separation, which is well within the capabilities of current low-cost computing facilities. The existing code base is made publicly available under a GNU General Public Library (GPL) license.

We constrained the level of polarized anomalous microwave emission (AME) on large angular scales using Planck Low-Frequency Instrument (LFI) and WMAP polarization data within a Bayesian cosmic microwave background (CMB) analysis framework. We modeled synchrotron emission with a power-law spectral energy distribution, as well as the sum of AME and thermal dust emission through linear regression with the Planck High-Frequency Instrument (HFI) 353 GHz data. This template-based dust emission model allowed us to constrain the level of polarized AME while making minimal assumptions on its frequency dependence. We neglected CMB fluctuations, but show through simulations that these fluctuations have a minor impact on the results. We find that the resulting AME polarization fraction confidence limit is sensitive to the polarized synchrotron spectral index prior. In addition, for prior means βsâ

We present a Bayesian calibration algorithm for cosmic microwave background (CMB) observations as implemented within the global end-to-end BEYONDPLANCK framework and applied to the Planck Low Frequency Instrument (LFI) data. Following the most recent Planck analysis, we decomposed the full time-dependent gain into a sum of three nearly orthogonal components: one absolute calibration term, common to all detectors, one time-independent term that can vary between detectors, and one time-dependent component that was allowed to vary between one-hour pointing periods. Each term was then sampled conditionally on all other parameters in the global signal model through Gibbs sampling. The absolute calibration is sampled using only the orbital dipole as a reference source, while the two relative gain components were sampled using the full sky signal, including the orbital and Solar CMB dipoles, CMB fluctuations, and foreground contributions. We discuss various aspects of the data that influence gain estimation, including the dipole-polarization quadrupole degeneracy and processing masks. Comparing our solution to previous pipelines, we find good agreement in general, with relative deviations of 0.67% (0.84%) for 30 GHz, 0.12% (0.04%) for 44 GHz and 0.03% (0.64%) for 70 GHz, compared to Planck PR4 and Planck 2018, respectively. We note that the BEYONDPLANCK calibration was performed globally, which results in better inter-frequency consistency than previous estimates. Additionally, WMAP observations were used actively in the BEYONDPLANCK analysis, which both breaks internal degeneracies in the Planck data set and results in an overall better agreement with WMAP. Finally, we used a Wiener filtering approach to smoothing the gain estimates. We show that this method avoids artifacts in the correlated noise maps as a result of oversmoothing the gain solution, which is difficult to avoid with methods like boxcar smoothing, as Wiener filtering by construction maintains a balance between data fidelity and prior knowledge. Although our presentation and algorithm are currently oriented toward LFI processing, the general procedure is fully generalizable to other experiments, as long as the Solar dipole signal is available to be used for calibration.

We present a Gibbs sampling solution to the mapmaking problem for cosmic microwave background (CMB) measurements that builds on existing destriping methodology. Gibbs sampling breaks the computationally heavy destriping problem into two separate steps: noise filtering and map binning. Considered as two separate steps, both are computationally much cheaper than solving the combined problem. This provides a huge performance benefit as compared to traditional methods and it allows us, for the first time, to bring the destriping baseline length to a single sample. Here, we applied the Gibbs procedure to simulated Planck 30 GHz data. We find that gaps in the time-ordered data are handled efficiently by filling them in with simulated noise as part of the Gibbs process. The Gibbs procedure yields a chain of map samples, from which we are able to compute the posterior mean as a best-estimate map. The variation in the chain provides information on the correlated residual noise, without the need to construct a full noise covariance matrix. However, if only a single maximum-likelihood frequency map estimate is required, we find that traditional conjugate gradient solvers converge much faster than a Gibbs sampler in terms of the total number of iterations. The conceptual advantages of the Gibbs sampling approach lies in statistically well-defined error propagation and systematic error correction. This methodology thus forms the conceptual basis for the mapmaking algorithm employed in the BEYONDPLANCK framework, which implements the first end-to-end Bayesian analysis pipeline for CMB observations.

We present Planck Low Frequency Instrument (LFI) frequency sky maps derived within the BEYONDPLANCK framework. This framework draws samples from a global posterior distribution that includes instrumental, astrophysical, and cosmological parameters, and the main product is an entire ensemble of frequency sky map samples, each of which corresponds to one possible realization of the various modeled instrumental systematic corrections, including correlated noise, time-variable gain, as well as far sidelobe and bandpass corrections. This ensemble allows for computationally convenient end-to-end propagation of low-level instrumental uncertainties into higher-level science products, including astrophysical component maps, angular power spectra, and cosmological parameters. We show that the two dominant sources of LFI instrumental systematic uncertainties are correlated noise and gain fluctuations, and the products presented here support -for the first time -full Bayesian error propagation for these effects at full angular resolution. We compared our posterior mean maps with traditional frequency maps delivered by the Planck Collaboration, and find generally good agreement. The most important quality improvement is due to significantly lower calibration uncertainties in the new processing, as we find a fractional absolute calibration uncertainty at 70 GHz of δg0/g0â =â 5Ã - 105, which is nominally 40 times smaller than that reported by Planck 2018. However, we also note that the original Planck 2018 estimate has a nontrivial statistical interpretation, and this further illustrates the advantage of the new framework in terms of producing self-consistent and well-defined error estimates of all involved quantities without the need of ad hoc uncertainty contributions. We describe how low-resolution data products, including dense pixel-pixel covariance matrices, may be produced from the posterior samples directly, without the need for computationally expensive analytic calculations or simulations. We conclude that posterior-based frequency map sampling provides unique capabilities in terms of low-level systematics modeling and error propagation, and may play an important role for future Cosmic Microwave Background (CMB) B-mode experiments aiming at nanokelvin precision.

We describe the BEYONDPLANCK project in terms of our motivation, methodology, and main products, and provide a guide to a set of companion papers that describe each result in more detail. Building directly on experience from ESA's Planck mission, we implemented a complete end-to-end Bayesian analysis framework for the Planck Low Frequency Instrument (LFI) observations. The primary product is a full joint posterior distribution P(Ï â £d), where Ï represents the set of all free instrumental (gain, correlated noise, bandpass, etc.), astrophysical (synchrotron, free-free, thermal dust emission, etc.), and cosmological (cosmic microwave background -CMB -map, power spectrum, etc.) parameters. Some notable advantages of this approach compared to a traditional pipeline procedure are seamless end-to-end propagation of uncertainties; accurate modeling of both astrophysical and instrumental effects in the most natural basis for each uncertain quantity; optimized computational costs with little or no need for intermediate human interaction between various analysis steps; and a complete overview of the entire analysis process within one single framework. As a practical demonstration of this framework, we focus in particular on low-â CMB polarization reconstruction with Planck LFI. In this process, we identify several important new effects that have not been accounted for in previous pipelines, including gain over-smoothing and time-variable and non-1/f correlated noise in the 30 and 44 GHz channels. Modeling and mitigating both previously known and newly discovered systematic effects, we find that all results are consistent with the Î CDM model, and we constrained the reionization optical depth to Ï â =â 0.066±0.013, with a low-resolution CMB-based Ï 2 probability to exceed of 32%. This uncertainty is about 30% larger than the official pipelines, arising from taking a more complete instrumental model into account. The marginal CMB solar dipole amplitude is 3362.7±1.4â μK, where the error bar was derived directly from the posterior distribution without the need of any ad hoc instrumental corrections. We are currently not aware of any significant unmodeled systematic effects remaining in the Planck LFI data, and, for the first time, the 44 GHz channel is fully exploited in the current analysis. We argue that this framework can play a central role in the analysis of many current and future high-sensitivity CMB experiments, including LiteBIRD, and it will serve as the computational foundation of the emerging community-wide COSMOGLOBE effort, which aims to combine state-of-the-art radio, microwave, and submillimeter data sets into one global astrophysical model.