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Abstract Background We aimed to develop risk tools for dementia, stroke, myocardial infarction (MI), and diabetes, for adults aged ≥ 65 years using shared risk factors. Methods Data were obtained from 10 population-based cohorts (N = 41,755) with median follow-up time (years) for dementia, stroke, MI, and diabetes of 6.2, 7.0, 6.8, and 7.4, respectively. Disease-free participants at baseline were included, and 22 risk factors (sociodemographic, medical, lifestyle, laboratory biomarkers) were evaluated. Two risk tools (DemNCD and DemNCD-LR based on Fine and Gray sub-distribution and logistic regression [LR], respectively) were developed and validated. Predictive accuracies of these risk tools were assessed using Harrel’s C-statistics and area under the curve (AUC) and 95% confidence interval (CI). Model calibration was conducted using Hosmer–Lemeshow goodness of fit test along calibration plots. Results Both the DemNCD and DemNCD-LR resulted in similar predictive accuracy for each outcome. The overall AUC (95% CI) for dementia, stroke, MI, and diabetes risk tool were 0·68 (0·65, 0·70), 0·58 (0·54, 0·61), 0·65 (0·61, 0·68), and 0·68 (0·64, 0·72), respectively, for males. For females, these figures were 0·65 (0·63, 0·67), 0·55 (0·52, 0·57), 0·65 (0·62, 0·68), and 0·61 (0·57, 0·65). Conclusions The DemNCD is the first tool to predict both dementia and multiple cardio-metabolic diseases using comprehensive risk factors and provided similar predictive accuracy to existing risk tools. It has similar predictive accuracy as tools designed for single outcomes in this age-group. DemNCD has the potential to be used in community and clinical settings as it includes self-reported and routinely available clinical measures.

Abstract Background Marine sediments represent one of the planet’s largest carbon stores. Bottom trawl fisheries constitute the most widespread physical disturbance to seabed habitats, which exert a large influence over the oceanic carbon dioxide (CO2) sink. Recent research has sparked concern that seabed disturbance from trawling can therefore turn marine sediments into a large source of CO2, but the calculations involved carry a high degree of uncertainty. This is primarily due to a lack of quantitative understanding of how trawling mixes and resuspends sediments, how it alters bioturbation, bioirrigation, and oxygenation rates, and how these processes translate into carbon fluxes into or out of sediments. Methods The primary question addressed by this review protocol is: how does mobile bottom fishing affect benthic carbon processing and storage? This question will be split into the following secondary questions: what is the effect of mobile bottom fishing on: (i) the amount and type of carbon found in benthic sediments; (ii) the magnitude and direction of benthic-pelagic carbon fluxes; (iii) the biogeochemical, biological, and physical parameters that control the fate of benthic carbon; and (iv) the biogeochemical, biological, and physical parameters that control the fate of resuspended carbon. Literature searches will be conducted in Web of Science, SCOPUS, PROQUEST, and a range of grey and specialist sources. An initial scoping search in Web of Science informed the final search string, which has been formulated according to Population Intervention Comparator Outcome (PICO) principles. Eligible studies must contain data concerning a change in a population of interest caused by mobile bottom fishing. Eligible study designs are Before and After, Control and Impact, and Gradient studies. Studies included at full-text screening will be critically appraised, and study findings will be extracted.Extracted data will be stored in an Excel spreadsheet. Results will be reported in narrative and quantitative syntheses using a variety of visual tools including forest plots. Meta-analysis will be conducted where sufficient data exists.

Abstract Background Organizational adoption is a key but understudied step in translating evidence-based interventions into practice. The purpose of this study was to report recruitment strategies and factors associated with church enrollment and intervention adoption in a national implementation study of the Faith, Activity, and Nutrition (FAN) program. Methods We worked with partners using multiple strategies to disseminate intervention availability. Interested churches completed an online form. To enroll, the church coordinator (FAN coordinator) and pastor completed baseline surveys and then received intervention online training access. We compared enrolled vs. non-enrolled churches on how they heard about the study and church characteristics. We compared intervention-adopting vs. non-adopting churches on Consolidated Framework for Implementation Research (CFIR) constructs using Fisher’s exact tests, χ2, or independent sample t-tests and reported differences where p

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (

Abstract HIV-1 envelope glycoproteins (Envs) of most primary HIV-1 strains exist in closed conformation and infrequently sample open states, limiting access to internal epitopes. Thus, immunogen design aims to mimic the closed Env conformation as preferred target for eliciting broadly neutralizing antibodies (bnAbs). Here we identify incompletely closed Env conformations of 6 out of 13 transmitted/founder (T/F) strains that are sensitive to antibodies that recognize internal epitopes typically exposed on open Envs. A 3.6 Å cryo-electron microscopy structure of unliganded, incompletely closed T/F Envs (1059-SOSIP) reveals protomer motion that increased sampling of states with incompletely closed trimer apex. We reconstruct de novo the post-transmission evolutionary pathway of a second T/F. Evolved viruses exhibit increased Env resistance to cold, soluble CD4 and 19b, all of which correlate with closing of the adapted Env trimer. Lastly, we show that the ultra-broad N6 bnAb efficiently recognizes different Env conformations and exhibits improved antiviral breadth against VRC01-resistant Envs isolated during the first-in-humans antibody-mediated-prevention trial.

Abstract Background Acid sphingomyelinase deficiency (ASMD) or Niemann–Pick disease types A, A/B, and B is a progressive, life-limiting, autosomal recessive disorder caused by sphingomyelin phosphodiesterase 1 (SMPD1) gene mutations. There is a need to increase the understanding of morbidity and mortality across children to adults diagnosed with ASMD. Methods This observational retrospective survey analysed medical records of patients with ASMD with retrievable data from 27 hospitals in France, diagnosed/followed up between 1st January 1990 and 31st December 2020. Eligible records were abstracted to collect demographic, medical/developmental history, and mortality data. Survival outcomes were estimated from birth until death using Kaplan–Meier survival analyses; standardised mortality ratio (SMR) was also explored. Results A total of 118 medical records of patients with ASMD (type B [n = 94], type A [n = 15], and type A/B [n = 9]) were assessed. The majority of patients were males (63.6%); the median [range] age at diagnosis was 8.0 [1.0–18.0] months (type A), 1.0 [0–3] year (type A/B), and 5.5 [0–73] years (type B). Overall, 30 patients were deceased at the study completion date; the median [range] age at death for patients with ASMD type A (n = 14) was 1 [0–3.6] year, type A/B (n = 6) was 8.5 [3.0–30.9] years, and type B (n = 10) was 57.6 [3.4–74.1] years. The median [95% confidence interval (CI)] survival age from birth in patients with ASMD type A and type A/B was 2.0 [1.8–2.7] years and 11.4 [5.5–18.5] years, respectively. Survival analysis in ASMD type B was explored using SMR [95% CI] analysis (3.5 [1.6–5.9]), which showed that age-specific deaths in the ASMD type B population were 3.5 times more frequent than those in the general French population. The causes of death were mostly severe progressive neurodegeneration (type A: 16.7%), cancer (type B: 16.7%), or unspecified (across groups: 33.3%). Conclusions This study illustrated a substantial burden of illness with high mortality rates in patients with ASMD, including adults with ASMD type B, in France.

Background: Insomnia is a prevalent health concern in the general population associated with a range of adverse health effects. New, effective, safe and low-cost treatments, suitable for long-term use, are urgently required. Previous studies have shown the potential of electrical vestibular nerve stimulation (VeNS) in improving insomnia symptoms, however only one sham-controlled trial has been conducted on people with chronic insomnia. Objectives/Hypothesis: Repeated VeNS delivered by the Modius Sleep device prior to sleep onset will show superior improvement in Insomnia Severity Index (ISI) scores over a 4-week period compared to sham stimulation. Methods: In this double-blinded, multi-site, randomised, sham-controlled study, 147 participants with moderate to severe insomnia (ISI≥15) were recruited and allocated a VeNS or a sham device (1:1 ratio) which they were asked to use at home for 30 min daily (minimum 5 days per week) for 4 weeks. Results: After 4 weeks, mean ISI score reduction was 2.26 greater in the VeNS treatment group than the sham group (p = 0.002). In the per protocol analysis, the treatment group had a mean ISI score decrease of 5.8 (95 % CI [-6.8, −4.81], approaching the clinically meaningful threshold of a 6-point reduction, with over half achieving a clinically significant decrease. Furthermore, the treatment group showed superior improvement to the sham group in the SF-36 (Quality of Life) energy/fatigue component (PP p = 0.004, effect size 0.26; ITT p = 0.006, effect size 0.22). Conclusions: Modius sleep has the potential to provide a viable, non-invasive and safe clinically meaningful alternative treatment option for insomnia.

Abstract Introduction Pain is the most common reason for seeking medical treatment. Despite extensive research efforts and effective analgesics modulating pain, there is still a major therapeutic gap in addressing the root causes of pain. Pain is associated with tissue damage induced by oxidative stress and induction of inflammatory mediators following high consumption of antioxidants. The role of antioxidants in general, and the administration of l-ascorbate in particular, is still controversially discussed and underestimated in the daily clinical practice. Methods The current literature on the therapeutic effect of l-ascorbate, ascorbic acid, and vitamin C on various pain conditions was evaluated against the background of evidence-based medicine. Those articles, obtained from systematic search in PubMed, were critically assessed and rated in terms of evidence level and methodological quality by two independent experts. The primary purpose of this work was to establish specific pain therapy guidance for intravenous l-ascorbate. Results A PubMed search revealed 14 suitable articles comprising controlled clinical trials and meta-analyses. An additional ten publications could be identified via secondary literature. There is supporting evidence for the efficacy of ascorbate treatment in inflammatory pain conditions, in the complex regional pain syndrome, in post zoster neuralgia, in neuropathic pain, in post-operative pain conditions, and in tumor-related pain. However, the considered studies differ in the type of administration, in dosage, in duration of treatment, as well as in quality of research. Despite all study heterogeneity, it became evident that research of high scientific quality is in support of the efficacy of l-ascorbate in pain treatment. Discussion Oxidative stress is present in almost all pain conditions. Because oral administration of most magistral formulas of vitamin C does not provide biological availability, parenteral administration should be preferred and can be supported by an oral dose with high bioavailability on days without intravenous treatment. l-ascorbate should be preferred for parenteral high dosage, rather than ascorbic acid, as it does not release acid valences under physiological conditions. Conclusions l-ascorbate is an effective, safe, and economically favorable integrative treatment option for various pain conditions, addressing the root cause of tissue damage and inflammatory mediator burst. Graphical Abstract

Abstract Background Checkpoint inhibitors (CPIs) are widely used in cancer treatment, with transformative impacts on survival. They nonetheless carry a significant risk of toxicity in the form of immune-related adverse events (IrAEs), which may be sustained and life-altering. IrAEs may require high-dose and/or prolonged steroid use and represent a significant healthcare burden. They mimic immune-mediated inflammatory diseases (IMIDs) but understanding of their pathogenesis is limited. The MEDALLION project aims to determine targetable mechanisms of immune dysregulation in IrAE development, employing an immune monitoring approach to determine changes in circulating and tissue resident cells of CPI recipients who do/do not develop them and assessing the contribution of the microbiome in parallel. Methods MEDALLION is a non-randomised longitudinal cohort study aiming to recruit 66 cancer patient recipients of anti-PD1/PD-L1, anti-CTLA-4 or combination therapy. Eligible participants include those with malignant melanoma in the adjuvant or metastatic setting, mesothelioma and non-small cell lung carcinoma (NSCLC) treated in the metastatic setting. Comprehensive clinical evaluation is carried out alongside blood, skin swab and stool sampling at the time of CPI initiation (baseline) and during subsequent routine hospital visits on 6 occasions over a 10-month follow-up period. It is conservatively anticipated that one third of enrolled patients will experience a “significant IrAE” (SirAE), defined according to pre-determined criteria specific to the affected tissue/organ system. Those developing such toxicity may optionally undergo a biopsy of affected tissue where appropriate, otherwise being managed according to standard of care. Peripheral blood mononuclear cells will be analysed using multi-parameter flow cytometry to investigate immune subsets, their activation status and cytokine profiles. Stool samples and skin swabs will undergo DNA extraction for 16 S ribosomal RNA (rRNA) sequencing and internal transcribed spacer (ITS) gene sequencing to determine bacterial and fungal microbiome diversity, respectively, including species associated with toxicity. Stored tissue biopsies will be available for in situ and single-cell transcriptomic evaluation. Analysis will focus on the identification of biological predictors and precursors of SirAEs. Discussion The pathogenesis of IrAEs will be assessed through the MEDALLION cohort, with the potential to develop tools for their prediction and/or strategies for targeted prevention or treatment. Trial Registration The study was registered on 18/09/2023 in the ISRCTN registry (43,419,676).

Abstract Background Evidence continues to accumulate regarding the potential long-term health consequences of COVID-19 in the population. To distinguish between COVID-19-related symptoms and health limitations from those caused by other conditions, it is essential to compare cases with community controls using prospective data ensuring case-control status. The RESPIRA study addresses this need by investigating the lasting impact of COVID-19 on Health-related Quality of Life (HRQoL) and symptomatology in a population-based cohort in Costa Rica, thereby providing a robust framework for controlling HRQoL and symptoms. Methods The study comprised 641 PCR-confirmed, unvaccinated cases of COVID-19 and 947 matched population-based controls. Infection was confirmed using antibody tests on enrollment serum samples and symptoms were monitored monthly for 6 months post-enrolment. Administered at the 6-month visit (occurring between 6- and 2-months post-diagnosis for cases and 6 months after enrollment for controls), HRQoL and Self-Perceived Health Change were assessed using the SF-36, while brain fog, using three items from the Mental Health Inventory (MHI). Regression models were utilized to analyze SF-36, MHI scores, and Self-Perceived Health Change, adjusted for case/control status, severity (mild case, moderate case, hospitalized) and additional independent variables. Sensitivity analyses confirmed the robustness of the findings. Results Cases showed significantly higher prevalences of joint pain, chest tightness, and skin manifestations, that stabilized at higher frequencies from the fourth month post-diagnosis onwards (2.0%, 1.2%, and 0.8% respectively) compared to controls (0.9%, 0.4%, 0.2% respectively). Cases also exhibited significantly lower HRQoL than controls across all dimensions in the fully adjusted model, with a 12.4 percentage-point difference [95%CI: 9.4-14.6], in self-reported health compared to one year prior. Cases reported 8.0% [95%CI: 4.2, 11.5] more physical limitations, 7.3% [95%CI: 3.5, 10.5] increased lack of vitality, and 6.0% [95%CI: 2.4, 9.0] more brain fog compared to controls with similar characteristics. Undiagnosed cases detected with antibody tests among controls had HRQoL comparable to antibody negative controls. Differences were more pronounced in individuals with moderate or severe disease and among women. Conclusions PCR-confirmed unvaccinated cases experienced prolonged HRQoL reductions 6 months to 2 years after diagnosis, this was particularly the case in severe cases and among women. Mildly symptomatic cases showed no significant long-term sequelae.

Background: Atopic dermatitis (AD) is a skin barrier dysfunction characterized by tissue eosinophilia. Objective: In patients with AD, we evaluated the effect of eosinophil depletion with benralizumab on markers of inflammation in skin after intradermal allergen challenge. Methods: A total of 20 patients with moderate-to-severe AD completed a randomized, double-blind, placebo-controlled parallel-group study comparing 3 doses of benralizumab (30 mg each) administered subcutaneously every 4 weeks (n = 9) with placebo (n = 11). Allergen and saline control intradermal challenges were conducted before and after treatment, with skin biopsy samples collected 24 hours after challenge. Early and late cutaneous responses were measured by skin wheal size. Levels of eosinophils and IL-5 receptor-α–bearing cells, including eosinophil progenitor (EoP) cells, basophils, and mast cells, in papillary dermis were measured by immunofluorescence microscopy, and levels of EoP cells, hematopoietic progenitor cells, and type 2 innate lymphoid cells in the blood were measured by flow cytometry. Outcomes were compared between the placebo and benralizumab treatment groups by using the Mann-Whitney U test. Results: Benralizumab reduced eosinophil counts in the blood (P < .0001) and allergen-challenged skin, as measured by hematoxylin and eosin staining and eosinophil cationic protein antibody concentration (P < .05). Benralizumab lowered the levels of EoP cells, mast cells, and basophils in the skin, as well as the levels of EoP cells, hematopoietic progenitor cells, and type 2 innate lymphoid cells in the blood (all P < .05). There was a trend toward improvement in the early cutaneous response (P = .095) but no effect on the late cutaneous response. Conclusion: In patients with moderate-to-severe AD, benralizumab treatment significantly inhibited accumulation of eosinophils and other IL-5 receptor-α–expressing cells in the papillary dermis after intradermal allergen challenge. Targeting IL-5 receptor-α–positive cells did not modulate the size of the allergen-induced skin wheal (ClincialTrials.gov identifier NCT03563066).

BackgroundPrevious studies have explored the association between social media use and mental health among adolescents. However, few studies using nationally representative longitudinal data have explored this relationship for adults and how the effect might change depending on how people use social media. ObjectiveThis study investigated the longitudinal relationship between the frequency of viewing and posting on social media and mental health problems among UK adults. MethodsThis study included 15,836 adults (aged 16 years and older) who participated in Understanding Society, a UK longitudinal survey. Social media use was measured with questions about the frequency of viewing social media and posting on social media in Understanding Society Wave 11 (2019-2021). We explored viewing and posting separately, as well as a combined exposure: (1) high viewing, high posting; (2) high viewing, low posting; (3) low viewing, high posting; and (4) low viewing, low posting. Mental health problems were measured in Wave 12 (2020-2022) using the General Health Questionnaire (GHQ-12), a validated scale for identifying symptoms of common mental health problems, where higher scores indicated more mental health problems (0 to 36). Unadjusted and adjusted linear regression models were estimated for viewing social media and posting on social media, adjusting for the baseline GHQ score, gender, age, ethnicity, employment, and education. We found no evidence for effect modification by gender and age so overall associations were reported. ResultsIn our adjusted models, we found no evidence of an association between the frequency of viewing social media and mental health problems in the following year. We found that adults who posted daily on social media had more mental health problems than those who never posted on social media, corresponding to a 0.35-point increase in GHQ score (β=0.35, 95% CI 0.01-0.68; P=.04). When we considered both social media behaviors, we found that those who frequently viewed and posted on social media scored 0.31 points higher on the GHQ score (β=0.31, 95% CI 0.04-0.58; P=.03) in the following year compared to those who rarely viewed or posted on social media. ConclusionsWe found that a high frequency of posting on social media was associated with increased mental health problems a year later. However, we did not find evidence of a similar association based on the frequency of viewing social media content. This provides evidence that some types of active social media use (ie, posting) have a stronger link to mental health outcomes than some types of passive social media use (viewing). These results highlighted that the relationship between social media use and mental health is complex, and more research is needed to understand the mechanisms underlying these patterns to inform targeted interventions and policies.

ABSTRACT The cell wall of monoderm bacteria consists of peptidoglycan and glycopolymers in roughly equal proportions and is crucial for cellular integrity, cell shape, and bacterial vitality. Despite the immense value of Streptomyces in biotechnology and medicine as antibiotic producers, we know very little about their cell wall biogenesis, composition, and functions. Here, we have identified the LCP-LytR_C domain protein CglA (Vnz_13690) as a key glycopolymer ligase, which specifically localizes in zones of cell wall biosynthesis in S. venezuelae. Reduced amount of glycopolymers in the cglA mutant results in enlarged vegetative hyphae and failures in FtsZ-rings formation and positioning. Consequently, division septa are misplaced leading to the formation of aberrant cell compartments, misshaped spores, and reduced cell vitality. In addition, we report our discovery that c-di-AMP signaling and decoration of the cell wall with glycopolymers are physiologically linked in Streptomyces since the deletion of cglA restores growth of the S. venezuelae disA mutant at high salt. Altogether, we have identified and characterized CglA as a novel component of cell wall biogenesis in Streptomyces, which is required for cell shape maintenance and cellular vitality in filamentous, multicellular bacteria.IMPORTANCEStreptomyces are our key producers of antibitiotics and other bioactive molecules and are, therefore, of high value for medicine and biotechnology. They proliferate by apical extension and branching of hyphae and undergo complex cell differentiation from filaments to spores during their life cycle. For both, growth and sporulation, coordinated cell wall biogenesis is crucial. However, our knowledge about cell wall biosynthesis, functions, and architecture in Streptomyces and in other Actinomycetota is still very limited. Here, we identify CglA as the key enzyme needed for the attachment of glycopolymers to the cell wall of S. venezuelae. We demonstrate that defects in the cell wall glycopolymer content result in loss of cell shape in these filamentous bacteria and show that division-competent FtsZ-rings cannot assemble properly and fail to be positioned correctly. As a consequence, cell septa placement is disturbed leading to the formation of misshaped spores with reduced viability.

In grape and wine production, one of the main relevant and recurrent diseases is downy mildew, caused by the fungus Plamospara viticola. It is frequently present in wine production worldwide, with a significant high annual incidence in some regions. Since the discovery of Bordeaux mixture (copper sulphate and lime) in the 1880’s, many formulations based on copper (Cu) have been developed and used in viticulture production. https://coppereplace.com/.

Health-related stigma plays a significant role in the burden of various health conditions such as neglected tropical diseases and mental illnesses, and undermines successful health outcomes. Stigmatised individuals can face lifelong socioeconomic consequences because of their condition. It is broadly recognised that culturally salient factors interact with the way stigma is expressed in different local contexts. This study aimed to capture cultural capabilities that shape health-related stigma in Indonesia, using the ‘what matters most’ (WMM) stigma framework. In this qualitative research, 15 in-depth interviews with experts in the field of Indonesian culture and health studies were conducted, followed by a group discussion. Data were collected between April and September 2021, and analysed using thematic content analysis. The analysis shows that cultural values such as communal participation in local networks and the ‘shame culture’ shapes experiences of stigma in Indonesia. Moreover, the participants explained that achieving full standing in the Indonesian context meant contributing to the collective interest and maintaining the family reputation. Personhood is also related to socially defined gender roles. For example, community participation was often influenced by patriarchal values, which lead to differences in access to life opportunities, while recognition in the family was often connected to complying with gender roles. This study contributes to research on the cultural shaping of health-related stigma involving the WMM framework in the Indonesian context. Future research should focus on the perspectives of those who are affected by stigmatised conditions and on integrating these insights in the assessment and reduction of health-related stigma.

Abstract Background Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, potentially fatal lysosomal storage disease that exhibits a broad spectrum of clinical phenotypes. There is a need to expand the knowledge of disease mortality and morbidity in Germany because of limited information on survival analysis in patients with chronic ASMD (type B or type A/B). Methods This observational, multicentre, retrospective cohort study was conducted using medical records of patients with the first symptom onset/diagnosis of ASMD type B or type A/B between 1st January 1990 and 31st July 2021 from four German medical centres. Eligible medical records were abstracted to collect data on demographic characteristics, medical history, hospitalisation, mortality, and causes of death from disease onset to the last follow-up/death. Survival outcomes were estimated using the Kaplan–Meier analysis. Standardised mortality ratio (SMR) was also explored. Results This study included 33 chart records of patients with ASMD type B (n = 24) and type A/B (n = 9), with a median (interquartile range [IQR]) age of 8.0 [3.0–20.0] years and 1.0 [1.0–2.0] years, respectively, at diagnosis. The commonly reported manifestations were related to spleen (100.0%), liver (93.9%), and respiratory (77.4%) abnormalities. Nine deaths were reported at a median [IQR] age of 17.0 [5.0–25.0] years, with 66.7% of overall patients deceased at less than 18 years of age; the median [IQR] age at death for patients with ASMD type B (n = 4) and type A/B (n = 5) was 31.0 [11.0–55.0] and 9.0 [4.0–18.0] years, respectively. All deaths were ASMD-related and primarily caused by liver or respiratory failures or severe progressive neurodegeneration (two patients with ASMD type A/B). The median (95% confidence interval [CI]) overall survival age since birth was 45.4 (17.5–65.0) years. Additionally, an SMR [95% CI] analysis (21.6 [9.8–38.0]) showed that age-specific deaths in the ASMD population were 21.6 times more frequent than that in the general German population. Conclusions This study highlights considerable morbidity and mortality associated with ASMD type B and type A/B in Germany. It further emphasises the importance of effective therapy for chronic ASMD to reduce disease complications.

Caesalpinioideae is the second largest subfamily of legumes (Leguminosae) with ca. 4680 species and 163 genera. It is an ecologically and economically important group formed of mostly woody perennials that range from large canopy emergent trees to functionally herbaceous geoxyles, lianas and shrubs, and which has a global distribution, occurring on every continent except Antarctica. Following the recent re-circumscription of 15 Caesalpinioideae genera as presented in Advances in Legume Systematics 14, Part 1, and using as a basis a phylogenomic analysis of 997 nuclear gene sequences for 420 species and all but five of the genera currently recognised in the subfamily, we present a new higher-level classification for the subfamily. The new classification of Caesalpinioideae comprises eleven tribes, all of which are either new, reinstated or re-circumscribed at this rank: Caesalpinieae Rchb. (27 genera / ca. 223 species), Campsiandreae LPWG (2 / 5–22), Cassieae Bronn (7 / 695), Ceratonieae Rchb. (4 / 6), Dimorphandreae Benth. (4 / 35), Erythrophleeae LPWG (2 /13), Gleditsieae Nakai (3 / 20), Mimoseae Bronn (100 / ca. 3510), Pterogyneae LPWG (1 / 1), Schizolobieae Nakai (8 / 42–43), Sclerolobieae Benth. & Hook. f. (5 / ca. 113). Although many of these lineages have been recognised and named in the past, either as tribes or informal generic groups, their circumscriptions have varied widely and changed over the past decades, such that all the tribes described here differ in generic membership from those previously recognised. Importantly, the approximately 3500 species and 100 genera of the former subfamily Mimosoideae are now placed in the reinstated, but newly circumscribed, tribe Mimoseae. Because of the large size and ecological importance of the tribe, we also provide a clade-based classification system for Mimoseae that includes 17 named lower-level clades. Fourteen of the 100 Mimoseae genera remain unplaced in these lower-level clades: eight are resolved in two grades and six are phylogenetically isolated monogeneric lineages. In addition to the new classification, we provide a key to genera, morphological descriptions and notes for all 163 genera, all tribes, and all named clades. The diversity of growth forms, foliage, flowers and fruits are illustrated for all genera, and for each genus we also provide a distribution map, based on quality-controlled herbarium specimen localities. A glossary for specialised terms used in legume morphology is provided. This new phylogenetically based classification of Caesalpinioideae provides a solid system for communication and a framework for downstream analyses of biogeography, trait evolution and diversification, as well as for taxonomic revision of still understudied genera.

The fruit and vegetable sector produce waste significantly, causing social, environmental, and economic loss. Thus, a study was conducted at Pasig Mega Market, Pasig City to describe the fruit and vegetable vendors' waste management practices. Vendors and government employees participated in focus group discussions and key informant interviews. Results showed an average of 100-200 kilograms of waste were collected in the market daily, with leafy vegetables, watermelon, melon, and saba as common types. Focus group discussions revealed that discounted prices for suboptimal items, quality assurance methods, adherence to First-In-First-Out principles, and marketing strategies were the vendors' efforts to reduce waste. The identified approaches in handling wastes were, giving them as animal feed, creating alternative products, and returning damaged products to suppliers. Key informant interviews disclosed that the local government and market administration practices in waste management were composting and donation as animal feed for the local zoo. Moreover, it revealed improvement in the management of implementing the ordinances. Problems encountered were focused on supplier issues, weather, market competition, and consumer preferences. Overall, their waste management reduces food waste disposed of in landfills. Recommended strategies for vendors and administration are valorizing food waste, organizing awareness and livelihood programs, and conducting regular evaluations.

Abstract Background The Illumina family of Infinium Methylation BeadChip microarrays has been widely used over the last 15 years for genome-wide DNA methylation profiling, including large-scale and population-based studies, due to their ease of use and cost effectiveness. Succeeding the popular HumanMethylationEPIC BeadChip (EPICv1), the recently released Infinium MethylationEPIC v2.0 BeadChip (EPICv2) claims to extend genomic coverage to more than 935,000 CpG sites. Here, we comprehensively characterise the reproducibility, reliability and annotation of the EPICv2 array, based on bioinformatic analysis of both manifest data and new EPICv2 data from diverse biological samples. Results We find a high degree of reproducibility with EPICv1, evidenced by comparable sensitivity and precision from empirical cross-platform comparison incorporating whole genome bisulphite sequencing (WGBS), and high correlation between technical sample replicates, including between samples with DNA input levels below the manufacturer’s recommendation. We provide a full assessment of probe content, evaluating genomic distribution and changes from previous array versions. We characterise EPICv2’s new feature of replicated probes and provide recommendations as to the superior probes. In silico analysis of probe sequences demonstrates that probe cross-hybridisation remains a significant problem in EPICv2. By mapping the off-target sites at single nucleotide resolution and comparing with WGBS we show empirical evidence for preferential off-target binding. Conclusions Overall, we find EPICv2 a worthy successor to the previous Infinium methylation microarrays, however some technical issues remain. To support optimal EPICv2 data analysis we provide an expanded version of the EPICv2 manifest to aid researchers in understanding probe design, data processing, choosing appropriate probes for analysis and for integration with methylation datasets from previous versions of the Infinium Methylation BeadChip.

Objectives The Action To promote brain HEalth iN Adults study aimed to determine the feasibility and applicability of recruitment using home blood pressure (BP) monitoring, routine blood biochemistry and videoconference measures of cognition, in adults at high risk of dementia.Design A decentralised double-blind, placebo-controlled, randomised feasibility trial with a four-stage screening process.Setting Conducted with participants online in the state of New South Wales, Australia.Participants Participants were aged 50–70 years with moderately elevated BP (systolic >120 and 80 and

ABSTRACT Background An estimated 2.2 million people from Central and Eastern Europe (CEE) live in the United Kingdom. It has been documented that CEE migrants underutilise health services in the United Kingdom and, as an alternative, seek healthcare in their home country. However, reasons for seeking healthcare abroad are not always clear. This review aims to identify the reasons for the uptake of transnational healthcare among CEE migrants resident in the United Kingdom. Methods Informed by discussions with community members, medical stakeholders and academics, a systematic scoping review was undertaken following the nine‐stage Joanna Briggs Institute framework for scoping reviews. A search strategy with MeSH terms, where relevant, was used and adapted in five academic databases, two grey literature databases and Google Scholar. Included records encompassed four concepts: migration, CEE nationalities, UK nations and healthcare utilisation, which were written in English and published between May 2004 and 2022. Data from the literature were coded, grouped and organised into themes. Results A total of 16 publications fulfilled the inclusion criteria. There is evidence that some CEE migrants exclusively use healthcare services in the United Kingdom. However, many CEE migrants utilise healthcare both in the United Kingdom and their country of origin. Four themes were identified from the literature as to why migrants travelled to their country of origin for healthcare: cultural expectations of medical services, distrust in the UK NHS, barriers and transnational ties. Conclusion Push factors led CEE migrants to seek healthcare in their country of origin, facilitated by ongoing transnational ties. CEE migrants frequently combine visits to their country of origin with medical appointments. Utilising healthcare in their country of origin as opposed to the United Kingdom can result in fragmented and incomplete records of medications, medical tests and surgeries and risk of unnecessary treatments and complications. This review highlights the need for more targeted health outreach with CEE groups within the United Kingdom, as well as the need for further research on the impact of national events, for example, COVID‐19 and Brexit, on transnational healthcare‐seeking behaviours. Patient or Public Contribution The concept for this scoping review was informed by discussions with community members, medical professionals and academics, who identified it as a current issue. The results of this scoping review were discussed with healthcare stakeholders.

Over the last two decades, there have been numerous initiatives to improve undergraduate student outcomes in STEM. One model for scalable reform is the inclusive Research Education Community (iREC). In an iREC, STEM faculty from colleges and universities across the nation are supported to adopt and sustainably implement course-based research – a form of science pedagogy that enhances student learning and persistence in science. In this study, we used pathway modeling to develop a qualitative description that explicates the HHMI Science Education Alliance (SEA) iREC as a model for facilitating the successful adoption and continued advancement of new curricular content and pedagogy. In particular, outcomes that faculty realize through their participation in the SEA iREC were identified, organized by time, and functionally linked. The resulting pathway model was then revised and refined based on several rounds of feedback from over 100 faculty members in the SEA iREC who participated in the study. Our results show that in an iREC, STEM faculty organized as a long-standing community of practice leverage one another, outside expertise, and data to adopt, implement, and iteratively advance their pedagogy. The opportunity to collaborate in this manner and, additionally, to be recognized for pedagogical contributions sustainably engages STEM faculty in the advancement of their pedagogy. Here, we present a detailed pathway model of SEA that, together with underpinning features of an iREC identified in this study, offers a framework to facilitate transformations in undergraduate science education.

Pubesamides A and B are structurally unusual monoterpene N-benzoyltyramides isolated from Casimiroa pubescens, a tropical fruiting tree with known psychotropic properties. Herein we report the structural affirmation of both natural products through a chemical synthesis that features a Lewis-acid assisted cross-metathesis reaction between a 1,1-disubstituted alkene and a dienone in the presence of the Hoveyda-Grubbs second generation catalyst. Stereochemically pure samples of pubesamide A and B isomerise upon standing, suggesting they are both genuine natural products.

Summary: Double labeling to identify different markers in the same tissue section represents a useful tool either for in situ diagnosis or characterization of molecular associations. Here, we present a protocol to detect senescence-associated β-galactosidase (SA-βGal) and immunoperoxidase (IPO) activity in fresh-frozen murine tissues. We describe steps for tissue collection, solution preparation, SA-βGal staining, IPO staining, hematoxylin counterstaining, microscopic observation, and signal quantification. This protocol can be used to detect in situ proteins alongside SA-βGal activity.For complete details on the use and execution of this protocol, please refer to Pacheco-Rivera et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Background Social isolation and low levels of physical activity are strong drivers for frailty, which is linked to poor health outcomes and transition to long-term care. Frailty is multifactorial, and thus an integrated approach is needed to maintain older adults’ health and well-being. Intergenerational programs represent a novel multifactorial approach to target frailty, social isolation and physical decline but these have not yet been rigorously tested in Australia. Here, we present the results of our pilot study which aimed to test the feasibility of a 10-week intergenerational program between older adults and preschool children. Methods A non-randomised wait-listed controlled trial was conducted. Participants were allocated to either the intervention or wait-list control group. The intervention group received 10 weekly 2-h intergenerational sessions led by trained child educators; the control group continued with their usual routine and received their intergenerational program after the 10-week control period. All participants were assessed at baseline and 10 weeks. The primary outcome was the feasibility and acceptability of the program including measures of recruitment eligibility, adherence and effective data collection across the multiple domains important for frailty, including functional mobility and balance, grip strength, cognitive function, mood, social engagement, quality of life and concerns about falling. Results Nineteen adults were included, with nine in the intervention and ten in the control group. A total of 42% of older adults screened were eligible, 75% of participants were present at each intervention session and the overall attrition rate was 21% (n = 4). The reasons for participant absence were primarily health-related. Missing data was minimal for the majority of assessments but more apparent for the cognitive testing where completion rates ranged from 53 to 79% for baseline tests and 73 to 100% for those who received follow-up testing. Conclusions The high program compliance and low attrition show that a 10-week intergenerational program embedded in the local community, designed for community-living older adults and preschool children, is feasible and acceptable to older adults. Our next trial will test the efficacy of intergenerational programs in this setting.

Abstract Age is a significant but heterogeneous risk factor for acute neuropsychiatric disturbances such as delirium. Neuroinflammation increases with aging but the determinants of underlying risk for acute dysfunction upon systemic inflammation are not clear. We hypothesised that, with advancing age, mice would become progressively more vulnerable to acute cognitive dysfunction and that neuroinflammation and neuronal integrity might predict heterogeneity in such vulnerability. Here we show region-dependent differential expression of microglial transcripts, but a ubiquitously observed primed signature: chronic Clec7a expression and exaggerated Il1b responses to systemic bacterial LPS. Cognitive frailty (vulnerability to acute disruption under acute stressors LPS and double stranded RNA; poly I:C) was increased in aged animals but showed heterogeneity and was significantly correlated with reduced myelin density, synaptic loss and severity of white matter microgliosis. The data indicate that white matter disruption and neuroinflammation may be key substrates of the progressive but heterogeneous risk for delirium in aged individuals.

Abstract The Light Dark Matter eXperiment (LDMX) is an electron-beam fixed-target experiment designed to achieve comprehensive model independent sensitivity to dark matter particles in the sub-GeV mass region. An upgrade to the LCLS-II accelerator will increase the beam energy available to LDMX from 4 to 8 GeV. Using detailed GEANT4-based simulations, we investigate the effect of the increased beam energy on the capabilities to separate signal and background, and demonstrate that the veto methodology developed for 4 GeV successfully rejects photon-induced backgrounds for at least 2 × 1014 electrons on target at 8 GeV.

Abstract Stroke remains a global health concern, necessitating early prediction for effective management. Atherosclerosis-induced internal carotid and intra cranial stenosis contributes significantly to stroke risk. This study explores the relationship between blood pressure and stroke prediction, focusing on internal carotid artery (ICA) branches: middle cerebral artery (MCA), anterior cerebral artery (ACA), and their role in hemodynamics. Computational fluid dynamics (CFD) informed by the Windkessel model were employed to simulate patient-specific ICA models with introduced stenosis. Central to our investigation is the impact of stenosis on blood pressure, flow velocity, and flow rate across these branches, incorporating Fractional Flow Reserve (FFR) analysis. Results highlight differential sensitivities to blood pressure variations, with M1 branch showing high sensitivity, ACA moderate, and M2 minimal. Comparing blood pressure fluctuations between ICA and MCA revealed heightened sensitivity to potential reverse flow compared to ICA and ACA comparisons, emphasizing MCA's role. Blood flow adjustments due to stenosis demonstrated intricate compensatory mechanisms. FFR emerged as a robust predictor of stenosis severity, particularly in the M2 branch. In conclusion, this study provides comprehensive insights into hemodynamic complexities within major intracranial arteries, elucidating the significance of blood pressure variations, flow attributes, and FFR in stenosis contexts. Subject-specific data integration enhances model reliability, aiding stroke risk assessment and advancing cerebrovascular disease understanding.

This study aimed to compare the percentage of bioceramic sealer penetration and maximum penetration sealer depending on the fluorescent staining method when evaluated with confocal laser scanning microscopy (CLSM). In total, 42 single-rooted premolars were instrumented. Two groups of 20 teeth each were filled using the single cone technique. TotalFill BC Sealer® mixed with Rhodamine B was used for the first group and TotalFill BC Sealer® mixed with Fluo-3 for the second group. Two teeth made up the control group. All teeth were sectioned at 3 and 6 mm from the apex and were analyzed with CLSM. The canal perimeter where the tubular penetration happened and the maximum penetration of each sample were calculated. There were no significant differences between the two groups in either the apical or medial sections. In terms of maximum penetration, Rhodamine B had greater tubular penetration in the apical sections, and it had similar results to Fluo-3 in the medial sections. TotalFill BC Sealer® has a higher tubular penetration in the medial slices than in the apical slices regardless of the fluorescent stain used. Rhodamine B has higher results than Fluo-3 in terms of the percentage of sealer penetration and maximum penetration.

IntroductionIn French Guiana, a European territory in Guiana shield in the Amazon area, close to 40% of the current population was born abroad. In this context, it is important to listen to the experiences of migrants to better understand the difficulties encountered within the healthcare pathways. This is the aim of ANRS Parcours d’Haïti project, an epidemiological, biographical and socio-anthropological study conducted on a representative sample of the Haitian community in French Guiana and focusing on the social determinants of health.MethodologyWithin the framework of this study, the Infectious and Tropical Diseases clinical team of Cayenne Hospital has established close collaboration with health mediators and the ethnobotanist anthropologist of the study. To illustrate the contribution of a personalized approach to health mediation, we report the case of a migrant woman of Haitian origin admitted to the Infectious and Tropical Diseases Unit. We highlight the different socio-cultural aspects addressed and their place in the care process through a thematic discussion and socio-anthropological analysis of the care relationship, based on participatory ethnography and inductive analysis of an in-depth interview with the patient.ResultThis example illustrates the need for a multidisciplinary approach to ensure culturally adapted care for patients. Personal interviews are important because they allow to better take into account the cultural specificities of patients’ experiences and the socio-cultural environment in which they live (and especially, in the case of Haitian patients, their religious affiliation). By allowing them to speak and express themselves freely, they integrate not only their own cultural baggage, but also their own expectations and representations of the disease they suffer from and how it should be treated. Ultimately, this tripartite collaboration between patient, caregiver, and anthropologist or health mediator leads to a better therapeutic alliance.ConclusionThe analysis of this health care relationship is emblematic of the issue of cultural competence and pre-conceptualizes what intercultural mediation in health care could be, as close as possible to the caregiver and the individual.

The article is based on a series of interviews (61) and a multi-sited ethnography conducted during 2019–2021 which traced archival records of 20 feminist organizations in Israel: local women’s peace organizations (FPAs) and Rape Crisis Centres (RCCs). We describe the study and the complex methodological concerns and meta-questions relating to the study of feminist community archives in relation to content (types of testimonials or records), method of organization (archival practices like cataloging or digitization) and activists’ perspectives concerning future preservation and access. In order to overcome these challenges, we suggest six methodological principles which may apply to the study of civil society organizations that were established between the 1970s–1990s: the importance of identifying researchers’ positionality vis a-vis the archive; the politics of knowledge and intersectional identities; avoiding judgment of informal archival practices; identifying who sets the rules; silence and self-silencing; and recognition of invisible labor.

The response to the diverse needs along the cassava value chain, the urge to increase genetic gain, and the need for rapid varietal turnover will necessitate not only technological innovations but also transformation of public breeding programs in sub-Saharan Africa (SSA). We developed guiding, flexible and adaptative tools for portfolio management of cassava breeding. The cassava breeding and product development pipeline process was mapped to illustrate activities of each stage, as well as to clarify key decision points. Stakeholders involved at all stages of breeding were identified. This allowed for identification of gaps and new crucial functions. To clarify accountability and reduce complexity in the decision-making at key decision points, the roles were mapped against decision-rights at each stage-gate. Cassava crop calendars for the different regions in SSA were developed to facilitate better planning. A product advancement template was developed to guide product advancement. The tools that have been developed and stage-gate mapping, will support regional efforts to establish more structured, transparent, participatory, efficient, inclusive, and demand-driven cassava breeding in the region. These approaches could be customized to other commodities.

Background Neutropenic sepsis is a common complication of systemic anticancer treatment. There is variation in practice in timing of switch to oral antibiotics after commencement of empirical intravenous antibiotic therapy. Objectives To establish the clinical and cost effectiveness of early switch to oral antibiotics in patients with neutropenic sepsis at low risk of infective complications. Design A randomised, multicentre, open-label, allocation concealed, non-inferiority trial to establish the clinical and cost effectiveness of early oral switch in comparison to standard care. Setting Nineteen UK oncology centres. Participants Patients aged 16 years and over receiving systemic anticancer therapy with fever (≥ 38°C), or symptoms and signs of sepsis, and neutropenia (≤ 1.0 × 109/l) within 24 hours of randomisation, with a Multinational Association for Supportive Care in Cancer score of ≥ 21 and receiving intravenous piperacillin/tazobactam or meropenem for

Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, and potentially fatal lysosomal storage disease. This two-part international study aimed to understand physician, patient, and caregivers' experiences during the ASMD diagnostic journey. Qualitative interviews were conducted with patients with ASMD type B or A/B, caregivers (for patients

Background: Acid sphingomyelinase deficiency (ASMD), historically known as Niemann–Pick disease type A, A/B, and B, is a rare lysosomal storage pathology with multisystemic clinical manifestations. The aims of this study were to estimate the survival probability in patients in the United States with chronic ASMD (ASMD types B and A/B), and to describe the disease characteristics of these patients. Methods: This observational retrospective study included medical chart records of patients with chronic ASMD with retrievable data abstracted by 69 participating physicians from 25 medical centers in the United States. Included patients had a date of ASMD diagnosis or first presentation to a physician for ASMD symptoms (whichever occurred first) between January 01, 1990, and February 28, 2021. Medical chart records were excluded if patients were diagnosed with ASMD type A. Eligible medical chart records were abstracted to collect demographic, medical and developmental history, and mortality data. Survival outcomes were analyzed using Kaplan–Meier survival analyses from birth until death. Results: The overall study population (N = 110) included 69 patients with ASMD type B, nine with type A/B, and 32 with ASMD “non-type A'' (ASMD subtype was unknown, but patients were confirmed as not having ASMD type A). The majority of patients were male with a median age at diagnosis of 3.8 years. Thirty-eight patients died during the study observation period, at a median age of 6.8 years. The median (95% confidence interval) survival age from birth was 21.3 (10.2; 60.4) years. At diagnosis or first presentation, 42.7% patients had ≥1 ASMD-related complication; splenic (30.0%) and hepatobiliary (20.9%) being the most common, and 40.9% required ≥1 medical visit due to complications. Conclusion: Patients with chronic ASMD in the United States have poor survival and significant burden of illness.

Abstract Background The cattle industry contributes to Uganda's agricultural output. It faces challenges that include theft and parentage ascertainment. These challenges can benefit from recent molecular genomics and bioinformatics technologies. Objectives We employed genomic analyses to establish potential ownership of a group of nine cattle that were being claimed by two farmers in Uganda. We investigated the genetic relationship of Ugandan cattle with regional indigenous breeds as well as exotic breeds that are currently present in Uganda. In addition, we investigated regions that are likely to be under selection in the Ugandan cattle. Methods Hair samples were collected from seven and two animals from farmers A and B, respectively. They were genotyped for 53,218 Single Nucleotide Polymorphism markers. To establish genetic relationships between the sampled animals, we performed genomic analyses including, principal component analysis (PCA), hierarchical clustering analysis and identity by state/descent. We also performed admixture and runs of homozygosity analyses to assess the ancestry composition and identify regions potentially under selection in Ugandan cattle, respectively. Results The seven animals from Farmer A were genetically close to each other but showed minimal relationship with the disputed animals. The two animals from Farmer B were genetically distant from each other but showed greater similarity to four of the disputed animals. Four of the disputed animals showed great dissimilarity from the animals of both farmers. Comparison of these with the reference breeds revealed minimal European exotic genetic introgression into these animals, but rather high similarity to the Sheko. Results also revealed high homozygosity in the major histocompatibility complex regions. Conclusions Our results demonstrate the use of currently available genomic tools to empirically establish the ownership of cattle; these could be scaled up as a resourceful and viable tool that could be employed to support conflict resolution where reliable livestock identification is unavailable.

Abstract Background Clinical methods for assessing quality of movement and functional tests are important to clinicians. Typical deviations from normal kinematics during the clinical test of Forward Step Down Test (FSDT) are pelvic tilt and hip adduction which are associated with the risk of knee pain. Objectives (1) to examine the correlation between clinical assessment of the FSDT and joint angle measurements of pelvis, hip, knee and ankle joints in males and females; (2) to examine the differences in joint angles between individuals rated as good, fair or poor in a FSDT performance test. Methods Ninety-two healthy individuals performing FSDT were video-taped with two-dimensional digital video cameras. The clinical assessment of the FSDT was rated by two experienced physical therapists as good, fair, or poor based on a Crossley et al. (2011) validated scale. Measurements of pelvic drop, hip adduction and knee valgus were taken using Image J software. Results Out of 177 lower limbs, 74 (37 in each limb) were clinically rated as “good/fair” (41.80%) while 103 (52 in the dominant leg and 51 in the non-dominant leg) were rated as “poor” (58.19%). No significant differences were observed between dominant and non-dominant legs or between males and females in clinical rating of the FSDT. Pelvic drop angle was significantly higher and hip adduction angle was significantly lower for “poor” clinical rating compared to “good/fair” in both dominant and non-dominant legs (p

Abstract Background The first COVID-19 lockdown decreed in Spain by the government resulted in a significant disruption in the daily lives of youth that may have affected their mental health. The aim of this study was to identify factors that influenced youth mental health during this period. Methods: Between March and May 2020, a sample of 1205 youths (age range 18–24 years) from across Spain completed a questionnaire that assessed sociodemographic, mental health, loneliness, coping with humour and healthy habits. Data were analysed using Structural Equation Modelling. Results The proposed model showed good fit values, and significant variables explained 37% of mental health. loneliness, coping humour, healthy and unhealthy habits, and gender significantly predicted youth mental health. Conclusions The consequences of the pandemic and confinement derived from COVID-19 seemed to be especially severe for youth, increasing their mental health vulnerability. It is recommended that evaluating the long-term effects of confinement on this population, the mental health needs they may have and the support resources that would help meet them in situations of isolation, paying special attention to females.

Abstract Theoretical and empirical accounts suggest that adolescence is associated with heightened reward learning and impulsivity. Experimental tasks and computational models that can dissociate reward learning from the tendency to initiate actions impulsively (action initiation bias) are thus critical to characterise the mechanisms that drive developmental differences. However, existing work has rarely quantified both learning ability and action initiation, or it has relied on small samples. Here, using computational modelling of a learning task collected from a large sample (N = 742, 9-18 years, 11 countries), we test differences in reward and punishment learning and action initiation from childhood to adolescence. Computational modelling reveals that whilst punishment learning rates increase with age, reward learning remains stable. In parallel, action initiation biases decrease with age. Results are similar when considering pubertal stage instead of chronological age. We conclude that heightened reward responsivity in adolescence can reflect differences in action initiation rather than enhanced reward learning.

Summary: Background: The protection of fourth dose mRNA vaccination against SARS-CoV-2 is relevant to current global policy decisions regarding ongoing booster roll-out. We aimed to estimate the effect of fourth dose vaccination, prior infection, and duration of PCR positivity in a highly-vaccinated and largely prior-COVID-19 infected cohort of UK healthcare workers. Methods: Participants underwent fortnightly PCR and regular antibody testing for SARS-CoV-2 and completed symptoms questionnaires. A multi-state model was used to estimate vaccine effectiveness (VE) against infection from a fourth dose compared to a waned third dose, with protection from prior infection and duration of PCR positivity jointly estimated. Findings: 1298 infections were detected among 9560 individuals under active follow-up between September 2022 and March 2023. Compared to a waned third dose, fourth dose VE was 13.1% (95% CI 0.9 to 23.8) overall; 24.0% (95% CI 8.5 to 36.8) in the first 2 months post-vaccination, reducing to 10.3% (95% CI −11.4 to 27.8) and 1.7% (95% CI −17.0 to 17.4) at 2–4 and 4–6 months, respectively. Relative to an infection >2 years ago and controlling for vaccination, 63.6% (95% CI 46.9 to 75.0) and 29.1% (95% CI 3.8 to 43.1) greater protection against infection was estimated for an infection within the past 0–6, and 6–12 months, respectively. A fourth dose was associated with greater protection against asymptomatic infection than symptomatic infection, whilst prior infection independently provided more protection against symptomatic infection, particularly if the infection had occurred within the previous 6 months. Duration of PCR positivity was significantly lower for asymptomatic compared to symptomatic infection. Interpretation: Despite rapid waning of protection, vaccine boosters remain an important tool in responding to the dynamic COVID-19 landscape; boosting population immunity in advance of periods of anticipated pressure, such as surging infection rates or emerging variants of concern. Funding: UK Health Security Agency, Medical Research Council, NIHR HPRU Oxford, Bristol, and others.

Vaccines have played a significant role in reducing infectious disease burden. However, vaccine hesitancy remains a persistent challenge in public health, including for pharmacists who often interact with patients regarding vaccines. Thus, this study assesses the impact of motivational interviewing (MI) training and the MI-based vaccine hesitancy discussion tools (MOTIVE) on pharmacists’ management of vaccine hesitancy. Pharmacists in eight Midwestern pharmacy practices who completed MI and MOTIVE training and engaged with vaccine-hesitant patients participated in this study. The pharmacist participants completed post-encounter surveys identifying the vaccine discussed, the tool utilized, and the outcome of the conversation. Descriptive results from 362 encounters indicated that the primary reasons for hesitancy were safety (39%), care coordination (31.5%), and efficacy (30.4%). Post encounter, 35.4% of patients received vaccines, 26% planned to, 25.1% considered it, and 13.5% were uninterested. The findings highlight the importance of patient-centered communication, such as MI, between patients and pharmacists to identify and address reasons for vaccine hesitancy. Pharmacists, equipped with conversation tools such as the MOTIVE tools, may effectively influence vaccine acceptance. Future research should evaluate the utility of MI and the MOTIVE tools in other settings and regions.

microRNA (miR)-146a emerges as a promising post-transcriptional regulator in various inflammatory diseases with different roles for the two isoforms miR-146a-5p and miR-146a-3p. The present study aimed to examine the dual role of miR-146a-5p and miR-146a 3p in the modulation of inflammation in human pulmonary epithelial and immune cells in vitro as well as their expression in patients with inflammatory lung diseases. Experimental inflammation in human A549, HL60, and THP1 via the NF-kB pathway resulted in the major upregulation of miR-146a-5p and miR-146a-3p expression, which was partly cell-specific. Modulation by transfection with miRNA mimics and inhibitors demonstrated an anti-inflammatory effect of miR-146a-5p and a pro-inflammatory effect of miR-146a-3p, respectively. A mutual interference between miR-146a-5p and miR-146a-3p was observed, with miR-146a-5p exerting a predominant influence. In vivo NGS analyses revealed an upregulation of miR-146a-3p in the blood of patients with cystic fibrosis and bronchiolitis obliterans, while miR-146a-5p levels were downregulated or unchanged compared to controls. The reverse pattern was observed in patients with SARS-CoV-2 infection. In conclusion, miR-146a-5p and miR-146a-3p are two distinct but interconnected miRNA isoforms with opposing functions in inflammation regulation. Understanding their interaction provides important insights into the progression and persistence of inflammatory lung diseases and might provide potential therapeutic options.

Background: The immune response dynamics in COVID-19 patients remain a subject of intense investigation due to their implications for disease severity and treatment outcomes. We examined changes in leukocyte levels, eosinophil activity, and cytokine profiles in patients hospitalized with COVID-19. Methods: Serum samples were collected within the first 10 days of hospitalization/confirmed infection and analyzed for eosinophil granule proteins (EGP) and cytokines. Information from medical records including comorbidities, clinical symptoms, medications, and complete blood counts were collected at the time of admission, during hospitalization and at follow up approximately 3 months later. Results: Serum levels of eotaxin, type 1 and type 2 cytokines, and alarmin cytokines were elevated in COVID-19 patients, highlighting the heightened immune response (p < 0.05). However, COVID-19 patients exhibited lower levels of eosinophils and eosinophil degranulation products compared to hospitalized controls (p < 0.05). Leukocyte counts increased consistently from admission to follow-up, indicative of recovery. Conclusion: Attenuated eosinophil activity alongside elevated chemokine and cytokine levels during active infection, highlights the complex interplay of immune mediators in the pathogenesis COVID-19 and underscores the need for further investigation into immune biomarkers and treatment strategies.

Background: Work and home stress, productivity, and self-care of academic medicine faculty in Spring 2021 was contrasted to faculty's experience in the Spring of 2020, both of which were relatively compared with the prepandemic period. Methods: A 93-question survey was sent to academic medicine faculty at an urban public university medical center in March 2020 and again in March 2021. Demographic, family, and academic characteristics, work distribution and productivity before and during the pandemic, perceived stress related to work and home activities, and self-care data compared with the prepandemic period were collected. Differences were assessed using chi-square or Fisher exact tests. Student t-test was used for the difference in mean values, while logistic regression was used to determine predictors of work stress. Results: Two hundred thirty-one faculty completed the survey in Spring 2020 and 118 faculty responded in Spring 2021. The proportion of faculty reporting increased work and home stress decreased in Spring 2021 compared with Spring 2020. A higher proportion of women compared with men reported increased work stress in both surveys. In Spring 2021, work stress decreased significantly for men but not for women. Home stress decreased significantly for women in Spring 2021 but remained stable for the men faculty. Research productivity increased for both genders in Spring 2021, but a greater percentage of women reported disturbed sleep and diet. There were no differences in home stress levels between genders when caring for young children. Conclusions: Men faculty are more likely to adapt to the ?new normal? by lowering work stressors and increasing productivity, whereas women's continued high work stress and increased productivity may occur at the expense of decreased self-care. The challenges associated with having young children continue to affect the productivity and well-being of all faculty.

Abstract Introduction Variability in household secondary attack rates and transmission risks factors of SARS-CoV-2 remain poorly understood. Methods We conducted a household transmission study of SARS-CoV-2 in Costa Rica, with SARS-CoV-2 index cases selected from a larger prospective cohort study and their household contacts were enrolled. A total of 719 household contacts of 304 household index cases were enrolled from November 21, 2020, through July 31, 2021. Blood specimens were collected from contacts within 30–60 days of index case diagnosis; and serum was tested for presence of spike and nucleocapsid SARS-CoV-2 IgG antibodies. Evidence of SARS-CoV-2 prior infections among household contacts was defined based on the presence of both spike and nucleocapsid antibodies. We fitted a chain binomial model to the serologic data, to account for exogenous community infection risk and potential multi-generational transmissions within the household. Results Overall seroprevalence was 53% (95% confidence interval (CI) 48–58%) among household contacts. The estimated household secondary attack rate is 34% (95% CI 5–75%). Mask wearing by the index case is associated with the household transmission risk reduction by 67% (adjusted odds ratio = 0.33 with 95% CI: 0.09–0.75) and not sharing bedroom with the index case is associated with the risk reduction of household transmission by 78% (adjusted odds ratio = 0.22 with 95% CI 0.10–0.41). The estimated distribution of household secondary attack rates is highly heterogeneous across index cases, with 30% of index cases being the source for 80% of secondary cases. Conclusions Modeling analysis suggests that behavioral factors are important drivers of the observed SARS-CoV-2 transmission heterogeneity within the household.

Abstract Background Older patients are increasingly showing multi-comorbidities, including advanced chronic diseases. When admitted to the emergency department (ED), the decision to pursue life-prolonging treatments or to initiate a palliative care approach is a challenge for clinicians. We test for the first time the diagnostic accuracy of the Supportive and Palliative Care Indicators Tool (SPICT) in the ED to identify older patients at risk of deteriorating and dying, and timely address palliative care needs. Methods We conducted a prospective bicentric cohort study on 352 older patients (≥ 75 years) admitted to two EDs in Belgium between December 2019 and March 2020 and between August and November 2020. SPICT (French version, 2019) variables were collected during the patients’ admission to the ED, along with socio-demographic, medical and functional data. The palliative profile was defined as a positive SPICT assessment. Survival, symptoms and health degradation (≥ 1 point in ADL Katz score or institutionalisation and death) were followed at 12 months by phone. Main accuracy measures were sensitivity, specificity and likelihood ratios (LR) as well as cox regression, survival analysis using the Kaplan Meier method, and ordinal regression. Results Out of 352 patients included in the study (mean age 83 ± 5.5 years, 43% male), 167 patients (47%) had a positive SPICT profile. At one year follow up, SPICT positive patients presented significantly more health degradation (72%) compared with SPICT negative patients (35%, p

In a 2019 Internet Archaeology article, Elizabeth Pearson posed the question 'are we back in the Dark Ages?'. This question was made in reference to a developer-funded archaeology sector that was generating vast quantities of evidence and, particularly, in recent years, specialist environmental data, but was failing to mobilise this in a theoretical framework that generated meaningful advancement in terms of research. The introduction to the 2021 Internet Archaeology special issue on Digital Archiving in Archaeology (Richards et al. 2021) went on to address 'a digital resource that is now in jeopardy' – not only because of the risk of technical obsolescence, but also because of crucial limitations to its interoperability and discoverability. This article builds on these arguments and complements vital work underway on high-level, internationally focused data infrastructure initiatives (e.g. Wright and Richards 2018). We emphasise here the importance of parallel discussions at a community level, particularly with the people who routinely produce archaeological data, as key to enhancing data synthesis and research potential. Specifically, we report on two surveys conducted by the 'Rewilding' Later Prehistory project at Oxford Archaeology, in collaboration with Historic England and Bournemouth University, which originated in the 'Rewilding' project's concern with improving access to palaeoenvironmental data produced within Britain. Substantial amounts of zooarchaeological and archaeobotanical data remain buried in grey literature, limited-access publications and archive reports (not to mention floppy disks, CDs and microfiche), with no integrative means of searching for particular periods or categories of evidence. This lack of accessibility inhibits specialists from contextualising their findings, and was exemplified recently by the Archaeology on Furlough project tripling the known number of aurochs finds in Britain by trawling online records, journals and museum records (Wiseman 2020). The results of the surveys presented here, which targeted both environmental archaeologists specifically and the wider sector, demonstrate a significant appetite amongst archaeologists to improve data networks and for their work to contribute meaningfully to research agendas. Contextualised within a disciplinary landscape that is increasingly dynamic in its approach to tackling the openness and connectivity of 'big data', we argue that better data synthesis in environmental archaeology, and the developer-funded sector more broadly, can be more than just a mirage on the horizon, particularly once the people who produce the data are given an active voice in the matter.