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Abstract Pharmacokinetic studies are important for understanding drug disposition in the human body. However, pregnant and lactating women are often excluded from primary pharmacokinetic studies and as such there is often limited dosing information regarding drug use in pregnant and/or lactating women. The objectives of this interim analysis were to define the transfer of rifampicin to a breastfed infant and to determine the area under the concentration–time curve of rifampicin in maternal plasma, breastmilk and infant plasma. Performing this interim analysis enabled us to substantiate whether prior assumptions we made on several study design issues including patient sample size and pharmacokinetic sampling times held and whether we needed to amend our protocol or not. We enrolled lactating mothers on treatment for tuberculosis with their breastfeeding infants (below 12 months of age), performed intensive pharmacokinetic sampling (0–24 h post‐dose) on plasma samples from both the mother, infant(s) and breastmilk samples from the mother on two separate occasions (once during the initiation phase and another during the continuation phase of tuberculosis treatment). The initial study design, including sampling times, was informed by a stochastic simulation and estimation exercise, with very limited prior breastmilk data. An interim analysis after recruiting 6 mother–infant pairs ascertained that our initial assumptions were ideal for achieving our study objectives and no amendments to the sampling times were necessary. Initial data from 6 mother–infant pairs show that rifampicin penetrates breastmilk with an approximate milk‐to‐plasma ratio of 0.169 and 0.189 on two separate visits. However, it was undetectable in most infants.

Abstract Background Artemisinin-based combination therapy (ACT) is currently recommended for treatment of uncomplicated malaria. However, the emergence and spread of partial artemisinin resistance threatens their effectiveness for malaria treatment in sub-Saharan Africa where the burden of malaria is highest. Early detection and reporting of validated molecular markers (pfk13 mutations) in Plasmodium falciparum is useful for tracking the emergence and spread of partial artemisinin resistance to inform containment efforts. Methods Genomic surveillance was conducted at 50 surveillance sites across four regions of Uganda in Karamoja, Lango, Acholi and West Nile from June 2021 to August 2023. Symptomatic malaria suspected patients were recruited and screened for presence of parasites. In addition, dried blood spots (DBS) were collected for parasite genomic analysis with PCR and sequencing. Out of 563 available dried blood spots (DBS), a random subset of 240 P. falciparum mono-infections, confirmed by a multiplex PCR were selected and used for detecting the pfk13 mutations by Sanger sequencing using Big Dye Terminator method. Regional variations in the proportions of pfk13 mutations were assessed using the chi square or Fisher’s exact tests while Kruskal–Wallis test was used to compare absolute parasite DNA levels between wild type and mutant parasites. Results Overall, 238/240 samples (99.2%) contained sufficient DNA and were successfully sequenced. Three mutations were identified within the sequenced samples; pfk13 C469Y in 32/238 (13.5%) samples, pfk13 A675V in 14/238 (5.9%) and pfk13 S522C in (1/238 (0.42%) samples across the four surveyed regions. The prevalence of pfk13 C469Y mutation was significantly higher in Karamoja region (23.3%) compared to other regions, P = 0.007. The majority of parasite isolates circulating in West Nile are of wild type (98.3), P = 0.002. Relative parasite DNA quantity did not differ in samples carrying the wild type, C469Y and A675V alleles (Kruskal–Wallis test, P = 0.6373). Conclusion Detection of validated molecular markers of artemisinin partial resistance in multiple geographical locations in this setting provides additional evidence of emerging threat of artemisinin partial resistance in Uganda. In view of these findings, periodic genomic surveillance is recommended to detect and monitor levels of pfk13 mutations in other regions in parallel with TES to assess potential implication on delayed parasite clearance and associated treatment failure in this setting. Future studies should consider identification of potential drivers of artemisinin partial resistance in the different malaria transmission settings in Uganda.

Objectives This study aimed to evaluate the performance of vaccine logistics management information systems at public health facilities in Amhara Region, Ethiopia. Methods An institution-based concurrent explanatory mixed design was used at public health facilities in Amhara Region, Ethiopia. In total, 102 health facilities were selected using the multi-stage, stratified, random-sampling proportionate-to-size method. Data were collected using a structured data abstraction checklist from vaccine logistics management information system records. Additionally, experiences of Expanded Program for Immunization focal persons were gathered through interviewer-administered questionnaires. Results Among the 102 health facilities surveyed, 99 (97.1%) provided vaccination services during the study period. On the day of the visit, the average availability and utilization rates of 15 vaccine logistics management information system forms were 44.1% and 40.5%, respectively. The mean inventory accuracy for tracer vaccines stood at 58.3% ± 45.1%. The overall average accuracy percentages for urban and rural vaccine request form reports were 73.4% and 69.6%, respectively. Conclusions The performance of vaccine logistics management information systems in these public health facilities was suboptimal. Key issues identified include inconsistent use of recording forms, shortages of reporting forms, lack of digitalization, poor data quality, and a shortage of qualified staff. These findings underscore the urgent need for standardization of the vaccine logistics management information system and enhancement of data quality.

Background Nearly 24,000 new cases of oropharyngeal cancers (OPCs) are reported per year in India, constituting 3.9% of cancers in all sites. By 2009, Human papilloma virus (HPV), in particular HPV-16, was established as an etiological factor and even a causative agent in OPCs being associated with up to 70% OPCs. Prior imaging-based studies have described certain differentiating factors between HPV-mediated and HPV-negative OPC, highlighting computed tomography and magnetic resonance characteristics that could help differentiate the two groups. Our study aimed to evaluate any imaging differences between HPV-mediated and non-HPV-mediated oropharyngeal malignancies in the Indian subcontinent population. Methods Seventy-nine patients from the Indian subcontinent who were referred to a tertiary center in southern India between the period of January 2019 to September 2020 (19 months) were included in the study. Imaging descriptors were documented by blinded radiologists, and univariate and multivariate analysis of various imaging descriptors and imaging differences between HPV-mediated and non-HPV cases were attempted to be identified. Results We found no statistically significant imaging differences between HPV-mediated and non-HPV-mediated oropharyngeal malignancies. The only epidemiologically significant difference in the two groups was that in women and nonsmokers, HPV-mediated malignancies were more common. Conclusion HPV-mediated and HPV-negative malignancies have similar primary tumor as well as nodal imaging characteristics. Previously cited differences in the two groups, in Western literature, could not be demonstrated in our population. It implores further research into whether downstaging of treatment and better prognosis of HPV-mediated malignancies is actually applicable in the Indian subcontinent setting.

Particle boards are commonly manufactured from wood-based material bound with a thermosetting adhesive based on the reaction of formaldehyde with phenol, urea, melamine, or co-condensates. The use of formaldehyde is a cause for concern due to its harmful emissions. This study investigates the use of an alternative binder combined with particles derived from a short-cycle crop as an alternative to timber derived particles. A low density particle board was developed using hemp shiv as an aggregate with a binder made with crude glycerol, derived from the waste stream of the bio-diesel industry, esterified with citric acid under heat activation. This board was characterized and found to have good mechanical properties, low thermal conductivity, and good moisture buffering. Dimensional stability was compromised by swelling when exposed to water, but it will be possible to address this shortcoming using hydrophobic additives. The acoustic properties of the board were also found to be excellent, showing potential for use as a thermally insulating acoustic separator for internal walls.

Abstract Electrical storm (ES) is a life-threatening condition of recurrent ventricular arrhythmias (VA) in a short period of time. Percutaneous stellate ganglion blockade (SGB) is frequently used – however the efficacy is undefined. The objective of our systematic review was to determine the efficacy of SGB in reducing VA events and mortality among patients with ES. A search of Medline, EMBASE, Scopus, CINAHL and CENTRAL was performed on February 29, 2024 to include studies with adult patients (≥ 18 years) with ES treated with SGB. Our outcomes of interest were VA burden pre- and post-SGB, and in-hospital/30-day mortality. A total of 553 ES episodes in 542 patients from 15 observational studies were included. Treated VAs pre- and post-SGB were pooled from eight studies including 383 patients and demonstrated a decrease from 3.5 (IQR 2.25–7.25) to 0 (IQR 0–0) events (p = 0.008). Complete resolution after SGB occurred in 190 of 294 patients (64.6%). Despite this, in-hospital or 30-day mortality remained high occurring in 140 of 527 patients (random effects prevalence 22%). Repeat SGB for recurrent VAs was performed in 132 of 490 patients (random effects prevalence 21%). In conclusion, observational data suggests SGB may be effective in reducing VAs in ES. Definitive studies for SGB in VA management are needed. Study protocol: PROSPERO - registration number CRD42023430031.

Abstract Background Integrating spiritual aspects into treatment plans can release essential resources for coping with chronic pain. However, some spiritual aspects may also induce distress and hinder the coping process. There is a lack of evidence regarding how to perform the clinical tasks of exploring spiritual aspects and of instruments assessing related competencies. Therefore, we developed a web-based learning module to provide education on the subject alongside corresponding assessment instruments. The module presents the InSpiRe (Integration of Spirituality and/or Religion in patient encounters) protocol. The instruments encompass cognitive, affective, and behavioral dimensions. Methods This paper aims to determine (i) the learning effects associated with completing the web-based spiritual-care learning module and (ii) the reliability and validity of the instruments employed. To address these aims, we conducted a pre-test/post-test trial with N = 32 randomly selected fourth-year medical students. During the pre-test, we assessed the students’ knowledge, attitudes, and self-efficacy regarding exploring spiritual aspects. For this purpose, we developed a short-answer knowledge test, an attitude questionnaire, and a self-efficacy scale. Additionally, the students explored spiritual aspects with a simulated patient portraying a person with chronic pain. Three trained raters evaluated the students’ performances using a self-developed scale. In the intervention phase, the students completed the 45-minute learning module on a personal computer. The module presented InSpiRe-related content as text and step-by-step video demonstrations, including hints that denote critical actions. The subsequent post-test was identical to the pre-test. Results The internal consistency was suitable for all respective instruments, and there was an indication of solid validity of the performance test. After completing the spiritual care learning module, the students showed statistically significant increases in knowledge scores and significant positive shifts in their attitudes and levels of self-efficacy regarding exploring spiritual aspects. They also attained significantly higher performance scores in the same regard. Conclusions Completing the spiritual-care module is associated with meaningful learning effects on cognitive, affective, and behavioral dimensions related to exploring spiritual aspects, as demonstrated in the post-test conducted shortly after the intervention. Due to good reliability and validity scores, the self-developed instruments can be applied appropriately.

Abstract Landscape fragmentation is statistically correlated with both increases and decreases in wildfire burned area (BA). These different directions-of-impact are not mechanistically understood. Here, road density, a land fragmentation proxy, is implemented in a CMIP6 coupled land-fire model, to represent fragmentation edge effects on fire-relevant environmental variables. Fragmentation caused modelled BA changes of over ±10% in 16% of [0.5°] grid-cells. On average, more fragmentation decreased net BA globally (−1.5%), as estimated empirically. However, in recently-deforested tropical areas, fragmentation drove observationally-consistent BA increases of over 20%. Globally, fragmentation-driven fire BA decreased with increasing population density, but was a hump-shaped function of it in forests. In some areas, fragmentation-driven decreases in BA occurred alongside higher-intensity fires, suggesting the decoupling of fire severity traits. This mechanistic model provides a starting point for quantifying policy-relevant fragmentation-fire impacts, whose results suggest future forest degradation may shift fragmentation from net global fire inhibitor to net fire driver.

Abstract This study investigates user satisfaction with e-learning systems in higher education institutions, examining the perspectives of students, lecturers, and elearning officers and heads of the department of Information Technology as key informants. A total of 375 student respondents from Diploma, Bachelor, and Masters levels, 51 lecturers, and 15 key informants across different Ugandan institutions of higher learning participated in the study, providing insights into platform usage, system usability, stability, and support mechanisms. Rigorous analysis techniques, including means, correlation coefficient calculations, were employed to explore factors influencing satisfaction. Findings revealed positive correlations between satisfaction and variables such as ease of use, ease of access, system reliability, system stability, and prompt response to queries, among others. Recommendations include improving system stability, enhancing response time to queries, providing ongoing training, addressing connectivity issues, and developing customized mobile applications. The study highlights the need for institutions to optimize e-learning experiences by leveraging feedback from users and implementing targeted interventions.

Abstract Pregnant and breastfeeding women are often under-represented in clinical research, including pharmacokinetic studies, due to ethical and logistical challenges. This paper examines strategies to improve the recruitment and retention of this demographic in pharmacokinetic research, drawing on experiences from five studies conducted at the Infectious Diseases Institute, Makerere University, Uganda. Key strategies implemented include Community Advisory Board meetings, the involvement of Peer Mothers as Co-Investigators, established recruitment sites, the use of safety protocols, and the utilization of diverse communication platforms, including social media and stakeholder meetings. Despite these efforts, substantial barriers, such as scheduling conflicts and frequent staff turnover at recruitment sites, continue to threaten progress. The paper recommends flexible scheduling, strengthening public engagement, and transparent demonstration of adherence to ethical principles; justice, non-maleficence, respect, and beneficence to ensure the safety and inclusivity of pregnant and breastfeeding women. The inclusion of this population in pharmacokinetic studies is essential for providing evidence-based care that meets their unique health needs.

Abstract Background Current acute healthcare service metrics are not meaningful for older people living with frailty. Healthcare knowledge, situational security, and physical and psychosocial function are important outcomes typically not collected. The use of patient-reported outcome measures (PROMs) could support these assessments. Existing instruments are not comprehensive as they typically consider function, while older people with frailty also value enablement (self-determination and security in health and healthcare). This study field-tested and validated a PROM for older people with frailty receiving acute care (PROM-OPAC) to measure enablement. Methods People aged 65+ with Clinical Frailty Scale 5–8 were recruited within seventy-two hours of an emergency attendance. Iterations of the novel instrument were administered over three stages: (1) preliminary field-testing for reliability (response distribution and internal consistency) and structure (exploratory factor analysis, EFA); (2) intermediate field-testing of an improved instrument for reliability and structure; (3) final draft validation assessing reliability, structure (confirmatory factor analysis, CFA), and construct validity based on a priori hypotheses. Feasibility was appraised throughout using data completeness and response rates and times. Results 241 people participated. Three items of a preliminary seven-item measure had poor response distribution or loading and were accordingly improved. The intermediate instrument had interpretability issues and three items required further improvement. The final eight-item draft had acceptable reliability (Cronbach’s alpha: 0.71), structure (two factors for self-determination and security; RMSEA: 0.065; TLI: 0.917; CFI: 0.944), and construct validity (lower scores from respondents waiting longer and requiring admission). Feasibility was promising (response rate 39%; 98% responses complete; median completion time 11 (IQR: 12) minutes). Conclusions Administration of the PROM-OPAC appeared feasible and the instrument had acceptable psychometric properties. Further evaluation is required to assess generalisability.

Abstract Telehealth is defined as the provision of health care services over a distance. Major health systems, including outpatient clinics and check-ups alike, turned to telehealth and teleconsultation amid the COVID19 pandemic. There are many recognized advantages of telehealth and its increasing implementation, however, not much is known about the specific impact of remote consultation on the quality of non-consultant hospital doctors (NCHD) training experiences in medicine. This study aimed to gain rich descriptive insights into the specific impact of remote consultation on the quality of medical NCHD training experiences and their perceptions, through purposeful sampling. Data was collected via semi-structured virtual interviews of fifteen NCHD participants. The interviews were recorded, transcribed and analysed using thematic analysis. The collective transcripts were analysed using NVIVO data software for common themes. The themes identified suggested that there were both advantages and disadvantages to telehealth and its impact on training across a spectrum of entities including; doctor-patient relationships, peer relationships, service provision, work morale, working hours, clinical skills experience and general feedback as a trainee. NCHD perspectives expressed were mixed across all themes. Further research is recommended to advance understanding of the potential impact of telehealth on current and prospective doctors in training. With a greater understanding of general insights, future changes, including telehealth training programmes, could be implemented to build confidence and familiarity with telehealth utilization and potentiate its conceivable benefits.

Abstract A new release of the Monte Carlo event generator Herwig (version 7.3) has been launched. This iteration encompasses several enhancements over its predecessor, version 7.2. Noteworthy upgrades include: the implementation of a process-independent electroweak angular-ordered parton shower integrated with QCD and QED radiation; a new recoil scheme for initial-state radiation improving the behaviour of the angular-ordered parton shower; the incorporation of the heavy quark effective theory to refine the hadronization and decay of excited heavy mesons and heavy baryons; a dynamic strategy to regulate the kinematic threshold of cluster splittings within the cluster hadronization model; several improvements to the structure of the cluster hadronization model allowing for refined models; the possibility to extract event-by-event hadronization corrections in a well-defined way; the possibility of using the string model, with a dedicated tune. Additionally, a new tuning of the parton shower and hadronization parameters has been executed. This article discusses the novel features introduced in version 7.3.0.

Abstract Background KORTUC (0.5% hydrogen peroxide (H2O2) in 1% sodium-hyaluronate) releases cytotoxic levels of H2O2 in tissues after intratumoural injection. High levels of tumour control after radiotherapy plus KORTUC are reported in breast cancer patients. Here, we use human xenograft models to test the hypothesis that oxygen microbubbles released post-KORTUC are effective in modifying the hypoxic tumour microenvironment. Methods and materials Pimonidazole and Image-iT™ Red (live hypoxia marker) were utilised to assess dose-dependent changes in hypoxia post-H2O2 in HCT116 and LICR-LON-HN5 spheroids. Using a dual 2-nitroimidazole-marker technique and phospho-ATM we evaluated changes in hypoxia and reactive oxygen species (ROS) respectively, in HCT116 and LICR-LON-HN5 xenografts following intratumoural KORTUC. Results A significant reduction in Image-iT™ Red fluorescence was observed in spheroids 1 h post-H2O2 at ≥1.2 mM, maintained at 24 h. Ultrasound demonstrated sustained release of oxygen microbubbles within tumours, 1 h post-KORTUC. Hypoxia markers demonstrated significant tissue reoxygenation in both models post-KORTUC and significantly increased phospho-ATM foci reflecting increased ROS production. Conclusion Intratumoural KORTUC represents a novel oxygen delivery method, which can be exploited to enhance radiation response. If efficacy is confirmed in the ongoing phase 2 breast trial it could improve treatment of several tumour types where hypoxia is known to affect radiotherapy outcomes.

Abstract Vbfnlo is a flexible parton level Monte Carlo program for the simulation of vector boson fusion (VBF), QCD-induced single and double vector boson production plus two jets, and double and triple vector boson production (plus jet) in hadronic collisions at next-to-leading order (NLO) in the strong coupling constant, as well as Higgs boson plus two and three jet production via gluon fusion at the one-loop level. For the new version – Version 3.0 – several major enhancements have been included. An interface according to the Binoth Les Houches Accord (BLHA) has been added for all VBF and di/tri-boson processes including fully leptonic decays. For all dimension-8 operators affecting vector boson scattering (VBS) processes, a modified T-matrix unitarization procedure has been implemented. Several new production processes have been added, namely the VBS $$Z\gamma jj$$ Z γ j j and $$\gamma \gamma jj$$ γ γ j j processes at NLO, $$\gamma \gamma jj $$ γ γ j j , WWj and ZZj production at NLO including the loop-induced gluon-fusion contributions and the gluon-fusion one-loop induced $$\varPhi jjj$$ Φ j j j ( $$\varPhi $$ Φ is a CP-even or CP-odd scalar boson) process at LO, retaining the full top-mass dependence. Finally, the code has been parallelized using Openmpi.

Abstract The authors introduce an unsupervised Intrusion Detection System designed to detect zero‐day distributed denial of service (DDoS) attacks in Internet of Things (IoT) networks. This system can identify anomalies without needing prior knowledge or training on attack information. Zero‐day attacks exploit previously unknown vulnerabilities, making them hard to detect with traditional deep learning and machine learning systems that require pre‐labelled data. Labelling data is also a time‐consuming task for security experts. Therefore, unsupervised methods are necessary to detect these new threats. The authors focus on DDoS attacks, which have recently caused significant financial and service disruptions for many organisations. As IoT networks grow, these attacks become more sophisticated and harmful. The proposed approach detects zero‐day DDoS attacks by using random projection to reduce data dimensionality and an ensemble model combining K‐means, Gaussian mixture model, and one‐class SVM with a hard voting technique for classification. The method was evaluated using the CIC‐DDoS2019 dataset and achieved an accuracy of 94.55%, outperforming other state‐of‐the‐art unsupervised learning methods.

Abstract Musculoskeletal traumatic injuries (MTI) involve soft tissue lesions adjacent to a bone fracture leading to fibrous nonunion. The impact of MTI on the inflammatory response to fracture and on the immunomodulation of skeletal stem/progenitor cells (SSPCs) remains unknown. Here, we used single-nucleus transcriptomic analyses to describe the immune cell dynamics after bone fracture and identified distinct macrophage subsets with successive pro-inflammatory, pro-repair and anti-inflammatory profiles. Concurrently, SSPCs transition via a pro- and anti-inflammatory fibrogenic phase of differentiation prior to osteochondrogenic differentiation. In a preclinical MTI mouse model, the injury response of immune cells and SSPCs is disrupted leading to a prolonged pro-inflammatory phase and delayed resolution of inflammation. Macrophage depletion improves bone regeneration in MTI demonstrating macrophage involvement in fibrous nonunion. Finally, pharmacological inhibition of macrophages using the CSF1R inhibitor Pexidartinib ameliorates healing. These findings reveal the coordinated immune response of macrophages and skeletal stem/progenitor cells as a driver of bone healing and as a primary target for the treatment of trauma-associated fibrosis.

Abstract We present a Cartan-like first-order action principle for electric Carrollian gravity. The action is invariant under the local homogeneous Carroll group, albeit in a different representation than the one obtained by gauging the Carroll algebra. Additionally, we show that this first-order action can be derived from a smooth Carrollian limit of the Einstein-Cartan action. The connection with the Hamiltonian and metric forms of the action for electric Carrollian gravity, as well as with previous works in the literature, is also discussed.

Abstract Anti-angiogenic agents elicit considerable immune modulatory effects within the tumor microenvironment, underscoring the rationale for synergistic clinical development of VEGF and immune checkpoint inhibitors in advanced gastric cancer (AGC). Early phase studies involving Asian patients demonstrated encouraging anti-tumor efficacies. We report the results of the REGOMUNE phase II study, in which Caucasian patients were administered regorafenib, a multi-tyrosine kinase inhibitor, in combination with avelumab, a PD-L1-targeting monoclonal antibody. This therapeutic regimen resulted in deep and durable responses in 19% of patients, with the median duration of response not yet reached. Notwithstanding, a significant proportion of AGC patients exhibited no therapeutic advantage, prompting investigations into mechanisms of inherent resistance. Comprehensive biomarker profiling elucidated that non-responders predominantly exhibited an augmented presence of M2 macrophages within the tumor microenvironment and a marked overexpression of S100A10 by neoplastic cells, a protein previously implicated in macrophage chemotaxis. Additionally, peripheral biomarker assessments identified elevated levels of cytokines, including CSF-1, IL-4, IL-8, and TWEAK, correlating with adverse clinical outcomes, thereby accentuating the role of macrophage infiltration in mediating resistance. These insights furnish an invaluable foundation for elucidating, and potentially circumventing, resistance mechanisms in current AGC therapeutic paradigms, emphasizing the integral role of tumor microenvironmental dynamics and immune modulation.

Abstract Climate change is likely to exacerbate land to water phosphorus (P) transfers, causing a degradation of water quality in freshwater bodies in Northwestern Europe. Planning for mitigation measures requires an understanding of P loss processes under such conditions. This study assesses how climate induced changes to hydrology will likely influence the P transfer continuum in six contrasting river catchments using Irish national observatories as exemplars. Changes or stability of total P (TP) and total reactive P (TRP) transfer processes were estimated using far-future scenarios (RCP4.5 and RCP8.5) of modelled river discharge under climate change and observed links between hydrological regimes (baseflow and flashiness indices) and transfer processes (mobilisation and delivery indices). While there were no differences in P mobilisation between RCP4.5 and RCP8.5, both mobilisation and delivery were higher for TP. Comparing data from 2080 (2070–2099) with 2020 (2010–2039), suggests that P mobilisation is expected to be relatively stable for the different catchments. While P delivery is highest in hydrologically flashy catchments, the largest increases were in groundwater-fed catchments in RCP8.5 (+ 22% for TRP and + 24% for TP). The inter-annual variability of P delivery in the groundwater-fed catchments is also expected to increase. Since the magnitude of a P source may not fully define its mobility, and hydrological connections of mobilisation areas are expected to increase, we recommend identifying critical mobilisation areas to target future mitigation strategies. These are hydrologically connected areas where controls such as soil/bedrock chemistry, biological activity and hydrological processes are favourable for P mobilisation.

Abstract Microbial carbon use efficiency (CUE) affects the fate and storage of carbon in terrestrial ecosystems, but its global importance remains uncertain. Accurately modeling and predicting CUE on a global scale is challenging due to inconsistencies in measurement techniques and the complex interactions of climatic, edaphic, and biological factors across scales. The link between microbial CUE and soil organic carbon relies on the stabilization of microbial necromass within soil aggregates or its association with minerals, necessitating an integration of microbial and stabilization processes in modeling approaches. In this perspective, we propose a comprehensive framework that integrates diverse data sources, ranging from genomic information to traditional soil carbon assessments, to refine carbon cycle models by incorporating variations in CUE, thereby enhancing our understanding of the microbial contribution to carbon cycling.

Abstract Nitrogen (N) is an important nutrient element needed by cassava for optimum yield and it is a vital component of nucleotides (nucleic acids), enzymes, amino acids (proteins), chlorophyll molecules and hormones, among other essential compounds required for growth and development of cassava. Nitrogen stress is a major cassava production constraint, the study aimed to examine genotype by environment interaction (GEI) effects and fresh root yield stability of 203 diverse cassava clones to identify genotypes with stable performance under low and optimum nitrogen regimes across environments using AMMI and GGE biplot analysis. Experiments were conducted using an augmented block design with three replications for two years in three locations in Nigeria. There were significant differences (p

Abstract The emergence of the Middle Palaeolithic, and its variability over time and space are key questions in the field of prehistoric archaeology. Many sites have been documented in the south-eastern margins of the Massif central and the middle Rhône valley, a migration path that connects Northern Europe with the Mediterranean. Well-dated, long stratigraphic sequences are essential to understand Neanderthals dynamics and demise, and potential interactions with Homo sapiens in the area, such as the one displayed at the Maras rock shelter (“Abri du Maras”). The site is characterised by exceptional preservation of archaeological remains, including bones dated using radiocarbon (14C) and teeth using electron spin resonance combined with uranium series (ESR/U-series). Optically stimulated luminescence was used to date the sedimentary deposits. By combining the new ages with previous ones using Bayesian modelling, we are able to clarify the occupation time over a period spanning 200,000 years. Between ca. 250 and 40 ka, the site has been used as a long-term residence by Neanderthals, specifically during three interglacial periods: first during marine isotopic stage (MIS) 7, between 247 ± 34 and 223 ± 33 ka, and then recurrently during MIS 5 (between 127 ± 17 and 90 ± 9 ka) and MIS 3 (up to 39,280 cal BP).

Abstract The inhibitor of κB (IκB) kinase (IKK) is a central regulator of NF-κB signaling. All IKK complexes contain hetero- or homodimers of the catalytic IKKβ and/or IKKα subunits. Here, we identify a YDDΦxΦ motif, which is conserved in substrates of canonical (IκBα, IκBβ) and alternative (p100) NF-κB pathways, and which mediates docking to catalytic IKK dimers. We demonstrate a quantitative correlation between docking affinity and IKK activity related to IκBα phosphorylation/degradation. Furthermore, we show that phosphorylation of the motif’s conserved tyrosine, an event previously reported to promote IκBα accumulation and inhibition of NF-κB gene expression, suppresses the docking interaction. Results from integrated structural analyzes indicate that the motif binds to a groove at the IKK dimer interface. Consistently, suppression of IKK dimerization also abolishes IκBα substrate binding. Finally, we show that an optimized bivalent motif peptide inhibits NF-κB signaling. This work unveils a function for IKKα/β dimerization in substrate motif recognition.

Precise localization and dissection of gene promoters are key to understanding transcriptional gene regulation and to successful bioengineering applications. The core RNA polymerase II initiation machinery is highly conserved among eukaryotes, leading to a general expectation of equivalent underlying mechanisms. Still, less is known about promoters in the plant kingdom. In this study, we employed cap analysis of gene expression (CAGE) at three embryonic developmental stages in barley to accurately map, annotate, and quantify transcription initiation events. Unsupervised discovery of de novo sequence clusters grouped promoters based on characteristic initiator and position-specific core-promoter motifs. This grouping was complemented by the annotation of transcription factor binding site (TFBS) motifs. Integration with genome-wide epigenomic data sets and gene ontology (GO) enrichment analysis further delineated the chromatin environments and functional roles of genes associated with distinct promoter categories. The TATA-box presence governs all features explored, supporting the general model of two separate genomic regulatory environments. We describe the extent and implications of alternative transcription initiation events, including those that are specific to developmental stages, which can affect the protein sequence or the presence of regions that regulate translation. The generated promoterome dataset provides a valuable genomic resource for enhancing the functional annotation of the barley genome. It also offers insights into the transcriptional regulation of individual genes and presents opportunities for the informed manipulation of promoter architecture, with the aim of enhancing traits of agronomic importance.

Background and study aims Patients with primary sclerosing cholangitis and inflammatory bowel disease (IBD) have a high risk of colorectal cancer. There is no agreement on the best technique for surveillance for colorectal neoplasia. We aimed to assess whether chromoendoscopy and/or high-definition endoscopy is associated with increased detection of neoplasia in patients with primary sclerosing cholangitis undergoing surveillance compared with when they were not used.

The addition of methane-reducing compounds (MRCs) to livestock drinking water presents an alternative method for enteric methane mitigation in extensive systems where these compounds cannot be fed through the diet. This work evaluated several such compounds with the potential to be deployed in this manner. Methane-reducing compounds were selected based on the existing literature and likelihood of dissolution when combined with a commercially available water-based nutrient supplement (uPRO) (uPRO ORANGE®, DIT AgTech, QLD, Australia). This, in turn, would demonstrate the capacity for MRCs to be administered through animal drinking water when such supplements are in use. This technique requires the analysis of MRC solubility and stability in solution, which was completed via Fourier transform infrared-attenuated total reflectance spectroscopy. The uPRO supplement is comprised of urea, urea phosphate, and ammonium sulfate, providing nitrogen, phosphorus, and sulfur—limiting nutrients for ruminants grazing extensive systems during drier periods of the year. Accordingly, medium-quality Rhodes grass hay was used in fermentation runs to simulate a basal diet during the dry season. Methane-reducing compounds were assessed in accordance with each variable measured (gas/methane production, dry matter digestibility, stability under different environmental conditions) along with existing research in the field to determine the most suitable compound for co-administration. Whilst most compounds examined in this study appeared to retain their structure in solution with uPRO, fermentation results varied in terms of successful methane mitigation. The additive Agolin Ruminant L emerged as the most promising compound for further in vivo investigation.

Abstract Background A conceptual model of effective symptom management was previously developed from interviews with multidisciplinary healthcare professionals (HCP) working in English hospices. Here we aimed to answer the question; does a HCP data-derived model represent the experience of patients and carers of people with advanced cancer? Methods Semi-structured interviews were undertaken with six patients with advanced cancer and six carers to gain an in-depth understanding of their experience of symptom management. Analysis was based on the framework method; transcription, familiarisation, coding, applying analytical framework (conceptual model), charting, interpretation. Inductive framework analysis was used to align data with themes in the existing model. A deductive approach was also used to identify new themes. Results The experience of patients and carers aligned with key steps of engagement, decision making, partnership and delivery in the HCP-based model. The data aligned with 18 of 23 themes. These were; Role definition and boundaries, Multidisciplinary team decision making, Availability of services/staff, Clinician-Patient relationship/rapport, Patient preferences, Patient characteristics, Quality of life versus treatment need, Staff time/burden, Psychological support -informal, Appropriate understanding, expectations, acceptance and goals- patients, Appropriate understanding, expectations, acceptance and goals-HCPs, Appropriate understanding, expectations, acceptance and goals- family friends, carers, Professional, service and referral factors, Continuity of care, Multidisciplinary team working, Palliative care philosophy and culture, Physical environment and facilities, Referral process and delays. Four additional patient and carer-derived themes were identified: Carer Burden, Communication, Medicines management and COVID-19. Constructs that did not align were Experience (of staff), Training (of staff), Guidelines and evidence, Psychological support (for staff) and Formal psychological support (for patients). Conclusions A healthcare professional-based conceptual model of effective symptom management aligned well with the experience of patients with advanced cancer and their carers. Additional domains were identified. We make four recommendations for change arising from this research. Routine appraisal and acknowledgement of carer burden, medicine management tasks and previous experience in healthcare roles; improved access to communication skills training for staff and review of patient communication needs. Further research should explore the symptom management experience of those living alone and how these people can be better supported.

Background and Aim: Zinc (Zn) is important for various physiological processes in broiler chickens, including protein and carbohydrate metabolism, growth, and reproduction. The gastrointestinal absorption of Zn in broiler chickens was notably low. One approach that has been explored for enhancing the bioavailability of Zn is the development of Zn nanoparticles (NPs). Zn is required for various physiological processes in broiler chickens, including protein and carbohydrate metabolism, growth, and reproduction. Therefore, this study aimed to assess the impact of conventional Zn and Zn NPs on broiler chickens using a meta-analysis methodology. Materials and Methods: A database was built from published literature to evaluate the effects of the addition of Zn NPs and conventional Zn on broiler chicken responses, including the following parameters: production performance; carcass cuts; visceral organ weight; lymphoid organ weight; nutrient digestibility; intestinal villi; mineral Zn, calcium, and phosphorus concentrations; hematology; blood parameters; immunoglobulin; and intestinal bacterial population. Various scientific platforms, including Scopus, Web of Science, PubMed Central, and Google Scholar, were used to search for peer-reviewed articles. A database was created from 25 studies that met the inclusion criteria. The data were then processed for a meta-analysis using a mixed-model methodology. Different types of Zn (NPs versus conventional) were considered fixed effects, different studies were treated as random effects, and p-values were used as model statistics. Results: Across the parameters observed in this study, the use of Zn NPs was more efficient in Zn utilization than conventional Zn, as evidenced by the average dose of Zn NPs being much lower than that of conventional Zn (79.44 vs. 242.76 mg/kg) yet providing similar (p > 0.05) or even significantly better effects (p < 0.05) compared to conventional Zn usage. Conclusion: This investigation revealed the beneficial influence of Zn NPs in broiler chickens compared to the conventional utilization of Zn through an all-encompassing meta-analysis. Moreover, Zn NPs have proven to be more effective in Zn utilization when juxtaposed with conventional Zn, as demonstrated by the significantly lower quantity of Zn NPs administered compared to conventional Zn, while yielding comparable or even superior outcomes compared to the traditional utilization of Zn. A limitation of this study is that the Zn NPs used were sourced from inorganic Zn NPs. Therefore, future research should focus on evaluating the efficiency of organic Zn NPs in broiler chicken feed.

Abstract Broadening gene therapy applications requires manufacturable vectors that efficiently transduce target cells in humans and preclinical models. Conventional selections of adeno-associated virus (AAV) capsid libraries are inefficient at searching the vast sequence space for the small fraction of vectors possessing multiple traits essential for clinical translation. Here, we present Fit4Function, a generalizable machine learning (ML) approach for systematically engineering multi-trait AAV capsids. By leveraging a capsid library that uniformly samples the manufacturable sequence space, reproducible screening data are generated to train accurate sequence-to-function models. Combining six models, we designed a multi-trait (liver-targeted, manufacturable) capsid library and validated 88% of library variants on all six predetermined criteria. Furthermore, the models, trained only on mouse in vivo and human in vitro Fit4Function data, accurately predicted AAV capsid variant biodistribution in macaque. Top candidates exhibited production yields comparable to AAV9, efficient murine liver transduction, up to 1000-fold greater human hepatocyte transduction, and increased enrichment relative to AAV9 in a screen for liver transduction in macaques. The Fit4Function strategy ultimately makes it possible to predict cross-species traits of peptide-modified AAV capsids and is a critical step toward assembling an ML atlas that predicts AAV capsid performance across dozens of traits.

Introduction: Preterm delivery is of considerable concern to clinicians and researchers being a leading cause of infant morbidity and mortality in the industrialized countries and also contributes to substantial complications among survivors. Sub-Saharan Africa, including Nigeria accounts for significant proportion of preterm births, with over million deaths due to complication of prematurity. Objectives: The study aimed to determine the prevalence and associated morbidities of preterm deliveries at the University of Maiduguri Teaching Hospital, Maiduguri, North-Eastern Nigeria. Patients and methods: This is a retrospective review of neonates delivered before 37 completed weeks of gestation and admitted into the Special Care Baby Unit (SCBU) of the University of Maiduguri Teaching Hospital, from 1st January 2008 to 31st December 2015. Results: There were 3435 admissions into the Special Care baby Unit (SCBU) during the 8 year period. Out of these 1129 were preterm babies giving a prevalence of 32.9%. Of the 1129 preterm babies managed in SCBU, 714 case records were retrieved and analyzed giving a retrieval rate of 63%. There were 372 (52.1%) males and 342 (47.9%) females; with the male to female ratio of 1:1.08. There were 17(2.3%) extreme low birth weight ( 288 (40.3%) very low birth weight (1000-1499 g), 406 (56.9%) low birth weight (1500- 2499 g) babies. The range of admission weights was 700-2500g with mean of 1600±900g. Conclusion: The burden, complications and mortality from preterm newborns remain significant public health challenges to care givers in Nigeria.

Background and Aim: Citronella grass (Cymbopogon nardus) waste, produced by distilling citronella to produce essential oil, has a high potential for use as animal feed. However, the presence of high lignin content could limit its digestibility, prompting the need for treatment to improve its quality. This study aimed to improve the nutritional value and in vitro digestibility of ammoniated and fermented citronella waste (CW). Materials and Methods: The treatments of CW included CW without treatment as a control (T0), ammoniation of CW with urea (T1), fermentation of CW with Trichoderma harzianum (T2), and a combination of ammoniation and fermentation (amofer) of CW (T3). This study employed a randomized block design with five replicates for each of the four treatments. If there was a significant effect (p < 0.05), a post hoc Duncan’s multiple range test was performed to analyze the variance of the data. Results: The process of ammoniation and fermentation led to a notable increase in crude protein (2%–6%) while decreasing crude fiber (2%–6%), neutral detergent fiber (NDF) (5%–14%), acid detergent fiber (ADF) (5%–9%), lignin (4%–9%), and cellulose (2%–10%). The treatments enhanced the digestibility of dry matter, organic matter (OM), NH3, and total volatile fatty acid by 4%–12%, 6%–19%, 0.9–10 mM, and 35–142 mM, respectively. The decrease in NDF, ADF, acid detergent lignin (ADL), and cellulose fractions was accompanied by an improvement in dry matter and OM digestibility in CW. Ammoniated-fermented (amofer) CW, followed by fermentation with T. harzianum and ammoniated urea treatment, significantly enhanced the nutritional content and in vitro digestibility. The decrease in NDF, ADF, ADL, and cellulose fractions led to an improvement in dry matter and OM digestibility in CW. Conclusion: The application of amofer treatment with T. harzianum maximizes CW’s nutritional value and digestibility, making it the most efficient preservation method. Research is needed to explore the potential use of Aspergillus spp. and Pleurotus spp. for fermenting CW as ruminant fodder.

Abstract Background HIV/AIDS continues to be a significant contributor to illness and death, particularly in sub-Saharan Africa. In this study, we conducted a qualitative assessment to understand Client and Healthcare Provider Perspectives on Differential Service Delivery Models in Uganda. The purpose was to establish strengths and weaknesses within the services delivery models, inform policy and decision-making, and to facilitate context specific solutions. Methods Between February and April 2023, a qualitative cross-sectional study was utilised to gather insights from a targeted selection of individuals, including People Living with HIV (PLHIV), healthcare workers, HIV focal persons, community retail pharmacists, and various stakeholders. The data collection process included eleven in-depth interviews, nine key informant interviews, and eight focus group discussions carried out across eight districts in Central Uganda. The collected data was analyzed through inductive thematic analysis with the aid of Excel. Results The various Differentiated Service Delivery Models (DSDMs), notably Community-Client-Led Drug Distribution (CCLAD), Community Drug Distribution Point (CDDP), Community Retail Pharmacy Drug Distribution Point (CRPDDP), and the facility-based Facility Based Individual Model (FBIM), were reported to have several positive impacts. These included improved treatment adherence, efficient management of antiretroviral (ARV) supplies, reduced exposure to infectious diseases, enhanced healthcare worker hospitality, minimized travel time for ART refills, stigma reduction, and decreased waiting times. Concern was raised about the lack of improvement in HIV status disclosure, opportunistic infection treatment, adherence to seasonal appointments, and sustainability due to the overreliance of the DSDMs on donor funding, suggesting potential discontinuation without funding. Doubts about health workers’ commitment surfaced. Notably, the CCLAD model displayed self-sustainability, with clients financially supporting group members to collect medicines. Conclusion Community-based DSDMs, such as CCLAD and CDDP, improve ART refill convenience, social support, and client experiences. These models reduce travel and waiting times, lowering infection risks. Addressing challenges and enhancing facility-based models is vital. In order to maintain funding after donor funding ends, sustainability measures like cross-subsidization can be used. If well implemented, the DSDMs have the potential to produce better or comparable ART outcomes compared to the FBIM model.

Abstract Papaver bracteatum, known for its high thebaine content and absence of morphine, has emerged as a promising alternative to opium poppy for codeine production. In this study, our objective was to create a diverse panel representing the natural variation of this species in Iran. To achieve this, we employed genotyping-by-sequencing to obtain genome-wide distributed single-nucleotide polymorphisms (SNPs) for phylogeographic analysis, population structure assessment, and evaluation of genetic diversity within P. bracteatum populations. A total of 244 P. bracteatum individuals from 13 distinct populations formed seven genetic groups, along with one highly admixed population. We observed a clear split between the populations inhabiting the Alborz Mts. in the east and Zagros Mts. in the west. In between these mountain ranges, the population of Kachal Mangan exhibited a high degree of genetic admixture between both genetic groups. At or after the end of the last glacial maximum, when climate conditions rapidly changed, all P. bracteatum populations experienced a strong demographic bottleneck reducing the already small effective population sizes further before they increased to their recent strengths. Our results suggest that the ongoing climate change together with human pressure on the species’ habitats and limited seed-dispersal ability are potential factors contributing today to rising genetic isolation of P. bracteatum populations. Our results provide genetic data that can be used for conservation measures to safeguard the species’ genetic diversity as a resource for future breeding approaches in this medicinally important species.

Abstract Hookworm infection remains a significant public health concern, particularly in low- and middle-income countries, where mass drug administration has not stopped reinfection. Developing a vaccine is crucial to complement current control measures, which necessitates a thorough understanding of host immune responses. By leveraging controlled human infection models and high-dimensional immunophenotyping, here we investigated the immune remodeling following infection with 50 Necator americanus L3 hookworm larvae in four naïve volunteers over two years of follow-up and compared the profiles with naturally infected populations in endemic areas. Increased plasmacytoid dendritic cell frequency and diminished responsiveness to Toll-like receptor 7/8 ligand were observed in both controlled and natural infection settings. Despite the increased CD45RA+ regulatory T cell (Tregs) frequencies in both settings, markers of Tregs function, including inducible T-cell costimulatory (ICOS), tumor necrosis factor receptor 2 (TNFR2), and latency-associated peptide (LAP), as well as in vitro Tregs suppressive capacity were higher in natural infections. Taken together, this study provides unique insights into the immunological trajectories following a first-in-life hookworm infection compared to natural infections.

Abstract Granuloprival degeneration is an uncommon form of cerebellar cortical degeneration (CCD). A 3‐month‐old Yorkshire Terrier and a 7‐month‐old Lagotto Romagnolo dog were presented with a history of progressive cerebellar dysfunction including wide‐based stance, cerebellar ataxia, intention tremors, and loss of menace response despite normal vision. Magnetic resonance imaging of the brain identified marked diffuse decrease of the cerebellum size. Euthanasia was performed in both cases because of progression of clinical signs. Histopathological examination identified marked diffuse thinning of the granular cell layer with almost complete loss of the granular cell neurons, providing a definitive diagnosis of granuloprival CCD. Granuloprival CCD should be considered as a differential diagnosis in Yorkshire Terrier and Lagotto Romagnolo dogs with post‐natal progressive clinical signs of cerebellar dysfunction.

Abstract Imaging with undetected photons relies upon nonlinear interferometry to extract the spatial image from an infrared probe beam and reveal it in the interference pattern of an easier-to-detect visible beam. Typically, the transmission and phase images are extracted using phase-shifting techniques and combining interferograms from multiple frames. Here we show that off-axis digital holography enables reconstruction of both transmission and phase images at the infrared wavelength from a single interferogram, and hence a single frame, recorded in the visible. This eliminates the need for phase stepping and multiple acquisitions, thereby greatly reducing total measurement time for imaging with long acquisition times at low flux or enabling video-rate imaging at higher flux. With this single-frame acquisition technique, we are able to reconstruct transmission images of an object in the infrared beam with a signal-to-noise ratio of $$3.680\,\pm \,0.004$$ 3.680 ± 0.004 at 10 frames per second, and record a dynamic scene in the infrared beam at 33 frames per second.

Abstract Objective Bartonella are emerging bacterial zoonotic pathogens. Utilization of clotted blood samples for surveillance of these bacteria in wildlife has begun to supersede the use of tissues; however, the efficacy of these samples has not been fully investigated. Our objective was to compare the efficacy of spleen and blood samples for DNA extraction and direct detection of Bartonella spp. via qPCR. In addition, we present a protocol for improved DNA extraction from clotted, pelleted (i.e., centrifuged) blood samples obtained from wild small mammals. Results DNA concentrations from kit-extracted blood clot samples were low and A260/A280 absorbance ratios indicated high impurity. Kit-based DNA extraction of spleen samples was efficient and produced ample DNA concentrations of good quality. We developed an in-house extraction method for the blood clots which resulted in apposite DNA quality when compared to spleen samples extracted via MagMAX DNA Ultra 2.0 kit. We detected Bartonella in 9/30 (30.0%) kit-extracted spleen DNA samples and 11/30 (36.7%) in-house-extracted blood clot samples using PCR. Our results suggest that kit-based methods may be less suitable for DNA extraction from blood clots, and that blood clot samples may be superior to tissues for Bartonella detection.

The atmospheric concentration of carbon dioxide is continuously rising mostly due to the consumption of fossil fuels. Renewable fuels, such as synthetic methane and methanol, for which production hydrogen and carbon dioxide are needed, have the potential to mitigate climate change by substituting fossil-based energy carriers. The core objective of this paper is to investigate the utilization of carbon dioxide from biomass-based processes for the production of e-methane and e-methanol, as well as to analyze their future prospects. Different scenarios including the most relevant impact parameters, such as possible learning rates or number of full load hours, are derived. Finally, the strengths, weaknesses, opportunities and threats of synthetic methane and methanol are compared with direct hydrogen utilization from an economic and technical point of view. In spite of the possible cost reductions due to technological learning and economies of scale, the production costs of e-methane and e-methanol will remain very high in the main scenario. Therefore, low electricity prices and a high number of full-load hours are key to enhance the economic viability.

Low-Speed Pre-Ignition (LSPI) is a destructive combustion event associated primarily with new, ultra-efficient, downsized gasoline engines, which provide efficiency benefits in general operation. Biofuels, specifically bio-gasoline, are an alternative fuel that attempts to reduce the harmful emissions output by modern Internal Combustion Engines (ICEs). This study attempts to understand the effect of biofuel use on LSPI, through the use of a numerical simulation tool developed in Ricardo Wave. Development of the tool includes the integration of RFlame, an extension capable of modeling autoignition within a 1D domain. Use of the tool highlights the impact of five ethanol blends, E10, E20, E30, E50 and E85, with clear impacts on both the severity and frequency of LSPI events correlated with chemical properties, such as the enthalpy of vaporization (HoV) and octane number. E30 is highlighted as the critical blend for LSPI severity, with both increased severity and intensity seen with a 30% concentration, and a greater sensitivity to effects such as the start of ignition (SOI). Higher-concentration biofuels, such as E50 and E85 bio-gasoline, show much more favorable behaviors, such as a vast reduction in end-gas knock events, but are limited in their use due to their deployment being both cost-prohibitive and potentially damaging in current hardware. Future work on this topic will surround the further development of the simulation tool to integrate 3D solving elements, understand the role of fluid interactions in LSPI, and study optimal fuel characteristics for future use in ICEs.

Abstract Eukaryotic membranes are compartmentalized into distinct micro- and nanodomains that rearrange dynamically in response to external and internal cues. This lateral heterogeneity of the lipid bilayer and associated clustering of distinct membrane proteins contribute to the spatial organization of numerous cellular processes. Here, we show that membrane microdomains within the endoplasmic reticulum (ER) of yeast cells are reorganized during metabolic reprogramming and aging. Using biosensors with varying transmembrane domain length to map lipid bilayer thickness, we demonstrate that in young cells, microdomains of increased thickness mainly exist within the nuclear ER, while progressing cellular age drives the formation of numerous microdomains specifically in the cortical ER. Partitioning of biosensors with long transmembrane domains into these microdomains increased protein stability and prevented autophagic removal. In contrast, reporters with short transmembrane domains progressively accumulated at the membrane contact site between the nuclear ER and the vacuole, the so-called nucleus-vacuole junction (NVJ), and were subjected to turnover via selective microautophagy occurring specifically at these sites. Reporters with long transmembrane domains were excluded from the NVJ. Our data reveal age-dependent rearrangement of the lateral organization of the ER and establish transmembrane domain length as a determinant of membrane contact site localization and autophagic degradation.

Abstract People regularly read multi-line texts in different formats and publishers, internationally, must decide how to present text to make reading most effective and efficient. Relatively few studies have examined multi-line reading, and fewer still Chinese multi-line reading. Here, we examined whether texts presented in single or double columns, and either left-justified or fully-justified affect Chinese reading. Text format had minimal influence on overall reading time; however, it significantly impacted return-sweeps (large saccades moving the eyes from the end of one line of text to the beginning of the next). Return-sweeps were launched and landed further away from margins and involved more corrective saccades in single- than double-column format. For left- compared to fully-justified format, return-sweeps were launched and landed closer to margins. More corrective saccades also occurred. Our results showed more efficient return-sweep behavior for fully- than left-justified text. Moreover, there were clear trade-off effects such that formats requiring increased numbers of shorter return-sweeps produced more accurate targeting and reduced numbers of corrective fixations, whereas formats requiring reduced numbers of longer return-sweeps caused less accurate targeting and an increased rate of corrective fixations. Overall, our results demonstrate that text formats substantially affect return-sweep eye movement behavior during Chinese reading without affecting efficiency and effectiveness, that is, the overall time it takes to read and understand the text.

Abstract Background Disruptions in malaria control due to COVID-19 mitigation measures were predicted to increase malaria morbidity and mortality in Africa substantially. In Uganda, long-lasting insecticidal nets (LLINs) are distributed nationwide every 3–4 years, but the 2020–2021 campaign was altered because of COVID-19 restrictions so that the timing of delivery of new nets was different from the original plans made by the National Malaria Control Programme. Methods A transmission dynamics modelling exercise was conducted to explore how the altered delivery of LLINs in 2020–2021 impacted malaria burden in Uganda. Data were available on the planned LLIN distribution schedule for 2020–2021, and the actual delivery. The transmission model was used to simulate 100 health sub-districts, and parameterized to match understanding of local mosquito bionomics, net use estimates, and seasonal patterns based on data collected in 2017–2019 during a cluster-randomized trial (LLINEUP). Two scenarios were compared; simulated LLIN distributions matching the actual delivery schedule, and a comparable scenario simulating LLIN distributions as originally planned. Model parameters were otherwise matched between simulations. Results Approximately 70% of the study population received LLINs later than scheduled in 2020–2021, although some areas received LLINs earlier than planned. The model indicates that malaria incidence in 2020 was substantially higher in areas that received LLINs late. In some areas, early distribution of LLINs appeared less effective than the original distribution schedule, possibly due to attrition of LLINs prior to transmission peaks, and waning LLIN efficacy after distribution. On average, the model simulations predicted broadly similar overall mean malaria incidence in 2021 and 2022. After accounting for differences in cluster population size and LLIN distribution dates, no substantial increase in malaria burden was detected. Conclusions The model results suggest that the disruptions in the 2020–2021 LLIN distribution campaign in Uganda did not substantially increase malaria burden in the study areas.

Recently, the Horn of Africa witnessed a swift increase in the incidence of desert locust (Schistocerca gregaria) invasion. During outbreaks, pesticides are applied through aerial or ground spraying to kill the insects, and/or to prevent their spread to new grounds. However, after decades of extensive use, many drawbacks such as contamination of the environment, toxicity to non-target organisms, harmful residues on food, pest resistance, and bioaccumulation in the food chains emerged. Entomopathogenic fungi offer viable alternatives to chemical pesticides against many insect invasions, but few studies have tested their bio-efficacy in desert locusts. Therefore, the current study aimed at isolating, formulating local isolates 231, 334, 333, 341, 349, 351, 339 of Beauveria bassiana, and testing their bio-efficacy against larval and adult desert locusts. The 21-day experiment was conducted under controlled conditions in a greenhouse. Soil samples were collected from two agroecological zones in Isiolo and Laikipia Counties in Kenya. B. bassiana was isolated from the soil samples using the Galleria bait method and cultivated in Sabouraud Dextrose Agar Yeast (SDAY). The isolates were identified based on molecular techniques (DNA and PCR amplification). The conidia of the isolates were screened and bioassays on 30 locusts was conducted for 14 days. The best isolates eliciting over 90 % mortality during screening were used for formulations using three carrier materials (liquid paraffin, Diatomaceous Earth, and whey) which were again tested against adult and 3rd nymphal instars of the locusts. The stability of the formulations was also tested after 1 and 2 months. All the tested isolates of B. bassiana significantly outperformed the control and thus pathogenic to the adults and 3rd nymphal instars of S. gregaria under laboratory conditions. They caused mortality ranging from 57.8–100 % after 14 days post-incubation. The isolates 341, 231, and, 334 elicited 50 % mortality responses at concentrations 1.1 × 105 conidia/ml, 2.5 × 105 conidia/ml and 1.7 × 106 conidia/ml respectively in adults and 1.1 × 105 conidia/ml, 2.5 × 105 conidia/ml and, 1.7 × 106 conidia/ml respectively in 3rd nymphal instars. Formulations with 341–1, 341–2, and, 334–1 had the highest efficacy (>99 %) against the adult locusts. There was a significant 3-way interaction (P < 0.05) of isolate for the formulation, carrier material and, time in determining the Cfu of the B. bassiana formulations. After 1 month, the best Cfu occurred in formulation with isolates 231 and 341 formulated using Diatomaceous Earth, while the highest Cfu was observed in formulation with isolate 334 formulated with either liquid paraffin or whey. After 2 months, the highest Cfu occurred in formulation with isolates 231, 341, and, 334 formulated using liquid paraffin. This study provides encouraging data for the development of potential biopesticides formulated with different carrier materials against desert locusts.

Summary: A poor maternal diet during pregnancy predisposes the infant to severe lower respiratory tract infections (sLRIs), which, in turn, increases childhood asthma risk; however, the underlying mechanisms remain poorly understood. Here, we show that the offspring of high-fat diet (HFD)-fed mothers (HFD-reared pups) developed an sLRI following pneumovirus inoculation in early life and subsequent asthma in later life upon allergen exposure. Prior to infection, HFD-reared pups developed microbial dysbiosis and low-grade systemic inflammation (LGSI), characterized by hyperneutropoiesis in the liver and elevated inflammatory cytokine expression, most notably granulocyte-colony stimulating factor (G-CSF), interleukin-17A (IL-17A), IL-6 and soluble IL-6 receptor (sIL-6R) (indicative of IL-6 trans-signaling) in the circulation and multiple organs but most prominently the liver. Inhibition of IL-6 trans-signaling using sgp130Fc transgenic mice or via specific genetic deletion of IL-6Ra on neutrophils conferred protection against both diseases. Taken together, our findings suggest that a maternal HFD induces neonatal LGSI that predisposes to sLRI and subsequent asthma via neutrophil-mediated IL-6 trans-signaling.

Immune system and vaccine responses vary across geographical locations worldwide, not only between high and low-middle income countries (LMICs), but also between rural and urban populations within the same country. Lifestyle factors such as housing conditions, exposure to microorganisms and parasites and diet are associated with rural-and urban-living. However, the relationships between these lifestyle factors and immune profiles have not been mapped in detail. Here, we profiled the immune system of 100 healthy Tanzanians living across four rural/urban areas using mass cytometry. We developed a lifestyle score based on an individual's household assets, housing condition and recent dietary history and studied the association with cellular immune profiles. Seventeen out of 80 immune cell clusters were associated with living location or lifestyle score, with eight identifiable only using lifestyle score. Individuals with low lifestyle score, most of whom live in rural settings, showed higher frequencies of NK cells, plasmablasts, atypical memory B cells, T helper 2 cells, regulatory T cells and activated CD4+ T effector memory cells expressing CD38, HLA-DR and CTLA-4. In contrast, those with high lifestyle score, most of whom live in urban areas, showed a less activated state of the immune system illustrated by higher frequencies of naïve CD8+ T cells. Using an elastic net machine learning model, we identified cellular immune signatures most associated with lifestyle score. Assuming a link between these immune profiles and vaccine responses, these signatures may inform us on the cellular mechanisms underlying poor responses to vaccines, but also reduced autoimmunity and allergies in low- and middle-income countries.

ABSTRACT The Eastern Arc Mountains (EAM) and Coastal forests of Tanzania are renowned for harboring large number of threatened and endemic vertebrate species, yet most of these areas have been partially studied. The Kimboza Nature Forest Reserve (KNFR) is a small forest which is in transition between the EAM and Coastal forests, and among the poorly surveyed areas for amphibians and reptiles. We conducted systematic surveys across the KNFR in 2012 and between 2020 and 2023 using a range of approaches with the aim of establishing a comprehensive and updated list of reptile and amphibian species and assess the contribution of EAM and Coastal forests to the KNFR's herpetofauna. We identified 77 species, 29 amphibians and 48 reptiles, substantially updating previous species lists. Three of these species (Kinyongia magomberae, Trachylepis boulengeri and Philothamnus macrops) represent range extensions from previously known ranges. Fourteen species are endemic to East Africa, 11 of them being restricted to Tanzania. These results make the KNFR the richest forest reserve for herpetofauna per square km in Tanzania, and most similar in its composition to the Coastal, rather than Eastern Arc forests. With the caveats concerning taxonomic uncertainties and the inequalities of sampling intensity across the region, this study shows that the KNFR is an important area that deserves conservation attention. The KNFR, like other Coastal forests, is under significant pressure from anthropogenic activities which call for an urgent action to protect this small but rich forest.

The prevalence of hemorrhagic diseases of the central nervous system of dogs and cats is low compared to other diseases such as neoplasia and inflammation. However, the clinical consequences can be devastating. Several etiological and localization-based classification systems have been reported for intracerebral and spinal cord hemorrhage or hematomyelia in humans but similar systems do not exist in veterinary medicine. The authors propose an etiologic classification system for both intraparenchymal hemorrhagic encephalopathy and myelopathy following a review of the literature detailing the presentation, diagnosis, therapy, and prognosis of these diseases. A summary of the investigative and therapeutic approach to these cases is also provided.

ABSTRACT Introduction The term “Mediterranean lifestyle” has gained increasing prominence in recent years, yet a specific definition remains elusive. In response, the Mediterranean Lifestyle Medicine Institute Board of Directors convened a multidisciplinary panel comprising international experts and leaders in lifestyle medicine. Their goal was to review existing literature and formulate a consensus definition of the “traditional Mediterranean lifestyle (tMedL),” referring to the historical way of living of the people in the Mediterranean region. This paper presents the agreed consensus statement and a comprehensive holistic definition of the term “traditional Mediterranean lifestyle.” Methods Major medical and social sciences electronic databases from inception to February 2023 were searched, employing keywords relevant to the Mediterranean lifestyle and its constituent elements (diet, physical activity, sleep, stress, socialization). Subsequently, definitions for each pillar were created and synthesized to derive a comprehensive definition of the “traditional Mediterranean lifestyle.” Results This proposed definition received ratification from the Mediterranean Lifestyle Medicine Institute's expert working group during the First International Mediterranean Lifestyle Medicine Conference held in June 2023 on the island of Leros, Greece. “The traditional Mediterranean lifestyle is characterized by its diverse and adaptable nature. Key facets encompass conviviality, lifelong social connectedness, purposeful living, strong community and familial bonds, harmony with nature and the environment, profound spirituality, adherence to religious practices, preservation of local customs, resilience cultivated through adversity, and a commitment to moderation across all spheres of life.” Conclusions This definition comprehensively outlines the primary lifestyle factors ingrained in Mediterranean inhabitants across generations. Its holistic nature furnishes a crucial conceptual framework for directing lifestyle medicine practitioners in assisting patients to mitigate diseases, promote overall well‐being, devise research initiatives to investigate the health ramifications of this lifestyle, and inform curriculum development.