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Abstract In clinical movement biomechanics, kinematic measurements are collected to characterise the motion of articulating joints and investigate how different factors influence movement patterns. Representative time-series signals are calculated to encapsulate (complex and multidimensional) kinematic datasets succinctly. Exacerbated by numerous difficulties to consistently define joint coordinate frames, the influence of local frame orientation and position on the characteristics of the resultant kinematic signals has been previously proven to be a major limitation. Consequently, for consistent interpretation of joint motion (especially direct comparison) to be possible, differences in local frame position and orientation must first be addressed. Here, building on previous work that introduced a frame orientation optimisation method and demonstrated its potential to induce convergence towards a consistent kinematic signal, we present the REference FRame Alignment MEthod (REFRAME) that addresses both rotational and translational kinematics, is validated here for a healthy tibiofemoral joint, and allows flexible selection of optimisation criteria to fittingly address specific research questions. While not claiming to improve the accuracy of joint kinematics or reference frame axes, REFRAME does enable a representation of knee kinematic signals that accounts for differences in local frames (regardless of how these differences were introduced, e.g. anatomical heterogeneity, use of different data capture modalities or joint axis approaches, intra- and inter-rater reliability, etc.), as evidenced by peak root-mean-square errors of 0.24° ± 0.17° and 0.03 mm ± 0.01 mm after its implementation. By using a self-contained optimisation approach to systematically re-align the position and orientation of reference frames, REFRAME allows researchers to better assess whether two kinematic signals represent fundamentally similar or different underlying knee motion. The openly available implementation of REFRAME could therefore allow the consistent interpretation and comparison of knee kinematic signals across trials, subjects, examiners, or even research institutes.

Abstract In modern knee arthroplasty, surgeons increasingly aim for individualised implant selection based on data-driven decisions to improve patient satisfaction rates. The identification of an implant design that optimally fits to a patient’s native kinematic patterns and functional requirements could provide a basis towards subject-specific phenotyping. The goal of this study was to achieve a first step towards identifying easily accessible and intuitive features that allow for discrimination between implant designs based on kinematic data. A squat-cycle was simulated on eight fresh frozen specimens mounted in a weight-bearing knee rig, each initially tested under native conditions, and then after implantation with four different implant types (CR/CS, MS, LS, and PS). The kinematic signals of these five configurations were compared to determine whether key differences between implants could be detected leveraging two methodological approaches: (1) statistical parametric mapping to directly compare waveforms and (2) simple paired t-tests to compare the three-dimensional coordinates of the functional centres of rotation determined using a previously published REference FRame Alignment Method (REFRAME). While statistical parametric mapping of the kinematic data revealed only small differences in certain comparisons (e.g. LS vs. PS, and MS vs. LS) under lenient statistical testing conditions, the application of REFRAME showed clear differences between implants (for all implant combinations except for CR/CS vs. LS), even under conservative statistical testing. Since for most implant combinations, significant differences in the centres of rotation were found using REFRAME, this approach could present a suitable tool for discriminating between the kinematics of different implant types. Preoperative assessment of joint kinematics, combined with this REFRAME application, could therefore provide a key approach for improved clinical selection of implant type.

Abstract Background Falls and fall-related injuries among older adults in Singapore are a serious health problem that require early intervention. In previous research, exercise interventions have been effective in improving functional outcomes and reducing falls for a broad group of older adults. However, results from multi-domain, multi-component falls prevention programs for high fall risk older adults in the community remain equivocal. One reason for these results is that there is significant heterogeneity in falls risk factors amongst high falls risk older adults which makes tailoring multicomponent interventions complex. The objective of the trial is to evaluate the effectiveness of an enhanced version of the predecessor program, SAFE. The Steps to Avoid Falls in the Elderly—a TECHnology enhanced intervention (SAFE-TECH) is designed for older adults in the community who are at high risk of falls, with candidate selection and program tailoring based on gait variables derived from wearable sensors and various questionnaire-based features. Methods SAFE-TECH is a 12-month randomized controlled trial involving 400 older adults at high risk of falling, who are randomly allocated to an intervention or control group in a 1:1 ratio. Participants will be assessed at baseline, 3rd-month and 12th-month for functional status, physical performance, cognitive status, quality of life, and medical history. Monthly phone calls will assess fall status, healthcare utilization, physical activity, and exercise self-efficacy. Participants in the intervention group will undergo a tailored, multi-domain, multi-component falls prevention program. The active intervention phase will last for 12-weeks with exercises focusing on strength, balance, coordination, flexibility, and aerobic endurance; and weekly educational sessions on falls risk with personalized feedback based on participant’s falls risk assessments and environmental checklist. Discussions SAFE-TECH seeks to evaluate enhanced existing falls prevention programs by addressing the heterogeneity of falls risk through rapid assessments and personalisation of exercise and education components while maintaining the efficiency of the group setting. Our findings will inform practical efforts to reduce falls and falls-related injuries among community-dwelling older adults. Trial registration ClinicalTrials.gov. Clinical Trial Number: NCT06102954|| 22–10-2023.

Abstract Background Experimental knee implant wear testing according to ISO 14243 is a standard procedure, but it inherently possesses limitations for preclinical evaluations due to extended testing periods and costly infrastructure. In an effort to overcome these limitations, we hereby develop and experimentally validate a finite-element (FE)-based algorithm, including a novel cross-shear and contact pressure dependent wear and creep model, and apply it towards understanding the sensitivity of wear outcomes to the applied boundary conditions. Methods Specifically, we investigated the application of in vivo data for level walking from the publicly available “Stan” data set, which contains single representative tibiofemoral loads and kinematics derived from in vivo measurements of six subjects, and compared wear outcomes against those obtained using the ISO standard boundary conditions. To provide validation of the numerical models, this comparison was reproduced experimentally on a six-station knee wear simulator over 5 million cycles, testing the same implant Stan’s data was obtained from. Results Experimental implementation of Stan’s boundary conditions in displacement control resulted in approximately three times higher wear rates (4.4 vs. 1.6 mm3 per million cycles) and a more anterior wear pattern compared to the ISO standard in force control. While a force-controlled ISO FE model was unable to reproduce the bench test kinematics, and thus wear rate, due to a necessarily simplified representation of the simulator machine, similar but displacement-controlled FE models accurately predicted the laboratory wear tests for both ISO and Stan boundary conditions. The credibility of the in silico wear and creep model was further established per the ASME V&V-40 standard. Conclusions The FE wear model is suitable for supporting future patient-specific models and development of novel implant designs. Incorporating the Stan data set alongside ISO boundary conditions emphasized the value of using measured kinematics in displacement control for reliably replicating in vivo joint mechanics in wear simulation. Future work should focus on expanding the range of daily activities simulated and addressing model sensitivity to contact mechanics to further enhance predictive accuracy.

Abstract Background Low back pain (LBP) is a common health complaint and a prominent factor in the development of LBP among the working population is stress. Mostly, stress is addressed as a general problem, which is why LBP prevention programs are often imprecise. Accordingly, a closer look at the association between specific stress types and the development of LBP is necessary. Therefore, this paper aims (1) to identify the stress types most closely associated with LBP; (2) to examine the relationship between stress accumulation and LBP. Methods n = 100 call-center workers were approached for participation. Stress levels and LBP were assessed with questionnaires (TICS, ERI, CPG, BPI) and hair cortisol levels were measured (ELISA-KIT, 3-months period). Mann-Whitney U tests were used to identify stress types most closely associated with LBP. Further, ANCOVA analysis was conducted to determine the association of the number of experienced stress types with LBP intensity and impairment. Results Finally, data from n = 68 participants (mean age: 43.2 (± 12.8) years; 62% female) were used for presented analysis. Participants, who were affected by work-related stress showed higher pain severity (excessive demands at work: 23.6 ± 21.8 vs. 42.4 ± 25.0 (p = 0.005)) and more impairment (excessive demands at work: 13.7 ± 17.6 vs. 28.7 ± 22.3 (p = 0.003); work overload: 15.4 ± 20.4 vs. 26.3 ± 17.4 (p = 0.009)) than their less affected colleagues. Other stress types (e.g. Effort, Reward) showed no significant association with LBP. Furthermore, participants who experienced two or more of the most associated stress types simultaneously suffered from stronger pain and more impairment (p

Background: Brain metastases in pediatric osteosarcoma are infrequent but associated with a dire prognosis. Methods: This retrospective study examined six pediatric patients at Johns Hopkins Hospital who developed brain metastases from osteosarcoma between April 2015 and November 2023. Results: Median survival post-brain metastasis was 2.5 months. The patients underwent various treatments, including chemotherapy, surgery, and radiation. Despite these interventions, outcomes were uniformly fatal. Notably, one patient survived over 13 months post-brain metastasis with a treatment regimen of cabozantinib and nivolumab along with surgical resection and radiation, highlighting the potential efficacy of multimodal treatment regimens. This case demonstrated changes in the immune microenvironment, hinting at an anti-tumoral response, although no histologic response was observed. Conclusions: These findings emphasize the critical need for vigilant clinical monitoring, especially in patients with new neurological symptoms. The study highlights the diagnostic challenges and the rapid progression of brain metastases, underscoring the necessity for further research. Prospective studies and clinical trials focusing on novel therapeutic strategies are essential to improve outcomes. Disease biology studies examining tumor features across primary, pulmonary, and brain metastatic sites may offer insights into the mechanisms of metastasis and potential therapeutic targets, providing a foundation for better management of this devastating complication.

Abstract ABCB6 has been implicated in dyschromatosis universalis hereditaria, a condition characterized by hyperpigmented and hypopigmented skin macules. Dyschromatosis universalis hereditaria can also present with hearing loss. Dyschromatosis universalis hereditaria-associated mutations in ABCB6 have been reported, but the role of this protein in the inner ear has not been studied. Here we determine a high-resolution (2.93 Å) cryo-EM structure of ABCB6 and functionally characterized several dyschromatosis universalis hereditaria mutants. We find that the L356P mutant abolishes ABCB6 function, and affirm the underlying loss of ATP binding mechanism using molecular dynamics simulations based on our cryo-EM structure. To test the role of ABCB6 in the inner ear, we characterize Abcb6 (the ABCB6 homolog) in zebrafish. We show that Abcb6 suppression by morpholinos reduces inner ear and lateral line hair cell numbers. Morphants also lack the utricular otolith, which is associated with vestibular function. Co-injecting morpholinos with human ABCB6 mRNA partially rescues the morphant phenotype, suggesting that Abcb6 plays a developmental role in inner ear structures. Further, we show that Abcb6 knockout mice exhibit an increased auditory brainstem response threshold, resulting in reduced hearing sensitivity. Taken together, these data suggest ABCB6 plays a role in inner ear development and function.

Abstract Background Invasive management strategies range from preventing new invasive species incursions to eliminating established populations, with all requiring effective monitoring to guide action. The use of DNA sampled from the environment (eDNA) is one such tool that provides the ability to surveille and monitor target invasive species through passive sampling. Technology being developed to eliminate invasive species includes genetic biocontrol in the form of gene drive. This approach would drive a trait through a population and could be used to eliminate or modify a target population. Once a gene drive organism is released into a population then monitoring changes in density of the target species and the spread of the drive in the population would be critical. Results In this paper, we use invasive Mus musculus as a model for development of an eDNA assay that detects wild-type M. musculus and gene drive M. musculus. We demonstrate successful development of an assay where environmental samples could be used to detect wild-type invasive M. musculus and the relative density of wild-type to gene drive M. musculus. Conclusions The development of a method that detects both wild-type M. musculus and a gene drive M. musculus (t CRISPR) from environmental samples expands the utility of environmental DNA. This method provides a tool that can immediately be deployed for invasive wild M. musculus management across the world. This is a proof-of-concept that a genetic biocontrol construct could be monitored using environmental samples.

Abstract Vitamin D deficiency is common in many societies and causes rickets and non-skeletal disorders in children. There are no published data on vitamin D deficiency in Afghanistan. We, therefore, investigated the prevalence and associated factors of vitamin D deficiency in Afghan school children in Kandahar City, Afghanistan. This cross-sectional analytical study was conducted from September 2022 to April 2023 in 510 primary school students aged 6–15 years from six randomly selected schools. Data were analyzed by using descriptive statistics, Chi-square test, and multivariate logistic regression. Of the 510 enrolled children, 54.3% were boys and 91.8% were poor. The mean serum 25(OH)D concentration was 9.3 ng/mL. Vitamin D deficiency (

Abstract Forests harbor extensive biodiversity and act as a strong global carbon and nitrogen sink. Although enhancing tree diversity has been shown to mitigate climate change by sequestering more carbon and nitrogen in biomass and soils in manipulative experiments, it is still unknown how varying environmental gradients, such as gradients in resource availability, mediate the effects of tree diversity on carbon and nitrogen accrual in natural forests. Here, we use Canada’s National Forest Inventory data to explore how the relationships between tree diversity and the accumulation of carbon and nitrogen in tree biomass and soils vary with resource availability and environmental stressors in natural forests. We find that the positive relationship between tree functional diversity (rather than species richness) and the accumulation of carbon in tree biomass strengthens with increasing light and soil nutrient availability. Moreover, the positive relationship between tree functional diversity and the accumulation of carbon and nitrogen in both organic and mineral soil horizons is more pronounced at sites with greater water and nutrient availabilities. Our results highlight that conserving and promoting functionally diverse forests in resource-rich environments could play a greater role than in resource-poor environments in enhancing carbon and nitrogen sequestration in Canada’s forests.

Abstract Malaria parasites are haploid within humans, but infections often contain genetically distinct groups of clonal parasites. When the per-infection number of genetically distinct clones (i.e., the multiplicity of infection, MOI) exceeds one, and per-infection genetic data are generated in bulk, important information are obfuscated. For example, the MOI, the phases of the haploid genotypes of genetically distinct clones (i.e., how the alleles concatenate into sequences), and their frequencies. This complicates many downstream analyses, including relatedness estimation. MOIs, parasite sequences, their frequencies, and degrees of relatedness are used ubiquitously in malaria studies: for example, to monitor anti-malarial drug resistance and to track changes in transmission. In this article, MrsFreqPhase methods designed to estimate statistically malaria parasite MOI, relatedness, frequency and phase are reviewed. An overview, a historical account of the literature, and a statistical description of contemporary software is provided for each method class. The article ends with a look towards future method development, needed to make best use of new data types generated by cutting-edge malaria studies reliant on MrsFreqPhase methods.

Abstract Postnatal kidney growth is substantial and involves expansion in kidney tubules without growth of new nephrons, which are the functional units of the kidney. Proliferation and differentiation pathways underpinning nephron elongation are not well defined. To address this, we performed sequential characterization of mouse kidney transcriptomics at the single cell level. Single nuclear RNA sequencing (snRNA-seq) was performed on kidney tissue from male and female mice at 1, 2, 4 and 12 weeks of age using the 10x Chromium platform. Unbiased clustering was performed on 68,775 nuclei from 16 animals. 31 discrete cellular clusters were seen, which were identified through comparison of their gene expression profiles to canonical markers of kidney cell populations. High levels of proliferation were evident at early time points in some cell types, especially tubular cells, but not in other cell types, for example podocytes. Proliferation was especially evident in Proximal Tubular Cells (PTCs) which are the most abundant cell type in the adult kidney. Uniquely when compared to other kidney cell types, PTCs demonstrated sex-specific expression profiles at late, but not early, time points. Mapping of PTC differentiation pathways using techniques including trajectory and RNA Velocity analyses delineated increasing PTC specialization and sex-specific phenotype specification. Our single-cell transcriptomics data characterise cellular states observed during kidney growth. We have identified PTC differentiation pathways that lead to sex-specific tubular cell phenotypes. Tubular proliferative responses are of central importance in postnatal kidney growth and have also been linked to kidney recovery versus fibrosis following injury. Our unbiased and comprehensive dataset of tubular cell development can be used to identify candidate pathways for therapeutic targeting.

Abstract Kinematic analysis is a central component of movement biomechanics, describing the relative motion of joint segments during different activities, in different subject cohorts, and at different timepoints. Establishing whether two sets of kinematic signals represent fundamentally similar or different underlying motion patterns is especially challenging, given 1) the lack of consensus around reference frame and joint axis definition, and 2) the substantial effect that minimal variations in frame position and orientation are known to have on signal magnitude and characteristics. As such, enormous variability in the reporting of tibiofemoral kinematics has resulted in joint movement patterns that remain controversially discussed. Previously, we demonstrated the ability of the REference FRame Alignment MEthod (REFRAME) to reorientate and reposition differently aligned local segment frames to achieve convergence in signals representing the same underlying motion, thereby offering a novel approach to consistently report joint motion. In this study, for the first time, we apply REFRAME to assess the rotational and translational in vivo tibiofemoral motion of ten healthy subjects during stair descent based on kinematic signals collected using a moving videofluoroscope. Kinematics were analysed before and after different REFRAME implementations, revealing generally neutral ab/adduction behaviour, accompanied by varying degrees of a sinusoidal int/external tibial rotation pattern over the activity cycle. Our data demonstrate that different selected implementations of REFRAME are able to highlight different characteristics of the motion patterns: Minimisation of the translational root-mean-square revealed proximodistal translation patterns with overall neutral progression, while anteroposterior translation showed seemingly different levels of correlation with flexion/extension in different subjects. On the other hand, REFRAME minimisation of translational variances exposed differences in the relative mean displacement between the femoral and tibial origins between subjects, highlighting differences in mean centre of rotation positions. This early application of REFRAME for providing an understanding of tibiofemoral kinematics demonstrates the potential of this novel approach to bring clarity to an otherwise complex representation of highly variable time-series signals, while highlighting the philosophical challenges of clinically interpretating kinematic signals in the first place.

Abstract Background Primaquine (PQ) has activity against mature P. falciparum gametocytes and proven transmission blocking efficacy (TBE) between humans and mosquitoes. WHO formerly recommended a single transmission blocking dose of 0.75 mg/kg but this was little used. Then in 2012, faced with the emergence of artemisinin-resistant P. falciparum (ARPf) in SE Asia, the WHO recommended a lower dose of 0.25 mg/kg to be added to artemisinin-based combination therapy in falciparum-infected patients in low transmission areas. This dose was considered safe in glucose-6-phosphate dehydrogenase deficiency (G6PDd) and not requiring G6PD testing. Subsequent single low-dose primaquine (SLDPQ) studies have demonstrated safety in different G6PD variants. Dosing remains challenging in children under the age of 5 because of the paucity of PQ pharmacokinetic (PK) data. We plan to assess the anti-infectivity efficacy of SLDPQ using an allometrically scaled, weight-based regimen, with a target dose of 0.25 mg/kg, in children with acute uncomplicated falciparum malaria. Methods This study is an open label, randomised 1:1, phase IIb study to assess TBE, tolerability, pharmacokinetics and acceptability of artesunate pyronaridine (ASPYR) administered alone or combined with SLDPQ in 56 Burkinabe children aged ≥ 6 months–

Abstract Differential equations are powerful tools in the study of correlation functions in conformal field theories (CFTs). Carrollian amplitudes behave as correlation functions of Carrollian CFT that holographically describes asymptotically flat spacetime. We derive linear differential equations satisfied by Carrollian MHV gluon and graviton amplitudes. We obtain non-distributional solutions for both the gluon and graviton cases. We perform various consistency checks for these differential equations, including compatibility with conformal Carrollian symmetries.

Abstract The Scibar Cosmic-Ray Telescope (SciCRT) is the most promising detector of the Sierra Negra Cosmic Rays Observatory (SN-CRO). At this location, being a target and a tracker of secondary cosmic rays, the SciCRT offers a high probability of observing solar energetic particles and lower energy galactic cosmic rays (LEGCR); also, it allows the identification of incoming particles by measuring their energy deposition. In this work we present a Geant4-based simulation of the energy deposited by neutrons, $$\gamma $$ γ -rays, protons, electrons and muons in the optimally running SciCRT components. We also calculated the detection efficiency of the SciCRT at its current state. Our simulation results provide new information about the SciCRT detection response that may be used as a basis to estimate and analyze the energy spectra of primary particles.

Abstract Background Gastric cancer (GC), a molecularly heterogeneous disease, is the third leading cause of cancer death worldwide. The majority of GC cases worldwide occur in East Asia, predominantly China. Mutational Signature Framework offers an elegant approach to identify mutational processes present in tumors. Methods To identify mutational signature patterns, we conducted whole exome sequencing (WES) analysis in Chinese patients with GC. Mutect2 and MutsigCV were used to identify significantly mutated genes in 175 Chinese GC cases using paired tumor-normal tissues. We investigated mutational signatures using Catalogue of Somatic Mutations in Cancer (COSMIC) Version 2 (V2) and Version 3 (V3). Results We identified 104 mutated genes with P

Aims: This study aimed to analyze kinematics and kinetics of the tibiofemoral joint in healthy subjects with valgus, neutral, and varus limb alignment throughout multiple gait activities using dynamic videofluoroscopy. Methods: Five subjects with valgus, 12 with neutral, and ten with varus limb alignment were assessed during multiple complete cycles of level walking, downhill walking, and stair descent using a combination of dynamic videofluoroscopy, ground reaction force plates, and optical motion capture. Following 2D/3D registration, tibiofemoral kinematics and kinetics were compared between the three limb alignment groups. Results: No significant differences for the rotational or translational patterns between the different limb alignment groups were found for level walking, downhill walking, or stair descent. Neutral and varus aligned subjects showed a mean centre of rotation located on the medial condyle for the loaded stance phase of all three gait activities. Valgus alignment, however, resulted in a centrally located centre of rotation for level and downhill walking, but a more medial centre of rotation during stair descent. Knee adduction/abduction moments were significantly influenced by limb alignment, with an increasing knee adduction moment from valgus through neutral to varus. Conclusion: Limb alignment was not reflected in the condylar kinematics, but did significantly affect the knee adduction moment. Variations in frontal plane limb alignment seem not to be a main modulator of condylar kinematics. The presented data provide insights into the influence of anatomical parameters on tibiofemoral kinematics and kinetics towards enhancing clinical decision-making and surgical restoration of natural knee joint motion and loading. Cite this article: Bone Joint Res 2024;13(9):485–496.

Abstract Challenges in classifying recurrent Plasmodium vivax infections constrain surveillance of antimalarial efficacy and transmission. Recurrent infections may arise from activation of dormant liver stages (relapse), blood-stage treatment failure (recrudescence) or reinfection. Molecular inference of familial relatedness (identity-by-descent or IBD) can help resolve the probable origin of recurrences. As whole genome sequencing of P. vivax remains challenging, targeted genotyping methods are needed for scalability. We describe a P. vivax marker discovery framework to identify and select panels of microhaplotypes (multi-allelic markers within small, amplifiable segments of the genome) that can accurately capture IBD. We evaluate panels of 50–250 microhaplotypes discovered in a global set of 615 P. vivax genomes. A candidate global 100-microhaplotype panel exhibits high marker diversity in the Asia-Pacific, Latin America and horn of Africa (median H E = 0.70–0.81) and identifies 89% of the polyclonal infections detected with genome-wide datasets. Data simulations reveal lower error in estimating pairwise IBD using microhaplotypes relative to traditional biallelic SNP barcodes. The candidate global panel also exhibits high accuracy in predicting geographic origin and captures local infection outbreak and bottlenecking events. Our framework is open-source enabling customised microhaplotype discovery and selection, with potential for porting to other species or data resources.

Abstract Background Undernutrition, which includes stunting, wasting, and underweight, is a global problem, especially among children of low- and middle-income countries. To our knowledge, this study is first of its type from Afghanistan. Its main objectives were to estimate the prevalence and associated risk factors of stunting, wasting/thinness, and underweight among urban primary school children in Kandahar city of Afghanistan. Methods This school-based cross-sectional study was conducted among 1205 primary school children aged 6–12 years during a period of six months (October 2022–March 2023). Anthropometric measurements and other data were collected from all the participants. Data were analyzed by using descriptive statistics, Chi square test (using crude odds ratio or COR), and multivariate logistic regression (using adjusted odds ratio or AOR). Results Among the 1205 enrolled government school students, 47.4%, 19.5%, and 25.6% had stunting, wasting/thinness, and underweight, respectively. Statistically significant factors associated with stunting were age group 6–9 years (AOR 1.3, 95% CI 1.1–1.7), being girl (AOR 2.3, 95% CI 1.8–3.0), poverty (AOR 2.2, 95% CI 1.5–3.2), large family (AOR 3.0, 95% CI 2.4–3.9), illiterate mother (AOR 1.6, 95% CI 1.0–2.6), jobless head of the family (AOR 3.3, 95% CI 2.3–4.8), and skipping breakfasts (AOR 1.7, 95% CI 1.2–2.3). Main factor associated with wasting/thinness were age group 6–9 years (AOR 30.5, 95% CI 11.8–78.7), skipping breakfasts (AOR 22.9, 95% CI 13.9–37.8), and history of sickness during the past two weeks (AOR 17.0, 95% CI 6.6–43.8). Also, main factors associated with underweight were age group 6–9 years (AOR 2.6, 95% CI 1.6–4.1), skipping breakfasts (AOR 2.6, 95% CI 1.8–3.6), and poor sanitation (AOR 1.9, 95% CI 1.1–3.2). Conclusions Stunting, wasting/thinness, and underweight are highly prevalent among primary school children (both girls and boys) in Kandahar city. It is recommended that local government (Afghanistan Ministry of Education and Ministry of Public Health) with the help of international organizations and donor agencies should implement comprehensive school-based feeding programs especially for girls. Health and nutrition education programs should be conducted with emphasis on nutrition of children aged 6–9 years as well as importance of healthy breakfast and good sanitation.

Black women faculty members face challenges in higher education, including limited identity-affirming mentorship and under-­recognition of their scholarship. However, little is known about their experiences in mathematics departments, where Black women are more severely underrepresented and disciplinary ideologies of neutrality mask social oppression. We interrogate the role of "mathematics epistemological values" (MEVs) in shaping departmental racialized--gendered oppression experienced by six Black women. Our findings illustrate that (a) quantification practices underpinning faculty evaluation disregard Black women's achievements; and (b) notions of proving as a solitary endeavor justify neglecting Black women's faculty development. We highlight departmental practices that support Black women faculty members, reframe MEVs to promote equity, and discuss implications for mathematics faculty and administrators working to advance equity.

Aims Compare the prevalence of age-related cataract and the cataract surgical coverage rate between Indigenous and non-Indigenous Australians and explore differences in these estimates across location and time.Methods The Joanna Briggs Institute guidance for systematic reviews of prevalence studies was followed. A systematic search of Medline, Embase, Web of Science and grey literature from database inception to June 2022 was performed. All studies reporting cataract prevalence in Australian populations were included. Pooled prevalence estimates were derived using meta-analyses with a random-effects model. Nine studies enrolling 36 302 participants were included. Most studies only reported the prevalence of cataract causing vision loss (visual acuity

The NANOGrav 15 yr data provide compelling evidence for a stochastic gravitational-wave (GW) background at nanohertz frequencies. The simplest model-independent approach to characterizing the frequency spectrum of this signal consists of a simple power-law fit involving two parameters: an amplitude A and a spectral index γ . In this Letter, we consider the next logical step beyond this minimal spectral model, allowing for a running (i.e., logarithmic frequency dependence) of the spectral index, ${\gamma }_{{\rm{run}}}(f)=\gamma +\beta \mathrm{ln}\left(f/{f}_{{\rm{ref}}}\right)$ . We fit this running-power-law (RPL) model to the NANOGrav 15 yr data and perform a Bayesian model comparison with the minimal constant-power-law (CPL) model, which results in a 95% credible interval for the parameter β consistent with no running, $\beta \in \left[-0.80,2.96\right]$ , and an inconclusive Bayes factor, ${ \mathcal B }\left({\rm{RPL}}\,{\rm{versus}}\,{\rm{CPL}}\right)=0.69\pm 0.01$ . We thus conclude that, at present, the minimal CPL model still suffices to adequately describe the NANOGrav signal; however, future data sets may well lead to a measurement of nonzero β . Finally, we interpret the RPL model as a description of primordial GWs generated during cosmic inflation, which allows us to combine our results with upper limits from Big Bang nucleosynthesis, the cosmic microwave background, and LIGO–Virgo–KAGRA.

Summary: The C. elegans nervous system is compact and well described, ideal for identifying genetic programs that drive neuron-specific development, function, and connectivity. Here, we present a protocol for isolating specific neuron types for gene expression profiling by bulk or single-cell RNA sequencing. We describe steps for worm synchronization, dissociation, and fluorescence-activated cell sorting (FACS) isolation. We then detail procedures for RNA extraction and preparing cells for single-cell sequencing. This protocol is applicable to the isolation of individual cell types from larval and adult animals.For additional details on the use and execution of this protocol, see Taylor et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Highly pathogenic avian influenza viruses (HPAIV) H5N1 clade 2.3.4.4b continue to have unprecedented global impacts on wild birds and mammals, with especially significant mortality observed in colonial surface-nesting seabirds and in some marine mammal species. In July of 2023 H5N1 HPAIV 2.3.4.4b was detected in Caspian terns nesting on Rat Island, Washington USA. An estimated 1,800–1,900 adult terns populated the breeding colony, based on aerial photographs taken at the start of the outbreak. On a near-weekly basis throughout July and August, we counted and removed carcasses, euthanized moribund birds, and collected swab and tissue samples for diagnostic testing and next-generation sequencing. We directly counted 1,101 dead Caspian tern adults and 520 dead chicks, indicating a minimum 56% loss of the adult colony population and potential impacts to reproductive success. Combining the observed mortality on Rat Island with HPAI-related Caspian tern deaths recorded elsewhere in Washington and Oregon, we estimate that 10–14% of the Pacific Flyway population was lost in the summer of 2023. Comparatively few adult Glaucous-winged gulls (hybrids) nesting on Rat Island died (~3% of the local population), although gull chick mortality was high. Sixteen harbor seals in the immediate or nearby area stranded during the outbreak, and H5N1 HPAIV was detected in brain and/or lung tissue of five seals. These cases are the first known detections of HPAIV in a marine mammal on the Pacific coast of North America. Phylogenetic analyses support the occurrence of at least three independent avian-mammalian virus spillover events (tern or gull to harbor seal). Whole genome sequencing indicated that H5N1 HPAIV may have been introduced to Washington from Caspian terns in Oregon. Ongoing monitoring and surveillance for H5N1 HPAIV in the marine environment is necessary to understand the epidemiology of this virus, assess conservation impacts to susceptible species, and provide support for data-driven management and response actions.

Summary: Background: Contemporary surgical practices for traumatic brain injury (TBI) remain unclear. We describe the clinical profile of an 18-centre US TBI cohort with cranial surgery. Methods: The prospective, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study (2014–2018; ClinicalTrials.gov #NCT02119182) enrolled subjects who presented to trauma centre and received head computed tomography within 24-h (h) post-TBI. We performed a secondary data analysis in subjects aged ≥17-years with hospitalisation. Clinical characteristics, surgery type/timing, hospital and six-month outcomes were reported. Findings: Of 2032 subjects (age: mean = 41.4-years, range = 17–89-years; male = 71% female = 29%), 260 underwent cranial surgery, comprising 65% decompressive craniectomy, 23% craniotomy, 12% other surgery. Subjects with surgery (vs. without surgery) presented with worse neurological injury (median Glasgow Coma Scale = 6 vs. 15; midline shift ≥5 mm: 48% vs. 2%; cisternal effacement: 61% vs. 4%; p

As of August 2022, clusters of acute severe hepatitis of unknown aetiology in children have been reported from 35 countries, including the USA1,2. Previous studies have found human adenoviruses (HAdVs) in the blood from patients in Europe and the USA3-7, although it is unclear whether this virus is causative. Here we used PCR testing, viral enrichment-based sequencing and agnostic metagenomic sequencing to analyse samples from 16 HAdV-positive cases from 1 October 2021 to 22 May 2022, in parallel with 113 controls. In blood from 14 cases, adeno-associated virus type 2 (AAV2) sequences were detected in 93% (13 of 14), compared to 4 (3.5%) of 113 controls (P

Abstract Efficient cellular fusion of mononuclear precursors is the prerequisite for the generation of fully functional multinucleated bone-resorbing osteoclasts. However, the exact molecular factors and mechanisms controlling osteoclast fusion remain incompletely understood. Here we identify RANKL-mediated activation of caspase-8 as early key event during osteoclast fusion. Single cell RNA sequencing-based analyses suggested that activation of parts of the apoptotic machinery accompanied the differentiation of osteoclast precursors into mature multinucleated osteoclasts. A subsequent characterization of osteoclast precursors confirmed that RANKL-mediated activation of caspase-8 promoted the non-apoptotic cleavage and activation of downstream effector caspases that translocated to the plasma membrane where they triggered activation of the phospholipid scramblase Xkr8. Xkr8-mediated exposure of phosphatidylserine, in turn, aided cellular fusion of osteoclast precursors and thereby allowed generation of functional multinucleated osteoclast syncytia and initiation of bone resorption. Pharmacological blockage or genetic deletion of caspase-8 accordingly interfered with fusion of osteoclasts and bone resorption resulting in increased bone mass in mice carrying a conditional deletion of caspase-8 in mononuclear osteoclast precursors. These data identify a novel pathway controlling osteoclast biology and bone turnover with the potential to serve as target for therapeutic intervention during diseases characterized by pathologic osteoclast-mediated bone loss. Proposed model of osteoclast fusion regulated by caspase-8 activation and PS exposure. RANK/RANK-L interaction. Activation of procaspase-8 into caspase-8. Caspase-8 activates caspase-3. Active capase-3 cleaves Xkr8. Local PS exposure is induced. Exposed PS is recognized by the fusion partner. FUSION. PS is re-internalized.

Abstract Background With only one 15 mg primaquine tablet registered by a stringent regulatory authority and marketed, more quality-assured primaquine is needed to meet the demands of malaria elimination. Methods A classic, two sequence, crossover study, with a 10-day wash out period, of 15 mg of IPCA-produced test primaquine tablets and 15 mg of Sanofi reference primaquine tablets was conducted. Healthy volunteers, aged 18–45 years, without glucose-6-phosphate dehydrogenase deficiency, a baseline haemoglobin ≥ 11 g/dL, creatinine clearance ≥ 70 mL/min/1.73 ms, and body mass index of 18.5–30 kg/m2 were randomized to either test or reference primaquine, administered on an empty stomach with 240 mL of water. Plasma primaquine and carboxyprimaquine concentrations were measured at baseline, then 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.333, 2.667, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0, 36.0, 48.0 and 72.0 h by liquid chromatography coupled to tandem mass spectrometry. Primaquine pharmacokinetic profiles were evaluated by non-compartmental analysis and bioequivalence concluded if the 90% confidence intervals (CI) of geometric mean (GM) ratios of test vs. reference formulation for the peak concentrations (C max) and area under the drug concentration–time (AUC0–t) were within 80.00 to 125.00%. Results 47 of 50 volunteers, median age 33 years, completed both dosing rounds and were included in the bioequivalence analysis. For primaquine, GM C max values for test and reference formulations were 62.12 vs. 59.63 ng/mL, resulting in a GM ratio (90% CI) of 104.17% (96.92–111.96%); the corresponding GM AUC0–t values were 596.56 vs. 564.09 ngxh/mL, for a GM ratio of 105.76% (99.76–112.08%). Intra-subject coefficient of variation was 20.99% for C max and 16.83% for AUC0–t. Median clearances and volumes of distribution were similar between the test and reference products: 24.6 vs. 25.2 L/h, 189.4 vs. 191.0 L, whilst the median half-lives were the same, 5.2 h. Conclusion IPCA primaquine was bioequivalent to the Sanofi primaquine. This opens the door to prequalification, registration in malaria endemic countries, and programmatic use for malaria elimination. Trial registration The trial registration reference is ISRCTN 54640699

Abstract Purpose: Although there is evidence that sport-related concussion (SRC) affects oculomotor function and perceptual ability, experiments are often poorly controlled and are not replicable. This study aims to test the hypothesis that there are decreased values when assessing oculomotor impairment indicating poorer performance in SRC patients. Methods: Fifteen DI athletes presenting with SRC (7 females, 8 males) and 15 student volunteers (CON) (12 females, 3 males) completed a dynamic visual acuity (DVA) task that involved answering the direction of a moving stimulus (Landolt C) while wearing a head-mounted binocular eye tracker. There were 120 trials total with 60 trials presenting at 30º per second and 60 presenting at 90º per second. Various eye movement measurements, including horizontal smooth pursuit eye movements (SPEM) gain and saccadic peak velocity, were analyzed between groups using univariate ANOVAs. Saccade count in SPEM trials, accuracy, and vision were analyzed using Kruskal–Wallis tests. Results: There was no statistical difference in saccadic peak velocity: SRC = 414.7 ± 42º/s, CON = 406.6 ± 40.6º/s. A significant difference was found between SRC patients and healthy controls in horizontal SPEM gain (SRC = 0.9 ± 0.04, CON = 0.86 ± 0.03, F(1,28) = 7.243, P = 0.012) indicating that patients demonstrated compensatory eye movements when tracking the target. There were significantly more saccades in all SPEM trials (P = 0.001). Conclusion: SRCoculomotor deficits manifest as elevated horizontal SPEM gain when assessed within 48 hours of injury and compared to healthy controls within the same age range. SRC demonstrates altered oculomotor ability. While accurate in tracking a stimulus, SRC patients may conduct less controlled eye movements.

Abstract This study investigates the effects of varying loading conditions on excitability in neural pathways and gait dynamics. We focussed on evaluating the magnitude of the Hoffman reflex (H‐reflex), a neurophysiological measure representing the capability to activate motor neurons and the timing and placement of the foot during walking. We hypothesized that weight manipulation would alter H‐reflex magnitude, footfall and lower body kinematics. Twenty healthy participants were recruited and subjected to various weight‐loading conditions. The H‐reflex, evoked by stimulating the tibial nerve, was assessed from the dominant leg during walking. Gait was evaluated under five conditions: body weight, 20% and 40% additional body weight, and 20% and 40% reduced body weight (via a harness). Participants walked barefoot on a treadmill under each condition, and the timing of electrical stimulation was set during the stance phase shortly after the heel strike. Results show that different weight‐loading conditions significantly impact the timing and placement of the foot and gait stability. Weight reduction led to a 25% decrease in double limb support time and an 11% narrowing of step width, while weight addition resulted in an increase of 9% in step width compared to body weight condition. Furthermore, swing time variability was higher for both the extreme weight conditions, while the H‐reflex reduced to about 45% between the extreme conditions. Finally, the H‐reflex showed significant main effects on variability of both stance and swing phases, indicating that muscle‐motor excitability might serve as feedback for enhanced regulation of gait dynamics under challenging conditions.

The identification of climate anomalies associated with large-scale stand disturbances can help inform climate-focused forest management. In the spring and summer of 2018, an unusual spike in balsam fir (Abies balsamea) mortality was reported in multiple areas across its southern distribution range limit, from Wisconsin, United States, to New Brunswick, Canada. Such an event was previously reported in 1986 in the study region and referred to as Stillwell’s Syndrome. To identify the role of climate anomalies in the 2018 event, we used monthly climate anomalies as explanatory variables in a Random Forest model predicting the presence of mortality from air and field-based surveys across the Maritimes region of eastern Canada. Results were validated by (1) comparing common climate predictors of mortality from this model and a separate Random Forest model fitted on the 1986 event, and (2) using the 2018 model to predict areas of mortality in 1986. Both the 1986 and 2018 models identified multiple common climate anomalies. Areas with unusually high water deficit and temperatures in the previous growing season, followed by thick April snowpack and high May temperatures the same year, were associated with balsam fir mortality. Such climate anomalies have been previously associated with water stress and desiccation in trees. When using the 2018 model to map the occurrence of mortality in 1986 using historical climate data, we report a 95% accuracy in prediction (kappa = 0.88). The approach used here in conjunction with mapped records of past stand disturbances could help with understanding the impacts of future climate anomalies and adaptive management strategies to deal with these events.

Abstract Roadside habitat has been touted as a conservation opportunity for insect pollinators, including the declining monarch butterfly. The spectacular monarch migration is under threat from the loss of habitat and the decline of their milkweed host plants. In the northern part of their range, roadsides could potentially produce millions of monarchs annually due to high densities of milkweed; however, roadside milkweed can accumulate chemicals from roads, such as sodium from road salt. Controlled lab studies have shown mixed effects of sodium on monarch development: small increases can be beneficial as sodium is an important micronutrient in brain and muscle development, but large increases can sometimes decrease survival. It is unclear how dietary sodium affects performance in ecologically relevant conditions and the migration itself. In this experiment, we raised monarchs outdoors, in migration‐inducing conditions, on milkweed sprayed with three levels of sodium chloride. We released 2464 tagged monarchs and held an additional 246 for further lab assays. While our recovery rates to the wintering grounds were low (N = 7 individuals), individuals from all three sodium chloride treatments made it to Mexico. Butterflies reared on control milkweed and low salt concentrated sodium in their tissues, while those on high salt diets excreted sodium, suggesting high salt levels were above a physiological optimum. There were no effects of treatment on wing coloration, survival, body size, immunity, or parasite prevalence. Taken together, our results suggest that monarchs are robust to levels of sodium in milkweeds found along roadsides, which is promising with respect to the toxicity of roadside plants.

Summary: Background: The inflammatory response in patients with traumatic brain injury (TBI) offers opportunities for stratification and intervention. Previous unselected approaches to immunomodulation in patients with TBI have not improved patient outcomes. Methods: Serum and plasma samples from two prospective, multi-centre observational studies of patients with TBI were used to discover (Collaborative European NeuroTrauma Effectiveness Research [CENTER-TBI], Europe) and validate (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] Pilot, USA) individual variations in the immune response using a multiplex panel of 30 inflammatory mediators. Mediators that were associated with unfavourable outcomes (Glasgow outcome score-extended [GOS-E] ≤ 4) were used for hierarchical clustering to identify patients with similar signatures. Findings: Two clusters were identified in both the discovery and validation cohorts, termed early-inflammatory and pauci-inflammatory. The early-inflammatory phenotype had higher concentrations of interleukin-6 (IL-6), IL-15, and monocyte chemoattractant protein 1 (MCP1). Patients with the early-inflammatory phenotype were older and more likely to have an unfavourable GOS-E at 6 months. There were no differences in the baseline injury severity scores between patients in each phenotype. A combined IL-15 and MCP1 signature identified patients with the early-inflammatory phenotype in both cohorts. Inflammatory processes mediated outcomes in older patients with moderate-severe TBI. Interpretation: Our findings offer a precision medicine approach for future clinical trials of immunomodulation in patients with TBI, by using inflammatory signatures to stratify patients. Funding: CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.

Understanding tendon mechanical properties, such as stiffness and hysteresis, can provide insights into injury mechanisms. This research addresses the inconsistency of previously reported in-vivo and in-vitro tendon hysteresis properties. Although limited, our preliminary findings suggest that in-vivo hystereses (Mean ± SD; 55% ± 9%) are greater than in-vitro hystereses (14% ± 1%) when directly comparing the same tendon for the same loading conditions in a sheep model in-vivo versus within 24 h post-mortem. Overall, it therefore appears that the tendon mechanical properties are affected by the testing environment, possibly related to differences in muscle-tendon interactions and fluid flow experienced in-vivo versus in-vitro. This communication advocates for more detailed investigations into the mechanisms resulting in the reported differences in tendon behaviour. Overall, such knowledge contributes to our understanding of tendon function towards improving modelling and clinical interventions, bridging the gap between in-vivo and in-vitro observations and enhancing the translational relevance of biomechanical studies.

Understanding the impacts of changing climate and disturbance regimes on forest ecosystems is greatly aided by the use of process-based models. Such models simulate processes based on first principles of ecology, which requires parameterization. Parameterization is an important step in model development and application, defining the characteristics of trees and their responses to the environment, i.e., their traits. For species-specific models, parameterization is usually done at the level of individual species. Parameterization is indispensable for accurately modeling demographic processes, including growth, mortality, and regeneration of trees, along with their intra- and inter-specific interactions. As it is time-demanding to compile the parameters required to simulate forest ecosystems in complex models, simulations are often restricted to the most common tree species, genera, or plant-functional types. Yet, as tree species composition might change in the future, it is important to account for a broad range of species and their individual responses to drivers of change explicitly in simulations. Thus, species-specific parameterization is a critical task for making accurate projections about future forest trajectories, yet species parameters often remain poorly documented in simulation studies.We compiled and harmonized all existing tree species parameters available for the individual-based forest landscape and disturbance model (iLand). Since its first publication in 2012, iLand has been applied in 50 peer-reviewed publications across three continents throughout the Northern Hemisphere (i.e., Europe, North America, and Asia). The model operates at individual-tree level and simulates ecosystem processes at multiple spatial scales, making it a capable process-based model for studying forest change. However, the extensive number of processes and their interactions as well as the wide range of spatio-temporal scales considered in iLand require intensive parameterization, with tree species characterized by 66 unique parameters in the model. The database presented here includes parameters for 150 temperate and boreal tree species and provenances (i.e., regional variations). Excluding missing values, the database includes a total of 9,249 individual parameter entries. In addition, we provide parameters for the individual susceptibility of tree species to wind disturbance (five parameters) for a subset of 104 tree species and provenances (498 parameter entries). To guide further model parameterization efforts, we provide an estimate of uncertainty for each species based on how thoroughly simulations with the respective parameters were evaluated against independent data.Our dataset aids the future parameterization and application of iLand, and sets a new standard in documenting parameters used in process-based forest simulations. This dataset will support model application in previously unstudied areas and can facilitate the investigation of new tree species being introduced to well-studied systems (e.g., simulating assisted migration in the context of rapid climate change). Given that many process-based models rely on similar underlying processes our harmonized parameter set will be of relevance beyond the iLand community. Our work could catalyze further research into improving the parameterization of process-based forest models, increasing the robustness of projections of climate change impacts and adaptation strategies.

Abstract Offshore oil and gas platforms support abundant reef fish and are popular fishing sites for recreational anglers. However, the rapid decommissioning and removal of active platforms have decreased such fishing opportunities in the Gulf of Mexico, raising concerns about fisheries impacts. Conversely, planned offshore energy structures like wind turbines may offer similar habitats and fishing sites. To inform spatial planning for marine energy infrastructure in the context of recreational fisheries, we created models of fish communities associated with oil and gas platforms using existing abundance data. We employed Random Forest analysis to predict the presence‐absence and abundance of Red Snapper (Lutjanus campechanus) and Greater Amberjack (Seriola dumerili) at platforms using 47 environmental and platform variables. Nonmetric multidimensional scaling on Bray−Curtis dissimilarities explored fish species composition among 37 species. Results showed variability in Red Snapper and Greater Amberjack incidence/abundance from shore to shelf‐edge, not attributed to surrounding habitat or climatological oceanographic variables. Incidence models were more robust than abundance models. Fish species composition was significantly influenced by location gradient, with less impact from other habitat features. Our findings guide selecting areas for artificial structures to enhance angler opportunities and maintain fish diversity, but identifying the drivers of finer scale abundance variation will require further sampling.

Abstract Monarch butterflies (Danaus plexippus) have undergone large scale population declines leading to multiple conservation organizations encouraging the creation of monarch butterfly habitat. Monarch Watch encourages volunteers to create and register monarch habitat as Monarch Waystations. During registration waystations can be named. Names reflect personal meanings, community attachments, and cultural insights and waystation names in particular can provide insights into what ideas and concepts volunteers associate with a habitat creation program. A total of 37,916 registered waystation names were examined to determine most commonly used names, words and word themes. The most common types of waystations were medium‐sized suburban gardens in the United States. The most common waystation names referenced yard placement with My Backyard the most frequently used. Place‐themed words were the most used followed by animal‐themed words. Within animal‐themed words, insect words were the most used followed by mammals and birds. Theological/mortality themed words were present with memorial the most common word, implying a permanence of waystations. The most common familial terms included mom and grandma suggesting inter‐generational gardening is occurring, which is known to strengthen communities and build well‐being. The frequency of positive emotion/feeling words implies that participating in habitat creation programs is a positive experience and participation may reduce conservation apathy. Further research into habitat creation programs and the longevity of habitat created as well as the motivations and demographics of participants can help tailor habitat volunteer programs to desired audiences and increase overall participation. Read the free Plain Language Summary for this article on the Journal blog.

Abstract Carrollian holography is supposed to describe gravity in four-dimensional asymptotically flat space-time by the three-dimensional Carrollian CFT living at null infinity. We transform superstring scattering amplitudes into the correlation functions of primary fields of Carrollian CFT depending on the three-dimensional coordinates of the celestial sphere and a retarded time coordinate. The power series in the inverse string tension is converted to a whole tower of both UV and IR finite descendants of the underlying field-theoretical Carrollian amplitude. We focus on four-point amplitudes involving gauge bosons and gravitons in type I open superstring theory and in closed heterotic superstring theory at the tree-level. We also discuss the limit of infinite retarded time coordinates, where the string world-sheet becomes celestial.

Introduction: Adrenocortical carcinoma (ACC) is a rare malignancy of the adrenal cortex. Whilst surgery is the preferred treatment, adjunctive therapy with mitotane may be offered post-surgically to minimise the risk of recurrence or, in the absence of surgery, to attenuate progression. Aim: The objective was to evaluate the effects of mitotane treatment on serum protein concentrations in patients treated for ACC with mitotane therapy and compare this to patients with other adrenal neoplasms and a normal pregnant cohort. Methods: Serum cortisol, thyroid function tests, adrenocorticotrophic hormone (ACTH), cortisol-binding globulin (CBG), thyroxine-binding globulin (TBG), gonadotrophins and androgens were measured on plasma and serum samples. Thirty-five patients with ACC were included, and mitotane levels were noted to be sub-/supra-therapeutic. Data were tested for normality, reported as mean ± s.d., and compared to other two cohorts using paired-sample t-test with a 5% P-value for significance and a 95% CI. Results: Patients on mitotane therapy had a higher mean serum CBG concentration compared to the adrenal neoplasm group (sub-therapeutic: 79.5 (95% CI: 33.6, 125.4 nmol/L), therapeutic: 85.3 (95% CI: 37.1–133.6 nmol/L), supra-therapeutic: 75.7 (95% CI: −19.3, 170.6 nmol/L) and adrenal neoplasm: 25.5 (95% CI: 17.5, 33.5 nmol/L). Negative correlations between serum cortisol and CBG concentration were demonstrated within the supra-therapeutic plasma mitotane and adrenal neoplasm groups. Conclusion: Patients with ACC and therapeutic plasma mitotane concentrations had higher serum CBG concentrations compared to those with adrenal neoplasms or pregnant women, and higher serum cortisol. Whilst there was no direct correlation with cortisol and mitotane level, the negative correlation of cortisol with CBG may suggest that the direct effect of mitotane in increasing cortisol may also reflect that mitotane has a direct adrenolytic effect.

Abstract Background Over the last decades, the number of malaria cases has drastically reduced in Cambodia. As the overall prevalence of malaria in Cambodia declines, residual malaria transmission becomes increasingly fragmented over smaller remote regions. The aim of this study was to get an insight into the burden and epidemiological parameters of Plasmodium infections on the forest-fringe of Cambodia. Methods 950 participants were recruited in the province of Mondulkiri in Cambodia and followed up from 2018 to 2020. Whole-blood samples were processed for Plasmodium spp. identification by PCR as well as for a serological immunoassay. A risk factor analysis was conducted for Plasmodium vivax PCR-detected infections throughout the study, and for P. vivax seropositivity at baseline. To evaluate the predictive effect of seropositivity at baseline on subsequent PCR-positivity, an analysis of P. vivax infection-free survival time stratified by serological status at baseline was performed. Results Living inside the forest significantly increased the odds of P. vivax PCR-positivity by a factor of 18.3 (95% C.I. 7.7–43.5). Being a male adult was also a significant predictor of PCR-positivity. Similar risk profiles were identified for P. vivax seropositivity. The survival analysis showed that serological status at baseline significantly correlated with subsequent infection. Serology is most informative outside of the forest, where 94.0% (95% C.I. 90.7–97.4%) of seronegative individuals survived infection-free, compared to 32.4% (95% C.I.: 22.6–46.6%) of seropositive individuals. Conclusion This study justifies the need for serological diagnostic assays to target interventions in this region, particularly in demographic groups where a lot of risk heterogeneity persists, such as outside of the forest.

Abstract Walking slowly after stroke reduces health and quality of life. This multi-site, prospective, interventional, 2-arm randomized controlled trial (NCT04121754) evaluated the safety and efficacy of an autonomous neurorehabilitation system (InTandemTM) designed to use auditory-motor entrainment to improve post-stroke walking. 87 individuals were randomized to 5-week walking interventions with InTandem or Active Control (i.e., walking without InTandem). The primary endpoints were change in walking speed, measured by the 10-meter walk test pre-vs-post each 5-week intervention, and safety, measured as the frequency of adverse events (AEs). Clinical responder rates were also compared. The trial met its primary endpoints. InTandem was associated with a 2x larger increase in speed (Δ: 0.14 ± 0.03 m/s versus Δ: 0.06 ± 0.02 m/s, F(1,49) = 6.58, p = 0.013), 3x more responders (40% versus 13%, χ2(1) ≥ 6.47, p = 0.01), and similar safety (both groups experienced the same number of AEs). The auditory-motor intervention autonomously delivered by InTandem is safe and effective in improving walking in the chronic phase of stroke.

Evidence has emerged for a stochastic signal correlated among 67 pulsars within the 15 yr pulsar-timing data set compiled by the NANOGrav collaboration. Similar signals have been found in data from the European, Indian, Parkes, and Chinese pulsar timing arrays. This signal has been interpreted as indicative of the presence of a nanohertz stochastic gravitational-wave background (GWB). To explore the internal consistency of this result, we investigate how the recovered signal strength changes as we remove the pulsars one by one from the data set. We calculate the signal strength using the (noise-marginalized) optimal statistic, a frequentist metric designed to measure the correlated excess power in the residuals of the arrival times of the radio pulses. We identify several features emerging from this analysis that were initially unexpected. The significance of these features, however, can only be assessed by comparing the real data to synthetic data sets. After conducting identical analyses on simulated data sets, we do not find anything inconsistent with the presence of a stochastic GWB in the NANOGrav 15 yr data. The methodologies developed here can offer additional tools for application to future, more sensitive data sets. While this analysis provides an internal consistency check of the NANOGrav results, it does not eliminate the necessity for additional investigations that could identify potential systematics or uncover unmodeled physical phenomena in the data.

The beam response to an external periodic excitation delivers relevant information about the optics, tune distribution, and stability of a circulating beam in a storage ring. In this contribution, the horizontal beam response to the excitation (transfer function) under conditions typical for slow extraction is presented for a coasting beam. The resulting spectrum exhibits a splitting behavior. The single particle dynamics is discussed and an interpretation based on the simulation results is presented.

Background and Clinical Significance: A brain abscess, defined as a localized intracranial infection that evolves into a purulent collection encased by a vascularized capsule, has higher prevalence among immunocompromised populations. Patients with sickle cell disease (SCD) are particularly vulnerable to bacterial infections due to their compromised immune systems, increasing their susceptibility to pathogens like Salmonella. While Salmonella is typically associated with gastroenteritis, osteomyelitis, and septicemia, its involvement in brain abscesses is exceedingly rare. There are few documented cases of Salmonella brain abscesses in the general population, and among patients with SCD, only one such case has been reported to date. In this report, we describe the second known case of a brain abscess caused by Salmonella infection in a patient with sickle cell disease, contributing to the limited literature on this rare and life-threatening condition. Case Presentation: A 32-year-old African American woman with sickle cell disease presented to the ER after a generalized seizure, reporting two weeks of worsening headaches, fevers, and left upper extremity weakness. Imaging revealed a right frontoparietal brain abscess, which was surgically drained, and cultures identified Salmonella enterica. After antibiotic treatment and a 23-day hospital stay, she was discharged. Four months later, she returned with another seizure during a sickle cell crisis, but follow-up MRI showed only minor scarring, and she was discharged on anticonvulsant therapy. Conclusions: This case emphasizes that Salmonella infections, though typically linked to osteomyelitis and sepsis, can also cause brain abscesses in immunocompromised patients like those with sickle cell disease. It highlights the need to consider infections alongside vascular causes in acute neurological cases and underscores the value of a multidisciplinary approach in managing such complex conditions.