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Abstract This study examined the moderating effect of self-compassion on the relationship between post-traumatic symptoms (PTS) and post-traumatic growth (PTG) among adults with trauma exposure. A sample of 413 participants (254 women, 155 men) aged 18 to 81 years (M = 33.8; SD = 12.9) completed questionnaires assessing trauma exposure, PTS, PTG, and self-compassion. The results indicated that women reported significantly higher PTS and lower self-compassion than men, while no significant gender differences were found for PTG. Correlational analyses revealed a significant positive association between PTS and PTG, and a significant negative association between PTS and self-compassion. Moderation analysis demonstrated that self-compassion significantly moderated the relationship between PTS and PTG, with higher levels of self-compassion linked to greater PTG, even at elevated levels of PTS. These findings underscore the importance of self-compassion as a protective factor in trauma recovery, promoting positive psychological transformation despite the presence of distress.

Abstract The composition of viral communities (i.e. viromes) can be dynamic and complex. Co-evolution may lead to virome host-specificity. However, eco-evolutionary factors may influence virome dynamics in wild host communities, potentially leading to disease emergence. Social bees are relevant models to address the drivers of virome composition: these important pollinators form multi-species assemblages, with high niche overlap and strong seasonality in their biotic interactions. We applied a microbial community approach to disentangle the role of host phylogeny and host ecology in shaping bee viromes, combining plant-pollinator networks with meta-transcriptomics, and small interfering RNAs as proxies for viral replication in pollinators and pollen. We identified over a hundred insect and plant viral sequences from ca. 4500 insect pollinator samples across three time points in one year. While host genetic distance drives the distribution of bee viruses, we find that plant-pollinator interactions and phenology drive plant virus communities collected by bees. This reveals the opportunities for virus spread in the bee assemblage. However, we show that transmission to multiple hosts is only realized for a fraction of insect viruses, with even fewer found to be actively replicating in multiple species, including the particularly virulent multi-host acute bee paralysis virus.

The genus Topiris Walker, 1863 is revised. This genus, previously neglected or deemed unrecognisable, comprised only Walker’s damaged and misrepaired type specimen of Topiris candidella Walker, 1863. Evidence is provided that this specimen was collected by Alfred Russel Wallace in 1855–56 in Sarawak, Malaysian Borneo. The mitogenome of this specimen was assembled using low coverage whole genome sequencing (genome skimming). The COI-5P portion of this mitogenome (658 bp) differs by 1–3 bp from two haplotypes sequenced from early 1990’s Brunei specimens. Another specimen recently discovered at NHMUK with an identical label to that of the type perfectly matches the Brunei specimens in its genitalia. Based on these four specimens, we present a fuller description of the morphology of T. candidella. Topiris includes the following additional species authored by Sterling and Lees: Topiris albidella sp. nov., T. albogrisella sp. nov., T. cinderella sp. nov., T. digiticosta sp. nov., T. lacteella sp. nov., T. madonna sp. nov., T. meyricki sp. nov., T. ochrotincta sp. nov., T. schneeweissella sp. nov., T. sericella sp. nov., and T. thunbergella sp. nov. The following new combinations are also established: T. salva (Meyrick, 1932), comb. nov. and T. sampitella (Lvovsky, 2014), comb. nov. The type of Athrypsiastis salva Meyrick is confirmed as lost and so a neotype and paraneotype of this species are designated. A published mitogenome of “Linoclostis gonatias” is shown to be correctly identified as T. salva, and references to L. gonatias, identified in some literature as a pest of Theaceae, are likely misidentified. The genus Topiris is divided into three groups, the candidella group, the salva group, and the albidella group, based on characters in the male genitalia. The candidella group and albidella group are supported sub-clades of Topiris. The phylogenetic placement of Topiris and Athrypsiastis within ‘core’ Xyloryctidae (as subtended by its type species, X. luteotactella) is confirmed by analysis of COI and seven nuclear genes, whereas the genera Eumenodora Meyrick, 1906 and Izatha Walker, 1864 do not fall within this clade. The morphology of Athrypsiastis phaeoleuca Meyrick, 1910 (the type species of Athrypsiastis; Xyloryctidae) is more fully described. The following new species authored by Sterling and Lees are described: Athrypsiastis cheesmanae sp. nov., A. edelweissella sp. nov., and A. penumbrella sp. nov. Two taxa are newly combined: Athrypsiastis halmaherella (Lvovsky, 2014), comb. nov. and Paralecta rosiflora (Meyrick, 1930), comb. nov.

Residual stress poses significant risks to the life management of key engineering components in nuclear fusion reactors. It is often induced within the narrow heat-affected zone (HAZ) during remote laser welding, essential for maintaining and assembling in-vessel components. Residual stress interacts with high temperatures, degrading mechanical properties and altering fracture mechanisms. Establishing a correlative methodology with microstructures to investigate these stresses and understand their effects on mechanical properties within the narrow HAZ is crucial for extending the reactor's lifetime. In this study, advanced residual stress measurements, including plasma-focused ion beam and digital image correlation, were employed to reveal heterogeneous stress distribution, discovering the peak tensile residual stress of 150 MPa at the interface of the fusion zone (FZ) and HAZ, and peak compressive residual stress of 550 MPa within HAZ. The residual stress effects on micro-hardness are quantitatively evaluated, showing a 25% hardening effect at HAZ/BM interface and a 10% softening effects at fusion line. The deformation mechanism is further analysed using tensile testing, where the residual stress effects were prominent in the low-stress field, reducing 6.5% strain evolution, while microstructures reinforced the material in the high-stress field. At elevated temperatures, the joint exhibited a significant reduction from 532 MPa to 345 MPa for yield strength and from 12 % to 8 % for elongation, with distinct fracture mechanisms observed through fractography compared to its behaviour at room temperature. These findings provide critical insights into enhancing laser welding processing and maintaining the structural integrity of in-service nuclear fusion reactor components.

Abstract Alzheimer’s disease (AD) ranks among the leading causes of morbidity and mortality worldwide. The objective was to evaluate the burden of AD and other dementias among the countries of the Middle East and North Africa (MENA) region by age and sex from 1990 to 2021. The data were sourced from the Global Burden of Disease (GBD) study 2021. The estimates are presented as counts and age-standardised rates per 100,000 accompanied by 95% uncertainty intervals (UIs). In 2021, AD and other dementias recorded an age-standardised prevalence of 772.7 per 100,000 in the MENA region (95% UI 671.2–877.6 per 100,000). This rate decreased by 4.9% in comparison to 1990, marking a statistically significant change. AD and other dementias also accounted for approximately 73.79 thousand deaths in the region in 2021, with the age-standardised rate decreasing by 8.6% compared to 1990. Moreover, the disability-adjusted life years (DALY) rate was 476.3 per 100,000 population (95% UI 225.6–1004.2), representing a 7.7% decrease from 1990 to 2021. Lebanon registered the highest point prevalence per 100,000 at 828.25, while the United Arab Emirates recorded the lowest at 652.43. The age-standardised point prevalence decreased from 1990 to 2021 in 13 of the MENA countries, while no significant changes were observed in eight of countries. Additionally, in 2021, women experienced higher prevalence rates, DALYs, compared to men. In the MENA region, age-standardised dementia prevalence rose with age in both sexes. The burden of dementia in MENA has decreased from 1990 to 2021, but it remains higher than global estimates. Furthermore, the findings indicate that dementia imposes a greater burden on the female population compared to males. To achieve a more accurate estimation of the burden of Alzheimer’s disease and other dementias, more systematic studies in low- to middle-income countries within the MENA region are required.

Abstract Background In the oral cavity, host-microbe interactions (HMI) continuously occur and greatly impact oral health. In contrast to the well-studied disease-associated HMI during, for example, periodontitis, HMI that are essential in maintaining oral health have been rarely investigated, especially in a human-relevant context. The aim of this study was to extensively characterize homeostatic HMI between saliva-derived biofilms and a reconstructed human gingiva (RHG). RHG was reconstructed following the structure of native gingiva, composed of a multilayered epithelium formed by keratinocytes and a fibroblast-populated compartment. To mimic the oral environment, RHG were inoculated with pooled human saliva resuspended in different saliva substitute media and incubated for 2 or 4 days. The co-cultured biofilms were retrieved and characterized by viable bacterial counting and compositional profiling (16S rRNA gene sequencing). RHG was investigated for metabolic activity (MTT assay), tissue histology (hematoxylin and eosin staining), epithelial proliferation (Ki67 staining), antimicrobial peptide expression, and cytokine secretion. Results Viable biofilms were detected up to day 4 of co-culturing. Bacterial counts indicated biofilm growth from the inoculation to day 2 and maintained thereafter at a similar level until day 4. All biofilms shared similar composition throughout 4 days, independent of co-culture time and different saliva substitute media used during inoculation. Biofilms were diverse with Streptococcus, Haemophilus, and Neisseria being the dominating genera. While supporting biofilm development, RHG displayed no significant changes in metabolic activity, tissue histology, or epithelial proliferation. However, in the presence of biofilms, the antimicrobial peptides elafin and human β-defensin-2 were upregulated, and the secretion of cytokines IL-6, CXCL1, CXCL8, CCL5, and CCL20 increased. Conclusion This model mimicked homeostatic HMI where a healthy gingiva supported a viable, diverse, and stable microbial community, incorporating bacterial genera found on native gingiva. The gingiva model maintained its tissue integrity and exerted protective responses in the presence of biofilms over time. This study adds to the evidence that shows the important role of the host in maintaining homeostatic HMI that are essential for oral health. Video Abstract

Abstract Esports is a fast-growing worldwide phenomenon encompassing hundreds of millions of competitive players. It is well-established that different game genres require distinct cognitive skills, but the biomechanical implications of playing different game genres have received little attention. This is the first study to quantify gamers’ kinematic behaviour across genres, demonstrating the importance of physical demands on performance and equipment in esports. The purpose of this study was to investigate whether the right upper limb kinematic behaviour differs among players across game genres. 63 esports players played a First Person Shooter (FPS), Multiplayer Online Battle Arena (MOBA), or Adventure game for 10 min. Three tri-axial accelerometers, positioned on each participant’s right upper limb (hand, forearm, arm), recorded kinematic data during gameplay. Hand acceleration magnitude, direction change, distance travelled (sum of all hand displacements over 10-min of gameplay), and displacement area (size and shape) were calculated in addition to hand, forearm, and arm acceleration ratios. There was a marked difference in movement patterns across players of different game genres. FPS players displayed greater hand acceleration magnitude (0.96 m.s−2 ± 0.07 SEM), moved their hand through a greater distance (38.96 m ± 2.47 SEM), and over a larger displacement area (119.13 cm2 ± 16.05 SEM) compared to MOBA and Adventure players. MOBA players exhibited greater hand acceleration magnitude (0.73 m.s−2 ± 0.05 SEM), changed direction more (2335 ± 172 SEM) and covered more distance (29.25 m ± 1.80 SEM) compared to Adventure players within a smaller overall area (70.49 cm2 ± 9.91 SEM). These findings have the potential to impact the design of gaming equipment and the training volumes of gamers across different game genres, so as to mitigate injury risk and improve overall gaming performance.

Abstract Globally, the number of refugees and displaced individuals has surpassed 100 million for the first time in history. Refugees are more likely than non-refugee populations to experience psychological distress and develop mental disorders. Early Adolescent Skills for Emotion (EASE), developed by the World Health Organization, is a potentially scalable task-sharing intervention targeting symptoms of internalizing disorders such as depression and anxiety for 10–15 years old and their caregiver. Prior to this study a randomized controlled trial in Amman, Jordan was conducted showing effectiveness of EASE reducing caregiver distress and inconsistent disciplinary parenting as well as reducing internalizing problems in adolescence. This study aims to explore individual and contextual barriers and facilitators for scaling the EASE intervention for Syrian refugees in Jordan. Ten semi-structured interviews and four focus group discussions were conducted between October 2020 and February 2023 with five key mental health and psychosocial support (MHPSS) informants, eight EASE providers, 11 adolescents, and 12 caregivers. Purposeful quota sampling technique was used to recruit participants with attention to sex and age and number of interviews and focus group discussions determined through empirical saturation. Inductive and deductive codes were utilized in a six-step thematic analysis. Participants reported a beneficial impact of EASE sessions in terms of reducing experienced anxiety levels, improved communication between adolescents and caregivers, reduced feelings of anger and jealousy, and improved familial relationships. Individual participation was hampered by transportation issues, scheduling conflicts, gender-mixed groups, and competing responsibilities. Scale-up facilitators included; increased mental health awareness, perceived low cost of EASE, feasibility of delivery by non-specialists, and an intervention engaging both adolescents and caregivers. Barriers included location, online sessions, sustainability, general implementation issues caused by individual barriers, and some concerns about non-specialists. Results add nuances not detected in the previous randomized control trial in Jordan and provide important context for understanding effectiveness results. Future research should investigate the cost-effectiveness of EASE along with stepped-care implementation models to provide EASE within existing health systems.

Abstract Peatlands are prevalent across northern regions, including bogs, fens, marshes, meadows, and select tundra wetlands that all vary in size (e.g., 0.01 s to 10 s km2) and shape (e.g., circular to elongated). However, our best remotely sensed products describing the regional-scale distribution of peatland extents are constrained to 1 km2 pixels, often representing notable sub-pixel heterogeneity and local-scale uncertainties. Here we develop a new 20 m spatial resolution wall-to-wall ~1.5 million km2 peatland map of Alaska, using peat cores, ground observations, and sub-meter resolution image interpretation. Ground-data were used to train machine learning classifiers to detect peatlands using a fusion of Sentinel-1 (Dual-polarized Synthetic Aperture Radar), Sentinel-2 (Multi-Spectral Imager), and derivatives from the Arctic Digital Elevation Model (ArcticDEM), that were spatially constrained by a peatland suitability model. Statewide peatland mapping (overall agreement:85%) identified peatlands to cover 4.6, 10.4, and 5.3% of polar, boreal, and maritime ecoregions, respectively, and 7.3% of the total terrestrial land area. This new dataset will improve the representation of peatland carbon, nutrient, and fire dynamics across Alaska.

Abstract Background To investigate the global, regional, and national burden of the diseases attributable to excess body weight (EBW) from 1990 to 2019, stratified by age, sex, underlying cause, and sociodemographic index (SDI). Methods Using the Comparative Risk Assessment approach of the Global Burden of Disease (GBD) study 2019, the burden of diseases attributable to EBW was reported for the period from 1990 to 2019. For adults, EBW was defined as a body mass index (BMI) exceeding 25 kg/m2, while for children aged 1 to 19 years, EBW was determined according to the standards set by the International Obesity Taskforce. The burden was reported in terms of numbers, proportions, and age-standardised rates per 100,000, accompanied by corresponding 95% uncertainty intervals (UIs). Results In 2019, there were an estimated 5.0 million deaths (95% UI: 3.2–7.1) and 160.3 million DALYs (106.0–218.9) attributable to EBW worldwide. The age-standardised DALY rate attributable to EBW increased by 18.0% (2.2–42.3) from 1990 to 2019, with notable regional variations. Southeast Asia and South Asia exhibited the highest age-standardised DALY rates. Conversely, the age-standardised death rate due to EBW showed no significant change, with an increase of 4.9% (-7.3 to 24.6) over the same period. Significant regional variations were again observed, particularly in Southeast Asia and South Asia, which recorded the highest age-standardised death rates. Moreover, a non-linear association was observed between the SDI and the regional age-standardised DALY rate of diseases attributable to EBW. Conclusions The global burden of EBW has increased over the past three decades. This trend aligns with socio-demographic indices and is influenced by the physical activity levels and dietary habits of these populations.

Abstract Eye-movement metrics like fixation location and duration are increasingly being used in infancy research. We tested whether fixation durations during meaningful social stimulus viewing involve common or different familial influences than fixation durations during viewing of abstract stimulus. We analysed the duration of fixations, and the allocation of fixations to face and motion, from 536 dizygotic and monozygotic 5-month-old twins in: naturalistic scenes including low- and high-level social features, and abstract scenes only having low-level features. We observed significant genetic influences in both conditions (h 2 naturalistic = 0.30, 95% confidence interval (CI) 0.14 to 0.44; h 2 abstract = 0.25, 95% CI 0.09 to 0.39), while shared environmental influences were negligible. Although some genetic influences were shared between the two conditions, unique genetic factors were linked to naturalistic scene viewing, indicating that fixation durations index different phenomena dependent on the context. Heritability for face looking was moderate (h 2 = 0.19, 95% CI 0.03 to 0.34), and no familial influences were found for motion looking. Exploratory polygenic score analyses revealed no significant associations with fixation measures. This study underscores the dissociable genetic influences on infants’ visual exploration of abstract versus naturalistic stimuli and the importance of considering context when interpreting eye-tracking data.

Abstract Epilepsy is characterized by recurrent, unpredictable seizures that impose significant challenges in daily management and treatment. One emerging area of interest is the identification of seizure cycles, including multiday patterns, which may offer insights into seizure prediction and treatment optimization. This study investigated multiday seizure cycles in a Tetanus Toxin (TT) rat model of epilepsy. Six TT-injected rats were observed over a 40-day period, with continuous EEG monitoring to record seizure events. Wavelet transform analysis revealed significant multiday cycles in seizure occurrences, with periods ranging from 4 to 7 days across different rats. Synchronization Index (SI) analysis demonstrated variable phase locking, with some rats showing strong synchronization of seizures with specific phases of the cycle. Importantly, the study revealed that these seizure cycles are dynamic and evolve over time, with some rats exhibiting shifts in cycle periods during the recording period. This suggests that the underlying neural mechanisms driving these cycles may change as the epileptic state progresses. The identification of stable and evolving multiday rhythms in seizure activity, independent of external factors, highlights a potential intrinsic biological basis for seizure timing. These findings offer promising avenues for improving seizure forecasting and designing personalized, timing-based therapeutic interventions in epilepsy. Future research should explore the underlying neural mechanisms and clinical applications of multiday seizure cycles.

Abstract Objective This research reports the incidence, mortality, and disability-adjusted life years (DALYs) associated with urinary tract infections (UTIs) in the Middle East and North Africa (MENA) region, stratified by sex, age, and Socio-demographic Index (SDI) from 1990 to 2021. Methods Data were sourced from the Global Burden of Disease 2021 study, encompassing all 21 countries in the region. Metrics such as absolute counts, age-standardised rates, and percentage changes from 1990 to 2021 are presented with 95% uncertainty intervals (UIs). Results In 2019, the MENA region recorded an incidence rate of 4,033.4 per 100,000 (95% UIs: 3,553.7–4,548.7) and 7,687 deaths (95% UIs: 6,663–8,969). The DALY rate was 41.3 per 100,000 (95% UIs: 36.1–47.2), which was highest among older adults, reaching a peak in the 80–89 age range, and increasing with age, particularly from the 50 + age groups. A non-linear relationship was identified between the burden of UTIs and the SDI, with higher-than-expected rates in lower SDI countries such as Syria and Lebanon. Conclusion Despite a substantial increase in the total number of UTI cases and DALYs in the region from 1990 to 2021, the age-standardised rates remained stable. The larger burden in lower SDI countries highlights the urgent need for targeted public health interventions. Improving healthcare access and antibiotic stewardship is crucial to mitigating the growing burden of UTIs, particularly among older populations in the region.

Abstract Objective To examine the burden of benign prostatic hyperplasia (BPH) in the Middle East and North Africa (MENA) region from 1990 to 2021 by age and sociodemographic index (SDI). Methods Data were sourced from the Global Burden of Disease (GBD) 2021 database. We analysed the incidence, prevalence, and years lived with disability (YLDs) attributable to BPH across the MENA region and its constituent countries. Results In 2021, the MENA region had an estimated 4.7 million prevalent cases of BPH, with an age-standardised prevalence rate of 2168.6 per 100,000. BPH contributed to 93.6 thousand YLDs, with an age-standardised YLD rate of 42.8 per 100,000. The highest prevalence and incidence rates were observed in Jordan, Qatar, and Iran, while Egypt and Yemen recorded the lowest rates. The burden of BPH was found to increase with age, peaking in the 65–69 age range. Conclusion This study reveals an increasing burden of BPH in the MENA region, primarily due to aging populations. These findings underscore the need for tailored public health policies and strategies to enhance early detection, prevention, and management of BPH, thereby reducing its impact on healthcare systems and individuals.

Abstract Background Synergists reduce insecticide metabolism in mosquitoes by competing with insecticides for the active sites of metabolic enzymes, such as cytochrome P450s (CYPs). This increases the availability of the insecticide at its specific target site. The combination of both insecticides and synergists increases the toxicity of the mixture. Given the demonstrated resistance to the classical insecticides in numerous Anopheles spp., the use of synergists is becoming increasingly pertinent. Tropical plants synthesize diverse phytochemicals, presenting a repository of potential synergists. Methods Extracts prepared from medicinal plants found in Jamaica were screened against recombinant Anopheles gambiae CYP6M2 and CYP6P3, and Anopheles funestus CYP6P9a, CYPs associated with anopheline resistance to pyrethroids and several other insecticide classes. The toxicity of these extracts alone or as synergists, was evaluated using bottle bioassays with the insecticide permethrin. RNA sequencing and in silico modelling were used to determine the mode of action of the extracts. Results Aqueous extracts of Piper amalago var. amalago inhibited CYP6P9a, CYP6M2, and CYP6P3 with IC50s of 2.61 ± 0.17, 4.3 ± 0.42, and 5.84 ± 0.42 μg/ml, respectively, while extracts of Kalanchoe pinnata, inhibited CYP6M2 with an IC50 of 3.52 ± 0.68 μg/ml. Ethanol extracts of P. amalago var. amalago and K. pinnata displayed dose-dependent insecticidal activity against An. gambiae, with LD50s of 368.42 and 282.37 ng/mosquito, respectively. Additionally, An. gambiae pretreated with K. pinnata (dose: 1.43 μg/mosquito) demonstrated increased susceptibility (83.19 ± 6.14%) to permethrin in a bottle bioassay at 30 min compared to the permethrin only treatment (0% mortality). RNA sequencing demonstrated gene modulation for CYP genes in anopheline mosquitoes exposed to 715 ng of ethanolic plant extract at 24 h. In silico modelling showed good binding affinity between CYPs and the plants’ secondary metabolites. Conclusion This study demonstrates that extracts from P. amalago var. amalago and K. pinnata, with inhibitory properties, IC50

Abstract Prostate cancer ranks among the most prevalent malignancies affecting males globally. This study sought to document the incidence, deaths and disability-adjusted life-years (DALYs) that were due to prostate cancer in the Middle East and North Africa (MENA) region, and its 21 countries, from 1990 to 2021. We analysed publicly accessible data from the Global Burden of Disease 2021 study to present findings on the incidence, deaths, and disability-adjusted life years (DALYs) associated with prostate cancer. These metrics were reported as counts and age-standardised rates, each accompanied by 95% uncertainty intervals. In 2021, the age-standardised incidence of prostate cancer in the region was 27.4 per 100,000 population, representing a 125.1% increase from 1990. The age-standardised mortality rate was 10.1, and the age-standardised DALY rate was 173.6, neither of which showed significant increases since 1990. Qatar recorded the highest age-standardised DALY rate in 2021, while Algeria had the lowest. The largest number of incident cases, deaths, and DALYs in 2021 were found in the 65–69, 80–84, and 70–74 age groups, respectively. Additionally, from 1990 to 2021, the burden of prostate cancer largely increased with the socio-demographic index (SDI) at the regional level. The burden of prostate cancer in the MENA region rose markedly between 1990 and 2021. Further studies into the underlying causes of this increasing incidence are essential to devise effective strategies for the early detection and prevention of the disease.

Synchrotron sourced Fourier transform infrared (SS FTIR) microspectroscopy was employed to investigate the biological effects on the neuron-like pheochromocytoma (PC 12) cells after exposure to synchrotron sourced terahertz (SS THz) radiation. Over 10 min of exposure, the PC 12 cells received a total energy of 600 J m2, with a total incident power density of ∼1.0 W m−2 (0.10 mW cm−2) at the beam extraction port (BEP) of the THz beamline at the Australian Synchrotron. To investigate the metabolic response of PC 12 cells after synchrotron THz radiation exposure, we utilized the FTIR microscope at the Infrared Microspectroscopy IRM beamline, which offers high photon flux and diffraction-limited spatial resolution enabling the detection of functional group variations in biological molecules at a single-cell level. Principal component analysis (PCA) based on the SS FTIR spectral data revealed a distinct separation of SS THz-exposed and control (non-exposed) cells. According to the PCA loadings, the key changes in the exposed cells involved lipid and protein compositions as indicated by the stretching vibrations of CH2/CH3 groups and amide I/II bands, respectively. An increase in lipids, such as cholesterol, or notable changes in their compositions and in some protein secondary structures were observed in the SS THz-exposed cells. The PCA analysis further suggests that PC 12 cells might maintain cell membrane stability after SS THz irradiation through higher volumes of cholesterol and cell morphology via regulation of the synthesis of cytoskeleton proteins such as actin-related proteins. The outcome of this study re-emphasized the exceptional SS FTIR capability to perform single-cell analysis directly, providing (i) unique biological information on cell variability within the population as well as between different groups, and (ii) evidence of molecular changes in the exposed cells that could lead to a deeper understanding of the effect of THz exposure at a single-cell level.

Abstract Background Gene signatures derived from transcriptomic-causal networks offer potential for tailoring clinical care in cancer treatment by identifying predictive and prognostic biomarkers. This study aimed to uncover such signatures in metastatic colorectal cancer (CRC) patients to aid treatment decisions. Methods We constructed transcriptomic-causal networks and integrated gene interconnectivity into overall survival (OS) analysis to control for confounding genes. This integrative approach involved germline genotype and tumor RNA-seq data from 1165 metastatic CRC patients. The patients were enrolled in a randomized clinical trial receiving either cetuximab or bevacizumab in combination with chemotherapy. An external cohort of paired CRC normal and tumor samples, along with protein-protein interaction databases, was used for replication. Results We identify promising predictive and prognostic gene signatures from pre-treatment gene expression profiles. Our study discerns sets of genes, each forming a signature that collectively contribute to define patient subgroups with different prognosis and response to the therapies. Using an external cohort, we show that the genes influencing OS within the signatures, such as FANCI and PRC1, are upregulated in CRC tumor vs. normal tissue. These signatures are highly associated with immune features, including macrophages, cytotoxicity, and wound healing. Furthermore, the corresponding proteins encoded by the genes within the signatures interact with each other and are functionally related. Conclusions This study underscores the utility of gene signatures derived from transcriptomic-causal networks in patient stratification for effective therapies. The interpretability of the findings, supported by replication, highlights the potential of these signatures to identify patients likely to benefit from cetuximab or bevacizumab.

The Kjell Henriksen Observatory (KHO) is the world’s largest optical observatory for auroral and airglow measurements, operated by the University Centre in Svalbard (UNIS). KHO is a unique site that lies underneath the dayside cusp, a funnel-shaped region where particles from the Sun can directly enter the Earth’s upper atmosphere, including the ionosphere. Building on the pioneering observations of its predecessor—the Auroral Station in Adventdalen, Svalbard—KHO has played a pivotal role in advancing our understanding of phenomena in the polar atmosphere. The Auroral Station and KHO have amassed climatological measurements over Svalbard for an impressive 40-year period. KHO’s diverse instrumentation, combined with other co-located optical and radar infrastructure, and in situ measurements from satellites and sounding rockets, has paved the way for impactful multi-instrument studies. Serving as an accessible testbed for instrument development, new types of instruments have recently been installed, both at KHO and on satellites. Beyond its scientific contributions, KHO has become an integral part of the Longyearbyen community, with students, visitors, and locals participating in tours and educational initiatives. This connection underscores KHO’s multi-functional role, not only as a centre for excellent research but also as a vital hub for public outreach and engagement.

Abstract Background Gout is one of the oldest known diseases and the most common form of inflammatory arthritis. The established risk factors for gout include hyperuricemia, chronic renal disease, genetic, alcohol consumption, dietary factors, diuretic use, hypertension, obesity, and metabolic syndrome. Patients with gout have an increased risk of all-cause mortality, particularly from cardiovascular disease, cancer, and infectious diseases. Gout is also associated with several complications, such as nephrolithiasis. This literature review describes the global epidemiology and trends associated with gout, before providing an overview of its risk factors and complications. Methods This research used the narrative review method. Thorough searches were performed in PubMed and Google scholar, up to June 15, 2024, for articles that evaluated the risk factors, comorbidities or complications associated with gout. Moreover, we also included studies that reported the epidemiological characteristics or burden of gout at the global, regional, or national level. Results Gout is more prevalent in developed countries, than in developing countries, although its prevalence is increasing globally. In addition, gout is much more prevalent among males than among females. Hyperuricemia has the largest role in the development of gout, although many risk factors contribute to the increasing prevalence of gout, including genes, several medications, and diet. Gout is associated with several comorbidities and complications, which need to be taken into consideration when managing gout. In recent years, gout has been found to be associated with several new comorbidities. Conclusions Our findings provide a comprehensive and informative overview that can be useful for the prevention, diagnosis, and management of gout.

Abstract Autosomal Dominant Polycystic Kidney Disease (ADPKD) results in progressive cysts that lead to kidney failure, and is caused by heterozygous germline variants in PKD1 or PKD2. Cyst pathogenesis is not definitively understood. Somatic second-hit mutations have been implicated in cyst pathogenesis, though technical sequencing challenges have limited investigation. We used unique molecular identifiers, high-depth massively parallel sequencing and custom analysis techniques to identify somatic second-hit mutations in 24 whole cysts from disparate regions of six human ADPKD kidneys, utilising replicate samples and orthogonal confirmation. Average depth of coverage of 1166 error-corrected reads for PKD1 and 539 reads for PKD2 was obtained. 58% (14/24) of cysts had a detectable PKD1 somatic variant, with 5/6 participants having at least one cyst with a somatic variant. We demonstrate that low-frequency somatic mutations are detectable in a proportion of cysts from end-stage ADPKD human kidneys. Further studies are required to understand the drivers of this somatic mutation.

A critical issue facing extraterrestrial expansion has always been long-term life support capabilities. The large energy requirements to move even small amounts of material from Earth necessitate the ability to reuse and recycle as much as possible, particularly waste. The weight of food supplies eventually starts to limit the length of the expedition. Hydroponic growth systems offer the ability to grow plants, and with them, a miniature ecosystem. This offers the ability to repurpose both carbon dioxide and waste salts such as ammonia and other compounds, such as those found in urine. A major issue facing hydroponic systems is the need to provide a stable water-based nutrient stream. Direct contact membrane distillation (DCMD) was tested for viability as a method of re-concentrating and stabilizing the nutrient-rich water stream. Polytetrafluoroethylene (PTFE)- and polyvinylidene (PVDF)-based polymer hydrophobic membranes were used to separate solutes from water. The DCMD method was tested with the feed stream operating at temperatures of 50 °C, 65 °C, and 80 °C. The results were analyzed using UV-Visible spectroscopy to determine concentrations. The benefits and limitations of the PTFE and PVDF membranes in DCMD were compared. The larger-pore PTFE membranes concentrated solutions effectively at 80 °C, while the PVDF membranes removed more water at lower temperatures, but permitted detectable phosphate ion leakage. Adjusting temperature and flow rates can help maintain stable ion and water transfer, benefiting hydroponic systems in achieving reliable nutrient levels.

Abstract We used machine learning to investigate the residual visual field (VF) deficits and macula retinal ganglion cell (RGC) thickness loss patterns in recovered optic neuritis (ON). We applied archetypal analysis (AA) to 377 same-day pairings of 10-2 VF and optical coherence tomography (OCT) macula images from 93 ON eyes and 70 normal fellow eyes ≥ 90 days after acute ON. We correlated archetype (AT) weights (total weight = 100%) of VFs and total retinal thickness (TRT), inner retinal thickness (IRT), and macular ganglion cell-inner plexiform layer (GCIPL) thickness. AA showed most ON eyes had a 10-2 VF pattern like the normal fellow eye VF, despite having markedly thinner GCIPL patterns. AA identified 7 VF and 11 retinal thickness ATs for each OCT model. The normal VF AT constituted 80% of ON eyes and 90% of normal fellow eyes. The most common GCIPL AT consisted of diffuse thinning. We identified significant correlations for the normal AT weights using OCT AT weights of five GCIPL ATs (r = 0.45), four TRT ATs (0.53) and two IRT ATs (0.42). Following acute ON, most eyes had complete 10-2 VF recovery despite significant GCIPL thinning, suggesting compensatory mechanisms for vision.

ABSTRACT Background Hip‐related pain (HRP) affects young to middle‐aged active adults and impacts physical activity, finances and quality of life. HRP includes conditions like femoroacetabular impingement syndrome and labral tears. Lateral hip muscle dysfunction and atrophy in HRP are more pronounced in advanced hip pathology, with limited evidence in younger populations. While MRI use for assessing hip muscle morphology is increasing, with automated deep‐learning techniques showing promise, studies assessing their accuracy are limited. Therefore, we aimed to compare hip intramuscular fat infiltrate (MFI) and muscle volume, in individuals with and without HRP as well as assess the reliability and accuracy of automated machine‐learning segmentations compared with human‐generated segmentation. Methods This cross‐sectional study included sub‐elite/amateur football players (Australian football and soccer) with a greater than 6‐month history of HRP [n = 180, average age 28.32, (standard deviation 5.88) years, 19% female] and a control group of sub‐elite/amateur football players without pain [n = 48, 28.89 (6.22) years, 29% female]. Muscle volume and MFI of gluteus maximus, medius, minimis and tensor fascia latae were assessed using MRI. Associations between muscle volume and group were explored using linear regression models, controlling for body mass index, age, sport and sex. A convolutional neural network (CNN) machine‐learning approach was compared with human‐performed muscle segmentations in a subset of participants (n = 52) using intraclass correlation coefficients and Sorensen–Dice index. Results When considering adjusted estimates of muscle volume, there were significant differences observed between groups for gluteus medius (adjusted mean difference 23 858 mm3 [95% confidence interval 7563, 40 137]; p = 0.004) and tensor fascia latae (6660 mm3 [2440, 13 075]; p = 0.042). No differences were observed between groups for gluteus maximus (18 265 mm3 [−21 209, 50 782]; p = 0.419) or minimus (3893 mm3 [−2209, 9996]; p = 0.21). The CNN was trained for 30 000 iterations and assessed its accuracy and reliability on an independent testing dataset, achieving high segmentation accuracy (mean Sorenson–Dice index >0.900) and excellent muscle volume and MFI reliability (ICC2,1 > 0.900). The CNN outperformed manual raters, who had slightly lower interrater accuracy (Sorensen–Dice index >0.800) and reliability (ICC2,1 > 0.800). Conclusions The increased muscle volumes in the symptomatic group compared with controls could be associated with increased myofibrillar size, sarcoplasmic hypertrophy or both. These changes may facilitate greater muscular efficiency for a given load, enabling the athlete to maintain their normal level of function. In addition, the CNNs for muscle segmentation was more efficient and demonstrated excellent reliability in comparison to manual segmentations.

Abstract River systems once safeguarded from water development are being developed. This includes intermittent rivers that annually dry to a series of pools. Describing fish species relationships between abundance and pool depth can help managers set water-take rules that protect fish in dry-season pools. We sampled fish in main-channel and floodplain pools that spanned a gradient of depths and overcame sampling challenges by accounting for interacting effects of species mean length, environmental attributes, and sampling attributes on fish capture probabilities. Fish abundance-depth relationships varied systematically with species mean length, mesohabitat type (main channel, floodplain), water turbidity, and structural complexity, highlighting system complexity and the potential generality of abundance-depth relationships. Similarly, fish length moderated the effects of environmental attributes on capture probability for all sampling methods. We evaluated impacts of hypothetical water-take regulations on fish species’ distributions. Results suggested that water-take rules prohibiting draining of main-channel pools below 1.65 m and reducing floodplain pools by no more than 14% minimises impacts to species’ distributions, promoting conservation of the fish community. Additionally, our approach demonstrates the capacity of species length for predicting distributional and sampling patterns of fish species.

Abstract Knowledge gaps regarding human immunity to Streptococcus pyogenes have impeded vaccine development. To address these gaps and evaluate vaccine candidates, we established a human challenge model of S. pyogenes pharyngitis. Here, we analyse antibody responses in serum and saliva against 19 antigens to identify characteristics distinguishing 19 participants who developed pharyngitis and 6 who did not. We show that pharyngitis elicits serum IgG responses to key vaccine antigens and a muted mucosal IgA response, whereas IgG responses are minimal and IgA responses more pronounced in participants without pharyngitis. Serum IgG responses to pharyngitis in adult participants resemble those in children and are inversely correlated with the magnitude of pre-existing responses. While a straightforward correlate of protection is not evident, baseline antibody signatures distinguish clinical and immunological outcomes following experimental challenge. This highlights the influence of a complex humoral imprint from previous exposure, relevant for interpreting immunogenicity in forthcoming vaccine trials.

Archival XMM and ROSAT X-Ray data are used to investigate the structure of the Abell 548–Abell 3367 region. Based on previous optical studies, this is a region likely to be rich in structure, although studies are in disagreement regarding the connection between Abell 3367 and Abell 548. We use the available archival X-Ray data together with kinematic data of counterpart galaxies to address this question and determine the structure in this region. The region is particularly rich in X-Ray structure elongated along a SW-NE axis and consisting of numerous extended X-Ray sources. In general, the structure consists of many galaxy groups and clusters which appear segregated in X-Ray luminosity, with the least luminous ~30% toward the outer region of the clusters, possibly tracing a filament. We find evidence to suggest a supercluster of three clusters at redshifts ~0.04, 0.045, and 0.06. Several of the X-Ray sources coincident with Abell 3367 have counterpart galaxy redshifts consistent with Abell 548, while others are significantly higher. This supports the formation of a supercluster consisting of Abell 548 and Abell 3667, with the higher-redshift X-Ray source being a background object. In addition, they are part of a larger structure consisting of a previously identified cluster at redshift 0.04 and two groups at redshift ~0.06. There is also filamentary structure at z ~0.103. The ubiquity of groups in the large-scale structure suggests that they provide an environment where galaxies are in close proximity and evolution via interaction can proceed well before the galaxies make their way into the dense central region of a cluster.

Abstract Background South Africa is facing a convergence of communicable diseases (CDs) and non-communicable diseases (NCDs). There are limited data about how tobacco use contributes to the burden of these conditions, especially in rural populations. Methods We analyzed the associations between current tobacco smoking and four important CDs and NCDs in Vukuzazi, a cross-sectional study of individuals aged 15 years and older conducted between 2018–2020 in a demographic surveillance area in KwaZulu-Natal, South Africa. Data on HIV, active tuberculosis (TB), hypertension and diabetes mellitus were collected via direct measurement from participants. Results Of 18,024 participants (68% female, median age 37 years [interquartile range 23–56 years]), 1,301 (7.2%) reported current smoking. Prevalence of HIV infection was similarly high among people who currently smoked (34.6%) and people who had never smoked (33.9%). However, among people living with HIV (PLWH), there was a higher prevalence of detectable viremia in people reporting current smoking compared to people who reported never smoking (28.8% vs. 16.6%; p-value

Abstract Production of cultivated meat requires defined medium formulations for the robust differentiation of myogenic cells into mature skeletal muscle fibres in vitro. Although these formulations can drive myogenic differentiation levels comparable to serum-starvation-based protocols, the resulting cultures are often heterogeneous, with a significant proportion of cells not participating in myofusion, limiting maturation of the muscle. To address this problem, we employed RNA sequencing to analyse heterogeneity in differentiating bovine satellite cells at single-nucleus resolution, identifying distinct cellular subpopulations including proliferative cells that fail to exit the cell cycle and quiescent ‘reserve cells’ that do not commit to myogenic differentiation. Our findings indicate that the MEK/ERK, NOTCH, and RXR pathways are active during the initial stages of myogenic cell fate determination, and by targeting these pathways, we can promote cell cycle exit while reducing reserve cell formation. This optimised medium formulation consistently yields fusion indices close to 100% in 2D culture. Furthermore, we demonstrate that these conditions enhance myotube formation and actomyosin accumulation in 3D bovine skeletal muscle constructs, providing proof of principle for the generation of highly differentiated cultivated muscle with excellent mimicry to traditional muscle.

Abstract Tropical peatland fires generate substantial quantities of airborne fine particulate matter (PM2.5) and in Indonesia are intensified during El Niño-related drought leading to severe air quality impacts affecting local and distant populations. Limited in-situ data often necessitates reliance on air quality models, like that of the Copernicus Atmosphere Monitoring Service, whose accuracy in extreme conditions is not fully understood. Here we demonstrate how a network of low-cost sensors around Palangka Raya, Central Kalimantan during the 2019 fire season, quantified extreme air quality and city-scale variability. The data indicates relatively strong model performance. Health impacts are substantial with estimates of over 1200 excess deaths in the Palangka Raya region, over 3200 across Central Kalimantan and more than 87,000 nationwide in 2019 due to fire-induced PM2.5 exposure. These findings highlight the need for urgent action to mitigate extreme fire events, including reducing fire use and landscape remediation to prevent peat fire ignition.

Cholangiocarcinoma (CCA) is a highly aggressive form of liver cancer and is an increasing cause of cancer‐related death worldwide. Despite its increasing incidence globally and alarming mortality, treatment options for CCA have largely remained unchanged, stressing the importance of developing new effective therapies. YAP activation is common in CCA, and its major transcriptional signaling partners are the TEAD proteins. CA3 is a small‐molecule YAP‐TEAD disrupter discovered utilizing a TEAD reporter assay. Utilizing CCA, gastric cancer cell lines, and patient‐derived xenograft models (PDX), we demonstrate that CA3 is effective in inducing cell death and delaying tumor growth in both FGFR2 fusion and wild‐type models. CA3 was associated with on‐target decreases in YAP‐TEAD target gene expression, TEAD reporter activity, and overall TEAD levels. Hippo pathway signaling was not altered as there was no change in YAP phosphorylation status in the cells exposed to CA3. RNA sequencing of gastric cancer and CCA models demonstrated upregulation of an androgen receptor–mediated transcriptional program following exposure to CA3 in five unique models tested. Consistent with this upstream regulator analysis, CA3 exposure in CCA cells was associated with increased AR protein levels, and combinatorial therapy with CA3 and androgen receptor blockade was associated with increased cancer cell death. CA3 behaves functionally as a YAP‐TEAD disrupter in the models tested and demonstrated therapeutic efficacy. Exposure to CA3 was associated with compensatory androgen receptor signaling and dual inhibition improved the therapeutic effect.

A new species of Sesiidae, Carmenta brachyclados Sterling & Lees, 2024 is described from adult specimens, pupal exuviae and larval borings which were accidentally transported to South Wales, United Kingdom. DNA barcoding and morphological evidence shows that this species is native to the Neotropics, where it feeds in the seedpods of the leguminous tree, Mora excelsa Benth. (Fabaceae: Caesalpinioideae) and that it is related to a group of seed-feeding species of clearwing moths within the genus Carmenta Edwards, 1881, naturally occurring in the Neotropics and southern Nearctic, although C. mimosa Eichlin & Passoa, 1984 has been introduced in Australia and elsewhere as a biological agent.

Abstract As the global prevalence of chronic liver disease continues to rise, the need to determine which patients will develop end-stage liver disease and require liver transplantation is increasingly important. However, current prognostic models perform sub-optimally. We aim to determine microRNA profiles associated with clinical decompensation and mortality/transplantation within 1 year. We examined microRNA expression profiles in plasma samples from patients across the spectrum of cirrhosis (n = 154), acute liver failure (ALF) (n = 22), sepsis (n = 20) and healthy controls (HC) (n = 20). We demonstrated that a microRNA-based model (miR-24 and -27a) associated with systemic inflammation differentiated decompensated cirrhosis states from compensated cirrhosis and HC (AUC 0.77 (95% CI 0.69–0.85)). 6 patients within the compensated cirrhosis group decompensated the subsequent year and their exclusion improved model performance (AUC 0.81 (95% CI 0.71–0.89)). miR-191 (associated with liver injury) predicted risk of mortality across the cohort when acutely decompensated and acute-on-chronic-liver failure patients were included. When they were excluded miR-24 (associated with systemic inflammation) predicted risk of mortality. Our findings demonstrate that microRNA associated with systemic inflammation and liver injury predict adverse outcomes in cirrhosis. miR-24 and -191 require further investigation as prognostic biomarkers and therapeutic targets for patients with liver disease.

Abstract Background Long COVID, also known as post-acute sequelae of COVID-19 (PASC), is a poorly understood condition with symptoms across a range of biological domains that often have debilitating consequences. Some have recently suggested that lingering SARS-CoV-2 virus particles in the gut may impede serotonin production and that low serotonin may drive many Long COVID symptoms across a range of biological systems. Therefore, selective serotonin reuptake inhibitors (SSRIs), which increase synaptic serotonin availability, may be used to prevent or treat Long COVID. SSRIs are commonly prescribed for depression, therefore restricting a study sample to only include patients with depression can reduce the concern of confounding by indication. Methods In an observational sample of electronic health records from patients in the National COVID Cohort Collaborative (N3C) with a COVID-19 diagnosis between September 1, 2021, and December 1, 2022, and a comorbid depressive disorder, the leading indication for SSRI use, we evaluated the relationship between SSRI use during acute COVID-19 and subsequent 12-month risk of Long COVID (defined by ICD-10 code U09.9). We defined SSRI use as a prescription for SSRI medication beginning at least 30 days before acute COVID-19 and not ending before SARS-CoV-2 infection. To minimize bias, we estimated relationships using nonparametric targeted maximum likelihood estimation to aggressively adjust for high-dimensional covariates. Results We analyzed a sample (n = 302,626) of patients with a diagnosis of a depressive condition before COVID-19 diagnosis, where 100,803 (33%) were using an SSRI. We found that SSRI users had a significantly lower risk of Long COVID compared to nonusers (adjusted causal relative risk 0.92, 95% CI (0.86, 0.99)) and we found a similar relationship comparing new SSRI users (first SSRI prescription 1 to 4 months before acute COVID-19 with no prior history of SSRI use) to nonusers (adjusted causal relative risk 0.89, 95% CI (0.80, 0.98)). Conclusions These findings suggest that SSRI use during acute COVID-19 may be protective against Long COVID, supporting the hypothesis that serotonin may be a key mechanistic biomarker of Long COVID.

Abstract Noonan Syndrome (NS) is associated with an increased risk of low-grade central nervous system tumours in children but only very rarely associated with high-grade gliomas. Here we describe the first reported case of a spinal high-grade astrocytoma with piloid features (HGAP) in a child with NS. This case was a diagnostic and treatment dilemma, prior to whole-genome germline and tumour sequencing, tumour transcriptome sequencing and DNA methylation analysis. The methylation profile matched strongly with HGAP and sequencing identified somatic FGFR1 and NF1 variants and a PTPN11 germline pathogenic variant. Therapeutic targets were identified but also alterations novel to HGAP such as differential expression of VEGFA and PD-L1. The germline PTPN11 finding has not been previously described in individuals with HGAP. This case underscores the power of precision medicine from a diagnostic, therapeutic and clinical management perspective, and describes an association between HGAP and NS which has not previously been reported.

Abstract Background HIV clinical guidelines recommend hypertension detection and management to lower cardiovascular disease risk, but these have not been effectively implemented for people living with HIV (PWH). Addressing this implementation gap requires community-engaged implementation studies focused on addressing implementation barriers specific to the HIV care context. Methods This protocol describes a type 2 effectiveness-implementation hybrid study conducted in nine primary care clinics in Johannesburg. The study will evaluate the effect of implementation strategies on guideline-recommended blood pressure assessment and management in HIV clinics and the effects of assessment/management on patient blood pressure. A stepped-wedge, cluster randomized study design was used to randomize clinics to the time at which they receive the implementation strategies and patient intervention. The implementation strategies tested include identifying and preparing care champions, changing record systems, conducting ongoing training, providing audit and feedback, and changing the physical structure/equipment. The patient intervention tested includes detection of elevated blood pressure, educational materials, lifestyle modification advice, and medication where needed. Implementation outcomes include adoption, fidelity (co-primary outcome), cost, and maintenance of the blood pressure assessment protocol in participating clinics, while patient outcomes include reach, effectiveness (co-primary outcome), and long-term effects of the intervention on patient blood pressure. These will be assessed via direct observation, study records, staff logs, medical chart reviews, and patient and healthcare worker surveys. To examine effects on the implementation (intervention fidelity) and effectiveness (patient blood pressure changes) co-primary outcomes, we will use the standard Hussey and Hughes model for analysis of stepped-wedge designs which includes fixed effects for both interventions and time periods, and a random effect for sites. Finally, we will examine the costs for the implementation strategies, healthcare worker time, and patient-facing intervention materials, as well as the cost-effectiveness and cost-utility of the intervention using study records, patient surveys, and a time and motion assessment. Discussion This study will address knowledge gaps around implementation of cardiovascular disease preventive practices in HIV care in South Africa. In doing so, it will provide a dual opportunity to promote evidence-based care in the South African HIV care context and help refine implementation research methods to better serve HIV populations globally. Trial registration ClinicalTrials.gov: NCT05846503. Registered on May 6, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05846503 .

Abstract Background PLA2G6-associated neurodegeneration (PLAN) comprises three diseases with overlapping features: infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (atypical NAD), and PLA2G6-related dystonia-parkinsonism. INAD is an early onset disease characterized by progressive loss of vision, muscular control, and mental skills. The prevalence of PLA2G6-associated diseases has not been previously calculated. Methods To provide the most accurate prevalence estimate, we utilized two independent approaches: database-based approach which included collecting variants from ClinVar, Human Gene Mutation Database (HGMD) and high confidence predicted loss-of-function (pLoF) from gnomAD (Rare Genomes Project Genetic Prevalence Estimator; GeniE), and literature-based approach which gathered variants through Mastermind Genomic Search Engine (Genomenon, Inc). Genetic prevalence of PLAN was calculated based on allele frequencies from gnomAD, assuming Hardy–Weinberg equilibrium. Results In the PLA2G6 gene, our analysis found 122 pathogenic, 82 VUS, and 15 variants with conflicting interpretations (pathogenic vs VUS) between two approaches. Allele frequency was available for 58 pathogenic, 42 VUS, and 15 conflicting variants in gnomAD database. If pathogenic and/or conflicting variants are included, the overall genetic prevalence was estimated to be between 1 in 987,267 to 1 in 1,570,079 pregnancies, with the highest genetic prevalence in African/African-American (1 in 421,960 to 1 in 365,197) and East-Asian (1 in 683,978 to 1 in 190,771) populations. Conclusion Our estimates highlight the significant underdiagnosis of PLA2G6-associated neurodegeneration and underscores the need for increased awareness and diagnostic efforts. Furthermore, our study revealed a higher carrier frequency of PLA2G6 variants in African and Asian populations, stressing the importance of expanded genetic sequencing in non-European populations to ensure accurate and comprehensive diagnosis. Future research should focus on confirming our findings and implementing expanded sequencing strategies to facilitate maximal and accurate diagnosis, particularly in non-European populations.

Abstract Background To develop and validate a novel administration device for holmium-166 transarterial radioembolisation (TARE) with the purpose of facilitating controlled fractional microsphere administration for a more flexible and image-guided TARE procedure. Methods A Controlled Administration Device (CAD) was developed using MR-conditional materials. The CAD contains a rotating syringe to keep the microspheres in suspension during administration. Different rotational speeds were tested ex vivo to optimise the homogeneity of microsphere fractions administered from the device. The technical performance, accuracy, and safety was validated in three patients in a clinical TARE setting by administering a standard clinical dose in 5 fractions (identifier: NCT05183776). MRI-based dosimetry was used to validate the homogeneity of the given fractions in vivo, and serious adverse device event ((S)A(D)E) reporting was performed to assess safety of the CAD. Results A rotational speed of 30 rpm resulted in the most homogeneous microsphere fractions with a relative mean deviation of 1.1% (range: -9.1-8.0%). The first and last fraction showed the largest deviation with a mean of -26% (std. 16%) and 7% (std. 13%). respectively. In the three patient cases the homogeneity of the microsphere fractions was confirmed given that MRI-based dosimetry showed near linear increase of mean absorbed target liver dose over the given fractions with R2 values of 0.98, 0.97 and 0.99. No (S)A(D)E’s could be contributed to the use of the CAD. Conclusions The newly developed CAD facilitates safe and accurate fractional microsphere administration during TARE, and can be used for multiple applications in the current and future workflows of TARE.

Ants are often the most ubiquitous and ecologically influential components of terrestrial systems, exhibiting an exceptionally high level of endemic diversity. Simultaneously, exotic ants can be amongst the most environmentally and economically devastating biological invaders. Distinguishing between exotic and related natives is essential for early detection and to reduce the chance of establishment, but at the species-level there remains a great deal of uncertainty among several of the most diverse, widespread and ecologically dominant genera. This taxonomic impediment negatively impacts the use of molecular techniques relying on reference databases, due to the poor state of ant DNA sequences in publicly available repositories, with many species not represented at all and others incorrectly identified. As a result, biosecurity screening for targeted exotic ants and assigning ant species-level identifications for biodiversity remain two separate areas of focus in Australia. Here we propose a workflow for the identification of ants that enables simultaneous processing of large numbers of “bulk” ant samples each containing many individuals, increasing resolution for taxonomic assignment, and generating a curated database linked to voucher specimens. We use a non-destructive DNA extraction method and compare two high throughput sequencing (HTS) metabarcoding platforms – MiSeq (Illumina) and MinION (Oxford Nanopore Technologies) – processing up to 180 bulk mixed ant samples per run. This approach allowed for the acquisition of curated DNA sequences from voucher specimens morphologically examined by expert taxonomists. This work highlights the advantages and current limitations of DNA-based identifications, the needs for standardisation, as well as the importance of a taxonomy-based curation of DNA database for both biodiversity and biosecurity.

The goal of the Paris Agreement is to keep global temperature rise well below 2°C. In this agreement—and its antecedents negotiated in Copenhagen and Cancun—the fear of crossing a dangerous climate threshold is supposed to serve as the catalyst for cooperation among countries. However, there are deep uncertainties about the location of the threshold for dangerous climate change, and recent evidence indicates this threshold uncertainty is a major impediment to collective action. Early warning signals of approaching climate thresholds are a potential remedy to this threshold uncertainty problem, and initial experimental evidence suggests such early detection systems may improve the prospects of cooperation. Here, we provide a direct experimental assessment of this early warning signal hypothesis. Using a catastrophe avoidance game, we show that large initial—and subsequently unreduced—threshold uncertainty undermines cooperation, consistent with earlier studies. An early warning signal that reduced uncertainty to within 10% (but not 30%) of the threshold value catalysed cooperation and reduced the probability of catastrophe occurring, albeit not reliably so. Our findings suggest early warning signals can trigger action to avoid a dangerous threshold, but additional mechanisms may be required to foster the cooperation needed to ensure the threshold is not breached.

Summary: Monoclonal antibodies have potential as rapidly developable agents for treatment and prevention of emerging viruses. The ACTIV-2 trial randomized persons with mild-moderate COVID-19 to the monoclonal antibody combination tixagevimab/cilgavimab via intramuscular injection (600 mg IM) or infusion (300 mg IV) versus placebo. We present final safety and laboratory outcomes; primary outcomes were previously reported. The analyzed IM group included 214 participants, and the IV group, 106 participants. Adverse events were not different between treatment and placebo. The half-life of both components was >90 days for IM or 75 days for IV. New anti-drug antibodies were about 3 times more likely in active vs. placebo recipients. SARS-CoV-2 neutralizing antibodies increased 157-fold at 7 days and 127-fold at 1 month (IM-treated) but were less robust in IV participants. These data can inform future development of monoclonal antibodies against SARS-CoV-2 and other viruses, even if this intervention is of low utility for contemporary SARS-CoV-2 variants.

Background. Perihilar cholangiocarcinoma (phCCA) has excellent outcomes following liver transplantation (LT). Neoadjuvant radiation-based locoregional therapy is standard-of-care. Gemcitabine and cisplatin (gem/cis) combination systemic therapies have improved outcomes in advanced settings, but their efficacy pre-LT has not been studied. Methods. We review our experience following neoadjuvant gem/cis alone versus radiation-based approaches. Patients with phCCA undergoing LT at a single center between January 2008 and February 2023 were identified retrospectively. Neoadjuvant therapy was categorized as gem/cis systemic therapy (ST) alone, or any ST and radiotherapy (RT). Outcomes were posttransplant overall survival (OS), recurrence-free survival (RFS), waitlist time, and pathologic tumor response. Results. During study period, 27 phCCA patients underwent LT. One patient decompensated with neoadjuvant therapy and was excluded. Median age was 61 y (interquartile range, 53–68 y) and 14 (54%) were male. Of 26 patients, 12 (46%) received ST and 14 (54%) RT. Six RT patients received gem/cis ST. Median waitlist time was 199 d (interquartile range, 98–405 d) and did not differ by neoadjuvant regimen. Explanted tumors were predominantly T1 stage, without lymphovascular invasion or nodal involvement. Neither pathologic features nor percent tumor necrosis differed by regimen. OS probabilities at 1 and 3 y were 84% and 55% for the cohort. There was no significant difference in OS and RFS when stratified by regimen. Conclusions. Post-LT OS, RFS, waitlist time, and tumor response were similar in the 2 groups. Patients with phCCA who do not undergo RT may still be considered for LT under appropriate institution-based protocols that adhere to other established criteria.

A recently introduced quantitative susceptibility mapping (QSM) technique, χ-separation, offers the capability to separate paramagnetic (χpara) and diamagnetic (χdia) susceptibility distribution within the brain. In-vivo high-resolution mapping of iron and myelin distribution, estimated by χ-separation, could provide a deeper understanding of brain substructures, assisting the investigation of their functions and alterations. This can be achieved using 7T MRI, which benefits from a high signal-to-noise ratio and susceptibility effects. However, applying χ-separation at 7T presents difficulties due to the requirement of an R2 map, coupled with issues such as high specific absorption rate (SAR), large B1 transmit field inhomogeneities, and prolonged scan time. To address these challenges, we developed a novel deep neural network, R2PRIMEnet7T, designed to convert a 7T R2* map into a 3T R2′ map. Building on this development, we present a new pipeline for χ-separation at 7T, enabling us to generate high-resolution χ-separation maps from multi-echo gradient-echo data. The proposed method is compared with alternative pipelines, such as an end-to-end network and linearly-scaled R2′, and is validated against χ-separation maps at 3T, demonstrating its accuracy. The 7T χ-separation maps generated by the proposed method exhibit similar contrasts to those from 3T, while 7T high-resolution maps offer enhanced clarity and detail. Quantitative analysis confirms that the proposed method surpasses the alternative pipelines. The proposed method results well delineate the detailed brain structures associated with iron and myelin. This new pipeline holds promise for analyzing iron and myelin concentration changes in various neurodegenerative diseases through precise structural examination.

Rationale & Objective: Equations for estimated glomerular filtration rate (eGFR) have previously included a coefficient for African American race. We evaluated and compared risk of incident stroke and dementia between old and new equations of eGFR for African American and non-African American participants. Study Design: Prospective observational study. Setting & Participants: Baseline values were collected from 6,814 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort between 2000 and 2002. Participants were followed up until 2018. The analytic sample consisted of 6,646 participants (mean [SD] age 62 [10] years; 53% female; 39% White, 27% African American, 12% Chinese American, and 22% Hispanic/Latino). Exposure: eGFR equation from 2021 based on serum creatinine and cystatin C levels without race. Outcome: Incident stroke and dementia. Analytical Approach: Cox proportional regression adjusting for demographic, lifestyle, and clinical variables was performed to estimate associations between different eGFR measures and risk of incident stroke and dementia. Results: During a median follow-up period of 17 years, 349 (5.3%) participants experienced an incident stroke event, and 574 (8.6%) participants experienced incident dementia. In the fully adjusted model, overall participants with eGFR 90 mL/min/1.73 m2 were at significantly increased risk of dementia (HR, 95% CI: 1.73, 1.21-2.45). A lower eGFR was not significantly associated with incident stroke (1.30, 0.75-2.24). African American participants tended to be reclassified to a lower group of eGFR in the new equations, whereas non-African American participants were reclassified to a higher group of eGFR. When comparing older versus newer equations of eGFR in African American and non-African American participants in association with incident stroke and dementia, differences were minimal. Limitations: Incident dementia was ascertained through International Classification of Diseases (Ninth and Tenth Revisions) codes. Conclusions: Our findings illustrate participants with 2021 eGFR 90 mL/min/1.73 m2 have higher risk of dementia in both African American and non-African American participants, but not of stroke. Plain Language Summary: Existing research has established that declined kidney function is associated with stroke and dementia. Kidney function is commonly estimated using inputs of blood proteins alongside demographic inputs of age, sex at birth, and race. Inclusion of race to estimate kidney function has gained increased scrutiny given its problematic nature of being a societal construct rather than an inherent biological trait that affects function of the kidneys. Recommendations were recently made to remove race from this estimation, and data were lacking on the relationship between new estimates of kidney function with outcomes such as stroke and dementia. Our research provides updated risk estimates for stroke and dementia using the new estimation for kidney function in a large multiethnic cohort.

Aquaculture has traditionally focused on supporting human food production, but there is a growing need for aquaculture associated with environmental restoration. For example, the in situ and ex situ rearing of corals for coral reef restoration is now implemented worldwide, but its success is limited by the lack of reef herbivores to combat the phase shift from coral-to-macroalgae-dominance on reefs, especially in the Caribbean. Laboratory-based aquaculture of some reef herbivores is possible but labor-intensive and insufficient to supply the numbers needed for large-scale restoration. We examined whether this bottleneck could be alleviated by the semi-wild mariculture of the Caribbean King Crab (MaguiMithrax spinosissimus)in saltwater quarries for subsequent use in coral reef restoration in the Florida Keys, Florida (USA).We surveyed the physico-chemical characteristics of 16 saltwater quarries in the Florida Keys relative to conditions in the wild and, in four quarries where crabs occurred, we examined crab population dynamics in comparison to that in the wild. Water chemistry and the availability of food (macroalgae) and crevice shelters were suitable for crab mariculture down to depths of at least 6 m. Herbivore competitors and predators were few in quarries, and there was no difference in the population size structure, fecundity, predatory mortality, or health of crabs in quarries compared to that in the wild. Therefore, the low-cost semi-wild mariculture of large numbers M. spinosissimus is feasible in saltwater quarries and could alleviate a logistical bottleneck to herbivore restoration on Caribbean coral reefs.

The ability to cope with stress is imperative for performance in competitive gaming, yet there is a lack of research examining the impact of gaming and esports participation on physiological stress. One way to measure physiological stress is via heart rate variability (HRV). The current literature examining HRV during competitive gaming is limited, with most studies focusing on multiplayer online battle arena games. To better understand the physiological demands of gaming, investigation into the stress imposed on players during gameplay of various game genres is required. In this study, we compared the physiological stress incurred on players who played either a competitive (sports) or a non-competitive (action-adventure) video game. Forty participants played either a sports or action-adventure game, whilst having their heart rate and heart rate variability monitored. Results showed that, compared to a pre-gaming baseline, playing either game increased heart rate, lowered RR intervals, and reduced both vagally mediated time and frequency domain vmHRV. Playing the sport game for 10 min induced higher heart rate and lower RR intervals compared to playing the action-adventure game. However, 10 min of game play was not enough to identify meaningful differences in vmHRV based on game genre played. These findings advance our understanding of the impact of video gaming on heart rate and heart rate variability, providing a useful method for coaches and players to index player stress and recovery.

Abstract Serpentinization, a consequence of water‐rock interaction in mafic and ultramafic rocks, refers to the hydrothermal alteration of olivine and pyroxene with serpentine as the typical product. Magnetite is produced in variable amounts during this serpentinization process. Here, we conducted a systematic rock magnetic study on the serpentinite of Ocean Drilling Program (ODP) Hole 1070A from the Iberia Abyssal Plain. From bottom to top, three units are distinguished rock‐magnetically: (a) serpentinized peridotite dominated by single‐domain (SD) ± multidomain (MD) magnetite particles; (b) gabbro with SD ± vortex state magnetite; (c) breccia dominated by MD ± vortex and SD ± vortex state maghemite/hematite and magnetite. Samples of the three units are highly serpentinized with serpentinization degrees >60%. The magnetite content increases exponentially with the degree of serpentinization. Two phases of serpentinization are proposed: (a) massive serpentinization that occurred before mantle exhumation and (b) maghemitization‐serpentinization that occurred near or at the seafloor after the final exhumation of mantle peridotites. The latter reduces the magnetization of the breccia unit significantly. Serpentinized peridotite associated with strong magnetization is the dominant contributor to the marine magnetic anomalies in ocean to continent transition areas.

Studying lists of associatively related words often produces false recognition of non-studied critical lures (CL). This false memory illusion can be found both when word lists are directly related to a CL as in the DRM paradigm (e.g., water, bridge, run, for the CL river), and when words are indirectly related to CLs via non-presented mediators (e.g., faucet[water], London[bridge], jog[run], for the CL river). Mediated false memory is strong evidence for activation-monitoring processes over gist extraction as mediated lists lack a consistent gist theme. In the present study, we evaluated whether context details (font color) of studied lists are attributed to CLs when they are falsely recognized. Participants studied directly related and mediated word lists presented in one of two font colors, followed by a source test which required specification of the font color for recognized test items. When CLs were falsely recognized, participants were able to correctly identify the font color of the CL’s origin list for both list types at a higher rate than incorrect identification. Because mediated false recognition reflects implicit activation, this pattern indicates activation processes may include both semantic and perceptual source details.

ABSTRACT Group A Streptococcus (GAS) is a human-adapted pathogen responsible for a variety of diseases. The GAS M1UK lineage has contributed significantly to the recently reported increases in scarlet fever and invasive infections. However, the basis for its evolutionary success is not yet fully understood. During the transition to systemic disease, the M1 serotype is known to give rise to spontaneous mutations in the control of virulence two-component regulatory system (CovRS) that confer a fitness advantage during invasive infections. Mutations that inactivate CovS function result in the de-repression of key GAS virulence factors such as streptolysin O (SLO), a pore-forming toxin and major trigger of inflammasome/interleukin-1β-dependent inflammation. Conversely, expression of the streptococcal cysteine protease SpeB, which is required during initial stages of colonization and onset of invasive disease, is typically lost in such mutants. In this study, we identified and characterized a novel covS single nucleotide polymorphism detected in three separate invasive M1UK isolates. The resulting CovSAla318Val mutation caused a significant upregulation of SLO resulting in increased inflammasome activation in human THP-1 macrophages, indicating an enhanced inflammatory potential. Surprisingly, SpeB production was unaffected. Site-directed mutagenesis was performed to assess the impact of this mutation on virulence and global gene expression. We found that the CovSAla318Val mutation led to subtle, virulence-specific changes of the CovRS regulon compared to previously characterized covS mutations, highlighting an unappreciated level of complexity in CovRS-dependent gene regulation. Continued longitudinal surveillance is warranted to determine whether this novel covS mutation will expand in the M1UK lineage.IMPORTANCEThe M1UK lineage of GAS has contributed to a recent global upsurge in scarlet fever and invasive infections. Understanding how GAS can become more virulent is critical for infection control and identifying new treatment approaches. The two-component CovRS system, comprising the sensor kinase CovS and transcription factor CovR, is a central regulator of GAS virulence genes. In the M1 serotype, covRS mutations are associated with an invasive phenotype. Such mutations have not been fully characterized in the M1UK lineage. This study identified a novel covS mutation in invasive Australian M1UK isolates that resulted in a more nuanced virulence gene regulation compared to previously characterized covS mutations. A representative isolate displayed upregulated SLO production and triggered amplified interleukin-1β secretion in infected human macrophages, indicating an enhanced inflammatory potential. These findings underscore the need for comprehensive analyses of covRS mutants to fully elucidate their contribution to M1UK virulence and persistence.