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Neurodegenerative diseases are a group of disorders characterised by neuronal cell death causing a variety of physical and mental problems. While these disorders can be characterised by their phenotypic presentation within the nervous system, their aetiologies differ to varying degrees. Some disorders, such as Lewy body dementia and Parkinson’s disease, show overlap in the major proteins found in aggregates, and some diseases, like Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease, are influenced by the same non-neuronal cell types (microglia), suggesting partly shared aetiologies. The identification of shared genetic risk factors common to many neurodegenerative diseases may highlight fundamental biological processes involved in neurodegeneration and provide promising targets for treatment and drug repurposing. The majority of genetic evidence for overlap between neurodegenerative diseases has been pairwise, with little genetic evidence for genes or biological processes found across more than two neurodegenerative diseases. In this study, we aimed to identify overlap between the four investigated neurodegenerative disorders (Alzheimer’s disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson’s disease) at the variant, gene, genomic locus, gene-set, cell, or tissue level, with specific interest in overlap between three or more diseases. Using local genetic correlation, we found that the TMEM175 locus was a shared locus between amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson’s disease, and the HLA region was shared between Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease. We also highlighted genes, genomic loci, gene-sets, cell types, and tissue types which may be important to two or more disorders by analysing the association of variants with a common factor estimated from the four disorders. Our study successfully highlighted genetic loci and tissues associated with two or more neurodegenerative diseases.

Purpose: More than 7% of the U.S. population identifies as LGBTQ+ (lesbian, gay, bisexual, transgender, queer, and other identities), meaning clinical audiologists in all settings are likely to encounter LGBTQ+ patients seeking audiological services. This conceptual clinical focus article (a) introduces contemporary LGBTQ+ terms, definitions, and pertinent issues; (b) summarizes the current state of knowledge on barriers to equitable hearing health care access and utilization for people who identify as LGBTQ+; (c) explores the legal, ethical, and moral obligations for audiologists to provide equitable care to people who identify as LGBTQ+; and (d) provides resources to continue to learn about salient LGBTQ+ issues. Conclusions: This clinical focus article provides actionable guidance to clinical audiologists on providing inclusive equitable care to LGBTQ+ patients. Practical actionable guidance on how clinical audiologists can make their clinical practice more inclusive for their patients who identify as LGBTQ+ is provided.

BACKGROUND: Sustainable employability is increasingly important with current socio-economic challenges. Screening for resilience could contribute to early detection of either a risk, or a protector for sustainable employability, the latter being operationalized as workability and vitality. OBJECTIVE: To study the predictive value of Heart Rate Variability (HRV) measurements and the Brief Resilience Scale (BRS) for worker self-reported workability and vitality after 2–4 years. METHODS: Prospective observational cohort study with mean follow-up period of 38 months. 1,624 workers (18–65 years old) in moderate and large companies participated. Resilience was measured by HRV (one-minute paced deep breathing protocol) and the BRS at baseline. Workability Index (WAI), and the Vitality dimension of the Utrecht Work Engagement Scale-9 (UWES-9-vitality) were the outcome measures. Backward stepwise multiple regression analysis (p

OBJECTIVE Return-to-learn (RTL) after sport-related concussion (SRC) is an important yet understudied topic. The authors sought to do the following: 1) describe patterns of RTL among athletes by school level (i.e., middle school, high school, college); and 2) evaluate the predictive value of school level on RTL duration. METHODS A retrospective, single-institution cohort study of adolescent and young adult athletes 12–23 years old who sustained an SRC between November 2017 and April 2022 and who presented to a multidisciplinary specialty concussion clinic was conducted. The independent variable was school level, trichotomized into middle school, high school, and college. Time to RTL was the primary outcome and was defined as days from SRC to return to any academic activities. ANOVA was used to compare RTL duration across school levels. A multivariable linear regression was performed to evaluate for predictive value of school level on RTL duration. Covariates included the following: sex, race/ethnicity, learning disorder, psychiatric conditions, migraines, family history of psychiatric conditions/migraines, initial Post-Concussion Symptom Scale score, and number of prior concussions. RESULTS Of 1007 total athletes, 116 (11.5%) were in middle school, 835 (83.0%) were in high school, and 56 (5.6%) were in college. The mean RTL times (in days) were as follows: 8.0 ± 13.1 (middle school), 8.5 ± 13.7 (high school), and 15.6 ± 22.3 (college). One-way ANOVA showed a statistically significant difference between groups (F[2, 1007] = 6.93, p = 0.001). A Tukey post hoc test revealed a longer RTL duration in collegiate athletes when compared to middle school (p = 0.003) and high school (p < 0.001) athletes. Collegiate athletes had longer RTL duration compared to other school levels (β = 0.14, p < 0.001). There was no difference between middle school and high school athletes (p = 0.935). The subanalysis revealed a longer RTL duration in high school freshmen/sophomores (9.5 ± 14.9 days) when compared to juniors/seniors (7.6 ± 12.6 days; t = 2.05, p = 0.041), and being an older (junior/senior) high school athlete was predictive of shorter RTL duration (β = −0.11, p = 0.011). CONCLUSIONS When examining patients who presented to a multidisciplinary sport concussion center, RTL duration was longer in collegiate athletes when compared to middle and high school athletes. Younger high school athletes had longer time to RTL compared to their older counterparts. This study provides insight into how varying scholastic environments may contribute to RTL.

OBJECTIVE Accurately predicting early (≤ 14 days) versus typical (15–27 days) or delayed (≥ 28 days) recovery from sport-related concussion (SRC) may allow for improved resource utilization and precision in planning and carrying out rehabilitation. In this study, the authors sought to develop an algorithm that enables accurate differentiation of recovery periods and duration after SRC. The authors hypothesized that data regarding initial symptom burden as quantified by a Post-Concussion Symptom Scale (PCSS) score, time to presentation, and number of prior concussions would be the most useful for analyzing predictive factors for concussion recovery duration. METHODS A retrospective case-control study was conducted to assess the primary outcome of days to clinical recovery following SRC in pediatric patients. Data from patients 12–18 years old presenting within 28 days of injury to an SRC clinic between November 11, 2017, and October 10, 2020, were analyzed. Patients with positive evidence of injury on head imaging or incomplete records were excluded. The primary outcome was duration of clinical recovery, grouped as early (≤ 14 days), typical (15–27 days), or delayed (≥ 28 days). Recovery was defined as follows: 1) symptom resolution or return to baseline, or 2) initiation of graduated return to play. CHAID (chi-square automatic interaction detection) analysis was used to optimize a decision tree based on 16 input factors, including age, sex, initial PCSS score, time to clinic presentation, number of prior concussions, and presence of defined symptom clusters. The cohort was randomized into training (70%) and test (30%) samples for algorithm validation. RESULTS A total of 493 patients met the inclusion criteria (mean age 15.7 ± 1.5 years, 68.2% male, 70.0% White). The median time to presentation was 5 days (IQR 2–10 days). Most patients (52.3%) recovered within 14 days of injury, 21.5% recovered within 15–27 days, and 26.2% had a recovery period of 28 days or longer. The variables most predictive of recovery were initial PCSS score (cutoffs ≤ 6, 7–28, or ≥ 29), time to presentation (≤ 7 vs > 7 days), or prior concussions (0 vs ≥ 1). The model accurately discriminated between early versus typical or delayed recovery duration groupings (area under the curve 0.80, Youden index 0.44), and correctly classified > 90% of patients who recovered early. CONCLUSIONS This novel three-factor predictive tool enabled accurate discrimination of early versus typical or delayed SRC recovery to better allocate resources, counsel patients, and make timely referrals.

The Brazilian coast is recognised as a Southern Hemisphere humpback whale (Megaptera novaeangliae) wintering ground (IWC breeding stock ‘A’). The northeastern coast of Brazil was an important whaling ground in the 20th century. Shipboard sighting surveys were conducted in this area to evaluate large whales’ distribution and density in 1999 and 2000. Humpback whale sightings (n = 81, 153 individuals) were recorded using line transect methodology. Data from the 2000 survey were used to estimate abundance over the continental shelf from 5 to 12°S (20,040km2 ). A total of 872.1km were surveyed on effort. Humpback whales were distributed from nearshore to the 800m isobath, but 93.5% of sightings were recorded shoreward of the 300m isobath. The relatively high density off northeastern Brazil suggests that the species is reoccupying historical areas of distribution and the presence of newborn individuals indicates that calving and nursing occur in the area. The hazard rate model best fit perpendicular distance data. Abundance was estimated at 628 individuals (CV = 0.335, 95% CI = 327-1,157). This estimate probably corresponds to only a portion of the breeding population. Therefore, additional studies must be conducted to estimate the total size of the humpback whale population wintering off Brazil.

Cetaceans are sensitive to a variety of anthropogenic sounds because they normally use sound to navigate, communicate and capture prey. This paper reviews some fisheries that have taken advantage of this sensitivity by using sound to help capture numerous species of dolphins and whales. Fishermen in many parts of the world have independently developed methods that use sounds to drive (herd) various species of small cetaceans so that they can be killed and used for food, culled (i.e. to offset competition for fish), help capture fish (e.g. in the Eastern Tropical Pacific) or be taken into captivity. It is well documented that drive fisheries for small cetaceans have occurred for at least 650 years in Japan and Europe. With respect to large whales, the use of sound became widespread after World War II, with the advent of an early form of sonar (ASDIC) which was used for hunting both baleen and sperm whales. Baleen whales displayed a strong avoidance reaction to ASDIC by swimming rapidly away from the sound while remaining near the surface of the water. In contrast, sperm whales made longer dives in response to ASDIC. During the 20th Century, fishermen using these two acoustical methods killed millions of cetaceans (including those caught in the Eastern Tropical Pacific tuna fisheries), both small and large. The effectiveness of acoustic capture methods shows that a wide range of cetacean species have strong avoidance reactions to a variety of anthropogenic sounds. Research to better document the characteristics of these sounds, including those used in existing drive fisheries and those produced by ASDIC devices, would improve understanding of the types of anthropogenic sounds that could contribute to mass-stranding events and should be minimised in protected habitats for cetaceans.

Proxy phenotypes allow for the utilization of genetic data from large population cohorts to analyze late-onset diseases by using parental diagnoses as a proxy for genetic disease risk. Proxy phenotypes based on parental diagnosis status have been used in previous studies to identify common variants associated with Alzheimer’s disease. As of yet, proxy phenotypes have not been used to identify genes associated with Alzheimer’s disease through rare variants. Here we show that a proxy Alzheimer’s disease/dementia phenotype can capture known Alzheimer’s disease risk genes through rare variant aggregation. We generated a proxy Alzheimer’s disease/dementia phenotype for 148,508 unrelated individuals of European ancestry in the UK biobank in order to perform exome-wide rare variant aggregation analyses to identify genes associated with proxy Alzheimer’s disease/dementia. We identified four genes significantly associated with the proxy phenotype, three of which were significantly associated with proxy Alzheimer’s disease/dementia in an independent replication cohort consisting of 197,506 unrelated individuals of European ancestry in the UK biobank. All three of the replicated genes have been previously associated with clinically diagnosed Alzheimer’s disease (SORL1, TREM2, and TOMM40/APOE). We show that proxy Alzheimer’s disease/dementia can be used to identify genes associated with Alzheimer’s disease through rare variant aggregation.

OBJECTIVE This study sought to characterize resting-state functional MRI (fMRI) connectivity patterns of the posterior hypothalamus (pHTH) and the nucleus basalis of Meynert (NBM) in surgical patients with mesial temporal lobe epilepsy (mTLE), and to investigate potential correlations between functional connectivity of these arousal regions and neurocognitive performance. METHODS The study evaluated resting-state fMRI in 60 patients with preoperative mTLE and in 95 healthy controls. The authors first conducted voxel-wise connectivity analyses seeded from the pHTH, combined anterior and tuberal hypothalamus (atHTH; i.e., the rest of the hypothalamus), and the NBM ipsilateral (ipsiNBM) and contralateral (contraNBM) to the epileptogenic zone. Based on these results, the authors included the pHTH, ipsiNBM, and frontoparietal neocortex in a network-based statistic (NBS) analysis to elucidate a network that best distinguishes patients from controls. The connections involving the pHTH and ipsiNBM from this network were included in age-corrected pairwise region of interest (ROI) analysis, along with connections between arousal structures, including the pHTH, ipsiNBM, and brainstem arousal regions. Finally, patient functional connectivity was correlated with clinical neurocognitive testing scores for IQ as well as attention and concentration tests. RESULTS The voxel-wise analysis demonstrated that the pHTH, when compared with the atHTH, showed more widespread functional connectivity decreases in surgical mTLE patients when compared with controls. It was also observed that the ipsiNBM, but not the contraNBM, showed decreased functional connectivity in mTLE. The NBS analysis uncovered a perturbed network of frontoparietal regions, the pHTH, and ipsiNBM that distinguishes patients from controls. Age-corrected ROI analysis revealed functional connectivity decreases between the pHTH and bilateral superior frontal gyri, medial orbitofrontal cortices, rostral anterior cingulate cortices, and inferior parietal cortices in mTLE when compared with controls. For the ipsiNBM, there was reduced connectivity with bilateral medial orbitofrontal and rostral anterior cingulate cortices. Age-corrected ROI analysis also demonstrated upstream connectivity decreases from controls between the pHTH and the brainstem arousal regions, cuneiform/subcuneiform (CSC) nuclei, and ventral tegmental area, as well as the ipsiNBM and CSC nuclei. Reduced functional connectivity was also detected between the pHTH and ipsiNBM. Lastly, neurocognitive test scores for attention and concentration were found to be positively correlated with the functional connectivity between the pHTH and ipsiNBM, suggesting worse performance associated with connectivity perturbations. CONCLUSIONS This study demonstrated perturbed resting-state functional connectivity of arousal regions in surgical mTLE and is one of the first investigations to demonstrate decreased functional connectivity of the pHTH with frontoparietal regions and other arousal regions. Connectivity disturbances in arousal regions may contribute to neurocognitive deficits in surgical mTLE patients.

Background In the US, many patients forgo recommended care due to cost. The ANA Code of Ethics requires nurses to give care based on need. Therefore, US nurses are compelled to practice in a context which breaches their professional ethical code. Research Objectives This study sought to determine if nurses do care for patients who forgo treatment due to cost (PFTDC) and if so, does this result in an experience of moral distress (MD). Research Design Semi-structured interviews were transcribed and analyzed using a qualitative content analysis. Participants and Research Context A convenience sample of 20 nurses in practice for at least one year from a variety of health care setting participated. Ethical Considerations This project was approved by the Michigan State University Biomedical Institutional Review Board. Results There were 19 female and one male nurse-participants, averaging 47 years old with an average of 10 years in practice. 18 reported caring for PFTDC. These 17 nurse-participants experienced a moderate degree of MD as a result, averaging 5.4 of 10 on the Moral Distress Thermometer. In the interviews, the following themes were identified, strategies to help PFTDC, and the broken US health care system which had the subthemes of preference for business over patient-oriented benefit, PFTDC using the emergency department, and limited support for treatment/management of PFTDC. Conclusions The existence of this phenomenon places the profession of nursing in the US in a position of moral compromise and threatens to corrupt the institution of nursing in the US.

To determine the effect of a twice daily administration of SBD111 on safety and tolerability in healthy adults in a randomized, placebo-controlled trial over 28-days. Participants were randomized to either SBD111 (n=15) or placebo (n=17). The outcomes were the number, frequency, and severity of Gastrointestinal (GI) symptoms and the number and severity of adverse events (AEs) over 28-days. Stool samples were collected and analyzed at baseline, after 28- and 56-days. Groups were compared (P< 0.05) using an intention-to-treat approach. The two groups were similar at baseline. After 28-days, the presence of GI symptoms tended to be higher with SBD111 use vs placebo (P=0.08) but the total number, frequency/severity of GI symptoms did not significantly differ. The number of AEs possibly related to the study were higher with SBD111 use vs placebo (P=0.05), there were no significant differences in the mean number/severity of AEs. The majority of reported AEs were mild, some were moderate, but none were severe. There were no significant differences in alpha diversity indices between the two groups at baseline or follow-up. SBD111 strains were identified in stool, enriched metabolic pathways for menaquinone (vitamin K2) production at 28-days, and were not detected at 56-days. The relatively low frequency and mild severity of GI symptoms and AEs suggests that SBD111 at the level tested is safe for human consumption.

Human access to surface water resources in the Northern Great Plains (NGP) is challenged by availability and quality, and ecosystem health objectives for these characteristics have not been well developed. Here, we present a predictive multivariate model using the reference condition approach to inform goals for ecosystem health assessment. Benthic communities and abiotic variables were collected at 280 potential reference sites and 8 test sites, and of these, reference sites with least amount of human activity (n = 83) were classified into three community groups and summary metrics. Discriminant function analysis and cross-validation determined that stream order and ecoregion predicted 68.7% of the sites correctly, thus enabling comparison of sites with unknown condition to reference site groups. We then evaluated metrics through Test Site Analysis and stressor gradient analysis in each biological group. Beetle and amphipod fauna were found to be important for condition assessment in addition to traditional metrics of species richness, abundance, detritivory, Ephemeroptera/Plecoptera/Trichoptera dominance, and assemblage composition. These results provide least disturbed reference condition and ecological insights into land use impacts in the NGP. Ultimately, this model is an effective tool for evaluating biotic condition, enables prioritizing river management strategies, and can quantify the efficacy of mitigation measures.

We present a new python package sarabande for measuring 3- and 4-point correlation functions (3/4 PCFs) in $\mathcal {O} (N_{\mathrm{g}}\log N_{\mathrm{g}})$ time using fast Fourier transforms (FFTs), with Ng being the number of grid points used for the FFT. sarabande can measure both projected and full 3-point correlation function and 4-point correlation function on gridded two- and three-dimensional data sets. The general technique is to generate suitable angular basis functions on an underlying grid, radially bin these to create kernels, and convolve these kernels with the original gridded data to obtain expansion coefficients about every point simultaneously. These coefficients are then combined to give us the 3/4 PCF as expanded in our basis. We apply sarabande to simulations of the interstellar medium to show the results and scaling of calculating both the full and projected 3/4 PCFs.

Context Visceral adipose tissue (VAT) has been recognized to be a metabolically active fat depot that may have paracrine effects on surrounding tissues, including muscle. Since many adults accumulate VAT as they age, the effect of changes in VAT on muscle is of interest. Objective We determined the association between 6-year changes in VAT and paraspinal muscle density, an indicator of fatty infiltration. Methods This study included 1145 participants from the Framingham Study third-generation cohort who had both quantitative computed tomography scans of the spine at baseline and 6-year's follow-up, on whom muscle density was measured along with VAT. We implemented multiple regression to determine the association of muscle density at follow-up as primary outcome measure with changes in VAT (follow-up minus baseline divided by 100), adjusting for VAT at baseline, age, sex, height, menopausal status, presence of diabetes, and physical activity. Analyses were performed in men and women separately. Results After adjustment for covariates, individuals with the greatest accumulation of VAT over 6 years had significantly lower paraspinal density at the follow-up with an estimated 0.302 (95% CI, −0.380 to −0.224) and 0.476 (95% CI: −0.598 to −0.354) lower muscle density (HU) per 100-cm3 increase in VAT (both P values < .001) in men and women, respectively. Conclusion These results highlight that age-related accumulation of VAT in men and women is associated with lower muscle density. VAT may represent a modifiable risk factor for poor musculoskeletal outcomes with aging.

To study COVID-19 (Delta Variant) cases and close contacts co-located within households. Focusing on epidemiology of transmission of COVID-19, quarantine duration and utilisation of infection control behaviours under a telehealth model of care in an elimination setting.A retrospective cohort analysis examined household spread of infection, duration of quarantine and change in PCR CT value during illness. A survey explored infection control behaviours used by household members during isolation and quarantine.The cohort was 141 individuals in 35 households. Thirty-seven were index cases, and 48 became positive during quarantine, most within 10 days. Whole-household infection occurred in 12 households with multiple members. Behaviours focused on fomite transmission reduction rather than preventing aerosol transmission. The median duration of close contact household quarantine was 25 days. The majority of COVID-19 cases were de-isolated after 14 days with no evidence of further community transmission.Intrahousehold transmission was not universal and, if it occurred, usually occurred quickly. Behaviours utilised focused on fomites, suggesting a need for improved education regarding the potential utilisation of strategies to prevention the transmission of aerosols. Households experienced long durations of home-based quarantine.The impact of long quarantine durations must be considered, particularly where most community benefit from quarantine is achieved within 10 days from exposure in the setting of the Delta Variant. Education of households regarding aerosol risk reduction is a potential strategy in the household setting of individuals at risk of disease progression.

Within species, bird parents defend their nests with different levels of intensity. Previous studies have examined several hypotheses for this variation by looking at factors such as morphological characteristics of the parents and the characteristics of the brood, but few have controlled for multiple factors simultaneously. Here we examined a broad range of factors that may influence the nest defense behaviour of Mountain Bluebirds ( Sialia currucoides (Bechstein, 1798)), including the adult's morphology (sex, age, plumage colour, body size, and body condition) and characteristics of their brood (size, hatch date, and stage of nestling development). Parental aggression was triggered using a taxidermy mount of an American red squirrel ( Tamiasciurus hudsonicus (Erxleben, 1777)). We found no relationship between nest defense and any morphological characteristic of adults, but the intensity of nest defense was positively correlated with the stage of offspring development, clutch size, and hatch date consistent with parental investment theory. Males also defended nests more strongly than females, consistent with the premise of the renesting hypothesis that males have fewer future opportunities to breed and, therefore, are more invested in the current brood. Our results provide strong support for parental investment theory and renesting as the primary drivers of nest defense intensity in breeding birds.

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume. This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Programme, Neurodegenerative Disease Research (JPND). Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). Part of the work described in this study was carried out in the context of the Parelsnoer Institute (PSI). PSI was part of and funded by the Dutch Federation of University Medical Centers and has received initial funding from the Dutch Government (from 2007-2011). Since 2020, this work was carried out in the context of Parelsnoer clinical biobanks at Health-RI (https://www.health-ri.nl/initiatives/parelsnoer).Part of the genotyping included in this work was funded by the JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A). Alfredo Ramirez is also supported by the German Research Foundation (DFG) grants Nr: RA 1971/6-1, RA1971/7-1, and RA 1971/8-1. We would like to thank patients and controls who participated in this project. The Genome Research @ Fundacio ACE project (GR@ACE) is supported by Grifols SA, Fundacion bancaria 'La Caixa', Fundacio ACE, and CIBERNED. A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240 and PI19/01301. Accion Estrategica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de hacer Europa'). The position held by I.dR. is funded by grant. FI20/00215. PFIS Contratos Predoctorales de Formacion en Investigacion en Salud. We would like to thank UCL Genomics, London, UK, for performing the genotyping analyses of the samples within the Gothenburg H70 Birth Cohort Studies and Clinical AD Sweden. The recruitment and clinical characterization of research participants at Washington University were supported by NIH P30AG066444, and P01AG003991. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, the Neurogenomics and Informatics Center (NGI: https://neurogenom ics.wustl.edu/)and the Departments of Neurology and Psychiatry at Washington University School of Medicine. Research at the Belgian EADB site is funded in part by the Alzheimer Research Foundation (SAO-FRA), The Research Foundation Flanders (FWO), and the University of Antwerp Research Fund. FK is supported by a BOF DOCPRO fellowship of the University of Antwerp Research Fund. The work of Valdecilla was supported by grants from the Instituto de Salud Carlos III (Fondo de Investigacion Sanitario, PI08/0139, PI12/02288, PI16/01652, and PI20/01011), the JPND (DEMTEST PI11/03028), the CIBERNED, and the Siemens Healthineers. We thank the Valdecilla Biobank (PT17/0015/0019), integrated into the Spanish Biobank Network, for their support and collaboration in sample collection and management. Our heartfelt thanks to the participants of the Valdecilla Cohort for their generosity. The work of ADGEN was supported by EU Joint Programme-Neurodegenerative Disease Research (301220) and the Academy of Finland (338182). The DELCODE study (Study-ID:BN012) was supported and conducted by the German Center for Neurodegenerative Diseases (DZNE). The data samples were provided by the DELCODE study group. Details and participating sites can be found at www.dzne.de/en/research/studies/clinical-studies/delco de. The German Dementia Competence Network (KND) is funded by the German Federal Ministry of Education and Research (BMBF) grants Number: 01G10102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 04GI0434, 01GI0711. WF, SvdL, HHolstege, CT and PhS are recipients of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and HealthHolland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). More than 30 partners participate in ABOARD (www.aboard-project.nl).ABOARD also receives funding from de Hersenstichting, Edwin Bouw Fonds and Gieskes-Strijbisfonds. IEJ was partially supported by NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012). AZ was supported by the Swedish Alzheimer Foundation (AF-939988, AF-930582, AF-646061, AF-741361), and the Dementia Foundation (2020-04-13, 2021-0417). ISk was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALFagreement (ALF 716681), the Swedish Research Council (no 11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2019-01096), Swedish Research Council for Health, Working Life and Welfare (no 2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 20050762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 20132496), Swedish Brain Power, Hjarnfonden, Sweden (FO2016-0214, FO2018-0214, FO2019-0163), the Alzheimer's Association Zenith Award (ZEN-01-3151), the Alzheimer's Association Stephanie B. Overstreet Scholars (IIRG-00-2159), the Alzheimer's Association (IIRG-03-6168, IIRG-09-131338) and the Bank of Sweden Tercentenary Foundation. SK was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-81392, ALF GBG-771071), the Swedish Alzheimer Foundation (AF-842471, AF-737641, AF-939825), and the Swedish Research Council (2019-02075). MW was supported by the Swedish Research Council 2016-01590. DP was supported by BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (2018-02532), the European Research Council (681712), Swedish State Support for Clinical Research (ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (2018092016862), the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. KB was supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjarnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institute of Health (NIH), USA, (grant #1R01AG06839801), and the Alzheimer's Association 2021 Zenith Award (ZEN-21848495). CC receives support from the National Institutes of Health (R01AG044546, R01AG064877, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501, R01AG064614), and the Chuck Zuckerberg Initiative (CZI).

Background: Large-scale Parkinson's disease (PD) genome-wide association studies (GWAS) have, until recently, only been conducted on subjects with European-ancestry. Consequently, polygenic risk scores (PRS) constructed using PD GWAS data are likely to be less predictive when applied to non-European cohorts. Methods: Using GWAS data from the largest study to date, we constructed a PD PRS for a Latino PD cohort (1497 subjects from LARGE-PD) and tested it for association with PD status and age at onset. We validated the PRS performance by testing it in an independent Latino cohort (448 subjects) and by repeating the analysis in LARGE-PD with the addition of 440 external Peruvian controls. We also tested SNCA haplotypes for association with PD risk in LARGE-PD and a European-ancestry PD cohort. Results: The GWAS-significant PD PRS had an area under the receiver-operator curve (AUC) of 0.668 (95% CI: 0.640–0.695) in LARGE-PD. The inclusion of external Peruvian controls mitigated this result, dropping the AUC 0.632 (95% CI: 0.607–0.657). At the SNCA locus, haplotypes differ by ancestry. Ancestry-specific SNCA haplotypes were associated with PD status in both LARGE-PD and the European-ancestry cohort (p-value < 0.05). These haplotypes both include the rs356182 G-allele, but only share 14% of their variants overall. Conclusion: The PD PRS has potential for PD risk prediction in Latinos, but variability caused by admixture patterns and bias in a European-ancestry PD PRS data limits its utility. The inclusion of diverse subjects can help elucidate PD risk loci and improve risk prediction in non-European cohorts.

Background: Neuroinflammation is involved in the pathophysiology of Alzheimer's disease (AD), including immune-linked genetic variants and molecular pathways, microglia and astrocytes. Multiple Sclerosis (MS) is a chronic, immune-mediated disease with genetic and environmental risk factors and neuropathological features. There are clinical and pathobiological similarities between AD and MS. Here, we investigated shared genetic susceptibility between AD and MS to identify putative pathological mechanisms shared between neurodegeneration and the immune system. Methods: We analysed GWAS data for late-onset AD (N cases = 64,549, N controls = 634,442) and MS (N cases = 14,802, N controls = 26,703). Gaussian causal mixture modelling (MiXeR) was applied to characterise the genetic architecture and overlap between AD and MS. Local genetic correlation was investigated with Local Analysis of [co]Variant Association (LAVA). The conjunctional false discovery rate (conjFDR) framework was used to identify the specific shared genetic loci, for which functional annotation was conducted with FUMA and Open Targets. Results: MiXeR analysis showed comparable polygenicities for AD and MS (approximately 1800 trait-influencing variants) and genetic overlap with 20% of shared trait-influencing variants despite negligible genetic correlation (rg = 0.03), suggesting mixed directions of genetic effects across shared variants. conjFDR analysis identified 16 shared genetic loci, with 8 having concordant direction of effects in AD and MS. Annotated genes in shared loci were enriched in molecular signalling pathways involved in inflammation and the structural organisation of neurons. Conclusions: Despite low global genetic correlation, the current results provide evidence for polygenic overlap between AD and MS. The shared loci between AD and MS were enriched in pathways involved in inflammation and neurodegeneration, highlighting new opportunities for future investigation.

African swine fever (ASF) is a highly contagious disease that affects wild and domestic swine. Currently, the disease is present as a pandemic affecting pork production in Eurasia and the Caribbean region. The etiological agent of ASF is a large, highly complex structural virus (ASFV) harboring a double-stranded genome encoding for more than 160 proteins whose functions, in most cases, have not been experimentally characterized. We show here that deletion of the ASFV gene H240R from the genome of the highly virulent ASFV-Georgia2010 (ASFV-G) isolate partially decreases virus virulence when experimentally inoculated in domestic swine. ASFV-G-∆H240R, a recombinant virus harboring the deletion of the H240R gene, was produced to evaluate the function of the gene in the development of disease in pigs. While all animals intramuscularly inoculated with 102 HAD50 of ASFV-G developed a fatal form of the disease, forty percent of pigs receiving a similar dose of ASFV-G-∆H240R survived the infection, remaining healthy during the 28-day observational period, and the remaining sixty percent developed a protracted but fatal form of the disease compared to that induced by ASFV-G. Additionally, all animals inoculated with ASFV-G-∆H240R presented protracted viremias with reduced virus titers when compared with those found in animals inoculated with ASFV-G. Animals surviving infection with ASFV-G-∆H240R developed a strong virus-specific antibody response and were protected against the challenge of the virulent parental ASFV-G.

The emergence of advanced Natural Language Processing (NLP) models like ChatGPT has raised concerns among universities regarding AI-driven exam completion. This paper provides a comprehensive evaluation of the proficiency of GPT-4 and GPT-3.5 in answering a set of 42 exam papers derived from 10 distinct physics courses, administered at Durham University over the span of 2018 to 2022, totalling 593 questions and 2504 available marks. These exams, spanning both undergraduate and postgraduate levels, include traditional pre-COVID and adaptive COVID-era formats. Questions from the years 2018-2020 were designed for pre-COVID in person adjudicated examinations whereas the 2021-2022 exams were set for varying COVID-adapted conditions including open-book conditions. To ensure a fair evaluation of AI performances, the exams completed by AI were assessed by the original exam markers. However, due to staffing constraints, only the aforementioned 593 out of the total 1280 questions were marked. GPT-4 and GPT-3.5 scored an average of 49.4\% and 38.6\%, respectively, suggesting only the weaker students would potential improve their marks if using AI. For exams from the pre-COVID era, the average scores for GPT-4 and GPT-3.5 were 50.8\% and 41.6\%, respectively. However, post-COVID, these dropped to 47.5\% and 33.6\%. Thus contrary to expectations, the change to less fact-based questions in the COVID era did not significantly impact AI performance for the state-of-the-art models such as GPT-4. These findings suggest that while current AI models struggle with university-level Physics questions, an improving trend is observable. The code used for automated AI completion is made publicly available for further research., 9 pages, 6 figures

The complex motility of bacteria, ranging from single-swimmer behaviors such as chemotaxis to collective dynamics, including biofilm formation and active matter phenomena, is driven by their microscale propellers. Despite extensive study of swimming flagellated bacteria, the hydrodynamic properties of their helical-shaped propellers have never been directly measured. The primary challenges to directly studying microscale propellers are 1) their small size and fast, correlated motion, 2) the necessity of controlling fluid flow at the microscale, and 3) isolating the influence of a single propeller from a propeller bundle. To solve the outstanding problem of characterizing the hydrodynamic properties of these propellers, we adopt a dual statistical viewpoint that connects to the hydrodynamics through the fluctuation–dissipation theorem (FDT). We regard the propellers as colloidal particles and characterize their Brownian fluctuations, described by 21 diffusion coefficients for translation, rotation, and correlated translation–rotation in a static fluid. To perform this measurement, we applied recent advances in high-resolution oblique plane microscopy to generate high-speed volumetric movies of fluorophore-labeled, freely diffusing Escherichia coli flagella. Analyzing these movies with a bespoke helical single-particle tracking algorithm, we extracted trajectories, calculated the full set of diffusion coefficients, and inferred the average propulsion matrix using a generalized Einstein relation. Our results provide a direct measurement of a microhelix’s propulsion matrix and validate proposals that the flagella are highly inefficient propellers, with a maximum propulsion efficiency of less than 3%. Our approach opens broad avenues for studying the motility of particles in complex environments where direct hydrodynamic approaches are not feasible.

BACKGROUND: Dietary intake of antioxidants such as vitamins C and E protect against oxidative stress, and may also be associated with altered DNA methylation patterns. METHODS: We meta-analysed epigenome-wide association study (EWAS) results from 11,866 participants across eight population-based cohorts to evaluate the association between self-reported dietary and supplemental intake of vitamins C and E with DNA methylation. EWAS were adjusted for age, sex, BMI, caloric intake, blood cell type proportion, smoking status, alcohol consumption, and technical covariates. Significant results of the meta-analysis were subsequently evaluated in gene set enrichment analysis (GSEA) and expression quantitative trait methylation (eQTM) analysis. RESULTS: In meta-analysis, methylation at 4,656 CpG sites was significantly associated with vitamin C intake at FDR ≤ 0.05. The most significant CpG sites associated with vitamin C (at FDR ≤ 0.01) were enriched for pathways associated with systems development and cell signalling in GSEA, and were associated with downstream expression of genes enriched in the immune response in eQTM analysis. Furthermore, methylation at 160 CpG sites was significantly associated with vitamin E intake at FDR ≤ 0.05, but GSEA and eQTM analysis of the top most significant CpG sites associated with vitamin E did not identify significant enrichment of any biological pathways investigated. CONCLUSIONS: We identified significant associations of many CpG sites with vitamin C and E intake, and our results suggest that vitamin C intake may be associated with systems development and the immune response.

Chromium (Cr) is a redox-sensitive element and because Cr isotopes are fractionated by redox and/or biological processes, the Cr isotopic composition of ancient marine sediments may be used to infer changes in past seawater oxygenation or biological productivity. While there appears to be a ‘global correlation’ between the dissolved Cr concentration and Cr isotopic composition of seawater, there is ongoing debate about the relative importance of external sources and internal cycling on shaping the distribution of dissolved Cr that needs to be resolved to validate the efficacy of using Cr isotopes as a paleo proxy. Here, we present full water column depth profiles of total dissolved Cr (Cr(VI)+Cr(III)) and dissolved Cr isotopes (δ 53Cr), together with ancillary data, for three stations along a transect (GEOTRACES GApr08) across the sub-tropical North Atlantic. Concentrations of dissolved Cr ranged between 1.84 and 2.63 nmol kg -1, and δ 53Cr values varied from 1.06 to 1.42‰. Although atmospheric dust, hydrothermal vents and seabed sediments have the potential to modify the distribution of Cr in the oceans, based on our observations, there is no clear evidence for substantial input of Cr from these sources in our study region although benthic inputs of Cr may be locally important in the vicinity of hydrothermal vents. Subsurface waters (below the surface mixed layer to 700 m water depth) were very slightly depleted in Cr (by up to ~0.4 nmol kg -1), and very slightly enriched in heavy Cr isotopes (by up to ~0.14‰), relative to deeper waters and the lowest Cr concentrations and highest δ 53Cr values coincided with lowest concentrations of colloidal (0.02 to 0.2 μm size fraction) Fe. We found no direct evidence for biological uptake of dissolved Cr in the oligotrophic euphotic zone or removal of Cr in modestly oxygen depleted waters (O 2 concentrations ~130 μmol kg -1). Rather, we suggest removal of Cr (probably in the form of Cr(III)) in subsurface waters is associated with the formation of colloid aggregates of Fe-(oxyhydr)oxides. This process is likely enhanced by the high lithogenic particle load in this region, and represents a previously unrecognized export flux of Cr. Regeneration of Cr in deeper waters leads to subtly increased levels of Cr alongside decreased δ 53Cr values at individual sites, but this trend is more obvious at the global scale, with δ 53Cr values decreasing with increasing radiocarbon age of deep waters, from 1.16 ± 0.10‰ (1SD, n=11) in deep Atlantic waters to 0.77 ± 0.10‰ (1SD, n=25) in deep Pacific waters. Removal of relatively isotopically light Cr from subsurface waters onto particulate material and regeneration of this Cr back into the dissolved phase in deep waters partly accounts for the systematic relationship between δ 53Cr and Cr concentrations in seawater discussed by other studies.

ASFV is responsible for an extensively distributed pandemic causing important economic losses in the pork industry in Eurasia. The development of countermeasures is partially limited by the insufficient knowledge regarding the function of the majority of the more than 150 genes present on the virus genome.

Background Dysfunction in blood vessel dynamics may contribute to changes in muscle measures. Therefore, we examined associations of vascular health measures with grip strength and gait speed in adults from the Framingham Heart Study. Methods The cross-sectional study (1998–2001) included participants with 1 measure of grip strength (kg, dynamometer) or gait speed (4-m walk, m/s) and at least 1 measure of aortic stiffness (carotid–femoral pulse wave velocity, brachial pulse pressure, and brachial flow pulsatility index) or brachial artery structure and function (resting flow velocity, resting brachial artery diameter, flow-mediated dilation %, hyperemic brachial blood flow velocity, and mean arterial pressure [MAP]) assessed by tonometry and brachial artery ultrasound. The longitudinal study included participants with ≥1 follow-up measurement of gait speed or grip strength. Multivariable linear regression estimated the association of 1 standard deviation (SD) higher level of each vascular measure with annualized percent change in grip strength and gait speed, adjusting for covariates. Results In cross-sectional analyses (n = 2 498, age 61 ± 10 years; 56% women), higher resting brachial artery diameter (β ± standard error [SE] per 1 SD: 0.59 ± 0.24, p = .01) and MAP (β ± SE: 0.39 ± 0.17, p = .02) were associated with higher grip strength. Higher brachial pulse pressure (β ± SE: −0.02 ± 0.01, p = .07) was marginally associated with slower gait speed. In longitudinal analyses (n = 2 157), higher brachial pulse pressure (β ± SE: −0.19 ± 0.07, p = .005), was associated with slowing of gait speed but not with grip strength. Conclusions Higher brachial artery pulse pressure (measure of aortic stiffness) was associated with loss of physical function over ~11 years, although we found no evidence that microvascular function contributed to the relation.

This guidance updates 2021 GRADE recomendations regarding immediate allergic reactions following COVID-19 vaccines and addresses re-vaccinating individuals with 1 st dose allergic reactions and allergy testing to determine re-vaccination outcomes. Recent meta-analyses assessed the incidence of severe allergic reactions to initial COVID-19 vaccination, risk of mRNA-COVID-19 re-vaccination after an initial reaction, and diagnostic accuracy of COVID-19 vaccine and vaccine excipient testing in predicting reactions. GRADE methods informed rating the certainty of evidence and strength of recommenations. A modified Delphi panel consisting of experts in allergy, anaphylaxis, vaccinology, infectious diseases, emergency medicine, and primary care from Australia, Canada, Europe, Japan, South Africa, the UK, and the US formed the recommendations. We recommend vaccination for persons without COVID-19 vaccine excipient allergy, and re-vaccination after a prior immediate allergic reaction. We suggest against >15-minute post-vaccination observation. We recommend against mRNA vaccine or excipient skin testing to predict outcomes. We suggest re-vaccination of persons with an immediate allergic reaction to the mRNA vaccine or excipients be performed by a person with vaccine allergy expertise, in a properly equipped setting. We suggest against pre-medication, split-dosing, or special precautions because of a comorbid allergic history.

Cardiac physiologic pacing (CPP), encompassing cardiac resynchronization therapy (CRT) and conduction system pacing (CSP), has emerged as a pacing therapy strategy that may mitigate or prevent the development of heart failure (HF) in patients with ventricular dyssynchrony or pacing-induced cardiomyopathy. This clinical practice guideline is intended to provide guidance on indications for CRT for HF therapy and CPP in patients with pacemaker indications or HF, patient selection, pre-procedure evaluation and preparation, implant procedure management, follow-up evaluation and optimization of CPP response, and use in pediatric populations. Gaps in knowledge, pointing to new directions for future research, are also identified.

ObjectivesTo investigate the role of endogenous TSG-6 in human osteoarthritis (OA) and assess the disease-modifying potential of a TSG-6-based biological treatment in cell, explant and animal models of OA.MethodsKnee articular cartilages from OA patients were analysed for TSG-6 protein and mRNA expression using immunohistochemistry and RNAscope, respectively. The inhibitory activities of TSG-6 and its isolated Link module domain (Link_TSG6) on cytokine-induced glycosaminoglycan loss in OA cartilage explants were compared. Mesenchymal stem/stromal cell (MSC)-derived chondrocyte pellet cultures were used to determine the effects of Link_TSG6 and full-length TSG-6 on IL-1α-, IL-1β- or TNF-stimulated ADAMTS4, ADAMTS5 and MMP13 mRNA expression. Link_TSG6 was administered i.a. to the rat ACLTpMMx model and cartilage damage and tactile allodynia were assayed.ResultsTSG-6 is predominantly associated with chondrocytes in regions of cartilage damage and its expression is negatively correlated with MMP13, the major collagenase implicated in OA progression. Link_TSG6 is more potent than full-length TSG-6 at dose-dependently inhibiting cytokine-mediated matrix breakdown in human OA cartilage explants; about 50% of donor cartilages, from 59 tested, were responsive to Link_TSG6 treatment. Similarly, Link_TSG6 displayed more potent effects in 3D pellet cultures, suppressing aggrecanase and collagenase gene expression. Link_TSG6 treatment reduced touch-evoked pain and dose-dependently inhibited cartilage damage in a rodent model of surgically-induced OA.ConclusionsNative TSG-6 is associated with a low catabolic chondrocyte phenotype in OA cartilage. Link_TSG6, which has enhanced chondroprotective activity compared to the full-length TSG-6 protein, demonstrates potential as a disease modifying OA drug (DMOAD) and warrants further investigation and development.KEY MESSAGESWhat is already known about this subject?TSG-6, a protein with anti-inflammatory and protective effects in other tissues, is expressed in joints affected by osteoarthritis – a condition for which there are no disease-modifying drugs.What does this study add?A novel protective mechanism has been identified, whereby TSG-6 inhibits inflammatory cytokine-induced catabolic pathways in cartilage.The Link module of TSG-6 (Link_TSG6) has been shown to have greater potency than TSG-6 as an inhibitor of cartilage damage and is efficacious in a rat model of osteoarthritis.Data from cartilage explants indicate that OA patients can be stratified for Link_TSG6 responsiveness.How might this impact on clinical practice or future developments?Link_TSG6 has been identified as potential disease-modifying OA drug that mimics an intrinsic protective process.

Background Skeletal muscle development and regeneration depend on cellular fusion of myogenic progenitors to generate multinucleated myofibers. These progenitors utilize two muscle-specific fusogens, Myomaker and Myomerger, which function by remodeling cell membranes to fuse to each other or to existing myofibers. Myomaker and Myomerger expression is restricted to differentiating progenitor cells as they are not detected in adult myofibers. However, Myomaker remains expressed in myofibers from mice with muscular dystrophy. Ablation of Myomaker from dystrophic myofibers results in reduced membrane damage, leading to a model where persistent fusogen expression in myofibers, in contrast to myoblasts, is harmful. Methods Dox-inducible transgenic mice were developed to ectopically express Myomaker or Myomerger in the myofiber compartment of skeletal muscle. We quantified indices of myofiber membrane damage, such as serum creatine kinase and IgM+ myofibers, and assessed general muscle histology, including central nucleation, myofiber size, and fibrosis. Results Myomaker or Myomerger expression in myofibers independently caused membrane damage at acute time points. This damage led to muscle pathology, manifesting with centrally nucleated myofibers and muscle atrophy. Dual expression of both Myomaker and Myomerger in myofibers exacerbated several aspects of muscle pathology compared to expression of either fusogen by itself. Conclusions These data reveal that while myofibers can tolerate some level of Myomaker and Myomerger, expression of a single fusogen above a threshold or co-expression of both fusogens is damaging to myofibers. These results explain the paradigm that their expression in myofibers can have deleterious consequences in muscle pathologies and highlight the need for their highly restricted expression during myogenesis and fusion.

Tracking single molecules continues to provide new insights into the fundamental rules governing biological function. Despite continued technical advances in fluorescent and non-fluorescent labeling as well as data analysis, direct observations of trajectories and interactions of multiple molecules in dense environments remain aspirational goals. While confocal methods provide a means to deduce dynamical parameters with high temporal resolution, such as diffusion coefficients, they do so at the expense of spatial resolution. Indeed, on account of a confocal volume's symmetry, typically only distances from the center of the confocal spot can be deduced. Motivated by the need for true three dimensional high speed tracking in densely labeled environments, we propose a computational tool for tracking many fluorescent molecules traversing multiple, closely spaced, confocal measurement volumes providing independent observations. Various realizations of this multiple confocal volumes strategy have previously been used for long term, large area, tracking of one fluorescent molecule in three dimensions. What is more, we achieve tracking by directly using single photon arrival times to inform our likelihood and exploit Hamiltonian Monte Carlo to efficiently sample trajectories from our posterior within a Bayesian nonparametric paradigm. A nonparametric paradigm here is warranted as the number of molecules present are, themselves

Subthreshold depression is highly prevalent in adolescence, but compared to major depressive disorder, the clinical impact is under-researched. The aim of this review was to compare subthreshold depression and major depressive disorder in adolescents by reviewing available literature on epidemiology, risk factors, illness trajectories, brain anatomy and function, genetics, and treatment response.We conducted a scoping review of papers on subthreshold depression and major depressive disorder in adolescence published in English. Studies in adults were included when research in adolescence was not available.We found that individuals with subthreshold depression were similar to individuals with major depressive disorder in several regards, including female/male ratio, onset, functional impairment, comorbidity, health care utilization, suicidal ideation, genetic predisposition, brain alterations, and treatment response. Further, subthreshold depression was about two times more common than major depressive disorder.The definition of subthreshold depression is highly variable across studies. Adolescent-specific data are limited in the areas of neurobiology and treatment.The findings of the current review support the idea that subthreshold depression is of clinical importance and provide evidence for a spectrum, versus categorical model, for depressive symptomatology. Given the frequency of subthreshold depression escalating to major depressive disorder, a greater recognition and awareness of the significance of subthreshold depression in research, clinical practice and policy-making may facilitate the development and application of early prevention and intervention.