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BACKGROUND: Uterine leiomyomas and adenomyosis are both common and often associated with abnormal uterine bleeding (AUB), including the symptom of heavy menstrual bleeding (HMB). Understanding the prevalence of adenomyosis in women with uterine leiomyomas could inform clinicians and patients in a way that may improve therapeutic approaches. OBJECTIVE: To explore the prevalence of adenomyosis in a group of women who underwent hysterectomy for AUB-L, to determine the prevalence of submucous leiomyomas, and to examine the utility of preoperative ultrasound to detect the presence of adenomyosis. METHODS: The Kaiser Permanente Hysterectomy Database (KPHD) was searched for women aged 18-52 undergoing hysterectomy for leiomyoma-associated chronic AUB (AUB-L) in 2018 and 2019. A target sample of 400 comprised those with at least 3 years in the Health System. Radiologists evaluated preoperative pelvic ultrasound images to determine leiomyoma size and level 2 FIGO type (submucous or other), and the linked electronic medical record abstracted for clinical features, including histopathological evidence of adenomyosis. RESULTS: Of the 370 subjects that met the study criteria, adenomyosis was identified via histopathology in 170 (45.9%). There was no difference in the adenomyosis prevalence with (47.1%) and without (43.0%) at least one submucous leiomyoma. Subgroup analysis of ultrasound images by an expert radiologist for the presence of adenomyosis demonstrated a positive predictive value of 54.0% and a negative predictive value of 43.4%. CONCLUSIONS: Adenomyosis was present in almost half of this AUB-L cohort undergoing hysterectomy and was equally prevalent in those with and without submucous leiomyomas as determined by sonographic evaluation. The imaging findings are in accord with prior investigators and demonstrate that 2-D ultrasound is insensitive to the presence of adenomyosis when the uterus is affected by leiomyomas. Further research is necessary to determine the impact of various adenomyosis phenotypes on the presence and severity of the symptom of HMB.

ImportanceSARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis.MethodsRECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms.DiscussionRECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.RegistrationNCT05172024.

The present study aims to explore the hypothesis of a link between a population increase derived from intensified food production and the development from the widespread cultural diversity of the Middle Neolithic B (MNB) to the cultural unity towards the end of the Late Neolithic (LN) in Southern Scandinavia. We explore this through quantitative modelling of radiocarbon dates, aoristic time series of material culture and palynological data. On this basis, we propose three main results that may explain the transformation: (1) A supra-regional population increase, culminating in the middle of the LN (c. 2100 BCE). (2) A depopulation in Western Jutland at the transition from the MNB to the LN (c. 2400-2300 BCE) counterbalanced by a population increase in North and East Denmark. (3) A population boom in Southern Sweden around 2250-2000 BCE, possibly leading to migrations towards west. Furthermore, we propose an overall decline in population in the final LN (c. 1850 BCE).

Witnesses of moral violations stand up for their moral principles, despite facing substantial costs for intervening. Notwithstanding its importance, little is known whether responsibility attributions and the relation between the victim and a witness (i.e., kinship) have different effects on the intention to intervene in situations of different severity (e.g., moral courage situations). We predict an interaction between the situation's severity and the victims' responsibility for their plight. In less-severe situations, witnesses would be less willing to help when they perceive the victim to be responsible for their plight. However, those who are not seen as responsible would receive more help. For more-severe situations, responsibility is predicted to have no effect. Opposite effects are predicted for the relationship between the helper and the victim. We further predict that perceived costs for helping mediates witnesses' willingness to intervene. Two studies showed that people are more willing to help individuals who are perceived as being innocent, but only in less-severe situations. In more-severe situations, people's willingness to intervene increases, regardless of responsibility attributions. We did not observe effects for kinship. Moreover, we provide partial evidence that witnesses of more-severe situations indeed accept higher costs for intervention.

BackgroundThe association between rurality of patients' residence and hospital experience is incompletely described. The objective of the study was to compare hospital experience by rurality of patients' residence.MethodsFrom a US Midwest institution's 17 hospitals, we included 56,685 patients who returned a post-hospital Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey. We defined rurality using rural-urban commuting area codes (metropolitan, micropolitan, small town, rural). We evaluated the association of patient characteristics with top-box score (favorable response) for 10 HCAHPS items (six composite, two individual, two global). We obtained adjusted odds ratios (aOR [95% CI]) from logistic regression models including patient characteristics. We used key driver analysis to identify associations between HCAHPS items and global rating (combined overall rating of hospital and recommend hospital).ResultsOf all items, overall rating of hospital had lower odds of favorable response for patients from metropolitan (0.88 [0.81-0.94]), micropolitan (0.86 [0.79-0.94]), and small towns (0.90 [0.82-0.98]) compared with rural areas (global test, P = .003). For five items, lower odds of favorable response was observed for select areas compared with rural; for example, recommend hospital for patients from micropolitan (0.88 [0.81-0.97]) but not metropolitan (0.97 [0.89-1.05]) or small towns (0.93 [0.85-1.02]). For four items, rurality showed no association. In metropolitan, micropolitan, and small towns, men vs. women had higher odds of favorable response to most items, whereas in rural areas, sex-based differences were largely absent. Key driver analysis identified care transition, communication about medicines and environment as drivers of global rating, independent of rurality.ConclusionsRural patients reported similar or modestly more favorable hospital experience. Determinants of favorable experience across rurality categories may inform system-wide and targeted improvement.

ObjectivesOpposed to other spectral CT techniques, fat quantification in dual-layer detector CT (dlCT) has only recently been developed. The impact of concomitant iron overload and dlCT-specific protocol settings such as the dose right index (DRI), a measure of image noise and tube current, on dlCT fat quantification was unclear. Further, spectral information became newly available Material and methodsPhantoms with 0 and 8mg/cm3 iron; 0 and 5mg/cm3 iodine; 0, 10, 20, 35, 50, and 100% fat and liver equivalent, respectively, were scanned with a dlCT (CT7500, Philips, the Netherlands) at 100kV/20DRI, 120kV/20DRI, 140kV/20DRI, and at 120kV/16DRI, 120kV/24DRI. Material decomposition was done for fat, liver, and iodine (A1); for fat, liver, and iron (A2); and for fat, liver, and combined reference values of iodine and iron (A3). All scans were analyzed with reference values from 120kV/20DRI. For statistics, the intraclass correlation coefficient (ICC) and Bland-Altman analyses were used.ResultsIn phantoms with iron and iodine, results were best for A3 with a mean deviation to phantom fat of 1.3±2.6% (ICC 0.999 [95%-confidence interval 0.996-1]). The standard approach A1 yielded a deviation of -2.5±3.0% (0.998[0.994-0.999]), A2 of 6.1±4.8% (0.991[0.974-0.997]). With A3 and changing tube voltage, the maximal difference between quantified fat and the phantom ground truth occurred at 100kV with 4.6±2.1%. Differences between scans were largest between 100kV and 140kV (2.0%[-7.1-11.2]). The maximal difference of changing DRI occurred between 16 and 24 DRI with 0.4%[-2.2-3.0].ConclusionFor dlCT fat quantification in the presence of iron, material decomposition with combined reference values for iodine and iron delivers the most accurate results. Tube voltage-specific calibration of reference values is advisable while the impact of the DRI on dlCT fat quantification is neglectable.

Cardiac rehabilitation (CR) patients often do not sustain physical activity (PA) behaviour in the long run, once they progress into a self-management stage of secondary prevention. This study aimed to explore former CR patients' PA preferences, determinants (i.e., influencing factors) and motivation for sustained PA engagement. We conducted a cross-sectional multi-centre survey using an original questionnaire based on prior qualitative interviews with cardiac patients. Five CR centres in Austria posted 500 questionnaires to former CR patients who had completed CR approximately three years prior, and 117 patients (23%) responded. Descriptive analysis was used to analyse closed-ended questions, and self-determination theory (SDT) was applied as a qualitative framework to analyse open-ended questions concerning motivation for PA engagement. Patients were generally physically active, but the majority (75.3%) did not fulfil the World Health Organisation's recommendations for aerobic PA and muscle strengthening. Most patients preferred being physically active outdoors (70%), engaging in aerobic-related (95%), individual and non-competitive exercises, with cycling (52%), walking (32%) and hiking (25%) among the most popular activities. Main determinants of PA were health, pain and motivation for 80%, 68%, 67% of patients, respectively. A subset of patients (77%) expanded on their motivations behind PA. According to SDT, most reasons (90%) were regulated by autonomous motivation (either extrinsically autonomously-regulated or intrinsic motivation) and stemmed mostly from health-related goals (e.g., fitness, general health, weight control), future quality-of-life aspirations (e.g., self-sufficiency in old age, presence for loved ones, preserving mobility) and enjoyment of PA. Patients' responses underscore the importance of promoting not only general PA, but also muscle strengthening training in CR interventions to maximise optimal health benefits. Our data further suggest that interventions which are aligned to patients' health goals and foster autonomous motivation may be particularly beneficial in increasing adherence to PA in the long-term.

AimsThis study investigated whether an activated R-mode in patients carrying a cardiac implantable electronic device (CIED) is associated with worse prognosis during and after an episode of acutely decompensated heart failure (AHF).MethodsSix hundred and twenty-three patients participating in an ongoing prospective cohort study that phenotypes and follows patients admitted for AHF were studied. We compared CIED carriers with activated R-mode stimulation (CIED-R) to CIED carriers not in R-mode (CIED-0) and patients without CIEDs (no-CIED). The independent impact of R-mode activation on 12-month all-cause death was examined using uni- and multivariable Cox proportional hazards regression taking into account potential confounders, and hazard ratios (HR) with their 95% confidence intervals (CI) were reported.ResultsMean heart rate on admission was lower in CIED-R (n = 37, 16% women) vs. CIED-0 (n = 64, 23% women) or no-CIED (n = 511, 43% women): 70 bpm vs. 80 bpm or 82 bpm; both pConclusionIn patients admitted with AHF, R-mode stimulation was associated with a significantly increased 12-month mortality risk. Our findings shed new light on "admission heart rate" as a potentially treatable target in AHF. Our data are compatible with the concept that chronotropic incompetence contributes to an adverse outcome in these patients and may not be adequately treated through accelerometer-based R-mode stimulation.

Collective rituals, particularly those characterized by synchrony and pain, have been shown to yield positive social and emotional outcomes. The question arises as to whether these findings extend to low-arousal, family-centered rituals and how spiritual beliefs factor into these communal practices. This study set out to examine the interplay between belief, ritual participation, and their effects on anxiety, social cohesion, and prosocial behavior during a low-arousal collective ritual in Mikasa, Japan. Drawing upon a sample of 183 festival participants, we measured belief in ancestors using a novel scale, identifying significant and consistent associations between these beliefs and measures of social cohesion across multiple targets. Moreover, active participation as a festival dancer displayed a positive relationship with feelings of social cohesion, particularly towards other festival attendees and at the national level. On measures of prosocial behavior, ancestral beliefs were positively associated with generosity shown within the festival setting, whereas observers were less generous towards community members than a non-attending control group. Anxiety outcomes displayed a negative relationship with ancestral beliefs and ritual observation but not participation as seen in previous research, suggesting a complex interplay between rituals, emotions, and individual states. These findings provide novel insights into the importance of belief systems and active participation in shaping social bonds and behaviors in the context of collective rituals.

In steroid-responsive meningitis-arteritis (SRMA), inflammatory dysregulation is driven by neutrophilic granulocytes resulting in purulent leptomeningitis. Neutrophils can generate neutrophil extracellular traps (NET). Uncontrolled NET-formation or impaired NET-clearance evidently cause tissue and organ damage resulting in immune-mediated diseases. The aim of the study was to verify that NET-formation is detectable in ex vivo samples of acute diseased dogs with SRMA by visualizing and measuring NET-markers in serum and cerebrospinal fluid (CSF) samples. CSF-samples of dogs with acute SRMA (n = 5) and in remission (n = 4) were examined using immunofluorescence (IF)-staining of DNA-histone-1-complexes, myeloperoxidase and citrullinated Histone H3 (H3Cit). Immunogold-labeling of H3Cit and neutrophil elastase followed by transmission electron microscopy (TEM) were used to determine ultrastructural NET-formation in the CSF of one exemplary dog. H3Cit-levels and DNase-activity were measured in CSF and serum samples using an H3Cit-ELISA and a DNase-activity-assay, respectively in patients with the following diseases: acute SRMA (n = 34), SRMA in remission (n = 4), bacterial encephalitis (n = 3), meningioma with neutrophilic inflammation (n = 4), healthy dogs (n = 6). NET-formation was detectable with IF-staining in n = 3/5 CSF samples of dogs with acute SRMA but were not detectable during remission. Vesicular NET-formation was detectable in one exemplary dog using TEM. DNase-activity was significantly reduced in dogs suffering from acute SRMA compared to healthy control group (p < 0.0001). There were no statistical differences of H3Cit levels in CSF or serum samples of acute diseased dogs compared to dogs under treatment, dogs suffering from meningioma or bacterial encephalitis or the healthy control group. Our findings demonstrate that NET-formation and insufficient NET-clearance possibly drive the immunologic dysregulation and complement the pathogenesis of SRMA. The detection of NETs in SRMA offers many possibilities to explore the aetiopathogenetic influence of this defence mechanism of the innate immune system in infectious and non-infectious canine neuropathies.

Brain metastasis leads to increased mortality and is a major site of relapse for several cancers, yet the molecular mechanisms of brain metastasis are not well understood. In this study, we established and characterized a new leukemic cell line, FIA10, that metastasizes into the central nervous system (CNS) following injection into the tail vein of syngeneic mice. Mice injected with FIA10 cells developed neurological symptoms such as loss of balance, tremor, ataxic gait and seizures, leading to death within 3 months. Histopathology coupled with PCR analysis clearly showed infiltration of leukemic FIA10 cells into the brain parenchyma of diseased mice, with little involvement of bone marrow, peripheral blood and other organs. To define pathways that contribute to CNS metastasis, global transcriptome and proteome analysis was performed on FIA10 cells and compared with that of the parental stem cell line FDCP-Mix and the related FIA18 cells, which give rise to myeloid leukemia without CNS involvement. 188 expressed genes (RNA level) and 189 proteins were upregulated (log2 ratio FIA10/FIA18 ≥ 1) and 120 mRNAs and 177 proteins were downregulated (log2 ratio FIA10/FIA18 ≤ 1) in FIA10 cells compared with FIA18 cells. Major upregulated pathways in FIA10 cells revealed by biofunctional analyses involved immune response components, adhesion molecules and enzymes implicated in extracellular matrix remodeling, opening and crossing the blood-brain barrier (BBB), molecules supporting migration within the brain parenchyma, alterations in metabolism necessary for growth within the brain microenvironment, and regulators for these functions. Downregulated RNA and protein included several tumor suppressors and DNA repair enzymes. In line with the function of FIA10 cells to specifically infiltrate the brain, FIA10 cells have acquired a phenotype that permits crossing the BBB and adapting to the brain microenvironment thereby escaping immune surveillance. These data and our model system FIA10 will be valuable resources to study the occurrence of brain metastases and may help in the development of potential therapies against brain invasion.

A lack of comparative data across laboratories is often a barrier to the uptake and adoption of new technologies. Furthermore, data generated by different immunoassay methods may be incomparable due to a lack of harmonization. In this multicenter study, we describe validation experiments conducted in a single lab and cross-lab comparisons of assay results to assess the performance characteristics of the Q-plex™ 7-plex Human Micronutrient Array (7-plex), an immunoassay that simultaneously quantifies seven biomarkers associated with micronutrient (MN) deficiencies, inflammation and malarial antigenemia using plasma or serum; alpha-1-acid glycoprotein, C-reactive protein, ferritin, histidine-rich protein 2, retinol binding protein 4, soluble transferrin receptor, and thyroglobulin. Validations included repeated testing (n = 20 separately prepared experiments on 10 assay plates) in a single lab to assess precision and linearity. Seven independent laboratories tested 76 identical heparin plasma samples collected from a cohort of pregnant women in Niger using the same 7-plex assay to assess differences in results across laboratories. In the analytical validation experiments, intra- and inter-assay coefficients of variation were acceptable at

Moral vitalism refers to a tendency to view good and evil as actual forces that can influence people and events. The Moral Vitalism Scale had been designed to assess moral vitalism in a brief survey form. Previous studies established the reliability and validity of the scale in US-American and Australian samples. In this study, the cross-cultural comparability of the scale was tested across 28 different cultural groups worldwide through measurement invariance tests. A series of exact invariance tests marginally supported partial metric invariance, however, an approximate invariance approach provided evidence of partial scalar invariance for a 5-item measure. The established level of measurement invariance allows for comparisons of latent means across cultures. We conclude that the brief measure of moral vitalism is invariant across 28 cultures and can be used to estimate levels of moral vitalism with the same precision across very different cultural settings.

BACKGROUND AND PURPOSE: Anemia is associated with worse outcome in stroke, but the impact of anemia with intravenous thrombolysis or endovascular therapy has hardly been delineated. The aim of this study was to analyze the role of anemia on infarct evolution and outcome after acute stroke treatment. METHODS: 1158 patients from Bern and 321 from Los Angeles were included. Baseline data and 3 months outcome assessed with the modified Rankin Scale were recorded prospectively. Baseline DWI lesion volumes were measured in 345 patients and both baseline and final infarct volumes in 180 patients using CT or MRI. Multivariable and linear regression analysis were used to determine predictors of outcome and infarct growth. RESULTS: 712 patients underwent endovascular treatment and 446 intravenous thrombolysis. Lower hemoglobin at baseline, at 24h, and nadir until day 5 predicted poor outcome (OR 1.150-1.279) and higher mortality (OR 1.131-1.237) independently of treatment. Decrease of hemoglobin after hospital arrival, mainly induced by hemodilution, predicted poor outcome and had a linear association with final infarct volumes and the amount and velocity of infarct growth. Infarcts of patients with newly observed anemia were twice as large as infarcts with normal hemoglobin levels. CONCLUSION: Anemia at hospital admission and any hemoglobin decrease during acute stroke treatment affect outcome negatively, probably by enlarging and accelerating infarct growth. Our results indicate that hemodilution has an adverse effect on penumbral evolution. Whether hemoglobin decrease in acute stroke could be avoided and whether this would improve outcome would need to be studied prospectively.

This study examines the occurrence of humpback whale (Megaptera novaeangliae) song in the northeast Pacific from three years of continuous recordings off central California (36.713°N, 122.186°W). Song is prevalent in this feeding and migratory habitat, spanning nine months of the year (September-May), peaking in winter (November-January), and reaching a maximum of 86% temporal coverage (during November 2017). From the rise of song in fall through the end of peak occurrence in winter, song length increases significantly from month to month. The seasonal peak in song coincides with the seasonal trough in day length and sighting-based evidence of whales leaving Monterey Bay, consistent with seasonal migration. During the seasonal song peak, diel variation shows maximum occurrence at night (69% of the time), decreasing during dawn and dusk (52%), and further decreasing with increasing solar elevation during the day, reaching a minimum near solar noon (30%). Song occurrence increased 44% and 55% between successive years. Sighting data within the acoustic detection range of the hydrophone indicate that variation in local population density was an unlikely cause of this large interannual variation. Hydrographic data and modeling of acoustic transmission indicate that changes in neither habitat occupancy nor acoustic transmission were probable causes. Conversely, the positive interannual trend in song paralleled major ecosystem variations, including similarly large positive trends in wind-driven upwelling, primary productivity, and krill abundance. Further, the lowest song occurrence during the first year coincided with anomalously warm ocean temperatures and an extremely toxic harmful algal bloom that affected whales and other marine mammals in the region. These major ecosystem variations may have influenced the health and behavior of humpback whales during the study period.

IntroductionAdolescent girls and young women (AGYW) face barriers in accessing clinic-based HIV pre-exposure prophylaxis (PrEP) services and community-based models are a proposed alternative. Evidence from such models, however, is limited. We evaluated PrEP service coverage, uptake, and early persistence among AGYW receiving services through community and hybrid models in Namibia.MethodsWe analyzed routine data for AGYW aged 15-24 who initiated PrEP within HIV prevention programming. PrEP was delivered via three models: community-concierge (fully community-based services with individually-tailored refill locations), community-fixed (community-based initiation and refills delivered by community providers on a set schedule at fixed sites), and hybrid community-clinic (community-based initiation and referral to clinics for refills delivered by clinic providers). We examined proportions of AGYW engaged in services along a programmatic PrEP cascade, overall and by model, and assessed factors associated with PrEP uptake and early persistence (refill within 15-44 days after initiation) using multivariable generalized estimating equations.ResultsOver 10-months, 7593 AGYW participated in HIV prevention programming. Of these, 7516 (99.0%) received PrEP education, 6105 (81.2%) received HIV testing services, 6035 (98.9%) tested HIV-negative, and 2225 (36.9%) initiated PrEP. Of the 2047 AGYW expected for PrEP refill during the study period, 254 (12.4%) persisted with PrEP one-month after initiation. Structural and behavioral HIV risk factors including early school dropout, food insecurity, inconsistent condom use, and transactional sex were associated with PrEP uptake. AGYW who delayed starting PrEP were 2.89 times more likely to persist (95% confidence interval (CI): 1.52-5.46) and those receiving services via the community-concierge model were 8.7 times (95% CI: 5.44-13.9) more likely to persist (compared to the hybrid model).ConclusionCommunity-based models of PrEP service delivery to AGYW can achieve high PrEP education and HIV testing coverage and moderate PrEP uptake. AGYW-centered approaches to delivering PrEP refills can promote higher persistence.

ObjectivesAmbulatory antibiotic stewardship generally aims to address the appropriateness of antibiotics prescribed at in-person visits. The prevalence and appropriateness of antibiotics prescribed outside of in-person visits is poorly studied.Design and settingRetrospective cohort study of all ambulatory antibiotic prescribing in an integrated health delivery system in the United States.ParticipantsAntibiotic prescribers and patients receiving oral antibiotic prescriptions between January 2016 and December 2019.Main outcome measuresProportion of antibiotics prescribed with in-person visits or not-in-person encounters (e.g., telephone, refills). Proportion of prescriptions in in 5 mutually exclusive appropriateness groups: 1) chronic antibiotic use; 2) antibiotic-appropriate; 3) potentially antibiotic-appropriate; 4) non-antibiotic-appropriate; and 5) not associated with a diagnosis.ResultsOver the 4-year study period, there were 714,057 antibiotic prescriptions ordered for 348,739 unique patients by 2,391 clinicians in 467 clinics. Patients had a mean age of 41 years old, were 61% female, and 78% White. Clinicians were 58% women; 78% physicians; and were 42% primary care, 39% medical specialists, and 12% surgical specialists. Overall, 81% of antibiotics were prescribed with in-person visits and 19% without in-person visits. The most common not-in-person encounter types were telephone (10%), orders only (5%), and refill encounters (3%). Of all antibiotic prescriptions, 16% were for chronic use, 15% were antibiotic-appropriate, 39% were potentially antibiotic-appropriate, 22% were non-antibiotic-appropriate, and 8% were not associated with a diagnosis. Antibiotics prescribed in not-in-person encounters were more likely to be chronic (20% versus 15%); less likely to be associated with appropriate or potentially appropriate diagnoses (30% versus 59%) or non-antibiotic-appropriate diagnoses (8% versus 25%); and more likely to be associated with no diagnosis (42% versus ConclusionsAmbulatory stewardship interventions that focus only on in-person visits may miss a large proportion of antibiotic prescribing, inappropriate prescribing, and antibiotics prescribed in the absence of any diagnosis.

Reliable identification of plant species in the digestive tract of a deceased animal often represents the major key to diagnose a lethal intoxication with poisonous plants in veterinary pathology. In many cases, identification of the species is challenging or even impossible because the diagnostic morphological features have been degraded, and because the interpretation of such features requires a considerable expertise in plant anatomy and biodiversity. The use of DNA barcoding markers can support or even replace classical morphological assessment. While these markers have been widely used for plant taxonomy, their forensic application to clarify causes of animal poisoning is novel. In addition, we use specific single-nucleotide polymorphisms as fingerprints. This allows for a clear decision even in cases, where the conventionally used statistical e-values remain ambiguous. In the current work, we explore the feasibility of this strategy in a couple of exemplary cases, either in concert with anatomical diagnostics, or in cases where visual species identification is not possible, or where chemical toxin detection methods are not well established, complex, time consuming and expensive.

Astrocytic tumors are known for their high progression capacity and high mortality rates; in this regard, proteins correlated to prognosis can aid medical conduct. Although several genetic changes related to progression from grade 2 to grade 4 astrocytoma are already known, mRNA copies do not necessarily correlate with protein abundance and therefore could shadow further comprehension about this tumor's biology. This motivates us to seek for complementary strategies to study tumor progression at the protein level. Here we compare the proteomic profile of biopsies from patients with grade 2 (diffuse, n = 6) versus grade 4 astrocytomas (glioblastomas, n = 10) using shotgun proteomics. Data analysis performed with PatternLab for proteomics identified 5,206 and 6,004 proteins in the 2- and 4-grade groups, respectively. Our results revealed seventy-four differentially abundant proteins (p < 0.01); we then shortlist those related to greater malignancy. We also describe molecular pathways distinctly activated in the two groups, such as differences in the organization of the extracellular matrix, decisive both in tumor invasiveness and in signaling for cell division, which, together with marked contrasts in energy metabolism, are determining factors in the speed of growth and dissemination of these neoplasms. The degradation pathways of GABA, enriched in the grade 2 group, is consistent with a favorable prognosis. Other functions such as platelet degranulation, apoptosis, and activation of the MAPK pathway were correlated to grade 4 tumors and, consequently, unfavorable prognoses. Our results provide an important survey of molecular pathways involved in glioma pathogenesis for these histopathological groups.

Pig production has a short history in Uganda. The majority of pigs are kept by smallholder farmers in rural areas where access to veterinary services is limited, and pig keeping has been suggested as a potential pathway out of poverty for smallholders. Previous research has identified the disease of African swine fever (ASF) as a major threat, causing high mortalities in pigs. With no available cure or vaccine, the only option is to implement biosecurity measures, i.e. strategies that prevent the spread of ASF. This paper draws on data from four months of ethnographic fieldwork in rural northern Uganda. Combining methods of participant observation, semi-structured interviews, focus group discussions and a survey, the aim was to improve understanding of smallholders' perceptions and responses to pig health issues such as ASF. Applying the concept of practical knowledge, this paper analyses the potential and limitations of smallholders' practice-based knowledge as a means of dealing with pig health issues. The results show that while pigs were appreciated locally for providing an income, many informants found it difficult to deal with pig diseases effectively. Consequently, informants commonly expressed a need for other kinds of knowledge in their pig production, indicating that veterinary advice can play an important role in reducing the negative impact of pig health issues. For animal health provision to have relevance in this context, however, veterinary practitioners must pay close attention to smallholders' priorities and ways of knowing in their livestock keeping. Results further show that pig health issues made some informants abandon pig production altogether. To enhance the potential of pig production as a poverty mitigation strategy in Uganda, research and policy need to focus on ways of bettering general conditions for smallholder pig keeping, including improving the quality of and access to veterinary services in rural areas.

Differences in taste perception between species are thought to reflect evolutionary adaptations to dietary specialization. White-faced sakis (Pithecia pithecia) are commonly considered as frugivores but are unusual among primates as they do not serve as seed dispersers but rather prey upon the seeds of the fruits they consume and are thought to exploit the lipids and proteins that these seeds contain in high amounts. Using a two-bottle preference test of short duration we therefore assessed whether this dietary specialization affects the taste responsiveness of four adult white-faced sakis for five food-associated carbohydrates. We found that the sakis significantly preferred concentrations as low as 10 mM sucrose, 10-40 mM fructose, 20-30 mM glucose and maltose, and 30-40 mM lactose over tap water. When given the choice between all binary combinations of these five saccharides presented at equimolar concentrations of 100, 200, and 300 mM, respectively, the sakis displayed significant preferences for individual saccharides in the following order: sucrose > fructose > glucose ≥ maltose = lactose. These results demonstrate that seed-predating white-faced sakis have a well-developed taste sensitivity for food-associated carbohydrates which is not inferior to that of most other primates including seed-dispersing frugivores, but rather ranks among the more sweet-taste sensitive species. Further, they show that their pattern of relative preference for the five carbohydrates is similar to that found in other frugivorous primate species. These findings may represent an example of Liem's paradox as the sakis' morphological adaptations to efficiently predate on and exploit the lipid- and protein-rich hard-shelled seeds of fruits does not compromise their ability to detect the carbohydrates found in the pulp of fruits at low concentrations.

BackgroundCognitive flexibility (CF) enables individuals to readily shift from one concept or mode of practice/thoughts to another in response to changes in the environment and feedback, making CF vital to optimise success in obtaining goals. However, how CF relates to other executive functions (e.g., working memory, response inhibition), mental abilities (e.g., creativity, literacy, numeracy, intelligence, structure learning), and social factors (e.g., multilingualism, tolerance of uncertainty, perceived social support, social decision-making) is less well understood. The current study aims to (1) establish the construct validity of CF in relation to other executive function skills and intelligence, and (2) elucidate specific relationships between CF, structure learning, creativity, career decision making and planning, and other life skills.MethodsThis study will recruit up to 400 healthy Singaporean young adults (age 18-30) to complete a wide range of cognitive tasks and social questionnaires/tasks. The richness of the task/questionnaire battery and within-participant administration enables us to use computational modelling and structural equation modelling to examine connections between the latent constructs of interest.Significance and impactThe current study is the first systematic investigation into the construct validity of CF and its interrelationship with other important cognitive skills such as learning and creativity, within an Asian context. The study will further explore the concept of CF as a non-unitary construct, a novel theoretical proposition in the field. The inclusion of a structure learning paradigm is intended to inform future development of a novel intervention paradigm to enhance CF. Finally, the results of the study will be useful for informing classroom pedagogy and the design of lifelong learning policies and curricula, as part of the wider remit of the Cambridge-NTU Centre for Lifelong Learning and Individualised Cognition (CLIC).

People respond faster to smaller numbers in their left space and to larger numbers in their right space. Here we argue that movements in space contribute to the formation of spatial-numerical associations (SNAs). We studied the impact of continuous isometric forces along the horizontal or vertical cardinal axes on SNAs while participants performed random number production and arithmetic verification tasks. Our results suggest that such isometric directional force do not suffice to induce SNAs.

ImportanceSARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis.MethodsRECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms.DiscussionRECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.RegistrationNCT05172024.

BackgroundCommunicating well with patients is a competence central to everyday clinical practice, and communicating statistical information, especially in Bayesian reasoning tasks, can be challenging. In Bayesian reasoning tasks, information can be communicated in two different ways (which we call directions of information): The direction of Bayesian information (e.g., proportion of people tested positive among those with the disease) and the direction of diagnostic information (e.g., the proportion of people having the disease among those tested positive). The purpose of this study was to analyze the impact of both the direction of the information presented and whether a visualization (frequency net) is presented with it on patient's ability to quantify a positive predictive value.Material and methods109 participants completed four different medical cases (2⨯2⨯4 design) that were presented in a video; a physician communicated frequencies using different directions of information (Bayesian information vs. diagnostic information). In half of the cases for each direction, participants were given a frequency net. After watching the video, participants stated a positive predictive value. Accuracy and speed of response were analyzed.ResultsCommunicating with Bayesian information led to participant performance of only 10% (without frequency net) and 37% (with frequency net) accuracy. The tasks communicated with diagnostic information but without a frequency net were correctly solved by 72% of participants, but accuracy rate decreased to 61% when participants were given a frequency net. Participants with correct responses in the Bayesian information version without visualization took longest to complete the tasks (median of 106 seconds; median of 13.5, 14.0, and 14.5 seconds in other versions).DiscussionCommunicating with diagnostic information rather than Bayesian information helps patients to understand specific information better and more quickly. Patients' understanding of the relevance of test results is strongly dependent on the way the information is presented.

Arthrofibrosis following total knee arthroplasty is a fibroproliferative joint disorder marked by dysregulated biosynthesis of extracellular matrix proteins, such as collagens and proteoglycans. The underlying cellular events remain incompletely understood. Myofibroblasts are highly contractile matrix-producing cells characterized by increased alpha-smooth muscle actin expression and xylosyltransferase-I (XT-I) secretion. Human XT-I has been identified as a key mediator of arthrofibrotic remodeling. Primary fibroblasts from patients with arthrofibrosis provide a useful in vitro model to identify and characterize disease regulators and potential therapeutic targets. This study aims at characterizing primary synovial fibroblasts from arthrofibrotic tissues (AFib) regarding their molecular and cellular phenotype by utilizing myofibroblast cell culture models. Compared to synovial control fibroblasts (CF), AFib are marked by enhanced cell contractility and a higher XT secretion rate, demonstrating an increased fibroblast-to-myofibroblast transition rate during arthrofibrosis. Histochemical assays and quantitative gene expression analysis confirmed higher collagen and proteoglycan expression and accumulation in AFib compared to CF. Furthermore, fibrosis-based gene expression profiling identified novel modifier genes in the context of arthrofibrosis remodeling. In summary, this study revealed a unique profibrotic phenotype in AFib that resembles some traits of other fibroproliferative diseases and can be used for the future development of therapeutic interventions.

BackgroundData on calcineurin-inhibitor (CNI) free immunosuppression after lung transplantation (LTx) are limited. Aim of this study was to investigate CNI-free immunosuppression using mechanistic target of rapamycin (mTOR) inhibitors.MethodsThis retrospective analysis was performed at a single center. Adult patients after LTx without CNI during the follow-up period were included. Outcome was compared to those LTx patients with malignancy who continued CNI.ResultsAmong 2,099 patients in follow-up, fifty-one (2.4%) were converted median 6.2 years after LTx to a CNI-free regimen combining mTOR inhibitors with prednisolone and an antimetabolite, two patients were switched to mTOR inhibitors with prednisolone only. In 25 patients, malignancies without curative treatment options were the reason of the conversion, with a 1-year survival of 36%. The remaining patients had a 1-year survival of 100%. Most common non-malignant indication was neurological complications (n = 9). Fifteen patients were re-converted to a CNI-based regimen. The median duration of CNI-free immunosuppression was 338 days. No acute rejections were detected in 7 patients with follow-up biopsies. In multivariate analysis, CNI-free immunosuppression were not associated with improved survival after malignancy. The majority of patients with neurological diseases improved 12 months after conversion. Glomerular filtration rate increased by median 5 (25 and 75% percentiles -6; +18) ml/min/1.73 m2.ConclusionsmTOR inhibitor based CNI-free immunosuppression may be safely performed in selected patients after LTx. This approach was not associated with improved survival in patients with malignancy. Significant functional improvements were observed in patients with neurological diseases.

Aquatic ecosystems are currently facing a multitude of stressors from anthropogenic impacts, including climate change, pollution, and overfishing. Public aquariums positively contribute to ecosystems through conservation, education, and scientific advancement; but may also negatively detract from these systems through collection of animals from the wild and sourcing from commercial suppliers. Changes within the industry have occurred, although evidence-based assessments of 1) how aquariums collect and maintain their populations to determine sustainability of the environment they have harvested; and 2) the welfare of these harvested animals once within the aquariums are still needed. The objectives of this study were to assess the ecosystem health of locations aquariums frequently visit to collect fish from the wild, and then evaluate the wellbeing of fishes at aquariums after extended periods in captivity. Assessments included use of chemical, physical, and biological indicators at field sites, and use of a quantitative welfare assessment at aquariums for comparison to species reared through aquaculture. Anthropogenic pressures at field sites were observed, but no evidence of high degradation or compromised health of animals were found. Welfare assessments of aquarium exhibit tanks produced high-positive scores overall (> 70/84), demonstrating that both wild collected (avg. score 78.8) and aquaculture fishes (avg. score 74.5) were coping appropriately within their environments. Although findings indicated that fish can be taken from the wild at low-moderate rates without any deleterious impact on the environment and cope equally well in aquarium settings, alternatives such as aquaculture should be considered as a strategy to reduce pressure on known stressed aquatic environments or where significant numbers of fishes are being taken.

Smartphone use while driving (SUWD) is a major cause of accidents and fatal crashes. This serious problem is still too little understood to be solved. Therefore, the current research aimed to contribute to a better understanding of SUWD by examining factors that have received little or no attention in this context: problematic smartphone use (PSU), fear of missing out (FOMO), and Dark Triad. In the first step, we conducted a systematic literature review to map the current state of research on these factors. In the second step, we conducted a cross-sectional study and collected data from 989 German car drivers. A clear majority (61%) admitted to using the smartphone while driving at least occasionally. Further, the results showed that FOMO is positively linked to PSU and that both are positively associated with SUWD. Additionally, we found that Dark Triad traits are relevant predictors of SUWD and other problematic driving behaviors--in particular, psychopathy is associated with committed traffic offenses. Thus, results indicate that PSU, FOMO, and Dark Triad are relevant factors to explain SUWD. We hope to contribute to a more comprehensive understanding of this dangerous phenomenon with these findings.

BackgroundLassa fever (LF), a haemorrhagic illness caused by the Lassa fever virus (LASV), is endemic in West Africa and causes 5000 fatalities every year. The true prevalence and incidence rates of LF are unknown as infections are often asymptomatic, clinical presentations are varied, and surveillance systems are not robust. The aim of the Enable Lassa research programme is to estimate the incidences of LASV infection and LF disease in five West African countries. The core protocol described here harmonises key study components, such as eligibility criteria, case definitions, outcome measures, and laboratory tests, which will maximise the comparability of data for between-country analyses.MethodWe are conducting a prospective cohort study in Benin, Guinea, Liberia, Nigeria (three sites), and Sierra Leone from 2020 to 2023, with 24 months of follow-up. Each site will assess the incidence of LASV infection, LF disease, or both. When both incidences are assessed the LASV cohort (nmin = 1000 per site) will be drawn from the LF cohort (nmin = 5000 per site). During recruitment participants will complete questionnaires on household composition, socioeconomic status, demographic characteristics, and LF history, and blood samples will be collected to determine IgG LASV serostatus. LF disease cohort participants will be contacted biweekly to identify acute febrile cases, from whom blood samples will be drawn to test for active LASV infection using RT-PCR. Symptom and treatment data will be abstracted from medical records of LF cases. LF survivors will be followed up after four months to assess sequelae, specifically sensorineural hearing loss. LASV infection cohort participants will be asked for a blood sample every six months to assess LASV serostatus (IgG and IgM).DiscussionData on LASV infection and LF disease incidence in West Africa from this research programme will determine the feasibility of future Phase IIb or III clinical trials for LF vaccine candidates.

Background and purposeLimited data is available on sex differences in young stroke patients describing discrepant findings. This study aims to investigate the sex differences in young stroke patients.MethodsProspective cohort study comparing risk factors, etiology, stroke localization, severity on admission, management and outcome in patients aged 16-55 years with acute ischemic stroke consecutively included in the Bernese stroke database between 01/2015 to 12/2018 with subgroup analyses for very young (16-35y) and young patients (36-55y).Results689 patients (39% female) were included. Stroke in women dominated in the very young (53.8%, pConclusionsThe main finding of this study is that sex specific risk factors in women may contribute to a large extent to the higher incidence of stroke in the very young in women. Important modifiable stroke risk factors, such as arterial hypertension, diabetes mellitus and atrial fibrillation did not differ in women and men, either in the young as well as in the very young. These findings have major implications for primary preventive strategies of stroke in young people.

IntroductionFrontline Healthcare provider (HCP) burnout has dramatically increased due to the COVID 19 pandemic. Hospitals are supporting wellness programs and techniques to reduce burnout including the Transcendental Meditation (TM) technique. This study evaluated the use of TM on HCP symptoms of stress, burnout and wellness.MethodsA total of 65 HCPs at three South Florida hospitals were recruited and instructed in the TM technique which they practiced at home for 20 minutes twice a day. A parallel lifestyle as usual control group was enrolled. Validated measurement scales (Brief Symptom Inventory 18 (BSI-18), Insomnia Severity Index (ISI), Maslach Burnout Inventory-Human Services Survey [MBI-HSS (MP)] and the Warwick Edinburgh Mental Well Being Scale (WEMWBS) were administered at baseline, 2 weeks, one and three months.ResultsNo significant demographic differences were seen between the 2 groups; however, some baseline scales were higher in the TM group. TM average weekly session completion rate was very high at 83%. After 2-weeks, symptoms of somatization, depression, and anxiety in the TM group had all shown near 45% reductions, while insomnia, emotional exhaustion, and well-being had improved by 33%, 16%, and 11% respectively (P = 0.02 for somatization and < .001 for all others); no significant change was noted in the LAU group. At 3-months, in the TM group, the improvement in symptoms showed a mean reduction of in anxiety, 62%, somatization, 58%, depression, 50%, insomnia, 44%, emotional exhaustion 40%, depersonalization, 42%, and improvement of well-being 18% (for all pConclusionThe study confirmed the reported significant and rapid benefits of the practice of TM and demonstrated its positive psychological impact on healthcare workers in a high stress setting.

We showed previously that capsaicin, an active compound of chili peppers, can inhibit platelet-derived growth factor-induced proliferation in primary rat vascular smooth muscle cells (VSMCs). The inhibition of BrdU incorporation by capsaicin in these cells was revoked by BCTC, which might be explained by a role of TRPV1 in VSMCs proliferation. To further pursue the hypothesis of a TRPV1-dependent effect of capsaicin, we investigated TRPV1 expression and function. Commercially available antibodies against two different TRPV1 epitopes (N-terminus and C-terminus) were rendered invalid in detecting TRPV1, as shown: i) in western blot experiments using control lysates of TRPV1-expressing (PC-12 and hTRPV1 transfected HEK293T) and TRPV1-downregulated (CRISPR/Cas gene edited A10) cells, and ii) by substantial differences in staining patterns between the applied antibodies using fluorescence confocal microscopy. The TRPV1 agonists capsaicin, resiniferatoxin, piperine and evodiamine did not increase intracellular calcium levels in primary VSMCs and in A10 cells. Using RT qPCR, we could detect a rather low TRPV1 expression in VSMCs at the mRNA level (Cp value around 30), after validating the primer pair in NGF-stimulated PC-12 cells. We conclude that rat vascular smooth muscle cells do not possess canonical TRPV1 channel activity, which could explain the observed antiproliferative effect of capsaicin.

HIV infection remains incurable to date and there are no compounds targeted at the viral release. We show here HIV viral release is not spontaneous, rather requires caspases activation and shedding of its adhesion receptor, CD62L. Blocking the caspases activation caused virion tethering by CD62L and the release of deficient viruses. Not only productive experimental HIV infections require caspases activation for viral release, HIV release from both viremic and aviremic patient-derived CD4 T cells also require caspase activation, suggesting HIV release from cellular viral reservoirs depends on apoptotic shedding of the adhesion receptor. Further transcriptomic analysis of HIV infected CD4 T cells showed a direct contribution of HIV accessory gene Nef to apoptotic caspases activation. Current HIV cure focuses on the elimination of latent cellular HIV reservoirs that are resistant to infection-induced cell death. This has led to therapeutic strategies to stimulate T cell apoptosis in a "kick and kill" approach. Our current work has shifted the paradigm on HIV-induced apoptosis and suggests such approach would risk to induce HIV release and thus be counter-productive. Instead, our study supports targeting of viral reservoir release by inhibiting of caspases activation.

BackgroundHereditary hypothyroidism represents a concern for dog breeders; thus, surveillance programs have been established for several dog breeds.MethodsThyroid profiles (total thyroxine (TT4), thyrotropin (thyroid stimulating hormone (TSH)), and thyroglobulin autoantibodies (TgAA)) collected as part of a breed surveillance program in Eurasians (2009-2017) were retrospectively analyzed. The study included data from 1,501 Eurasians from a German breeding club. Classification was exclusively based on laboratory data. Hypothyroidism was defined as a combined decrease in TT4 and increase in TSH in serum and was classified as TgAA-positive and TgAA-negative hypothyroidism. Thyroglobulin autoantibodies (TgAA) independent of the concentrations of TT4 and TSH were determined. The overall prevalence of hypothyroidism, TgAA-positive hypothyroidism, TgAA-negative hypothyroidism and TgAA-positivity was assessed when the dogs entered the program. Follow-up laboratory data was available for 324 dogs without hypothyroidism on initial examination.ResultsThe initial screening was performed at a median age of 18 months (interquartile range (IQR): 15-29). The overall prevalence of hypothyroidism was 3.9% (n = 58; 95% CI: 2.9-4.8%) and the prevalence of a positive TgAA status was 7.9% (n = 118; 95% CI: 6.6-9.3%). The prevalence of TgAA-positive and TgAA-negative hypothyroidism was 1.7% (n = 26; 95% CI: 1.1-2.4%) and 2.1% (n = 32; 95% CI: 1.4-2.9%), respectively. 22.0% of dogs with positive TgAA status (26/118) were already hypothyroid on initial examination. Overall, 42.5% (17/40) of TgAA-positive dogs on initial examination developed hypothyroidism on follow-up.ConclusionThe results of this study demonstrate that the Eurasian dog breed exhibits a relevant risk for hypothyroidism and presence of TgAA. The predictive value of TgAA for hypothyroidism or developing hypothyroidism was high in this breed. Further investigations with longitudinal studies in individual dogs are warranted.

Our knowledge about the underlying pathomechanisms of craniocervical junction abnormalities (CCJA) in dogs mostly derives from measurements based on tomographic imaging. These images are static and the positioning of the dogs' head does not reflect the physiological in vivo position of the craniocervical junction (CCJ). Aberrant motion patterns and ranges of motion (ROM) in sound individuals of CCJA predisposed breeds may be a pathogenetic trigger. To further extend our limited knowledge of physiological motion of the CCJ, this prospective, comparative study investigates the in vivo motion patterns and ROM of the CCJ in walk and trot in sound Cavalier King Charles Spaniels and Chihuahuas. The Labrador retriever is used as a reference breed without predisposition for CCJA. This is the first detailed description of CCJ movement of trotting dogs. Biplanar fluoroscopy images, recorded in walking and trotting dogs, were matched to a virtual reconstruction of the skull and cranial cervical spine utilising Scientific Rotoscoping. Kinematic data reveal the same motion patterns among all breeds and gaits with individual temporal and spatial differences in each dog. A stride cycle-dependent lateral rotation of the cranial cervical spine and axial rotation of the atlantoaxial joint in trot in dogs is described for the first time. The ROM of the atlantoaxial and atlantooccipital joints in walk and trot were not statistically significantly greater in the CCJA-predisposed breeds CKCS and Chihuahua. ROM values of all translational and rotational degrees of freedom were larger in walk than trot, although this is only statistically significant for the atlantoaxial joint. Until proven otherwise, a more species-specific than breed-specific general motion pattern of the CCJ in walking and trotting, clinically sound dogs must be assumed. Species-specific anatomic properties of the CCJ seem to supersede breed-specific anatomical differences in clinically sound dogs.

Due to increasing advances in their manufacture and functionalization, nanoparticle-based systems have become a popular tool for in vivo drug delivery and biodetection. Recently, scintillating nanoparticles such as yttrium orthosilicate doped with cerium (Y2(SiO4)O:Ce) have come under study for their potential utility in optogenetic applications, as they emit photons upon low levels of stimulation from remote x-ray sources. The utility of such nanoparticles in vivo is hampered by rapid clearance from circulation by the mononuclear phagocytic system, which heavily restricts nanoparticle accumulation at target tissues. Local transcranial injection of nanoparticles may deliver scintillating nanoparticles to highly specific brain regions by circumventing the blood-brain barrier and avoiding phagocytic clearance. Few studies to date have examined the distribution and response to nanoparticles following localized delivery to cerebral cortex, a crucial step in understanding the therapeutic potential of nanoparticle-based biodetection in the brain. Following the synthesis and surface modification of these nanoparticles, two doses (1 and 3 mg/ml) were introduced into mouse secondary motor cortex (M2). This region was chosen as the site for RLP delivery, as it represents a common target for optogenetic manipulations of mouse behavior, and RLPs could eventually serve as an injectable x-ray inducible light delivery system. The spread of particles through the target tissue was assessed 24 hours, 72 hours, and 9 days post-injection. Y2(SiO4)O:Ce nanoparticles were found to be detectable in the brain for up to 9 days, initially diffusing through the tissue until 72 hours before achieving partial clearance by the final endpoint. Small transient increases in the presence of IBA-1+ microglia and GFAP+ astrocytic cell populations were detected near nanoparticle injection sites of both doses tested 24 hours after surgery. Taken together, these data provide evidence that Y2(SiO4)O:Ce nanoparticles coated with BSA can be injected directly into mouse cortex in vivo, where they persist for days and are broadly tolerated, such that they may be potentially utilized for remote x-ray activated stimulation and photon emission for optogenetic experiments in the near future.

Poison frogs acquire chemical defenses from the environment for protection against potential predators. These defensive chemicals are lipophilic alkaloids that are sequestered by poison frogs from dietary arthropods and stored in skin glands. Despite decades of research focusing on identifying poison frog alkaloids, we know relatively little about how environmental variation and subsequent arthropod availability impacts alkaloid loads in poison frogs. We investigated how seasonal environmental variation influences poison frog chemical profiles through changes in the diet of the Climbing Mantella (Mantella laevigata). We collected M. laevigata females on the Nosy Mangabe island reserve in Madagascar during the wet and dry seasons and tested the hypothesis that seasonal differences in rainfall is associated with changes in diet composition and skin alkaloid profiles of M. laevigata. The arthropod diet of each frog was characterized into five groups (i.e. ants, termites, mites, insect larvae, or other) using visual identification and cytochrome oxidase 1 DNA barcoding. We found that frog diet differed between the wet and dry seasons, where frogs had a more diverse diet in the wet season and consumed a higher percentage of ants in the dry season. To determine if seasonality was associated with variation in frog defensive chemical composition, we used gas chromatography / mass spectrometry to quantify alkaloids from individual skin samples. Although the assortment of identified alkaloids was similar across seasons, we detected significant differences in the abundance of certain alkaloids, which we hypothesize reflects seasonal variation in the diet of M. laevigata. We suggest that these variations could originate from seasonal changes in either arthropod leaf litter composition or changes in frog behavioral patterns. Although additional studies are needed to understand the consequences of long-term environmental shifts, this work suggests that alkaloid profiles are relatively robust against short-term environmental perturbations.

BackgroundThe collagenase of the bacterium Clostridium histolyticum (CCH) is already an established treatment for fibroproliferative diseases like M. Dupuytren and M. Peyronie Although results are comparable to surgical intervention, skin laceration is a severe and relevant side effect. Doxycycline (DOX) recently rose interest as an inhibitor of matrix-metalloproteinases alongside its capabilities of skin accumulation. It therefore might be a potential skin protective agent in the use of CCH.MethodsFor simulation of a fibroproliferative disease adjacent to the skin, we utilized a rodent model of capsular fibrosis involving silicone implants and subsequent fibrotic capsule formation. For in-vitro studies, fibrotic capsules were excised and incubated with 0.9 mg/ml CCH and four different doses of DOX. For in-vivo experiments, animals received 0.0, 0.3 or 0.9 mg/ml CCH injections into the fibrotic capsules with or without prior oral DOX administration. Outcome analysis included histology, immunohistochemistry, gene expression analysis, chemical collagen and DOX concentration measurements as well as μCT imaging.ResultsIn-vitro, DOX showed a dose-dependent inhibition of CCH activity associated with increasing capsule thickness and collagen density and content. In-vivo, oral DOX administration did neither interfere with capsule formation nor in effectiveness of CCH dissolving fibrotic capsule tissue. However, skin thickness and especially collagen density was significantly higher compared to control groups. This led to a reduced rate of clinical skin lacerations after DOX administration.ConclusionDOX inhibits CCH and accumulates in the skin. Thereby, DOX can effectively reduce skin laceration after CCH treatment.

BACKGROUND: Type-D personality, defined as a combination of high negative affect and high social isolation, has been associated with poor health outcomes. However, pathways underlying this association are largely unknown. We investigated the relationship between Type-D personality and several biological and behavioral pathways including the autonomic nervous system, the immune system, glucose regulation and sleep in a large, apparently healthy sample. METHODS: Data from a total of 646 respondents (age 41.6±11.5, 12,2% women) were available for analysis. Persons with Type-D (negative affect and social isolation score ≥10) were contrasted with those without Type-D. Measures of plasma fibrinogen levels, white blood cell count, high sensitivity C-reactive protein, fasting plasma glucose (FPG), cholesterol, high-density and low-density lipoprotein, glycated hemoglobin (HbA1c), creatinine, triglycerides, and albumin were derived from fasting blood samples. Urine norepinephrine and free cortisol were determined by high-performance liquid chromatography. Time-domain heart rate variability (HRV) measures were calculated for the 24hr recording period and for nighttime separately. RESULTS: Persons with Type-D had higher HbA1c, FPG, and fibrinogen, and lower nighttime HRV than those without Type-D, suggesting worse glycemic control, systemic inflammation and poorer autonomic nervous system modulation in Type-D persons. In addition, those with Type-D reported less social support and greater sleep difficulties while no group differences were observed for alcohol and cigarette consumption, physical activity and body mass index. CONCLUSIONS: Findings provide some of the first evidence for multiple possible biological and behavioral pathways between Type-D personality and increased morbidity and mortality.

BackgroundRegular fish and omega-3 consumption may have several health benefits and are recommended by major dietary guidelines. Yet, their intakes remain remarkably variable both within and across populations, which could partly owe to genetic influences.ObjectiveTo identify common genetic variants that influence fish and dietary eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) consumption.DesignWe conducted genome-wide association (GWA) meta-analysis of fish (n = 86,467) and EPA+DHA (n = 62,265) consumption in 17 cohorts of European descent from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium Nutrition Working Group. Results from cohort-specific GWA analyses (additive model) for fish and EPA+DHA consumption were adjusted for age, sex, energy intake, and population stratification, and meta-analyzed separately using fixed-effect meta-analysis with inverse variance weights (METAL software). Additionally, heritability was estimated in 2 cohorts.ResultsHeritability estimates for fish and EPA+DHA consumption ranged from 0.13-0.24 and 0.12-0.22, respectively. A significant GWA for fish intake was observed for rs9502823 on chromosome 6: each copy of the minor allele (FreqA = 0.015) was associated with 0.029 servings/day (~1 serving/month) lower fish consumption (P = 1.96x10-8). No significant association was observed for EPA+DHA, although rs7206790 in the obesity-associated FTO gene was among top hits (P = 8.18x10-7). Post-hoc calculations demonstrated 95% statistical power to detect a genetic variant associated with effect size of 0.05% for fish and 0.08% for EPA+DHA.ConclusionsThese novel findings suggest that non-genetic personal and environmental factors are principal determinants of the remarkable variation in fish consumption, representing modifiable targets for increasing intakes among all individuals. Genes underlying the signal at rs72838923 and mechanisms for the association warrant further investigation.

BACKGROUND: Work stress is associated with an increased risk of pre-diabetes, Type 2 diabetes, and inflammation, as well as decreased autonomic nervous system function as measured, for example, via heart rate variability. We investigated the extent to which the association between work stress and glycemic status is mediated by vagally-mediated heart rate variability (vmHRV) and/or inflammation. METHODS: Cross-sectional data from the Mannheim Industrial Cohort Study (MICS) with 9,937 participants were analyzed. The root mean squared successive differences (RMSSD) from long-term heart rate monitoring during work and night time periods was used to index vmHRV. Fasting plasma glucose and glycosylated hemoglobin were assessed to determine glycemic status. High sensitive C-reactive protein levels were observed as a measure of systemic inflammation and the Effort-Reward-Imbalance scale was used to evaluate work stress. Mediation models were adjusted for age, sex, and occupational status, and estimations were bootstrapped (5,000 replications). RESULTS: Effort-Reward-Imbalance was significantly negatively associated with RMSSD and both glycosylated hemoglobin and fasting plasma glucose during both work and night time periods. Effort-Reward-Imbalance was observed to have a significant direct effect on glycosylated hemoglobin and significant indirect effects, through RMSSD, on both glycemic measures during both time periods. Introducing C-reactive protein as a further mediator to the model did not alter the indirect effects observed. C-reactive protein, as an exclusive mediator, was observed to have smaller direct and indirect effects on the glycemic measures as compared to when Effort-Reward-Imbalance was included in the model. CONCLUSIONS: Our results suggest that the association between work stress and glycemic status is partially mediated through vmHRV independent of systemic inflammation as measured by C-reactive protein. We conclude that work stress may be an additional factor that promotes development of hyperglycemic-metabolic states. If supported by prospective evidence, these results may lead to new approaches for primary prevention of hyperglycemia in the workplace.

Domestication is the hallmark of evolution and civilization and harnesses biodiversity through selection for specific traits. In regions where domesticated lines are grown near wild relatives, congeneric sources of aggressive weedy genotypes cause major economic losses. Thus, the origins of weedy genotypes where no congeneric species occur raise questions regarding management effectiveness and evolutionary mechanisms responsible for weedy population success. Since eradication in the 1970s, California growers avoided weedy rice through continuous flood culture and zero-tolerance guidelines, preventing the import, presence, and movement of weedy seeds. In 2003, after decades of no reported presence in California, a weedy rice population was confirmed in dry-seeded fields. Our objectives were to identify the origins and establishment of this population and pinpoint possible phenotypes involved. We show that California weedy rice is derived from a different genetic source among a broad range of AA genome Oryzas and is most recently diverged from O. sativa temperate japonica cultivated in California. In contrast, other weedy rice ecotypes in North America (Southern US) originate from weedy genotypes from China near wild Oryza, and are derived through existing crop-wild relative crosses. Analyses of morphological data show that California weedy rice subgroups have phenotypes like medium-grain or gourmet cultivars, but have colored pericarp, seed shattering, and awns like wild relatives, suggesting that reversion to non-domestic or wild-like traits can occur following domestication, despite apparent fixation of domestication alleles. Additionally, these results indicate that preventive methods focused on incoming weed sources through contamination may miss burgeoning weedy genotypes that rapidly adapt, establish, and proliferate. Investigating the common and unique evolutionary mechanisms underlying global weed origins and subsequent interactions with crop relatives sheds light on how weeds evolve and addresses broader questions regarding the stability of selection during domestication and crop improvement.

Amidst the therapeutic void at the onset of the COVID-19 pandemic, a critical mass of scientific and clinical interest coalesced around COVID-19 convalescent plasma (CCP). To date, the CCP literature has focused largely on safety and efficacy outcomes, but little on implementation outcomes or experience. Expert opinion suggests that if CCP has a role in COVID-19 treatment, it is early in the disease course, and it must deliver a sufficiently high titer of neutralizing antibodies (nAb). Missing in the literature are comprehensive evaluations of how local CCP programs were implemented as part of pandemic preparedness and response, including considerations of the core components and personnel required to meet demand with adequately qualified CCP in a timely and sustained manner. To address this gap, we conducted an evaluation of a local CCP program at a large U.S. academic medical center, the University of North Carolina Medical Center (UNCMC), and patterned our evaluation around the dimensions of the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to systematically describe key implementation-relevant metrics. We aligned our evaluation with program goals of reaching the target population with severe or critical COVID-19, integrating into the structure of the hospital-wide pandemic response, adapting to shifting landscapes, and sustaining the program over time during a compassionate use expanded access program (EAP) era and a randomized controlled trial (RCT) era. During the EAP era, the UNCMC CCP program was associated with faster CCP infusion after admission compared with contemporaneous affiliate hospitals without a local program: median 29.6 hours (interquartile range, IQR: 21.2-48.1) for the UNCMC CCP program versus 47.6 hours (IQR 32.6-71.6) for affiliate hospitals; (P

Seroprevalence studies can contribute to a better assessment of the actual incidence of infection. Since long-term data for Germany are lacking, we determined the seroprevalence of immunoglobulin G (IgG) antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in residual plasma samples of 3,759 German regular blood donors between July 2020 and June 2021. Over almost the entire study period, the incidences determined based on our data were higher than those officially reported by the Robert Koch Institute, the public health institute in Germany. Using our serological testing strategy, we retrospectively detected natural infection in 206/3,759 (5.48%; 95% confidence interval (CI): 4.77-6.25) individuals. The IgG seroprevalence ranked from 5.15% (95% CI: 3.73-6.89) in Lower Saxony to 5.62% (95% CI: 4.57-6.84) in North Rhine Westphalia. The analyses of follow-up samples of 88 seropositive blood donors revealed a comparable fast decay of binding and neutralizing anti-SARS-CoV-2 IgG antibodies. The antibody avidity remained at a low level throughout the whole follow-up period of up to 181 days. Interestingly, female donors seem to express a stronger and longer lasting humoral immunity against the new coronavirus when compared to males. Conclusion: Overall, our data emphasizes that seroprevalence measurements can and should be used to understand the true incidence of infection better. Further characterization of follow-up samples from seropositive donors indicated rapid antibody waning with sex-specific differences concerning the strength and persistence of humoral immune response.