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Abstract Triple-negative breast cancer (TNBC) is often treated with neoadjuvant systemic therapy (NAST). We investigated if radiomic models based on multiparametric Magnetic Resonance Imaging (MRI) obtained early during NAST predict pathologic complete response (pCR). We included 163 patients with stage I-III TNBC with multiparametric MRI at baseline and after 2 (C2) and 4 cycles of NAST. Seventy-eight patients (48%) had pCR, and 85 (52%) had non-pCR. Thirty-six multivariate models combining radiomic features from dynamic contrast-enhanced MRI and diffusion-weighted imaging had an area under the receiver operating characteristics curve (AUC) > 0.7. The top-performing model combined 35 radiomic features of relative difference between C2 and baseline; had an AUC = 0.905 in the training and AUC = 0.802 in the testing set. There was high inter-reader agreement and very similar AUC values of the pCR prediction models for the 2 readers. Our data supports multiparametric MRI-based radiomic models for early prediction of NAST response in TNBC.

Introduction Chronic hyperglycemia affects neutrophil functions, leading to reduced pathogen killing and increased morbidity. This impairment has been directly linked to increased glycemia, however, how this specifically affects neutrophils metabolism and their differentiation in the bone marrow is unclear and difficult to study.Research design and methods We used high-resolution respirometry to investigate the metabolism of resting and activated donor neutrophils, and flow cytometry to measure surface CD15 and CD11b expression. We then used HL-60 cells differentiated towards neutrophil-like cells in standard media and investigated the effect of doubling glucose concentration on differentiation metabolism. We measured the oxygen consumption rate (OCR), and the enzymatic activity of carnitine palmitoyl transferase 1 (CPT1) and citrate synthase during neutrophil-like differentiation. We compared the surface phenotype, functions, and OCR of neutrophil-like cells differentiated under both glucose concentrations.Results Donor neutrophils showed significant instability of CD11b and OCR after phorbol 12-myristate 13-acetate stimulation at 3 hours post-enrichment. During HL-60 neutrophil-like cell differentiation, there was a significant increase in surface CD15 and CD11b expression together with the loss of mitochondrial mass. Differentiated neutrophil-like cells also exhibited higher CD11b expression and were significantly more phagocytic. In higher glucose media, we measured a decrease in citrate synthase and CPT1 activities during neutrophil-like differentiation.Conclusions HL-60 neutrophil-like differentiation recapitulated known molecular and metabolic features of human neutrophil differentiation. Increased glucose concentrations correlated with features described in hyperglycemic donor neutrophils including increased CD11b and phagocytosis. We used this model to describe metabolic features of neutrophil-like cell differentiation in hyperglycemia and show for the first time the downregulation of CPT1 and citrate synthase activity, independently of mitochondrial mass.

Abstract Background Green space exposures may promote child mental health and well-being across multiple domains and stages of development. The aim of this study was to investigate associations between residential green space exposures and child mental and behavioral health at age 4–6 years. Methods Children’s internalizing and externalizing behaviors in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) cohort in Shelby County, Tennessee, were parent-reported on the Child Behavior Checklist (CBCL). We examined three exposures—residential surrounding greenness calculated as the Normalized Difference Vegetation Index (NDVI), tree cover, and park proximity—averaged across the residential history for the year prior to outcome assessment. Linear regression models were adjusted for individual, household, and neighborhood-level confounders across multiple domains. Effect modification by neighborhood socioeconomic conditions was explored using multiplicative interaction terms. Results Children were on average 4.2 years (range 3.8-6.0) at outcome assessment. Among CANDLE mothers, 65% self-identified as Black, 29% as White, and 6% as another or multiple races; 41% had at least a college degree. Higher residential surrounding greenness was associated with lower internalizing behavior scores (-0.66 per 0.1 unit higher NDVI; 95% CI: -1.26, -0.07) in fully-adjusted models. The association between tree cover and internalizing behavior was in the hypothesized direction but confidence intervals included the null (-0.29 per 10% higher tree cover; 95% CI: -0.62, 0.04). No associations were observed between park proximity and internalizing behavior. We did not find any associations with externalizing behaviors or the attention problems subscale. Estimates were larger in neighborhoods with lower socioeconomic opportunity, but interaction terms were not statistically significant. Conclusions Our findings add to the accumulating evidence of the importance of residential green space for the prevention of internalizing problems among young children. This research suggests the prioritization of urban green spaces as a resource for child mental health.

Innovative conservation approaches are urgently needed to balance biodiversity conservation with human development. Safeguarding elephant populations often involves active management, leading to direct intentional, direct unintentional, and indirect consequences for animals, people, and ecosystems. Drawing from One Health and One Welfare principles, our study introduces a multicriteria framework for developing conservation strategies that enhance well-being across dimensions. This approach establishes priorities, acceptability zones, and One Well-being scores that guide decision making toward optimal outcomes. We applied our One Well-being framework to evaluate 12 elephant management interventions currently or historically used in South Africa. Examining data from 3306 instances of these interventions, including on-the-ground data, we assessed their relative impact on environmental, human, and animal well-being. Our analysis identified 250 consequences of these interventions, categorized as 58 direct intentional, 127 direct unintentional, and 65 indirect. Although most direct intentional consequences were beneficial (93.4%), the direct unintentional and indirect consequences were predominantly harmful (96.9% and 75.4%, respectively). Although most interventions improved environmental well-being, their consequences for animal and human well-being were less positive. This highlights a conflict among the three well-being dimensions, underscoring the importance of incorporating human and animal well-being into elephant management strategies. Recognizing the interconnected nature of these dimensions and aiming for multiple, mutually reinforcing gains is imperative. This iterative process helps address social-ecological vulnerabilities and risks while advocating for ethical conservation practices, fostering multidisciplinary collaboration, and garnering broader support for conservation efforts. Our approach aligns with global goals for sustainable and equitable wildlife management outcomes.

Abstract Background Previous studies have created plant-based diet indices to assess the health effects of specific dietary patterns. Objective To examine the association between the plant-based content of diet and fasting insulin in adults from the NHANES 2017–2018 database. Methods Demographic, dietary, lab and clinical data and fasting insulin were obtained from the NHANES 2017–2018 database. From two 24-h dietary recalls, we created a plant-based diet index (PDI) and a healthy plant-based diet index (hPDI). A high PDI score indicated more plants were consumed versus animal foods. A high hPDI score indicated healthier, plant materials (whole grains, whole fruits, vegetables, legumes, vegetable oils, seeds and nuts) were consumed. The relationships between the natural log of fasting insulin, PDI, and hPDI were analyzed using multiple linear regression adjusting for body mass index (BMI) and alanine aminotransferase (ALT). Results Analyses were based on 1,714 participants, 897 women and 817 men with a median age of 52 years. In this sample, 610 (35.6%) were white, 407 (23.8%) were black, 231 (13.5%) were Mexican, 207 (12.1%) were Asian, 157 (9.2%) were other Hispanic, and 102 (6%) were other or mixed race. Median fasting insulin was 9.74 μU/mL (IQR: 6.2, 15.56). For every 1 unit increase in PDI, the natural log of fasting insulin decreased 0.0068 ± 0.003 μU/mL (CI: -0.00097, -0.013) (p = 0.02). After adjusting for BMI and ALT, the PDI did not significantly predict fasting insulin as the association was not robust due to multicollinearity. The hPDI was inversely and significantly associated with the natural log of fasting insulin (-0.0027 ± 0.00134, CI: -0.000087, -0.0053) (p = 0.043) in a multivariable model including BMI and ALT. Conclusion A healthy plant-based diet is associated with a decrease in fasting insulin levels. Healthfulness of the diet is an important factor when considering the benefit of a plant-based diet.

Abstract Background Inflammation affecting the heart and surrounding tissues is a clinical condition recently reported following COVID-19 mRNA vaccination. Assessing trends of these events related to immunization will improve vaccine safety surveillance and best practices for forthcoming vaccine campaigns. However, the causality is unknown, and the mechanisms associated with cardiac myocarditis are not understood. Case presentation After the first dose, we reported an mRNA vaccine-induced perimyocarditis in a young patient with a history of recurrent myocardial inflammation episodes and progressive loss of cardiac performance. We tested this possible inflammatory cytokine-mediated cardiotoxicity after vaccination in the acute phase (ten days), and we found a significant elevation of MCP-1, IL-18, and IL-8 inflammatory mediators. Still, these cytokines decreased considerably at the recovery phase (42 days later). We used the cardiomyoblasts cell line to test the effect of serum on cell viability, observing that serum from the acute phase reduced the cell viability to 75%. We did not detect this toxicity in cells when we tested serum from the patient in the recovery phase. We also tested serum-induced hypertrophy, a phenomenon in myocarditis and heart failure. We found that acute phase-serum has hypertrophy effects, increasing 25% of the treated cardiac cells’ surface and significantly increasing B-type natriuretic peptide. However, we did not observe the hypertrophic effect in the recovery phase or sera from healthy controls. Conclusion Our results opened the possibility of the inflammatory cytokines or serum soluble mediators as key factors for vaccine-associated myocarditis. In this regard, identifying anti-inflammatory molecules that reduce inflammatory cytokines could help avoid vaccine-induced myocardial inflammation.

Long-and middle-wavelength cone photoreceptors, which are responsible for our visual acuity and color vision, comprise ~95% of our total cone population and are concentrated in the fovea of our retina. Previously, we characterized the disease mechanisms of the L/M-cone opsin missense mutations N94K, W177R, P307L, R330Q and G338E, all of which are associated with congenital blue cone monochromacy (BCM) or color-vision deficiency. Here, we used a similar viral vector-based gene delivery approach in M-opsin knockout mice to investigate the pathogenic consequences of the BCM or color-vision deficient associated L-cone opsin (OPN1LW) mutants K82E, P187S, and M273K. We investigated their subcellular localization, the pathogenic effects on cone structure, function, and cone viability. K82E mutants were detected predominately in cone outer segments, and its expression partially restored expression and correct localization of cone PDE6α’ and cone transducin γ. As a result, K82E also demonstrated the ability to mediate cone light responses. In contrast, expression of P187S was minimally detected by either western blot or by immunohistochemistry, probably due to efficient degradation of the mutant protein. M273K cone opsin appeared to be misfolded as it was primarily localized to the cone inner segment and endoplasmic reticulum. Additionally, M273K did not restore the expression of cone PDE6α’ and cone transducin γ in dorsal cone OS, presumably by its inability to bind 11-cis retinal. Consistent with the observed expression pattern, P187S and M273K cone opsin mutants were unable to mediate light responses. Moreover, expression of K82E, P187S, and M273K mutants reduced cone viability. Due to the distinct expression patterns and phenotypic differences of these mutants observed in vivo, we suggest that the pathobiological mechanisms of these mutants are distinct.

Abstract Background Sweetened beverage intake may play a role in non-alcoholic fatty liver disease (NAFLD) development, but scientific evidence on their role is limited. This study examined associations between sugar-sweetened beverages (SSB), low/no-calorie beverages (LNCB) and fruit juice (FJ) intakes and NAFLD in four European studies. Methods Data for 42,024 participants of Lifelines Cohort, NQPlus, PREDIMED-Plus and Alpha Omega Cohort were cross-sectionally analysed. NAFLD was assessed using Fatty Liver Index (FLI) (≥60). Restricted cubic spline analyses were used to visualize dose–response associations in Lifelines Cohort. Cox proportional hazard regression analyses with robust variance were performed for associations in individual cohorts; data were pooled using random effects meta-analysis. Models were adjusted for demographic, lifestyle, and other dietary factors. Results Each additional serving of SSB per day was associated with a 7% higher FLI-defined NAFLD prevalence (95%CI 1.03–1.11). For LNCB, restricted cubic spline analysis showed a nonlinear association with FLI-defined NAFLD, with the association getting stronger when consuming ≤1 serving/day and levelling off at higher intake levels. Pooled Cox analysis showed that intake of >2 LNCB servings/week was positively associated with FLI-defined NAFLD (PR 1.38, 95% CI 1.15–1.61; reference: non-consumers). An inverse association was observed for FJ intake of ≤2 servings/week (PR 0.92, 95% CI: 0.88–0.97; reference: non-consumers), but not at higher intake levels. Theoretical replacement of SSB with FJ showed no significant association with FLI-defined NAFLD prevalence (PR 0.97, 95% CI 0.95–1.00), whereas an adverse association was observed when SSB was replaced with LNCB (PR 1.12, 95% CI 1.03–1.21). Conclusions Pooling results of this study showed that SSB and LNCB were positively associated with FLI-defined NAFLD prevalence. Theoretical replacement of SSB with LNCB was associated with higher FLI-defined NAFLD prevalence. An inverse association was observed between moderate intake of FJ and FLI-defined NAFLD. Our results should be interpreted with caution as reverse causality cannot be ruled out.

Human papillomavirus (HPV) coopts mitosis for nuclear entry by tethering the viral DNA to mitotic chromosomes, a process facilitated by the viral minor capsid protein L2. Here, Rizzato et al. show that L2 contains conserved phosphorylation motifs within the chromosome-binding region and provide evidence that host master mitotic kinases CDK1 and PLK1 sequentially mediate phosphorylation of L2 at mitosis onset to allow timely tethering of viral DNA to mitotic chromosomes.

Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Neoadjuvant systemic therapy (NAST) followed by surgery are currently standard of care for TNBC with 50-60% of patients achieving pathologic complete response (pCR). We investigated ability of deep learning (DL) on dynamic contrast enhanced (DCE) MRI and diffusion weighted imaging acquired early during NAST to predict TNBC patients’ pCR status in the breast. During the development phase using the images of 130 TNBC patients, the DL model achieved areas under the receiver operating characteristic curves (AUCs) of 0.97 ± 0.04 and 0.82 ± 0.10 for the training and the validation, respectively. The model achieved an AUC of 0.86 ± 0.03 when evaluated in the independent testing group of 32 patients. In an additional prospective blinded testing group of 48 patients, the model achieved an AUC of 0.83 ± 0.02. These results demonstrated that DL based on multiparametric MRI can potentially differentiate TNBC patients with pCR or non-pCR in the breast early during NAST.

Objective:To determine key performance metrics of magnetic resonance imaging (MRI)-guided breast biopsies (MRGB) to help identify reference benchmarks.Materials and Methods:We identified studies reporting MRGB results up to 04.01.2021 in the Embase database, Ovid Medline (R) Process, Other Non-Indexed Citations, Ovid Medline (R) and completed a PRISMA checklist and sources of bias (QUADAS-2). The inclusion criteria were English language, available histopathological outcomes, or at least one imaging follow-up after biopsy. A random intercept logistic regression model was used to pool rates. Between-study heterogeneity was quantified by the I2 statistic.Results:A total of 11,215 lesions in 50 articles were analyzed. The technical success rate was 99.10% [95% confidence interval (CI): 97.89–99.62%]. The MRI indications were staging in 1,496 (28.05%, 95% CI: 26.85–29.28%), screening in 1,427 (26.76%, 95% CI: 25.57–27.97%), surveillance in 1,027 (19.26%, 95% CI: 18.21–20.34%), diagnostic in 1,038 (19.46%, 95% CI: 18.41–20.55%), unknown primary in 74 (1.39%, 95% CI: 1.09–1.74%), and other in 271 (5.08%, 95% CI: 4.51–5.71%). Histopathology was benign in 65.06% (95% CI: 59.15–70.54%), malignant in 29.64% (95% CI: 23.58–36.52%) and high risk in 16.69% (95% CI: 9.96–26.64%). Detection of malignancy was significantly lower in those patients who underwent MRI for screening purposes (odds ratio 0.47, 95% CI: 0.25–0.87; p = 0.02), while mass lesions were more likely to yield malignancy compared to non-mass and foci [27.39% vs 11.36% (non-mass),18.03% (foci); p

Abstract Background Physical activity is recommended for all pregnant individuals and can prevent excessive gestational weight gain. However, physical activity has not been assessed among military personnel and other TRICARE beneficiaries, who experience unique military lifestyles. The current study assessed physical activity among pregnant TRICARE beneficiaries, both active duty and non-active duty, as measured by accelerometry and self-report data to examine potential predictors of physical activity engagement in the third trimester, and if self-report data was consistent with accelerometry data. We expected having a lower BMI, being active-duty, and having higher baseline physical activity engagement to be associated with higher physical activity at 32-weeks. We also hypothesized that accelerometry data would show lower physical activity levels than the self-reported measure. Methods Participants were 430 TRICARE adult beneficiaries (204 Active Duty; 226 non-Active Duty) in San Antonio, TX who were part of a randomized controlled parent study that implemented a stepped-care behavioral intervention. Participants were recruited if they were less than 12-weeks gestation and did not have health conditions precluding dietary or physical activity changes (e.g., uncontrolled cardiovascular conditions) or would contribute to weight changes. Participants completed self-report measures and wore an Actical Activity Monitor accelerometer on their wrist to collect physical activity data at baseline and 32-weeks gestation. Results Based on the accelerometer data, 99% of participants were meeting moderate physical activity guidelines recommending 150 min of moderate activity per week at baseline, and 96% were meeting this recommendation at 32-weeks. Based on self-report data, 88% of participants at baseline and 92% at 32-weeks met moderate physical activity recommendations. Linear regression and zero-inflated negative binomial models indicated that baseline physical activity engagement predicted moderate physical activity later in pregnancy above and beyond BMI and military status. Surprisingly, self-reported data, but not accelerometer data, showed that higher baseline activity was associated with decreased vigorous activity at 32-weeks gestation. Additionally, self-report and accelerometry data had small correlations at baseline, but not at 32-weeks. Conclusions Future intervention efforts may benefit from intervening with individuals with lower pre-pregnancy activity levels, as those who are active seem to continue this habit. Trial Registration The trial is registered on clinicaltrials.gov (NCT 03057808).

Abstract Background Breastmilk is a dynamic fluid whose initial function is to provide the most adapted nutrition to the neonate. Additional attributes have been recently ascribed to breastmilk, with the evidence of a specific microbiota and the presence of various components of the immune system, such as cytokines and leukocytes. The composition of breastmilk varies through time, according to the health status of mother and child, and altogether contributes to the future health of the infant. Obesity is a rising condition worldwide that creates a state of systemic, chronic inflammation including leukocytosis. Here, we asked whether colostrum, the milk produced within the first 48 h post-partum, would contain a distinct leukocyte composition depending on the body mass index (BMI) of the mother. Methods We collected peripheral blood and colostrum paired samples from obese (BMI > 30) and lean (BMI < 25) mothers within 48 h post-partum and applied a panel of 6 antibodies plus a viability marker to characterize 10 major leukocyte subpopulations using flow cytometry. Results The size, internal complexity, and surface expression of CD45 and CD16 of multiple leukocyte subpopulations were selectively regulated between blood and colostrum irrespective of the study groups, suggesting a generalized cell-specific phenotype alteration. In obesity, the colostrum B lymphocyte compartment was significantly reduced, and CD16+ blood monocytes had an increased CD16 expression compared to the lean group. Conclusions This is the first characterization of major leukocyte subsets in colostrum of mothers suffering from obesity and the first report of colostrum leukocyte subpopulations in Latin America. We evidence various significant alterations of most leukocyte populations between blood and colostrum and demonstrate a decreased colostrum B lymphocyte fraction in obesity. This pioneering study is a stepping stone to further investigate active immunity in human breastmilk.

Abstract The gold-standard method to evaluate a functional antiviral immune response is to titer neutralizing antibodies (NAbs) against a viral pathogen. This is historically performed using an in vitro assay of virus-mediated infection, which requires BSL-3 facilities. As these are insufficient in Latin American countries, including Mexico, scant information is obtained locally about viral pathogens NAb, using a functional assay. An alternative solution to using a BSL-3 assay with live virus is to use a BSL-2-safe assay with a non-replicative pseudovirus. Pseudoviral particles can be engineered to display a selected pathogen’s entry protein on their surface, and to deliver a reporter gene into target cells upon transduction. Here we comprehensively describe the first development of a BSL-2 safe NAbs-measuring functional assay in Mexico, based on the production of pseudotyped lentiviral particles. As proof-of-concept, the assay is based on Nanoluc luciferase-mediated luminescence measurements from target cells transduced with SARS-CoV-2 Spike-pseudotyped lentiviral particles. We applied the optimized assay in a BSL-2 facility to measure NAbs in 65 serum samples, which evidenced the assay with 100% sensitivity, 86.6% specificity and 96% accuracy. Overall, this is the first report of a BSL-2 safe pseudovirus-based functional assay developed in Mexico to measure NAbs, and a cornerstone methodology necessary to measure NAbs with a functional assay in limited resources settings.

Theoretical and empirical studies discover that an integrative approach is particularly important in chronic disorders and multiple long-term conditions, such as chronic fatigue. Chronic fatigue syndrome (CFS) is a classic example of a potentially severe, multisystemic illness with a wide diversity of symptoms and the corresponding diagnostic complexity. The prevalence of CFS-like syndromes expanded in the context of the COVID-19 pandemic, increasing the disorder and treatment burden. Thus, this article aimed to draw attention to the possibilities to strengthen the integrative approach to diagnosing and treating chronic disorders and multiple long-term conditions. The main critical success factors identified for integrative approaches were: a holistic approach, that provides a more comprehensive diagnostic and personalized treatment strategy, a multidisciplinary team, and patient engagement. The strengths and weaknesses of these factors were explored and coaching was identified as a potential unifying and reinforcing element. Coaching has a wide spectrum of manifestations clearly representing a holistic approach, that has been successfully used in multidisciplinary team building. Moreover, coaching exposes support addressing the patient engagement issues identified by the Patient Needs-Resources Model (PN-R Model) such as low levels of self-efficacy, optimism, and subjective well-being. Coaching may assist patients to identify and prioritize their goals, becoming aware of their personal resources, developing strategies for managing symptoms, and building skills to increase their self-efficacy and active engagement in the treatment process. Therefore, the authors emphasize coaching as a perspective element of optimization of patient care, that requires additional theoretical and long-term empirical research.

Background and purposeIn breast cancer patients, the increasing de-escalation of axillary surgery and the improving resolution of diagnostic imaging results in a more frequent detection of residual, radiographically suspect lymph nodes (sLN) after surgery. If resection of the remaining suspect lymph nodes is not feasible, a simultaneous boost to the lymph node metastases (LN-SIB) can be applied. However, literature lacks data regarding the outcome and safety of this technique.Materials and methodsWe included 48 patients with breast cancer and sLN in this retrospective study. All patients received a LN-SIB. The median dose to the breast or chest wall and the lymph node system was 50.4 Gy in 28 fractions. The median dose of the LN-SIB was 58.8 Gy / 2.1 Gy (56-63 Gy / 2-2.25 Gy). The brachial plexus was contoured in every case and the dose within the plexus PRV (+0.3-0.5mm) was limited to an EQD2 of 59 Gy. All patients received structured radiooncological and gynecological follow-up by clinically experienced physicians. Radiooncological follow-ups were at baseline, 6 weeks, 3 months, 6 months and subsequent annually after irradiation.ResultsThe median follow-up time was 557 days and ranged from 41 to 3373 days. Overall, 28 patients developed I°, 18 patients II° and 2 patients III° acute toxicity. There were no severe late side effects (≥ III°) observed during the follow-up period. The most frequent chronic side effect was fatigue. One patient (2.1 %) developed pain and mild paresthesia in the ipsilateral arm after radiotherapy. After a follow-up of 557 days (41 to 3373 days), in 8 patients a recurrence was observed (16.7%). In 4 patients the recurrence involved the regional lymph node system. Hence, local control in the lymph node drainage system after a median follow-up of 557 days was 91.6 %.ConclusionIf surgical re-dissection of residual lymph nodes is not feasible or refused by the patient, LN-SIB-irradiation can be considered as a potential treatment option. However, patients need to be informed about a higher risk of regional recurrence compared to surgery and an additional risk of acute and late toxicity compared to adjuvant radiotherapy without regional dose escalation.

Abstract Background There is a continuing risk for COVID-19 transmission in school settings while transmission is ongoing in the community, particularly among unvaccinated populations. To ensure that schools continue to operate safely and to inform implementation of prevention strategies, it is imperative to gain better understanding of the risk behaviors of staff and students. This secondary analysis describes the prevalence of COVID-19 risk behaviors in an exposed population of students and school staff in the pre-vaccine era and identifies associations between these behaviors and testing positive for SARS-CoV-2. Methods From December 2020–January 2021, school staff and students exposed to confirmed COVID-19 cases in a Georgia school district were tested for SARS-CoV-2 and surveyed regarding risk behaviors in and out of school. Prevalence of risk behaviors was described by age group and school level, and associations with SARS-CoV-2 positivity were identified using chi squared tests. Results Overall, 717 students and 79 school staff participated in the investigation; SARS-CoV-2 positivity was 9.2%. In the 2 weeks prior to COVID-19 exposure, 24% of participants reported unmasked indoor time at school, 40% attended social gatherings with non-household members, and 71% visited out-of-school indoor locations, including 19% who ate indoors in restaurants. Frequencies of risk behaviors increased by age. Among students, 17% participated in school sports, of whom 86% participated without a mask. SARS-CoV-2 positivity was significantly associated with school sports and unmasked time in sports. Among K-5 students, positivity was associated with exposure to a teacher index case. Conclusions This analysis highlights the high prevalence of risk behaviors in an unvaccinated population exposed to COVID-19 in school and identifies an association between student sports participation and SARS-CoV-2 positivity. These findings illustrate the importance of school-level prevention measures to reduce SARS-CoV-2 transmission, including limiting close-contact indoor sports and promoting consistent mask use in unvaccinated individuals. Future research could explore the role of community vaccination programs as a strategy to reduce COVID-19 transmission and introductions into school settings.

Breast implants can be removed with breast explantation surgery (BES) for various reasons, including patient dissatisfaction, capsular contracture, implant infection or rupture, breast implant-associated anaplastic large cell lymphoma, and a recently emerging phenomenon called breast implant illness. There is very limited data on the imaging appearance after BES. A retrospective chart review was performed for patients with BES findings on imaging reports for the period between October 2016 and October 2021. When assessing BES techniques, a key element is determining whether the implant’s fibrous capsule requires removal. The second important question is if the patient requires an additional aesthetic procedure after BES. BES techniques include capsulotomy, and partial, total, or en bloc capsulectomy. Adjunctive aesthetic or reconstructive procedures after BES include fat grafting, mastopexy, augmentation, and reconstruction with flaps. The majority of post-BES breast imaging findings are related to the surgical scar/bed, thereby confirming that the type of explantation surgery is important. Imaging findings after BES include focal and global asymmetries, architectural distortions, calcifications, calcified and non-calcified fat necrosis, masses, hematomas, seromas, capsular calcifications, and silicone granulomas. Most importantly, since these patients have residual breast tissue, paying attention to imaging features that are suspicious for breast cancer is necessary.

Abstract Recovery and remission rates of adolescent anorexia nervosa (AN) following Family Based Treatment (FBT) have seen a relative decline over recent years. While reasonably successful in achieving physical recovery (i.e. weight restoration), both empirical and anecdotal accounts highlight a lack of attention to the psychological recovery of the adolescent within manualised FBT. As such, there is a need for innovation to explore treatment variations and alternatives for the proportion of adolescents with AN who do not respond favourably to this first-line treatment. This paper introduces a new treatment framework to the field for clinical consideration and empirical assessment. Adolescent and Parent Treatment (APT) for adolescent AN draws from both family-based and individual treatment models, applying a developmental lens. APT attends to physical and psychological recovery simultaneously and from the start of treatment, with capacity to tailor individual psychological modules to the adolescent formulation. While clearly in its infancy, APT provides an exciting new avenue for exploration within the field, as we seek new avenues to support young people and their families to effectively combat this deadly illness.

Background/MethodsProspective studies investigating sweet beverages and body weight associations show inconsistent results. Within the SWEET project, we examined prospective dose-response associations of sugar-sweetened beverages (SSB), low/no-calorie beverages (LNCB), and fruit juice with body weight-related outcomes among 78,286 Dutch adults followed for ~4 years. Baseline intakes were assessed using a validated food-frequency questionnaire (FFQ) with 150 ml representing a standard serving. Outcome variables were body weight change, waist circumference change, overweight/obesity, and abdominal obesity. Associations were investigated by using linear and non-linear dose-response analysis, as well as substitution models while adjusting for multiple socio-demographic, lifestyle, health, and dietary variables.ResultsParticipants were 46 ± 13 (mean ± SD) years old and 60% were women. Adjusted dose-response analyzes indicated an association between SSB and LNCB, and both body weight (+0.02 kg/year; SE 0.01 and +0.06 kg/year; SE 0.01) and waist circumference changes (+0.04 cm/year; SE: 0.01 and +0.11 cm/year; SE: 0.01). Associations for overweight/obesity and abdominal obesity incidence were +3% (95%CI: 1.00–1.06) and +2% (95%CI: 0.99–1.06) for SSB and +8% (95%CI: 1.06–1.11) and +5% (95%CI: 1.03–1.07) for LNCB, respectively. Substitution of SSB with LNCB was associated with higher weight change (+0.04 kg/year), waist circumference change (+0.09 cm/year), overweight/obesity incidence (+6%), but not abdominal obesity incidence. For fruit juice, we observed beneficial associations for intake levels below ~1 serving/day with weight, waist circumference change, and overweight/obesity incidence, and no association with abdominal obesity. Subsequent substitution analyzes indicated a small beneficial association for the replacement of SSB with fruit juice on weight (−0.04 kg/year) and waist circumference (−0.04 cm/year), but not with other outcomes.ConclusionsOverall, our results suggest that habitual consumption of both SSB and LNCB may adversely affect weight-related outcomes. In contrast, fruit juice consumption

Abstract Background Culicoides biting midges (Diptera: Ceratopogonidae) are biological vectors of internationally important arboviruses and inflict biting nuisance on humans, companion animals and livestock. In temperate regions, transmission of arboviruses is limited by temperature thresholds, in both replication and dissemination of arboviruses within the vector and in the flight activity of adult Culicoides. This study aims to determine the cold-temperature thresholds for flight activity of Culicoides from the UK under laboratory conditions. Methods Over 18,000 Culicoides adults were collected from the field using 4 W down-draught miniature ultraviolet Centers for Disease Control traps. Populations of Culicoides were sampled at three different geographical locations within the UK during the summer months and again in the autumn at one geographical location. Activity at constant temperatures was assessed using a bioassay that detected movement of adult Culicoides towards an ultraviolet light source over a 24-h period. Results The proportion of active adult Culicoides increased with temperature but cold temperature thresholds for activity varied significantly according to collection season and location. Populations dominated by the subgenus Avaritia collected in South East England had a lower activity threshold temperature in the autumn (4 °C) compared with populations collected in the summer (10 °C). Within the subgenus Avaritia, Culicoides scoticus was significantly more active across all temperatures tested than Culicoides obsoletus within the experimental setup. Populations of Culicoides impunctatus collected in the North East of England were only active once temperatures reached 14 °C. Preliminary data suggested flight activity of the subgenus Avaritia does not differ between populations in South East England and those in the Scottish Borders. Conclusions These findings demonstrate seasonal changes in temperature thresholds for flight and across different populations of Culicoides. These data, alongside that defining thresholds for virus replication within Culicoides, provide a primary tool for risk assessment of arbovirus transmission in temperate regions. In addition, the study also provides a comparison with thermal limits derived directly from light-suction trapping data, which is currently used as the main method to define adult Culicoides activity during surveillance.

Abstract Background Culicoides biting midges are biological vectors of arboviruses including bluetongue virus (BTV), Schmallenberg virus (SBV) and African horse sickness virus (AHSV). Zoos are home to a wide range of ‘at risk’ exotic and native species of animals. These animals have a high value both in monetary terms, conservation significance and breeding potential. To understand the risk these viruses pose to zoo animals, it is necessary to characterise the Culicoides fauna at zoos and determine which potential vector species are feeding on which hosts. Methods Light-suction traps were used at two UK zoos: the Zoological Society of London (ZSL) London Zoo (LZ) and ZSL Whipsnade Zoo (WZ). Traps were run one night each week from June 2014 to June 2015. Culicoides were morphologically identified to the species level and any blood-fed Culicoides were processed for blood-meal analysis. DNA from blood meals was extracted and amplified using previously published primers. Sequencing was then carried out to determine the host species. Results A total of 11,648 Culicoides were trapped and identified (n = 5880 from ZSL WZ; n = 5768 from ZSL LZ), constituting 25 different species. The six putative vectors of BTV, SBV and AHSV in northern Europe were found at both zoos and made up the majority of the total catch (n = 10,701). A total of 31 host sequences were obtained from blood-fed Culicoides. Culicoides obsoletus/C. scoticus, Culicoides dewulfi, Culicoides parroti and Culicoides punctatus were found to be biting a wide range of mammals including Bactrian camels, Indian rhinoceros, Asian elephants and humans, with Culicoides obsoletus/C. scoticus also biting Darwin’s rhea. The bird-biting species, Culicoides achrayi, was found to be feeding on blackbirds, blue tits, magpies and carrion crows. Conclusions To our knowledge, this is the first study to directly confirm blood-feeding of Culicoides on exotic zoo animals in the UK and shows that they are able to utilise a wide range of exotic as well as native host species. Due to the susceptibility of some zoo animals to Culicoides-borne arboviruses, this study demonstrates that in the event of an outbreak of one of these viruses in the UK, preventative and mitigating measures would need to be taken.

South Africa has many fenced reserves harbouring small to medium sized populations of African elephant (Loxodonta africana), most of which have been translocated. Elephants on fenced reserves may be exposed to various management interventions and practices (translocation, hunting, darting, high tourism impact, contraception programs, disruption due to infrastructure maintenance, etc.). These factors may impact the welfare of elephants. Poor elephant welfare may have serious consequences such as increased inter- and intra-species aggression that could result in fatalities. This is the first study to attempt to define behavioural and physiological welfare parameters for free-ranging elephants on small to medium sized reserves. The eight study sites incorporated reserves with different social structure combinations, elephant life-histories, reserve sizes, habitat, management, and tourism intensity. Data collection consisted of behavioural observations (10-minute videos) as well as faecal samples. By incorporating both behavioural and physiological (faecal glucocorticoid metabolite (fGCM) concentration) parameters, we aimed to investigate whether the two parameters showed similar trends. Five behavioural categories were identified (Arousal, Assessing, Ambivalent, Ambivalent/ Body care, and Frustrated behaviour), with various detailed behaviours demonstrated by the elephants that may indicate the influence of anthropogenic disturbance and possibly impact on animal welfare. The study showed significant differences between the selected detailed behaviours, behavioural categories and fGCM concentrations of elephants across the eight reserves. History seemed to be a decisive factor, as reserves with predominantly ex-captive elephants showed higher frequencies of certain behaviours as well as higher fGCM concentrations. Age, sex, reserve size and season were also found to contribute to our defined welfare indices and fGCM concentrations. This indicates that behavioural parameters, indicative of certain behavioural states, are valuable indicators of welfare, as supported by the physiological response of the elephants. The results also highlight the importance of taking multiple specified behaviours from a category into consideration when evaluating the welfare of elephants, to account for individual variation.

African elephants (Loxodonta africana) exhibit a long developmental period during which they acquire complex social and ecological knowledge through social networks. Central to this is that matriarchs and older individuals play an important role as repositories of information gained through experience. Anthropogenic interventions—including poaching, culling, translocation, and hunting—can disrupt elephants’ social networks, with implications for individual fitness and potential long-term population viability. Here, we draw on a unique long-running, individual-based dataset to examine the impacts of translocation on a population of elephants in South Africa, taking into consideration demographic rates, social dynamics, and ecological decision-making. Specifically, we compared two translocated groups: a group of unrelated culling Orphans and a family herd. We found that the Orphan group experienced accelerated reproductive rates when compared with the family herd. The Orphan group also fissioned more frequently and for longer periods of time, suggesting lower cohesiveness, and were less decisive in their large-scale movement decisions. These results add to the growing body of literature on the downstream impacts of social disruption for elephants. Whilst the translocation of culling Orphans is no longer practised in South Africa, we encourage careful consideration of any elephant translocation and the resulting social disruption.

Background: Cancer cachexia is a severe metabolic disorder characterized by progressive weight loss along with a dramatic loss in skeletal muscle and adipose tissue. Like cancer, cachexia progresses in stages starting with pre-cachexia to cachexia and finally to refractory cachexia. In the refractory stage, patients are no longer responsive to therapy and management of weight loss is no longer possible. It is therefore critical to detect cachexia as early as possible. In this study we applied a metabolomics approach to search for early biomarkers of cachexia.Methods: Multi-platform metabolomics analyses were applied to the murine Colon-26 (C26) model of cachexia. Tumor bearing mice (n = 5) were sacrificed every other day over the 14-day time course and control mice (n = 5) were sacrificed every fourth day starting at day 2. Linear regression modeling of the data yielded metabolic trajectories that were compared with the trajectories of body weight and skeletal muscle loss to look for early biomarkers of cachexia.Results: Weight loss in the tumor-bearing mice became significant at day 9 as did the loss of tibialis muscle. The loss of muscle in the gastrocnemius and quadriceps was significant at day 7. Reductions in amino acids were among the earliest metabolic biomarkers of cachexia. The earliest change was in methionine at day 4. Significant alterations in acylcarnitines and lipoproteins were also detected several days prior to weight loss.Conclusion: The results of this study demonstrate that metabolic alterations appear well in advance of observable weight loss. The earliest and most significant alterations were found in amino acids and lipoproteins. Validation of these results in other models of cachexia and in clinical studies will pave the way for a clinical diagnostic panel for the early detection of cachexia. Such a panel would provide a tremendous advance in cachectic patient management and in the design of clinical trials for new therapeutic interventions.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy partly due to frequent, severe cachexia. Serum activin correlates with cachexia and mortality, while exogenous activin causes cachexia in mice. Methods Isoform‐specific activin expression and activities were queried in human and murine tumours and PDAC models. Activin inhibition was by administration of soluble activin type IIB receptor (ACVR2B/Fc) and by use of skeletal muscle specific dominant negative ACVR2B expressing transgenic mice. Feed‐forward activin expression and muscle wasting activity were tested in vivo and in vitro on myotubes. Results Murine PDAC tumour‐derived cell lines expressed activin‐βA but not activin‐βB. Cachexia severity increased with activin expression. Orthotopic PDAC tumours expressed activins, induced activin expression by distant organs, and produced elevated serum activins. Soluble factors from PDAC elicited activin because conditioned medium from PDAC cells induced activin expression, activation of p38 MAP kinase, and atrophy of myotubes. The activin trap ACVR2B/Fc reduced tumour growth, prevented weight loss and muscle wasting, and prolonged survival in mice with orthotopic tumours made from activin‐low cell lines. ACVR2B/Fc also reduced cachexia in mice with activin‐high tumours. Activin inhibition did not affect activin expression in organs. Hypermuscular mice expressing dominant negative ACVR2B in muscle were protected for weight loss but not mortality when implanted with orthotopic tumours. Human tumours displayed staining for activin, and expression of the gene encoding activin‐βA (INHBA) correlated with mortality in patients with PDAC, while INHBB and other related factors did not. Conclusions Pancreatic adenocarcinoma tumours are a source of activin and elicit a systemic activin response in hosts. Human tumours express activins and related factors, while mortality correlates with tumour activin A expression. PDAC tumours also choreograph a systemic activin response that induces organ‐specific and gene‐specific expression of activin isoforms and muscle wasting. Systemic blockade of activin signalling could preserve muscle and prolong survival, while skeletal muscle‐specific activin blockade was only protective for weight loss. Our findings suggest the potential and need for gene‐specific and organ‐specific interventions. Finally, development of more effective cancer cachexia therapy might require identifying agents that effectively and/or selectively inhibit autocrine vs. paracrine activin signalling.

Abstract Background Cancer cachexia is a metabolic disorder involving perturbed energy balance and altered mitochondrial function. Chemotherapy is a primary treatment option for many types of cancer, but there is substantial evidence that some chemotherapeutic agents can also lead to the development and progression of cachexia. In this study, we apply a comprehensive and systems level metabolomics approach to characterize the metabolic perturbations in murine models of cancer‐induced and chemotherapy‐induced cachexia. Knowledge of the unique pathways through which cancer and chemotherapy drive cachexia is necessary in order to develop effective treatments. Methods The murine Colon26 (C26) adenocarcinoma xenograft model was used to study the metabolic derangements associated with cancer‐induced cachexia. In vivo administration of Folfiri (5‐fluorouracil, irinotecan, and leucovorin) was used to model chemotherapy‐induced cachexia. Comprehensive metabolic profiling was carried out using both nuclear magnetic resonance‐based and mass spectrometry‐based platforms. Analyses included plasma, muscle, and liver tissue to provide a systems level profiling. Results The study involved four groups of CD2F1 male mice (n = 4–5), including vehicle treated (V), C26 tumour hosts (CC), Folfiri treated (F), and C26 tumour hosts treated with Folfiri (CCF). Significant weight loss including skeletal muscle was observed for each of the experimental groups with the tumour hosts showing the most dramatic change (−3.74 g vs. initial body weight in the CC group). Skeletal muscle loss was evident in all experimental groups compared with V, with the CCF combination resulting in the most severe depletion of quadriceps mass (−38% vs. V; P

Objective:. A prospective, phase IV study was conducted to assess the effectiveness of Magseed to localize breast lesions requiring surgical excision. Background:. Since Food and Drug Administration approval in 2016, Magseed has been increasingly used to localize nonpalpable lesions due to advantages over wires or radioactive seeds. This is the first prospective, postmarketing trial of Magseed. Methods:. From January 2017 to February 2018, 107 women with lesions requiring localization were enrolled at a single institution. Primary endpoint was Magseed retrieval rate. Secondary endpoints were adverse events, accuracy of placement, surgery duration, and positive margin rate. Clinicians were surveyed for ease of use using a Likert scale. Descriptive statistics and Fisher exact test were performed to assess univariable associations with positive margins. Results:. There were 124 Magseeds placed including 1 marker in 93 subjects, 2 markers in 11, and 3 markers in 3. The majority of lesions were masses (63%) followed by calcifications (24%). All 124 Magseeds were placed within 10 mm of the target lesion and surgically retrieved with median operative time of 15 minutes (range, 4–47). No device-related adverse events occurred. Of the 98 malignant lesions, 9 had positive margins and 7 of them underwent a second surgery for additional margins. On univariable analysis, age ≤50 (25.0% vs 6.4%, P = 0.04), lesion histology (P = 0.03), and pathologic T stage (P = 0.04) were significantly associated with positive margins. Clinicians rated the Magseed very or fairly easy to use in most cases. Conclusions:. The Magseed system for localization of nonpalpable lesions was effective and safe; all markers were successfully retrieved with margin-negative resections in 91%. This study supports use of Magseed for localization of breast lesions.

The health issue addressed is the unmet need to universally screen and treat depression, which is one of the most common mental health disorders among adults in the United States. The US Preventive Services Task Force recommends screening adults for depression in primary care and using evidence-based protocols. This quality improvement project implemented VitalSign6, a measurement-based care program, to improve depression screening and treatment of adults in primary care at an academic medical center. A pre-post design was used to determine effectiveness of changes in screening, outcomes, and satisfaction. Of 1200 unique adult patients, 95.4% received initial screening. Providers diagnosed and administered measurement-based care to 236 patients. After 14 weeks, 27.5% returned for at least 1 follow-up. Results showed a statistically significant decrease in self-reported depression scores from baseline to follow-up. VitalSign6 was effective in improving identification and management of depression in primary care.

Cell therapy products exhibit great therapeutic potential but come with a deterring price tag partly caused by their costly manufacturing processes. The development of strategies that lead to cost-effective cell production is key to expand the reach of cell therapies. Growth factors are critical culture media components required for the maintenance and differentiation of cells in culture and are widely employed in cell therapy manufacturing. However, they are expensive, and their common use in soluble form is often associated with decreased stability and bioactivity. Immobilization has emerged as a possible strategy to optimize growth factor use in cell culture. To date, several immobilization techniques have been reported for attaching growth factors onto a variety of biomaterials, but these have been focused on tissue engineering. This review briefly summarizes the current landscape of cell therapy manufacturing, before describing the types of chemistry that can be used to immobilize growth factors for cell culture. Emphasis is placed to identify strategies that could reduce growth factor usage and enhance bioactivity. Finally, we describe a case study for stem cell factor.

This is a consensual multi-dyadic exploration of the diverse perspectives of seven community subgroups’ perceptions of events before, during, and after the 2014 police-involved shooting death of Michael Brown, Jr. in Ferguson, Missouri. Recognizing an enacted environment in the complex history that preceded the uprising, findings were contextualized and framed through the cosmology episode trauma model. A multicultural and visibly diverse research team conducted 34 interviews with involved citizens (protesters), law enforcement, clergy, politicians, business owners, media personnel, and educators. A culturally diverse cross-analysis team triangulated social perspective through consensus coding and audit. Consensual multi-dyadic method preserved the unique characteristics of each subgroup’s phenomenology, to ensure culturally sensitive and decolonized research methods, enabling an in depth look at the factors necessary for conciliation. Insight into motivational factors, narrative meaning-making, and implications for intervention and treatment are discussed.

Abstract Background Following the emergence of Schmallenberg virus (SBV) in Ireland in 2012, a sentinel herd surveillance program was established in the south of Ireland with the primary aim of investigating the species composition and abundance of Culicoides on livestock farms in the region. Methods Ultraviolet-light trapping for Culicoides was carried out on 10 sentinel farms. Each site was sampled fortnightly over 16 weeks (21st July to 5th November 2014). One Onderstepoort Veterinary Institute UV light trap was run overnight at each site and catches were transferred immediately into 70% ethanol. Culicoides were morphologically identified to species level. Collection site habitats were characterised using the Phase 1 habitat survey technique (Joint Nature Conservation Committee). Results A total of 23,929 individual Culicoides from 20 species was identified, including one species identified in Ireland for the first time, Culicoides cameroni. The most abundant species identified were Culicoides obsoletus/Culicoides scoticus (38%), Culicoides dewulfi (36%), Culicoides pulicaris (9%), Culicoides chiopterus (5%) and Culicoides punctatus (5%), comprising 93% of all Culicoides specimens identified. Collection site habitats were dominated by improved grassland and a combination of broadleaf woodland and native woodland species. Conclusions The most abundant species of Culicoides identified were the putative vectors of bluetongue virus (BTV) and SBV in northern Europe. Their presence and abundance demonstrates the potential for future transmission of arboviruses among livestock in this region.

Abstract Background Cachexia frequently occurs in women with advanced ovarian cancer (OC), along with enhanced inflammation. Despite being responsible for one third of all cancer deaths, cachexia is generally under‐studied in OC due to a limited number of pre‐clinical animal models. We aimed to address this gap by characterizing the cachectic phenotype in a mouse model of OC. Methods Nod SCID gamma mice (n = 6–10) were injected intraperitoneally with 1 × 107 ES‐2 human OC cells to mimic disseminated abdominal disease. Muscle size and strength, as well as bone morphometry, were assessed. Tumour‐derived effects on muscle fibres were investigated in C2C12 myotube cultures. IL‐6 levels were detected in serum and ascites from tumour hosts, as well as in tumour sections. Results In about 2 weeks, ES‐2 cells developed abdominal tumours infiltrating omentum, mesentery, and adjacent organs. The ES‐2 tumours caused severe cachexia with marked loss of body weight (–12%, P < 0.01) and ascites accumulation in the peritoneal cavity (4.7 ± 1.5 mL). Skeletal muscles appeared markedly smaller in the tumour‐bearing mice (approximately –35%, P < 0.001). Muscle loss was accompanied by fibre atrophy, consistent with reduced muscle cross‐sectional area (–34%, P < 0.01) and muscle weakness (–50%, P < 0.001). Body composition assessment by dual‐energy X‐ray absorptiometry revealed decreased bone mineral density (–8%, P < 0.01) and bone mineral content (–19%, P < 0.01), also consistent with reduced trabecular bone in both femurs and vertebrae, as suggested by micro‐CT imaging of bone morphometry. In the ES‐2 mouse model, cachexia was also associated with high tumour‐derived IL‐6 levels in plasma and ascites (26.3 and 279.6 pg/mL, respectively) and with elevated phospho‐STAT3 (+274%, P < 0.001), reduced phospho‐AKT (–44%, P < 0.001) and decreased mitochondrial proteins, as well as with increased protein ubiquitination (+42%, P < 0.001) and expression of ubiquitin ligases in the skeletal muscle of tumour hosts. Similarly, ES‐2 conditioned medium directly induced fibre atrophy in C2C12 mouse myotubes (–16%, P < 0.001), consistent with elevated phospho‐STAT3 (+1.4‐fold, P < 0.001) and altered mitochondrial homoeostasis and metabolism, while inhibition of the IL‐6/STAT3 signalling by means of INCB018424 was sufficient to restore the myotubes size. Conclusions Our results suggest that the development of ES‐2 OC promotes muscle atrophy in both in vivo and in vitro conditions, accompanied by loss of bone mass, enhanced muscle protein catabolism, abnormal mitochondrial homoeostasis, and elevated IL‐6 levels. Therefore, this represents an appropriate model for the study of OC cachexia. Our model will aid in identifying molecular mediators that could be effectively targeted in order to improve muscle wasting associated with OC.

This article describes the leadership journey of a nursing leader from the United States. Background information on the culture of the United States where the author was raised and educated is provided as is a discussion about how her leadership skills were influenced by American culture. She reflects on the similarities and differences in leadership journeys between the nurse leaders from five Asian countries who participated in the Women’s Leadership Workshop held at Duke University in 2017. The article concludes with suggestions for women in leadership, particularly nurses, across the globe.

Abstract Background By the traditional definition of unintended weight loss, cachexia develops in ~80% of patients with pancreatic ductal adenocarcinoma (PDAC). Here, we measure the longitudinal body composition changes in patients with advanced PDAC undergoing 5‐fluorouracil, leucovorin, irinotecan, and oxaliplatin therapy. Methods We performed a retrospective review of 53 patients with advanced PDAC on 5‐fluorouracil, leucovorin, irinotecan, and oxaliplatin as first line therapy at Indiana University Hospital from July 2010 to August 2015. Demographic, clinical, and survival data were collected. Body composition measurement by computed tomography (CT), trend, univariate, and multivariate analysis were performed. Results Among all patients, three cachexia phenotypes were identified. The majority of patients, 64%, had Muscle and Fat Wasting (MFW), while 17% had Fat‐Only Wasting (FW) and 19% had No Wasting (NW). NW had significantly improved overall median survival (OMS) of 22.6 months vs. 13.0 months for FW and 12.2 months for MFW (P = 0.02). FW (HR = 5.2; 95% confidence interval = 1.5–17.3) and MFW (HR = 1.8; 95% confidence interval = 1.1–2.9) were associated with an increased risk of mortality compared with NW. OMS and risk of mortality did not differ between FW and MFW. Progression of disease, sarcopenic obesity at diagnosis, and primary tail tumours were also associated with decreased OMS. On multivariate analysis, cachexia phenotype and chemotherapy response were independently associated with survival. Notably, CT‐based body composition analysis detected tissue loss of >5% in 81% of patients, while the traditional definition of >5% body weight loss identified 56.6%. Conclusions Distinct cachexia phenotypes were observed in this homogeneous population of patients with equivalent stage, diagnosis, and first‐line treatment. This suggests cellular, molecular, or genetic heterogeneity of host or tumour. Survival among patients with FW was as poor as for MFW, indicating adipose tissue plays a crucial role in cachexia and PDAC mortality. Adipose tissue should be studied for its mechanistic contributions to cachexia.

Abstract Background Inappropriate prescribing of antibiotics poses an urgent public health threat. Limited research has examined factors associated with antibiotic prescribing practices in outpatient settings. The goals of this study were to explore elements influencing provider decisions to prescribe antibiotics, identify provider recommendations for interventions to reduce inappropriate antibiotic use, and inform the clinical management of patients in the outpatient environment for infections that do not require antibiotics. Methods This was a qualitative study using semi-structured interviews with key informants. Seventeen outpatient providers (10 medical doctors and 7 advanced care practitioners) within a large healthcare system in Charlotte, North Carolina, participated. Interviews were audio recorded, transcribed, and analyzed for themes. Results Primary barriers to reducing inappropriate antibiotic prescribing included patient education and expectations, system-level factors, and time constraints. Providers indicated they would be interested in having system-wide, evidence-based guidelines to inform their prescribing decisions and that they would also be receptive to efforts to improve their awareness of their own prescribing practices. Results further suggested that providers experience a high demand for antibiotic prescriptions; consequently, patient education around appropriate use would be beneficial. Conclusions Findings suggest that antibiotic prescribing in the outpatient setting is influenced by many pressures, including patient demand and patient satisfaction. Training on appropriate antibiotic prescribing, guideline-based decision support, feedback on prescribing practices, and patient education are recommended interventions to improve levels of appropriate prescribing.

Chemosensory disorders, primarily olfactory, have diagnostic significance for prevalent human illnesses, but the multitude of smells makes measuring function appear daunting. The olfactory system operates under dynamic natural sensing conditions in which many individual odor chemicals are waxing and waning. Yet, in experimentally controlled simulations, mixture-component selective adaptation shows individual or shared prominent characteristic odors are detected but molecular stimulus features are not. As in other biological chemical signaling systems, including taste, odors activate dedicated receptors (OR). Given rapid OR adaptation with the passage of time, individual odor recognition is momentary. Receptive dendrites of the nearly 400 genetically variable human-OR in the olfactory epithelium critically project axons to the olfactory bulb through perforations in the cribriform plate of the skull. Analytic chemical-quality codes detect single odor-mixture components. However, identities of no more than 3 or 4 most salient odors are perceived due to central mixture-suppression, the mutual inhibition among diverse olfactory-bulb or cortical neurons. The componental codes allow olfaction to readily discern odor quality and valence of a wide range of unrelated chemicals, a few at a time. Head trauma may result in a partial or complete loss of smell and facial trauma a loss of taste-nerve function. Testing smell could plot the course of recovery from chronic traumatic encephalopathies that prevail in contact sports. Measuring brain function with olfaction would provide simpler and more direct monitoring of prognosis than biochemical sensors. Keywords: Mixture-component perception, Head trauma, Contact sports

Abstract Background Due to its capability to secrete large quantities of plant biomass degrading enzymes (PBDE), Trichoderma reesei is widely applied for industrial purposes. In nature, expression of PBDE is efficiently regulated in this fungus. Several factors involved in this regulatory network have been identified. However, most of them are transcription factors. Long noncoding RNAs (lncRNAs) emerged as common players acting on epigenetic or transcriptional regulation in several eukaryotic organisms. To date, no lncRNA has been described in filamentous fungi. Results A lncRNA termed HAX1 was identified in T. reesei QM9414. In this study, it was characterized and evidence for its regulatory impact on cellulase expression was provided. Interestingly, different versions of HAX1 were identified in different strains (namely, QM6a, QM9414, and Rut-C30), varying in terms of RNA length. Remarkably, considerable longer variants of this lncRNA are present in hypercellulolytic strains compared to the wild-type strain QM6a. Based on these results, a correlation between RNA length and the functional impact of HAX1 on PBDE expression was supposed. This assumption was verified by overexpressing the most abundant HAX1 versions identified in QM6a, QM9414, and Rut-C30. Such HAX1 overexpression on the one hand was suitable for regaining the function in hax1 disruption strains, and on the other hand resulted in notably higher cellulase activities in QM6a, especially by the expression of longer HAX1 versions. Conclusion With HAX1, for the first time the regulatory role of a lncRNA in filamentous fungi was uncovered. Besides this, a new player involved in the complex regulation of PBDE expression in T. reesei was identified. Due to its enhancing effect on cellulase activity, HAX1 was shown to be not only interesting for basic research, but also a promising candidate for expanding the set of biotechnological tools for industrial application of T. reesei.

Abstract Mycobacterium simiae (Karassova V, Weissfeiler J, Kraszanay E, Acta Microbiol Acad Sci Hung 12:275-82, 1965) is a slow-growing nontuberculous Mycobacterium species found in environmental niches, and recently evidenced as an opportunistic Human pathogen. We report here the genome of a clinical isolate of M. simiae (MsiGto) obtained from a patient in Guanajuato, Mexico. With a size of 6,684,413 bp, the genomic sequence of strain MsiGto is the largest of the three M. simiae genomes reported to date. Gene prediction revealed 6409 CDSs in total, including 6354 protein-coding genes and 52 RNA genes. Comparative genomic analysis identified shared features between strain MsiGto and the other two reported M. simiae genomes, as well as unique genes. Our data reveals that M. simiae MsiGto harbors virulence-related genes, such as arcD, ESAT-6, and those belonging to the antigen 85 complex and mce clusters, which may explain its successful transition to the human host. We expect the genome information of strain MsiGto will provide a better understanding of infective mechanisms and virulence of this emergent pathogen.

Abstract Background This field-based study examined the abundance and species complement of mosquitoes (Diptera: Culicidae) attracted to humans at four sites in the United Kingdom (UK). The study used a systematic approach to directly measure feeding by mosquitoes on humans at multiple sites and using multiple volunteers. Quantifying how frequently humans are bitten in the field by mosquitoes is a fundamental parameter in assessing arthropod-borne virus transmission. Methods Human landing catches were conducted using a standardised protocol by multiple volunteers at four rural sites between July and August 2013. Collections commenced two hours prior to sunset and lasted for a total of four hours. To reduce bias occurring due to collection point or to the individual attractiveness of the volunteer to mosquitoes, each collection was divided into eight collection periods, with volunteers rotated by randomised Latin square design between four sampling points per site. While the aim was to collect mosquitoes prior to feeding, the source of blood meals from any engorged specimens was also identified by DNA barcoding. Results Three of the four sites yielded human-biting mosquito populations for a total of 915 mosquitoes of fifteen species/species groups. Mosquito species composition and biting rates differed significantly between sites, with individual volunteers collecting between 0 and 89 mosquitoes (over 200 per hour) of up to six species per collection period. Coquillettidia richiardii (Ficalbi, 1889) was responsible for the highest recorded biting rates at any one site, reaching 161 bites per hour, whilst maximum biting rates of 55 bites per hour were recorded for Culex modestus (Ficalbi, 1889). Human-biting by Culex pipiens (L., 1758) form pipiens was also observed at two sites, but at much lower rates when compared to other species. Conclusions Several mosquito species are responsible for human nuisance biting pressure in southern England, although human exposure to biting may be largely limited to evening outdoor activities. This study indicates Cx. modestus can be a major human-biting species in the UK whilst Cx. pipiens f. pipiens may show greater opportunistic human-biting than indicated by earlier studies.

Abstract Background Cross-sectional relationships between physical activity and health have been explored extensively, but less is known about how physical activity changes with time in older people. The aim of this study was to assess baseline predictors of how objectively measured physical activity changes with time in older people. Methods Longitudinal cohort study using data from the Physical Activity Cohort Scotland. A sample of community-dwelling older people aged 65 and over were recruited in 2009–2011, then followed up 2–3 years later. Physical activity was measured using Stayhealthy RT3 accelerometers over 7 days. Other data collected included baseline comorbidity, health-related quality of life (SF-36), extended Theory of Planned Behaviour Questionnaire and Social Capital Module of the General Household Survey. Associations between follow-up accelerometer counts and baseline predictors were analysed using a series of linear regression models, adjusting for baseline activity levels and follow-up time. Results Follow up data were available for 339 of the original 584 participants. The mean age was 77 years, 185 (55%) were female and mean follow up time was 26 months. Mean activity counts fell by between 2% per year (age 80, deprivation decile 5–10) from baseline values. In univariate analysis age, sex, deprivation decile, most SF-36 domains, most measures of social connectedness, most measures from the extended Theory of Planned Behaviour, hypertension, diabetes mellitus, chronic pain and depression score were significantly associated with adjusted activity counts at follow-up. In multivariate regression age, satisfactory friend network, SF-36 physical function score, and the presence of diabetes mellitus were independent predictors of activity counts at follow up after adjustment for baseline count and duration of follow up. Conclusions Health status and social connectedness, but not extended Theory of Planned Behaviour measures, independently predicted changes in physical activity in community dwelling older people.

Abstract Background Preterm birth is in quantity and in severity the most important contributor of perinatal morbidity and mortality both in well- and low-resource countries. Cervical pessary and cervical cerclage are both considered as preventive treatments in women at risk for preterm birth. We aim to evaluate whether a cervical pessary can replace cervical cerclage for preventing recurrent preterm birth in women with a prior preterm birth due to cervical insufficiency or in women with a prior preterm birth and a short cervix in the current pregnancy. Methods/design A nationwide open-label multicentre randomised clinical trial will be set up to study women with a singleton pregnancy and a prior preterm birth before 34 weeks of gestation. Women are eligible in case of previous preterm birth based on cervical insufficiency (primary intervention,

Abstract Background The benefits of physical activity are well established, yet large numbers of people are not sufficiently active to gain health benefits. Certain population groups are less physically active than others, including older women from areas of high economic deprivation. The Well!Bingo project was established with the aim of engaging such women in the development of a health promotion intervention in a bingo club. This paper reports on the assessment of health status, physical activity and sedentary behaviour of women attending a bingo club in central Scotland, UK as part of the Well!Bingo project. Methods Women attending the bingo club were invited to provide information on demographic characteristics, and self-reported physical activity and sedentary behaviour via a self-complete questionnaire as part of a cross-sectional study (n = 151). A sub-sample (n = 29) wore an accelerometer for an average of 5.7 ± 1.4 days. Differences between younger (under 60 years) and older adults (60 years and over) were assessed using a chi-square test for categorical data and the independent samples t-test was used to assess continuous data (p

Viral late domains are used by many viruses to recruit the cellular endosomal sorting complex required for transport (ESCRT) to mediate membrane scission during viral budding. Unlike the P(S/T)AP and YPX(1-3)L late domains, which interact directly with the ESCRT proteins Tsg101 and ALIX, the molecular linkage connecting the PPXY late domain to ESCRT proteins is unclear. The mammarenavirus lymphocytic choriomeningitis virus (LCMV) matrix protein, Z, contains only one late domain, PPXY. We previously found that this domain in LCMV Z, as well as the ESCRT pathway, are required for the release of defective interfering (DI) particles but not infectious virus. To better understand the molecular mechanism of ESCRT recruitment by the PPXY late domain, affinity purification-mass spectrometry was used to identify host proteins that interact with the Z proteins of the Old World mammarenaviruses LCMV and Lassa virus. Several Nedd4 family E3 ubiquitin ligases interact with these matrix proteins and in the case of LCMV Z, the interaction was PPXY-dependent. We demonstrated that these ligases directly ubiquitinate LCMV Z and mapped the specific lysine residues modified. A recombinant LCMV containing a Z that cannot be ubiquitinated maintained its ability to produce both infectious virus and DI particles, suggesting that direct ubiquitination of LCMV Z alone is insufficient for recruiting ESCRT proteins to mediate virus release. However, Nedd4 ligases appear to be important for DI particle release suggesting that ubiquitination of targets other than the Z protein itself is required for efficient viral ESCRT recruitment.

Neutropenia is a common side-effect of acute myeloid leukemia (AML) chemotherapy characterized by a critical drop in neutrophil blood concentration. Neutropenic patients are prone to infections, experience poorer clinical outcomes, and require expensive medical care. Although transfusions of donor neutrophils are a logical solution to neutropenia, this approach has not gained clinical traction, primarily due to challenges associated with obtaining sufficiently large numbers of neutrophils from donors whilst logistically managing their extremely short shelf-life. A protocol has been developed that produces clinical-scale quantities of neutrophils from hematopoietic stem and progenitor cells (HSPC) in 10 L single-use bioreactors (1). This strategy could be used to mass produce neutrophils and generate sufficient cell numbers to allow decisive clinical trials of neutrophil transfusion. We present a bioprocess model for neutrophil production at relevant clinical-scale. We evaluated two production scenarios, and the impact on cost of goods (COG) of multiple model parameters including cell yield, materials costs, and process duration. The most significant contributors to cost were consumables and raw materials, including the cost of procuring HSPC-containing umbilical cord blood. The model indicates that the most cost-efficient culture volume (batch size) is ~100 L in a single bioreactor. This study serves as a framework for decision-making and optimization strategies when contemplating the production of clinical quantities of cells for allogeneic therapy.