Taz1-Shelterin Promotes Facultative Heterochromatin Assembly at Chromosome-Internal Sites Containing Late Replication Origins.

Facultative heterochromatin regulates gene expression, but its assembly is poorly understood. Previously, we identified facultative heterochromatin islands in the fission yeast genome and found that RNA elimination machinery promotes island assembly at meiotic genes. Here, we report that Taz1, a component of the telomere protection complex Shelterin, is required to assemble heterochromatin islands at regions corresponding to late replication origins that are sites of double-strand break formation during meiosis. The loss of Taz1 or other Shelterin subunits, including Ccq1 that interacts with Clr4/Suv39h, abolishes heterochromatin at late origins and causes derepression of associated genes. Moreover, the late-origin regulator Rif1 affects heterochromatin at Taz1-dependent islands and subtelomeric regions. We explore the connection between facultative heterochromatin and replication control and show that heterochromatin machinery affects replication timing. These analyses reveal the role of Shelterin in facultative heterochromatin assembly at late origins, which has important implications for genome stability and gene regulation.

Risk Factors for Early Lower Limb Re-Amputation in Vascular Diseases.

BACKGROUND: Numerous risk factors for lower limb amputations are known; however, this study aimed to identify risk factors for re-amputation in patients within 6 months from an initial lower limb amputation procedure. METHODS: This single-center retrospective cohort study was performed at the Hospital Regional Hans Dieter Schmidt in Brazil. The study included patients who were aged at least 18 years and had undergone lower limb amputation between 2013 and 2022. Patients who died while hospitalized and patients who were lost to follow-up after hospital discharge were excluded from the study. Patient age, sex, number of amputations, revision time, comorbidities, and potential risk factors were extracted from the physical therapy service database and electronic medical records of the hospital. Chi-squared test and student's t-test were used to identify statistical significance. RESULTS: A total of 652 patients were included, of which 35.2% (230) patients underwent re-amputation within 6 months of the first operation. We found that dialysis (P = 0.004; odds ratio [OR] 8.36, 95% confidence interval [CI] 3.09-20.5), smoking (P = 0.004; OR 1.67, 95% CI 1.18-2.35), and hypertension (P = 0.02; OR 1.55, 95% CI 1.09-2.19) were predictive factors for re-amputation within 6 months of lower limb amputation. CONCLUSIONS: Therefore, it is important to intervene early and provide additional support to patients undergoing lower limb amputation with these risk factors to reduce the potential for re-amputation in the future.

Exploring recent trends (2014-21) in preferencing and accepting Queensland medical internships in rural hospitals.

BACKGROUND: Medical internship is a key transition point in medical training from student to independent (junior) doctor. The national Regional Training Hubs (RTH) policy began across Australia in late 2017, which aims to build medical training pathways for junior doctors within a rural region and guide students, interns and trainees towards these. This study aims to explore preferencing and acceptance trends for rural medical internship positions in Queensland. Moreover, it focuses on internship preference and acceptance outcomes prior to and following the establishment of RTHs, and their association with key covariates such as rural training immersions offered by medical schools. METHODS: Data from all applicants to Queensland Health intern positions between 2014-2021 were available, notably their preference order and location of accepted internship position, classified as rural or metropolitan. Matched data from Queensland's medical schools were added for rural training time and other key demographics. Analyses explored the statistical associations between these factors and preferencing or accepting rural internships, comparing pre-RTH and post-RTH cohorts. RESULTS: Domestic Queensland-trained graduates first preferencing rural intern positions increased significantly (pre-RTH 21.1% vs post-RTH 24.0%, p = 0.017), reinforced by a non-significant increase in rural acceptances (27.3% vs 29.7%, p = 0.070). Rural interns were more likely to have previously spent ≥ 11-weeks training in rural locations within medical school, be rurally based in the year applying for internship, or enrolled in the rural generalist pathway. CONCLUSIONS: The introduction of the RTH was associated with a moderate increase of graduates both preferencing and accepting a rural internship, though a richer understanding of the dominant reasons for and against this remain less clear. An expansion of graduates who undertook longer periods of undergraduate rural training in the same period did not diminish the proportion choosing a rural internship, suggesting there remains an appetite for these opportunities. Overall, domestic graduates are identified as a reliable source of intern recruitment and retention to rural hospitals across Queensland, with entry to the rural generalist pathway and extended rural placement experiences enhancing uptake of rural practice.

HIV testing inside Brazilian female prisons: results of a national survey.

This study aimed to identify the prevalence of women in prisons who have already had an HIV test inside prison and the factors associated with this test. A cross-sectional study was carried out with 1327 women in 15 prisons in 9 states in Brazil. Almost 60% (95% CI: 57.8-63.7) of women have already been tested for HIV in prison. The factors associated with this HIV test were age ≥41 years (OR = 1.9; 95% CI = 1.2-2.9), highest level of education (OR = 1.9; 95% CI = 1.3-2.8), having been arrested 3 or more times (OR = 1.9; 95% CI = 1.3-2.8), having received information about HIV/STI in the lifetime (OR = 1.4; 95% CI = 1.1-1.9) and perceived themselves to be at no risk for HIV infection (OR = 1.7; 95% CI = 1.2-2.5), black or mixed race (OR = 0.7; 95% CI = 0.5-0.9) and having a male sexual partner (OR = 0.6; 95% CI = 0.5-0.9). The routine HIV testing in prisons needs to be expanded to promote HIV prevention for a population with limited access to these services outside of prison.

Highly socially vulnerable communities exhibit disproportionately increased viral loads as measured in community wastewater.

Wastewater surveillance has proven to be a useful tool for evidence-based epidemiology in the fight against the SARS-CoV-2 virus. It is particularly useful at the population level where acquisition of individual test samples may be time or cost-prohibitive. Wastewater surveillance for SARS-CoV-2 has typically been performed at wastewater treatment plants; however, this study was designed to sample on a local level to monitor the spread of the virus among three communities with distinct social vulnerability indices in Shreveport, Louisiana, located in a socially vulnerable region of the United States. Twice-monthly grab samples were collected from September 30, 2020, to March 23, 2021, during the Beta wave of the pandemic. The goals of the study were to examine whether: 1) concentrations of SARS-CoV-2 RNA in wastewater varied with social vulnerability indices and, 2) the time lag of spikes differed during wastewater monitoring in the distinct communities. The size of the population contributing to each sample was assessed via the quantification of the pepper mild mottle virus (PMMoV), which was significantly higher in the less socially vulnerable community. We found that the communities with higher social vulnerability exhibited greater viral loads as assessed by wastewater when normalized with PMMoV (Kruskal-Wallis, p < 0.05). The timing of the spread of the virus through the three communities appeared to be similar. These results suggest that interconnected communities within a municipality experienced the spread of the SARS-CoV-2 virus at similar times, but areas of high social vulnerability experienced more intense wastewater viral loads.

Using the social vulnerability index to assess COVID-19 vaccine uptake in Louisiana.

Using data from the Louisiana Department of Public Health, we explored the spatial relationships between the Social Vulnerability Index (SVI) and COVID-19-related vaccination and mortality rates. Publicly available COVID-19 vaccination and mortality data accrued from December 2020 to October 2021 was downloaded from the Louisiana Department of Health website and merged with the SVI data; geospatial analysis was then performed to identify the spatial association between the SVI and vaccine uptake and mortality rate. Bivariate Moran's I analysis revealed significant clustering of high SVI ranking with low COVID-19 vaccination rates (1.00, p < 0.001) and high smoothed mortality rates (0.61, p < 0.001). Regression revealed that for each 10% increase in SVI ranking, COVID-19 vaccination rates decreased by 3.02-fold (95% CI = 3.73-2.30), and mortality rates increased by a factor of 1.19 (95% CI = 0.99-1.43). SVI values are spatially linked and significantly associated with Louisiana's COVID-19-related vaccination and mortality rates. We also found that vaccination uptake was higher in whites than in blacks. These findings can help identify regions with low vaccination rates and high mortality, enabling the necessary steps to increase vaccination rates in disadvantaged neighborhoods.

Estimating the current and future prevalence of life-limiting conditions in children in England.

BACKGROUND: Previous studies showed increasing number of children with a life-limiting or life-threatening condition who may benefit from input from pediatric palliative care services. AIM: To estimate the current prevalence of children with a life-limiting condition and to model future prevalence of this population. DESIGN: Observational study using national inpatient hospital data. A population-based approach utilizing ethnic specific population projections was used to estimate future prevalence. SETTING/PARTICIPANTS: All children aged 0-19 years with a life-limiting condition diagnostic code recorded in Hospital Episodes Statistics data in England from 2000/01 to 2017/18. RESULTS: Data on 4,543,386 hospital episodes for 359,634 individuals were included. The prevalence of children with a life-limiting condition rose from 26.7 per 10,000 (95%CI 26.5-27.0) in 2001/02 to 66.4 per 10,000 (95% CI: 66.0-66.8) in 2017/18. Using a more restricted definition of a life-limiting condition reduced the prevalence from 66.4 to 61.1 per 10,000 (95%CI 60.7-61.5) in 2017/18. Highest prevalence was in the under 1-year age group at 226.5 per 10,000 and children with a congenital abnormality had the highest prevalence (27.2 per 10,000 (95%CI: 26.9-27.5)).The prevalence was highest among the most deprived group and in children of Pakistani origin.Predicted future prevalence of life-limiting conditions ranged from 67.0 (95%CI 67.7-66.3) to 84.22 (95%CI 78.66-90.17) per 10,000 by 2030. CONCLUSIONS: The prevalence of children with a life-limiting or life-threatening condition in England has risen over the last 17 years and is predicted to increase. Future data collections must include the data required to assess the complex health and social care needs of these children.

Client perceptions of the BreastScreen Australia remote radiology assessment model.

BACKGROUND: Telehealth and teleradiology are increasingly used around the world to facilitate health care provision when the health care provider and clients are separated by distance. The BreastScreen Australia Remote Radiology Assessment Model (RRAM) is an initiative developed to address the challenges of inadequate access to a local radiological workforce in regional Australia. With the growth in telehealth innovations more broadly, the RRAM represents a departure from the traditional onsite model where a radiologist would be co-located with practice staff during assessment clinics. Understanding client satisfaction is an important consideration with new models. This article explores client perceptions of the RRAM including awareness, satisfaction with experiences, confidence in the quality of care being received, and preferences regarding models of service delivery. METHODS: Clients in four BreastScreen services across three Australian states and territories were invited to provide feedback on their experiences of the RRAM. Brief face-to-face interviews based on a survey were conducted at the conclusion of assessment clinic visits. Clients also provided feedback through surveys completed and returned by post, and online. RESULTS: 144 clients completed the survey regarding their experiences of the RRAM. The majority were aged between 50 and 59 years (55/144, 38.2%). Most had attended a BreastScreen service for either screening or assessment on a total of two to five occasions (85/142, 59.9%) in the past. Nearly all women who attended a RRAM clinic expressed satisfaction with their experience (142/143, 99.3%). Clients were aware that the radiologist was working from another location (131/143, 91.6%) and the majority believed there wouldn't be any difference in the care they received between the RRAM and the onsite model (120/142, 84.5%). Clients generally had no particular preference for either the onsite or RRAM model of service delivery. CONCLUSIONS: Clients' high satisfaction with their clinic experiences, high confidence in care being received, and the majority having no preference for either the onsite or remote model indicates their acceptance of the RRAM. Client acceptance of the model supports continuation of the RRAM at these sites and expansion. Findings may inform future telehealth innovations where key health care team members are working remotely.

Association of a priori dietary patterns with depressive symptoms: a harmonised meta-analysis of observational studies.

BACKGROUND: Review findings on the role of dietary patterns in preventing depression are inconsistent, possibly due to variation in assessment of dietary exposure and depression. We studied the association between dietary patterns and depressive symptoms in six population-based cohorts and meta-analysed the findings using a standardised approach that defined dietary exposure, depression assessment and covariates. METHODS: Included were cross-sectional data from 23 026 participants in six cohorts: InCHIANTI (Italy), LASA, NESDA, HELIUS (the Netherlands), ALSWH (Australia) and Whitehall II (UK). Analysis of incidence was based on three cohorts with repeated measures of depressive symptoms at 5-6 years of follow-up in 10 721 participants: Whitehall II, InCHIANTI, ALSWH. Three a priori dietary patterns, Mediterranean diet score (MDS), Alternative Healthy Eating Index (AHEI-2010), and the Dietary Approaches to Stop Hypertension (DASH) diet were investigated in relation to depressive symptoms. Analyses at the cohort-level adjusted for a fixed set of confounders, meta-analysis used a random-effects model. RESULTS: Cross-sectional and prospective analyses showed statistically significant inverse associations of the three dietary patterns with depressive symptoms (continuous and dichotomous). In cross-sectional analysis, the association of diet with depressive symptoms using a cut-off yielded an adjusted OR of 0.87 (95% confidence interval 0.84-0.91) for MDS, 0.93 (0.88-0.98) for AHEI-2010, and 0.94 (0.87-1.01) for DASH. Similar associations were observed prospectively: 0.88 (0.80-0.96) for MDS; 0.95 (0.84-1.06) for AHEI-2010; 0.90 (0.84-0.97) for DASH. CONCLUSION: Population-scale observational evidence indicates that adults following a healthy dietary pattern have fewer depressive symptoms and lower risk of developing depressive symptoms.

A multi-institutional analysis of clinical outcomes and patterns of care of 1p/19q codeleted oligodendrogliomas treated with adjuvant or salvage radiation therapy.

PURPOSE: Practice patterns vary for adjuvant treatment of 1p/19q-codeleted oligodendroglioma patients. This study evaluates the outcomes of adjuvant (aRT) versus salvage radiation therapy (sRT) in a multi-institutional cohort. METHODS: Oligodendroglioma patients with confirmed 1p/19q codeletion who were treated with RT with or without chemotherapy from 2000 to 2017 at four tertiary centers were retrospectively reviewed. Overall survival (OS), post-RT progression-free survival (PFS), freedom-from-RT (FFRT), and radiation necrosis (RN) rates were determined using Kaplan-Meier analyses. OS1/PFS1 were defined from the initial surgery. OS2/PFS2 were defined from the RT start-date. Multivariable analyses (MVAs) of prognostic factors for OS and PFS were performed with Cox regression. RESULTS: One hundred eighty-six patients were identified: 124(67%) received aRT and 62(33%) received sRT; of sRT patients, 58% were observed after surgery while 42% received chemotherapy without aRT. The median time from initial diagnosis to sRT was 61 months, and 74% had reoperations before sRT. sRT had longer OS1 than aRT (94% vs. 69% at 10 years, p = 0.03) and PFS1 (10-year PFS of 80% vs. 68%, p = 0.03), though sRT was not associated with significantly different OS1/PFS1 on MVAs. Chemotherapy did not delay sRT compared to observation and had worse PFS2 (42% vs. 79% at 5 years, p = 0.08). Higher RT dose was not associated with improved clinical outcomes but was associated with higher symptomatic RN rate (15% vs. 0% at 2 years, p = 0.003). CONCLUSIONS: Delaying RT for selected oligodendroglioma patients appears safe. Adjuvant chemotherapy does not delay sRT longer than observation and may be associated with worse PFS after RT.

Association of food groups with depression and anxiety disorders.

PURPOSE: Adherence to the Mediterranean diet has been associated with fewer depressive symptoms, however, it is unknown whether this is attributed to some or to all components. We examined the association between the individual food groups of the Mediterranean Diet Score (MDS), in isolation and in combination, with depression and anxiety (symptom severity and diagnosis). METHODS: Data from 1634 adults were available from the Netherlands Study of Depression and Anxiety. Eleven energy-adjusted food groups were created from a 238-item food frequency questionnaire. In regression analysis, these were associated in isolation and combination with (1) depressive and anxiety disorders (established with the Composite International Diagnostic Interview) (current disorder n = 414), and (2) depression and anxiety severity [measured with the Inventory of Depressive Symptomatology (IDS), the Beck Anxiety Inventory (BAI) and the Fear Questionnaire (FEAR)]. RESULTS: Overall, the MDS score shows the strongest relationships with depression/anxiety [Diagnosis: odds ratio (OR) 0.77 per SD, 95% confidence interval (95% CI) 0.66-0.90, IDS: standardised betas (ß) - 0.13, 95% CI - 0.18, - 0.08] and anxiety (BAI: ß - 0.11, 95% CI - 0.16, - 0.06, FEAR: ß - 0.08, 95% CI - 0.13, - 0.03). Greater consumption of non-refined grains and vegetables was associated with lower depression and anxiety severity, whilst being a non-drinker was associated with higher symptom severity. Higher fruit and vegetable intake was associated with lower fear severity. Non-refined grain consumption was associated with lower odds and being a non-drinker with greater odds of current depression/anxiety disorders compared to healthy controls, these associations persisted after adjustment for other food groups (OR 0.82 per SD, 95% CI 0.71-0.96, OR 1.26 per SD 95% CI 1.08-1.46). CONCLUSION: We can conclude that non-refined grains, vegetables and alcohol intake appeared to be the driving variables for the associated the total MDS score and depression/anxiety. However, the combined effect of the whole diet remains important for mental health. It should be explored whether an increase consumption of non-refined grains and vegetables may help to prevent or reduce depression and anxiety.

Childhood overweight and obesity and the risk of depression across the lifespan.

BACKGROUND: Obesity has been longitudinally associated with depression but only few studies take a life course approach. This longitudinal study investigates whether being overweight or obese at age 8 and 13 years is associated with depressive symptoms more than 60 years later and whether this association is independent of late-life body mass index (BMI). We also investigated the association of being overweight/obese at age 8 or 13 years with ever having major depressive disorder (lifetime MDD). METHOD: This analysis is based on a sub-sample of 889 AGES-Reykjavik participants with measured BMI data from early life. Late-life depressive symptoms were measured with the Geriatric Depression Scale (GDS) and lifetime MDD was assessed at late-life using the Mini International Neuropsychiatric Interview. Logistic regression analysis was used to estimate the relationships between BMI (continuous and categorical) at age 8 or 13 years, and late-life depressive symptoms (measured as GDS ≥ 5) or lifetime MDD, adjusted for sex, education, physical activity, smoking status and alcohol use. In a separate model, additional adjustments were made for late-life BMI. RESULTS: One hundred and one subjects (11%) had depressive symptoms at late-life (GDS ≥ 5), and 39 subjects (4.4%) had lifetime MDD. Being overweight or obese at age 8 or 13 years was not associated with higher depressive symptoms during late-life, irrespective of late-life BMI. Being overweight or obese at age 8 years, but not age 13 years was associated with an increased risk of lifetime MDD (Odds Ratio (OR) (95% confidence interval [CI]) for age 8 = 4.03[1.16-13.96]P = 0.03 and age 13 = 2.65[0.69-10.26] P = 0.16, respectively). CONCLUSION: Being overweight in childhood was associated with increased odds of lifetime MDD, although the magnitude of the risk is uncertain given the small numbers of participants with lifetime MDD. No clear association was observed between childhood and adolescent overweight/obesity and late-life depressive symptoms irrespective of late life BMI.

"From the technology came the idea": safe implementation and operation of a high quality teleradiology model increasing access to timely breast cancer assessment services for women in rural Australia.

Breast cancer is the most commonly diagnosed cancer in Australian women. Providing timely diagnostic assessment services for screen-detected abnormalities is a core quality indicator of the population-based screening program provided by BreastScreen Australia. However, a shortage of local and locum radiologists with availability and appropriate experience in breast work to attend onsite assessment clinics, limits capacity of services to offer assessment appointments to women in some regional centres. In response to identified need, local service staff developed the remote radiology assessment model for service delivery. This study investigated important factors for establishing the model, the challenges and enablers of successful implementation and operation of the model, and factors important in the provision of a model considered safe and acceptable by service providers. METHODS: Semi-structured interviews were conducted with service providers at four assessment services, across three jurisdictions in Australia. Service providers involved in implementation and operation of the model at the service and jurisdictional level were invited to participate. A social constructivist approach informed the analysis. Deductive analysis was initially undertaken, using the interview questions as a classifying framework. Subsequently, inductive thematic analysis was employed by the research team. Together, the coding team aggregated the codes into overarching themes. RESULTS: 55 service providers participated in interviews. Consistently reported enablers for the safe implementation and operation of a remote radiology assessment clinic included: clinical governance support; ability to adapt; strong teamwork, trust and communication; and, adequate technical support and equipment. Challenges mostly related to technology and internet (speed/bandwidth), and maintenance of relationships within the group. CONCLUSIONS: Understanding the key factors for supporting innovation, and implementing new and safe models of service delivery that incorporate telemedicine, will become increasingly important as technology evolves and becomes more accessible. It is possible to take proposed telemedicine solutions initiated by frontline workers and operationalise them safely and successfully: (i) through strong collaborative relationships that are inclusive of key experts; (ii) with clear guidance from overarching bodies with some flexibility for adapting to local contexts; (iii) through establishment of robust teamwork, trust and communication; and, (iv) with appropriate equipment and technical support.

Family Support and Connection Groups: Long-Term Benefits for Inner-City Children?

Relatively few prevention trials have had long-term follow-up to determine if immediate impact translates to and explains long-term impact. The present report summarizes the long-term influence (measured when students are near the end of high school) of the SAFEChildren preventive intervention, which was applied during first grade. This program aims to facilitate and support developmental management, school-family connection, and social support among neigbhors through family groups and student tutoring and is focused on familes raising children in inner-city neighborhoods. Of the 424 families randomly assigned prior to first grade to intervention or no-intervention control, outcome data on at least one outcome was obtained for 375 (88.4%). Results indicate no long-term direct effects and a single mediated effect, with those in the intervention less likely to engage in risky sexual practices. Similar but non-significant trends were found for alcohol use and violence. These mixed results may suggest that family focused intervention that is relatively brief is not adequate to protect against multiple and ongoing developmental risk that arises in such communities. The limited impact is discussed in light of the uncertainty of subsequent condition on initial preventive benefits and the developmental ecology of the inner city. Implications for preventive intervention programming and for long-term evaluation are also addressed.

Leishmania HASP and SHERP Genes Are Required for In Vivo Differentiation, Parasite Transmission and Virulence Attenuation in the Host.

Differentiation of extracellular Leishmania promastigotes within their sand fly vector, termed metacyclogenesis, is considered to be essential for parasites to regain mammalian host infectivity. Metacyclogenesis is accompanied by changes in the local parasite environment, including secretion of complex glycoconjugates within the promastigote secretory gel and colonization and degradation of the sand fly stomodeal valve. Deletion of the stage-regulated HASP and SHERP genes on chromosome 23 of Leishmania major is known to stall metacyclogenesis in the sand fly but not in in vitro culture. Here, parasite mutants deficient in specific genes within the HASP/SHERP chromosomal region have been used to investigate their role in metacyclogenesis, parasite transmission and establishment of infection. Metacyclogenesis was stalled in HASP/SHERP mutants in vivo and, although still capable of osmotaxis, these mutants failed to secrete promastigote secretory gel, correlating with a lack of parasite accumulation in the thoracic midgut and failure to colonise the stomodeal valve. These defects prevented parasite transmission to a new mammalian host. Sand fly midgut homogenates modulated parasite behaviour in vitro, suggesting a role for molecular interactions between parasite and vector in Leishmania development within the sand fly. For the first time, stage-regulated expression of the small HASPA proteins in Leishmania (Leishmania) has been demonstrated: HASPA2 is expressed only in extracellular promastigotes and HASPA1 only in intracellular amastigotes. Despite its lack of expression in amastigotes, replacement of HASPA2 into the null locus background delays onset of pathology in BALB/c mice. This HASPA2-dependent effect is reversed by HASPA1 gene addition, suggesting that the HASPAs may have a role in host immunomodulation.

Blocking two-component signalling enhances Candida albicans virulence and reveals adaptive mechanisms that counteract sustained SAPK activation.

The Ypd1 phosphorelay protein is a central constituent of fungal two-component signal transduction pathways. Inhibition of Ypd1 in Saccharomyces cerevisiae and Cryptococcus neoformans is lethal due to the sustained activation of the 'p38-related' Hog1 stress-activated protein kinase (SAPK). As two-component signalling proteins are not found in animals, Ypd1 is considered to be a prime antifungal target. However, a major fungal pathogen of humans, Candida albicans, can survive the concomitant sustained activation of Hog1 that occurs in cells lacking YPD1. Here we show that the sustained activation of Hog1 upon Ypd1 loss is mediated through the Ssk1 response regulator. Moreover, we present evidence that C. albicans survives SAPK activation in the short-term, following Ypd1 loss, by triggering the induction of protein tyrosine phosphatase-encoding genes which prevent the accumulation of lethal levels of phosphorylated Hog1. In addition, our studies reveal an unpredicted, reversible, mechanism that acts to substantially reduce the levels of phosphorylated Hog1 in ypd1Δ cells following long-term sustained SAPK activation. Indeed, over time, ypd1Δ cells become phenotypically indistinguishable from wild-type cells. Importantly, we also find that drug-induced down-regulation of YPD1 expression actually enhances the virulence of C. albicans in two distinct animal infection models. Investigating the underlying causes of this increased virulence, revealed that drug-mediated repression of YPD1 expression promotes hyphal growth both within murine kidneys, and following phagocytosis, thus increasing the efficacy by which C. albicans kills macrophages. Taken together, these findings challenge the targeting of Ypd1 proteins as a general antifungal strategy and reveal novel cellular adaptation mechanisms to sustained SAPK activation.

Natural history, clinical course and predictors of interval time from initial diagnosis to development of subsequent NSCLC brain metastases.

PURPOSE: Non-small cell lung cancer (NSCLC) brain metastases are associated with substantial morbidity and mortality. During recent years, accompanying dramatic improvements in systemic disease control, NSCLC brain metastases have emerged as an increasingly relevant clinical problem. However, optimal surveillance practices remain poorly defined. This purpose of this study was to further characterize the natural history, clinical course and risk factors associated with earlier development of subsequent NSCLC brain metastases to better inform clinical practice and help guide survivorship care. METHODS: We retrospectively reviewed all institutional NSCLC brain metastasis cases treated with radiotherapy between 1997 and 2015. Exclusion criteria included presence of brain metastases at initial NSCLC diagnosis and incomplete staging information. Interval time to brain metastases and subsequent survival were characterized using Kaplan-Meier and multivariate Cox regression analyses. RESULTS: Among 105 patients within this cohort, median interval time to development of brain metastases was 16 months. Median interval times were 29, 19, 16 and 13 months for Stage I-IV patients, respectively (P = 0.016). Additional independent predictors for earlier development of NSCLC brain metastases included non-adenocarcinomatous histopathology (HR 3.036, P < 0.001), no prior surgical resection (HR 1.609, P = 0.036) and no prior systemic therapy (HR 3.560, P = 0.004). Median survival following intracranial progression was 16 months. Delayed development of brain metastases was associated with better prognosis (HR 0.970, P < 0.001) but not survival following intracranial disease onset. CONCLUSIONS: Collectively, our results provide valuable insights into the natural history of NSCLC brain metastases. NSCLC stage, histology, prior surgical resection and prior systemic therapy emerged as independent predictors for interval time to brain metastases.

Depression and eating styles are independently associated with dietary intake.

Depression and eating styles are two important, interrelated factors associated with dietary intake. However, it remains unclear whether depression and eating styles are independently associated with dietary intake, and whether associations between depression and dietary intake are mediated by eating styles. Therefore, the aim of the current study was to investigate the associations of, and interplay between depression and eating styles in relation to different aspects of dietary intake. Cross-sectional data from 1442 participants (healthy controls (22.7%), remitted (61.0%) and current patients (16.3%)) from the Netherlands Study of Depression and Anxiety were used. Linear regression analyses were used to determine associations of depressive disorders (DSM-IV based psychiatric interview), self-reported depressive symptoms (Inventory of Depressive Symptomatology), emotional, external and restrained eating (Dutch Eating Behavior Questionnaire) with 4 measures of dietary intake (total energy intake (kcal/d), Mediterranean diet score (MDS), intake of sweets foods (g/d), and snack/fast-food (g/d)) measured with a 238-item food frequency questionnaire. Statistical mediation analyses were used to study whether associations between depression and dietary intake were mediated by eating styles. Current depression diagnosis and severity were associated with lower MDS and higher intake of sweet foods and snack/fast-food. Emotional and external eating were associated with higher intakes of snack/fast-food; external eating was also associated with higher total energy intake. Restrained eating was associated with lower total energy and intake of sweet foods, and higher MDS. Associations between current depression or severity and intake of snack/fast-food were mediated by external eating. In general, depression and eating styles contributed independently to poorer diet quality and higher intake of sweet and snack/fast-food. The association between depression and higher intake of snack/fast-food was mediated by external eating.

Reciprocal Effects of Positive Future Expectations, Threats to Safety, and Risk Behavior Across Adolescence.

We examined the reciprocal relationships among positive future expectations, expected threats to future safety, depression, and individual substance use and delinquency using 4 waves of data (N = 248-338) from African American and Latino adolescent male participants in the Chicago Youth Development Study. Individual positive future expectations and expected threats to safety were assessed at each wave and modeled as latent constructs. Individual substance use and delinquency were assessed at each wave and represented as ordinal variables ranging from low to high. Categorical autoregressive cross-lagged structural models were used to examine the hypothesized reciprocal relationships between both aspects of future expectations construct and risk behavior across adolescence. Analyses show that future expectations has important effects on youth substance use and involvement in delinquency, both of which in turn decrease positive expectations and increase expectation of threats to future safety across adolescence. Similarly, low positive expectations for the future continued to predict increased substance use and involvement in delinquency. The expected threats to safety construct was significantly correlated with delinquency within time. These effects are observed across adolescence after controlling for youth depression and race. Findings support the reciprocal effects hypothesis of a negative reinforcing cycle in the relationships between future expectations and both substance use and involvement in delinquent behavior across adolescence. The enduring nature of these relationships underscores the importance of future expectation as a potential change mechanism for intervention and prevention efforts to promote healthy development; vulnerable racial and ethnic minority male adolescents may especially benefit from such intervention.

The Family Context and Adolescent Dating Violence: A Latent Class Analysis of Family Relationships and Parenting Behaviors.

Adolescent dating violence is a persistent public health concern, impacting many youths during their initial and formative relationships during middle school. Despite theoretical and empirical studies highlighting the essential role of family relationship dynamics and parenting practices in relation to youth violence, substantially less research has focused on associations between these factors and rates of adolescent dating violence. The current study examined aspects of the family context in relation to dating violence outcomes among a racially and ethnically diverse sample of middle school students from economically disadvantaged communities, a group of adolescents at a high risk for exposure to risk factors for dating violence. Participants included 495 adolescents (66% male; 63% African American). Data were collected at the beginning of sixth grade and three subsequent spring waves through eighth grade. The current study identified patterns of family factors using a latent class analysis and examined these classes in relation to dating violence and dating violence norms. Three classes emerged: a positive family context with mixed messages about parental support for fighting and nonviolence (42%), an average family context with consistent parental support for nonviolent responses to conflict (24%), and a poor family context with parental support for fighting (34%). The classes with average and positive family contexts showed the lowest levels of dating violence and dating violence norms. These findings support the development and integration of family context factors into adolescent dating violence prevention programs, especially within high-burden contexts where families may be more likely to endorse mixed messages about how to handle conflict and youth may be at a higher risk for dating violence outcomes.