Neuronal activity regulates Matrin 3 abundance and function in a calcium-dependent manner through calpain-mediated cleavage and calmodulin binding.

RNA-binding protein (RBP) dysfunction is a fundamental hallmark of amyotrophic lateral sclerosis (ALS) and related neuromuscular disorders. Abnormal neuronal excitability is also a conserved feature in ALS patients and disease models, yet little is known about how activity-dependent processes regulate RBP levels and functions. Mutations in the gene encoding the RBP Matrin 3 (MATR3) cause familial disease, and MATR3 pathology has also been observed in sporadic ALS, suggesting a key role for MATR3 in disease pathogenesis. Here, we show that glutamatergic activity drives MATR3 degradation through an NMDA receptor-, Ca2+-, and calpain-dependent mechanism. The most common pathogenic MATR3 mutation renders it resistant to calpain degradation, suggesting a link between activity-dependent MATR3 regulation and disease. We also demonstrate that Ca2+ regulates MATR3 through a nondegradative process involving the binding of Ca2+/calmodulin to MATR3 and inhibition of its RNA-binding ability. These findings indicate that neuronal activity impacts both the abundance and function of MATR3, underscoring the effect of activity on RBPs and providing a foundation for further study of Ca2+-coupled regulation of RBPs implicated in ALS and related neurological diseases.

Weight management and physical activity throughout the cancer care continuum.

Mounting evidence suggests that weight management and physical activity (PA) improve overall health and well being, and reduce the risk of morbidity and mortality among cancer survivors. Although many opportunities exist to include weight management and PA in routine cancer care, several barriers remain. This review summarizes key topics addressed in a recent National Academies of Science, Engineering, and Medicine workshop entitled, "Incorporating Weight Management and Physical Activity Throughout the Cancer Care Continuum." Discussions related to body weight and PA among cancer survivors included: 1) current knowledge and gaps related to health outcomes; 2) effective intervention approaches; 3) addressing the needs of diverse populations of cancer survivors; 4) opportunities and challenges of workforce, care coordination, and technologies for program implementation; 5) models of care; and 6) program coverage. While more discoveries are still needed for the provision of optimal weight-management and PA programs for cancer survivors, obesity and inactivity currently jeopardize their overall health and quality of life. Actionable future directions are presented for research; practice and policy changes required to assure the availability of effective, affordable, and feasible weight management; and PA services for all cancer survivors as a part of their routine cancer care. CA Cancer J Clin 2018;68:64-89. © 2017 American Cancer Society.

Landscape change and alien invasions drive shifts in native lady beetle communities over a century.

Understanding causes of insect population declines is essential for the development of successful conservation plans, but data limitations restrict assessment across spatial and temporal scales. Museum records represent a source of historical data that can be leveraged to investigate temporal trends in insect communities. Native lady beetle decline has been attributed to competition with established alien species and landscape change, but the relative importance of these drivers is difficult to measure with short-term field-based studies. We assessed distribution patterns for native lady beetles over 12 decades using museum records, and evaluated the relative importance of alien species and landscape change as factors contributing to changes in communities. We compiled occurrence records for 28 lady beetle species collected in Ohio, USA, from 1900 to 2018. Taxonomic beta-diversity was used to evaluate changes in lady beetle community composition over time. To evaluate the relative influence of temporal, spatial, landscape, and community factors on the captures of native species, we constructed negative binomial generalized additive models. We report evidence of declines in captures for several native species. Importantly, the timing, severity, and drivers of these documented declines were species-specific. Land cover change was associated with declines in captures, particularly for Coccinella novemnotata which declined prior to the arrival of alien species. Following the establishment and spread of alien lady beetles, processes of species loss/gain and turnover shifted communities toward the dominance of a few alien species beginning in the 1980s. Because factors associated with declines in captures were highly species-specific, this emphasizes that mechanisms driving population losses cannot be generalized even among closely related native species. These findings also indicate the importance of museum holdings and the analysis of species-level data when studying temporal trends in insect populations.

Tailored approach to participant recruitment and retention to maximize health equity in pediatric cancer research.

BACKGROUND: Lack of diversity in participants throughout the research process limits the generalizability of findings and may contribute to health disparities. There are unique challenges to recruitment of families to pediatric cancer research studies, especially for those from disadvantaged backgrounds. Thus, there is a need to evaluate the most effective recruitment and retention strategies to optimize equitable recruitment of diverse participants. METHODS: The present study adapted and implemented methods outlined previously in the literature. These previous efforts were developed to address barriers to pediatric research, behavioral health intervention research and research with Black adolescents. Recruitment and retention strategies are described across four different time points: pre-approach, initial connection, building connection and follow-up. Eligible families of children with a pediatric cancer diagnosis were approached during a routine oncology visit. Once consented, enrollment and retention rates over three timepoints of data collection were recorded and evaluated. RESULTS: Results indicated high rates of enrollment (86%) and retention (95%) for eligible participants. There were no trends in heightened attrition for any specific subgroup. CONCLUSIONS: The findings of this study are promising and suggest these recruitment and retention strategies may be useful in recruiting individuals from disadvantaged backgrounds.

Caregiver perceptions of child heath behaviors and weight during treatment for acute lymphoblastic leukemia.

BACKGROUND: Changes in health behaviors and weight are common during the early phases of pediatric acute lymphoblastic leukemia treatment, and may negatively impact treatment tolerability. Given that ALL is most prevalent in children, caregivers play an essential role in shaping health behaviors during treatment. This study presents a qualitative analysis of semi-structured interviews with caregivers of youth in the early phases of ALL treatment. PROCEDURE: Caregivers (N = 17, 95% female) of a child (M age = 6.76 years) diagnosed with ALL and on treatment for less than 1 year (M = 8.7 months since diagnosis) completed a semi-structured interview about perceptions of their child's nutrition, physical activity, sedentary time, and weight during ALL treatment. Thematic analysis followed Braun and Clark's six-step framework (2006). Two coders established reliability (alpha = .88) and used a multi-pass coding system to extract themes. RESULTS: Caregivers' concerns around their child's weight during ALL treatment primarily centered around avoiding malnutrition. Weight gain during treatment was less of a concern and often viewed as protective. Caregivers reported encouraging their child to eat palatable, calorie-dense foods to mitigate risk for weight loss. Caregivers also expressed concern that children were less active and more sedentary due to treatment-related pain. Caregivers discussed health behaviors during treatment as being child-directed, rather than parent- or provider-directed. CONCLUSION: Future interventions may consider strategies to engage in joint parent-child decisions and caregiver education around risks of excessive weight gain during treatment. Interventions should include anticipatory guidance and aim to support parents in developing skills to support their child's health behaviors during treatment.

Family Rules and Routines During the Early Phases of Pediatric Cancer Treatment: Associations With Child Emotional and Behavioral Health.

OBJECTIVE: Consistent family rules and routines promote positive adaptation to stress and may be protective to child emotional and behavioral functioning. Few studies have quantified family engagement in these behaviors during pediatric cancer treatment or examined associations with child emotional and behavioral health. METHODS: In this cross-sectional observational study, 86 primary caregivers of youth ages 2-14 years (M = 7.9) with an initial diagnosis of cancer within 16 weeks reported on their frequency of engagement in family rules and routines (e.g., sleep, schoolwork, and meal routines) before their child's cancer diagnosis and their current frequency of engagement in the same routines. Caregivers also reported demographics, psychosocial distress, and child emotional and behavioral health outcomes. Analyses examined demographic and psychosocial factors associated with engagement in rules and routines during cancer treatment, and associations with child emotional and behavioral health. RESULTS: Families reported a lower frequency of engagement in rules and routines during cancer treatment, compared to before treatment (mean difference 0.8 SDs [95% confidence interval 0.7-1.1 SDs]). Caregiver factors associated with lower engagement in rules and routines during treatment included being married, having lower educational attainment, and higher levels of psychosocial distress. Families who engaged in higher levels of rules and routines during treatment reported fewer child externalizing and behavioral challenges. There was limited evidence of association between family rules and routines and child internalizing outcomes. CONCLUSIONS: Results found that engaging in family rules and routines during cancer treatment was associated with fewer child behavioral challenges during treatment. Future directions include longitudinal examinations of family rules, routines, and child emotional/behavioral outcomes to examine directional impact over time.

Women Physicians and Promotion in Academic Medicine.

BACKGROUND: In 2000, a landmark study showed that women who graduated from U.S. medical schools from 1979 through 1997 were less likely than their male counterparts to be promoted to upper faculty ranks in academic medical centers. It is unclear whether these differences persist. METHODS: We merged data from the Association of American Medical Colleges on all medical school graduates from 1979 through 2013 with faculty data through 2018, and we compared the percentages of women who would be expected to be promoted on the basis of the proportion of women in the graduating class with the actual percentages of women who were promoted. We calculated Kaplan-Meier curves and used adjusted Cox proportional-hazards models to examine the differences between the early cohorts (1979-1997) and the late cohorts (1998-2013). RESULTS: The sample included 559,098 graduates from 134 U.S. medical schools. In most of the cohorts, fewer women than expected were promoted to the rank of associate or full professor or appointed to the post of department chair. Findings were similar across basic science and clinical departments. In analyses that included all the cohorts, after adjustment for graduation year, race or ethnic group, and department type, women assistant professors were less likely than their male counterparts to be promoted to associate professor (hazard ratio, 0.76; 95% confidence interval [CI], 0.74 to 0.78). Similar sex disparities existed in promotions to full professor (hazard ratio, 0.77; 95% CI, 0.74 to 0.81) and appointments to department chair (hazard ratio, 0.46; 95% CI, 0.39 to 0.54). These sex differences in promotions and appointments did not diminish over time and were not smaller in the later cohorts than in the earlier cohorts. The sex differences were even larger in the later cohorts with respect to promotion to full professor. CONCLUSIONS: Over a 35-year period, women physicians in academic medical centers were less likely than men to be promoted to the rank of associate or full professor or to be appointed to department chair, and there was no apparent narrowing in the gap over time. (Funded by the University of Kansas Medical Center Joy McCann Professorship for Women in Medicine and the American Association of University Women.).

Individual participant data meta-analysis of metabolomics on sustained knee pain in primary osteoarthritis patients.

OBJECTIVES: Knee pain is the major driver for OA patients to seek healthcare, but after pursuing both conservative and surgical pain interventions, ∼20% of patients continue to report long-term pain following total knee arthroplasty (TKA). This study aimed to identify a metabolomic signature for sustained knee pain after TKA to elucidate possible underlying mechanisms. METHODS: Two independent cohorts from St John's, NL, Canada (n = 430), and Toronto, ON, Canada (n = 495) were included in the study. Sustained knee pain was assessed using the WOMAC pain subscale (five questions) at least 1 year after TKA for primary OA. Those reporting any pain on all five questions were considered to have sustained knee pain. Metabolomic profiling was performed on fasted pre-operative plasma samples using the Biocrates Absolute IDQ p180 kit. Associations between metabolites and pair-wise metabolite ratios with sustained knee pain in each individual cohort were assessed using logistic regression with adjustment for age, sex and BMI. Random-effects meta-analysis using inverse variance as weights was performed on summary statistics from both cohorts. RESULTS: One metabolite, phosphatidylcholine (PC) diacyl (aa) C28:1 (odds ratio = 0.66, P = 0.00026), and three metabolite ratios, PC aa C32:0 to PC aa C28:1, PC aa C28:1 to PC aa C32:0, and tetradecadienylcarnitine (C14:2) to sphingomyelin C20:2 (odds ratios = 1.59, 0.60 and 1.59, respectively; all P < 2 × 10-5), were significantly associated with sustained knee pain. CONCLUSIONS: Though further investigations are needed, our results provide potential predictive biomarkers and drug targets that could serve as a marker for poor response and be modified pre-operatively to improve knee pain and surgical response to TKA.

A realist approach to understanding alliancing within Local Government public health and social care service provision.

BACKGROUND: Within the current context of continued austerity and post-pandemic recovery, it remains important that Local Government services address the increasing needs of residents as cost-effectively as possible. Alliancing, whereby services work collaboratively focusing on the 'whole-system', has gained popularity as a tool with the potential to support collaborative whole systems approaches. This synthesis aims to identify how alliancing can be successfully operationalised in the commissioning of public health, wider National Health Service (NHS) and social care-related services. METHODS: A realist literature synthesis was undertaken in order to identify underlying generative mechanisms associated with alliancing, the contextual conditions surrounding the implementation and operationalisation of the alliancing approach mechanisms, and the outcomes produced as a result. An iterative approach was taken, using a recent systematic review of the effectiveness of Alliancing, online database searches, and grey literature searches. RESULTS: Three mechanistic components were identified within the data as being core to the successful implementation of alliances in public health and social care-related services within Local Government: (i) Achieving a system-level approach; (ii) placing local populations at the heart of the system; and (iii) creating a cultural shift. Programme theories were postulated within these components. CONCLUSIONS: The alliancing approach offers an opportunity to achieve system-level change with the potential to benefit local populations. The realist synthesis approach taken within this study has provided insights into the necessary contextual and mechanistic factors of the Alliancing approach, above and beyond effectiveness outcomes typically collected through more conventional evaluation methodologies.

Phase II study of dichloroacetate, an inhibitor of pyruvate dehydrogenase, in combination with chemoradiotherapy for unresected, locally advanced head and neck squamous cell carcinoma.

Chemoradiotherapy (CRT) for locally-advanced head and neck squamous cell carcinoma (LA-HSNCC) yields 5-year survival rates near 50% despite causing significant toxicity. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase metabolic inhibitor, reduces tumor lactate production and has been used in cancer therapy previously. The safety of adding this agent to CRT is unknown. Our randomized, placebo-controlled, double-blind phase II study added DCA to cisplatin-based CRT in patients with LA-HNSCC. The primary endpoint was safety by adverse events (AEs). Secondary endpoints compared efficacy via 3-month end-of-treatment response, 5-year progression-free and overall survival. Translational research evaluated pharmacodynamics of serum metabolite response. 45 participants (21 DCA, 24 Placebo) were enrolled from May 2011-April 2014. Higher rates of all-grade drug related fevers (43% vs 8%, p = 0.01) and decreased platelet count (67% vs 33%, p = 0.02) were seen in DCA versus placebo. However, there were no significant differences in grade 3/4 AE rates. Treatment compliance to DCA/placebo, radiation therapy, and cisplatin showed no significant difference between groups. While end-of-treatment complete response rates were significantly higher in the DCA group compared to placebo (71.4% vs 37.5%, p = 0.0362), survival outcomes were not significantly different between groups. Treatment to baseline metabolites demonstrated a significant drop in pyruvate (0.47, p < 0.005) and lactate (0.61, p < 0.005) in the DCA group. Adding DCA to cisplatin-based CRT appears safe with no detrimental effect on survival and expected metabolite changes compared to placebo. This supports further investigation into combining metabolic agents to CRT. Trial registration number: NCT01386632, Date of Registration: July 1, 2011.

The association between the obesogenic environment and 6-month and 24-month weight change in a rural weight loss intervention trial in the United States.

The unique obesogenic environment may influence the ability to effectively maintain weight loss in rural areas. The aim of this study was to examine the contextual relationship of neighborhood disadvantage, distance to supermarkets and supercenters, and fast food, dollar store, and exercise facility environments on weight loss following a weight-loss intervention in the United States. This analysis (n = 1177) linked weight loss outcomes from a rural, primary care-based randomized controlled trial to contextual data collected from residential addresses. Outcomes include 6-month and 24-month percent weight loss. These outcomes were compared across contextual variables, including tract level disadvantage, food accessibility, and food/exercise availability. Covariates were included in ordinary least squares (OLS) multivariable regression models for 6-month and 24-month weight loss measures, across three weight loss interventions. Contextual variables were not significantly related to percent weight loss overall across treatment arms. Participants living in a 5-mile buffer to dollar stores experienced approximately a 2% (p < 0.05) lower weight loss, but only in the least effective counseling arm (individual clinic visits), while controlling for both individual and contextual factors. Our results suggest that specific contextual variables in rural populations may play an important role in moderating weight loss outcomes especially under the conditions of less effective interventions.

Unifying the analysis of continuous and categorical measures of weight loss and incorporating group effect: a secondary re-analysis of a large cluster randomized clinical trial using Bayesian approach.

BACKGROUND: Although frequentist paradigm has been the predominant approach to clinical studies for decades, some limitations associated with the frequentist null hypothesis significance testing have been recognized. Bayesian approaches can provide additional insights into data interpretation and inference by deriving posterior distributions of model parameters reflecting the clinical interest. In this article, we sought to demonstrate how Bayesian approaches can improve the data interpretation by reanalyzing the Rural Engagement in Primary Care for Optimizing Weight Reduction (REPOWER). METHODS: REPOWER is a cluster randomized clinical trial comparing three care delivery models: in-clinic individual visits, in-clinic group visits, and phone-based group visits. The primary endpoint was weight loss at 24 months and the secondary endpoints included the proportions of achieving 5 and 10% weight loss at 24 months. We reanalyzed the data using a three-level Bayesian hierarchical model. The posterior distributions of weight loss at 24 months for each arm were obtained using Hamiltonian Monte Carlo. We then estimated the probability of having a higher weight loss and the probability of having greater proportion achieving 5 and 10% weight loss between groups. Additionally, a four-level hierarchical model was used to assess the partially nested intervention group effect which was not investigated in the original REPOWER analyses. RESULTS: The Bayesian analyses estimated 99.5% probability that in-clinic group visits, compared with in-clinic individual visits, resulted in a higher percent weight loss (posterior mean difference: 1.8%[95% CrI: 0.5,3.2%]), a greater probability of achieving 5% threshold (posterior mean difference: 9.2% [95% CrI: 2.4, 16.0%]) and 10% threshold (posterior mean difference: 6.6% [95% CrI: 1.7, 11.5%]). The phone-based group visits had similar result. We also concluded that including intervention group did not impact model fit significantly. CONCLUSIONS: We unified the analyses of continuous (the primary endpoint) and categorical measures (the secondary endpoints) of weight loss with one single Bayesian hierarchical model. This approach gained statistical power for the dichotomized endpoints by leveraging the information in the continuous data. Furthermore, the Bayesian analysis enabled additional insights into data interpretation and inference by providing posterior distributions for parameters of interest and posterior probabilities of different hypotheses that were not available with the frequentist approach. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02456636 ; date of registry: May 28, 2015.

Lessons Learned From Beta-Testing a Facebook Group Prototype to Promote Treatment Use in the "Connecting Alaska Native People to Quit Smoking" (CAN Quit) Study.

Social media provides an effective tool to reach, engage, and connect smokers in cessation efforts. Our team developed a Facebook group, CAN Quit (Connecting Alaska Native People to Quit smoking), to promote use of evidence-based smoking cessation resources for Alaska Native people living in Alaska, which are underused despite their effectiveness. Often separated by geography and climate, Alaska Native people prefer group-based approaches for tobacco cessation that support their culture and values. Such preferences make Alaska Native people candidates for social media-based interventions that promote connection. This viewpoint discusses the steps involved and lessons learned in building and beta-testing our Facebook group prototype, which will then be evaluated in a pilot randomized controlled trial. We describe the process of training moderators to facilitate group engagement and foster community, and we describe how we developed and tested our intervention prototype and Facebook group. All parts of the prototype were designed to facilitate use of evidence-based cessation treatments. We include recommendations for best practices with the hope that lessons learned from the CAN Quit prototype could provide a model for others to create similar platforms that benefit Alaska Native and American Indian people in the context of smoking cessation.

Use of an RN-Initiated Protocol for Recognition, Management, and Documentation of Intradialytic Hypotension in Patients with End Stage Kidney Disease on In-Center Hemodialysis: A Quality Improvement Project.

Although intradialytic hypotension (IDH) is the most frequent complication of hemodialysis (HD), there is currently no standardized definition or uniform practice recommendations for response. A quality improvement project included nine registered nurses (RNs) and 96 adult patients receiving HD at a 30-station Midwest urban dialysis clinic. The project focused on development of an evidence-based RN-initiated protocol, RN education, and implementation of the RN-initiated protocol to recognize, treat, and document IDH. IDH was recognized in 7.02% of dialysis treatments, with protocol use doubling from Week 1 to Week 8. Most IDH episodes were resolved after one (36%) or two (49.33%) 10-minute ultrafiltration (UF) pauses with interventions. The use of an RN-initiated IDH protocol standardized care and led to positive patient outcomes in this dialysis clinic.

How long do population level field experiments need to be? Utilising data from the 40-year-old LTER network.

We utilise the wealth of data accessible through the 40-year-old Long-Term Ecological Research (LTER) network to ask if aspects of the study environment or taxa alter the duration of research necessary to detect consistent results. To do this, we use a moving-window algorithm. We limit our analysis to long-term (> 10 year) press experiments recording organismal abundance. We find that studies conducted in dynamic abiotic environments need longer periods of study to reach consistent results, as compared to those conducted in more moderated environments. Studies of plants were more often characterised by spurious results than those on animals. Nearly half of the studies we investigated required 10 years or longer to become consistent, where all significant trends agreed in direction, and four studies (of 100) required longer than 20 years. Here, we champion the importance of long-term data and bolster the value of multi-decadal experiments in understanding, explaining and predicting long-term trends.

National Cancer Institute support for targeted alpha-emitter therapy.

BACKGROUND: Radiopharmaceutical targeted therapy (RPT) has been studied for decades; however, recent clinical trials demonstrating efficacy have helped renewed interest in the modality. METHODS: This article reviews National Cancer Institute (NCI)'s support of RPT through communication via workshops and interest groups, through funding extramural programs in academia and small business, and through intramural research, including preclinical and clinical studies. RESULTS: NCI has co-organized workshops and organized interest groups on RPT and RPT dosimetry to encourage the community and facilitate rigorous preclinical and clinical studies. NCI has been supporting RPT research through various mechanisms. Research has been funded through peer-reviewed NCI Research and Program Grants (RPG) and NCI Small Business Innovation Research (SBIR) Development Center, which funds small business-initiated projects, some of which have led to clinical trials. The NCI Cancer Therapy Evaluation Program (CTEP)'s Radiopharmaceutical Development Initiative supports RPT in NCI-funded clinical trials, including Imaging and Radiation Oncology Core (IROC) expertise in imaging QA and dosimetry procedures. Preclinical targeted a-emitter therapy (TAT) research at the NCI's intramural program is ongoing, building on foundational work dating back to the 1980s. Ongoing "bench-to-bedside" efforts leverage the unique infrastructure of the National Institutes of Health's (NIH) Clinical Center. CONCLUSION: Given the great potential of RPT, our goal is to continue to encourage its development that will generate the high-quality evidence needed to bring this multidisciplinary treatment to patients.

Feasibility of a Weight Management Program Tailored for Overweight Men with Localized Prostate Cancer - A Pilot Study.

BACKGROUND: Overweight men with prostate cancer are more likely to suffer from recurrence and death following prostatectomy compared with healthy weight men. This study tested the feasibility of delivering a comprehensive program to foster weight loss before and weight maintenance after surgery in overweight men with localized prostate cancer. METHODS: Twenty overweight men scheduled for prostatectomy elected either the intervention (n = 15) or the nonintervention (n = 5). Anthropometrics, biomarkers, diet quality, nutrition literacy, quality of life, and long-term follow-up were assessed in both groups. RESULTS: The intervention led to 5.55 kg of weight loss including 3.88 kg of fat loss from baseline to surgery (mean = 8.3 weeks). The intervention significantly increased fiber, protein, fruit, nut, and vegetable intake; and decreased trans fats intake during weight loss. The intervention significantly reduced insulin, C-peptide, systolic blood pressure, leptin:adiponectin ratio, and visceral adiposity compared to the nonintervention. Post-surgically, weight loss was maintained. Changes in lipid profiles, nutrition literacy, and follow-up were not statistically significant in either group. CONCLUSION: Significant weight loss (≥5%) is feasible with a coaching intervention in overweight men preparing for prostatectomy and is associated with favorable cardiometabolic effects. This study is registered under NCT02252484 (www.clinicaltrials.gov).

The Dynamic Shift Detector: An algorithm to identify changes in parameter values governing populations.

Environmental factors interact with internal rules of population regulation, sometimes perturbing systems to alternate dynamics though changes in parameter values. Yet, pinpointing when such changes occur in naturally fluctuating populations is difficult. An algorithmic approach that can identify the timing and magnitude of parameter shifts would facilitate understanding of abrupt ecological transitions with potential to inform conservation and management of species. The "Dynamic Shift Detector" is an algorithm to identify changes in parameter values governing temporal fluctuations in populations with nonlinear dynamics. The algorithm examines population time series data for the presence, location, and magnitude of parameter shifts. It uses an iterative approach to fitting subsets of time series data, then ranks the fit of break point combinations using model selection, assigning a relative weight to each break. We examined the performance of the Dynamic Shift Detector with simulations and two case studies. Under low environmental/sampling noise, the break point sets selected by the Dynamic Shift Detector contained the true simulated breaks with 70-100% accuracy. The weighting tool generally assigned breaks intentionally placed in simulated data (i.e., true breaks) with weights averaging >0.8 and those due to sampling error (i.e., erroneous breaks) with weights averaging <0.2. In our case study examining an invasion process, the algorithm identified shifts in population cycling associated with variations in resource availability. The shifts identified for the conservation case study highlight a decline process that generally coincided with changing management practices affecting the availability of hostplant resources. When interpreted in the context of species biology, the Dynamic Shift Detector algorithm can aid management decisions and identify critical time periods related to species' dynamics. In an era of rapid global change, such tools can provide key insights into the conditions under which population parameters, and their corresponding dynamics, can shift.

Affective disorders, weight change, and patient engagement in a rural behavioral weight loss trial.

BACKGROUND: Adults in rural areas have a higher prevalence of obesity and some mental health conditions. The degree to which mental health influences weight loss among rural residents remains unclear. This study evaluated changes in body weight, physical activity, diet, and program engagement outcomes in a cohort of participants with vs. without an affective disorder in a behavioral weight loss trial. METHODS: A sample of 1407 adults with obesity were recruited from rural U.S. primary care practices to participate in a weight loss trial. In this secondary analysis, participants were stratified by those with vs. without an affective disorder at baseline. Mixed models were used to estimate changes in outcomes over 24 months. RESULTS: One-third of participants (n = 468) had an affective disorder. After covariate adjustment, both groups experienced significant weight loss over 24 months, but weight loss was significantly less among those with an affective disorder at all follow-up times (all p's < 0.001; 24-month weight loss -2.7 ±â€¯0.4 vs. -4.8 ±â€¯0.3 kg). Compared to those without an affective disorder, participants with an affective disorder also had significantly less improvement in physical activity and fruit/vegetable consumption, lower attendance at weight loss sessions, and less engagement in setting weight loss goals and strategies. CONCLUSION: Participants with an affective disorder lost less body weight and less improvement in lifestyle measures over 24 months. These trends paralleled reduced engagement in critical intervention activities such as weight loss session attendance. Future interventions should consider additional methods to minimize disengagement in adults with underlying affective disorders.

A knowledge-based, structural-aided discovery of a novel class of 2-phenylimidazo[1,2-a]pyridine-6-carboxamide H-PGDS inhibitors.

Through an internal virtual screen at GlaxoSmithKline a distinct class of 2-phenylimidazo[1,2-a]pyridine-6-carboxamide H-PGDS inhibitors were discovered. Careful evaluation of crystal structures and SAR led to a novel, potent, and orally active imidazopyridine inhibitor of H-PGDS, 20b. Herein, describes the identification of 2 classes of inhibitors, their syntheses, and their challenges.