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Abstract Background: The Ability to Perform Physical Activities of Daily Living Questionnaire (APPADL) measures the self-reported ability of individuals with type 2 diabetes mellitus (T2DM) and obesity to perform daily physical activities. The primary objective of this study was to estimate APPADL test-retest reliability, responsiveness, and minimal important change (MIC). Subjects and Methods: Study participants were individuals with T2DM and body mass index >=30 kg/m(2) enrolled in clinical weight loss programs in the United States. Data were obtained for clinical measures, APPADL, and other patient-reported instruments. APPADL test-retest reliability was estimated with intraclass correlation coefficient. To estimate responsiveness in a subgroup of participants, baseline and 6-month data were analyzed using paired t test and calculation of responsiveness indices (e.g., effect size [ES]). To estimate MIC, both distribution-based and anchor-based methods were used. Results: Test-retest data for 106 study participants (mean age, 52 years; 69% female; 31% white; mean body mass index, 38 kg/m(2)) yielded an intraclass correlation coefficient of 0.91. In the subgroup (n=40) used to estimate responsiveness, weight was significantly less at end point than at baseline (mean, 222.0 vs. 231.9 pounds; P<0.001, ES=0.24), and APPADL scores were significantly better than at baseline (mean, 77.0 vs. 70.8; P=0.01, ES=0.32). Results of distribution- and anchor-based methods to establish MIC suggest values of 6-14 points (0-100 scale). Conclusions: The APPADL has demonstrated reliability and validity. In addition, it has demonstrated responsiveness to weight loss in individuals with T2DM and obesity, thereby making it a potentially valuable tool in the evaluation of weight loss interventions (e.g., antihyperglycemic medications that produce weight loss) targeted toward patients with T2DM. [ABSTRACT FROM AUTHOR]

Rationale: Timeliness is one of six important dimensions of health care quality recognized by the Institute of Medicine.Objectives: To evaluate timeliness of lung cancer care and identify institutional characteristics associated with timely care within the Veterans Affairs (VA) health care system.Methods: We used data from a VA nation-wide retrospective chart review and an independent audit of VA cancer programs to examine the association between time to first treatment and potentially explanatory institutional characteristics (e.g., volume of lung cancer patients) for 2,372 veterans diagnosed with lung cancer between 1 January 2002 and 1 September 2005 at 127 VA medical centers. We developed linear mixed effects models to control for clustering of patients within hospitals and we stratified analyses by stage.Measurements and Main Results: Median time to treatment varied widely between (23 to 182 d) and within facilities. Median time to treatment was 90 days in patients with stage I or II cancer and 52 days in those with more advanced disease (P < 0.0001). Factors associated with shorter times to treatment included a nonacademic setting and the existence of a specialized diagnostic clinic (in patients with limited-stage disease), performing a patient flow analysis (in patients with advanced disease), and leadership beliefs about providing timely care (in both groups). However, institutional characteristics explained less than 1% of the observed variation in treatment times.Conclusions: Time to lung cancer treatment in U.S. veterans is highly variable. The numerous institutional characteristics we examined explained relatively little of this variability, suggesting that patient, clinician, and/or unmeasured institutional characteristics may be more important determinants of timely care. [ABSTRACT FROM AUTHOR]

Background: Respiratory syncytial virus (RSV) causes significant morbidity and mortality, especially in young children. Why RSV infection in children is more severe compared to healthy adults is not fully understood., Methods: We used ex-vivo human nasal organoid platforms from infants and adults to investigate the underlying mechanism of this disease disparity at the initial site of RSV replication, the nasal epithelium., Results: Infant-derived human nasal organoid-air liquid interface (HNO-ALIs) lines were more susceptible to early RSV replication. Moreover, infant-derived HNO-ALIs elicited a statistically significant greater overall cytokine response, enhanced mucous production, and greater cellular damage compared to their adult counterparts. Furthermore, the adult cytokine response was associated with a superior regulatory cytokine response, which could explain less cellular damage than in infant lines., Conclusions: Our data highlights substantial differences in how infant and adult upper respiratory tract epithelium responds to RSV infection at the cellular level. These differences in epithelial cellular response can lead to impaired mucociliary clearance, a more dysregulated innate immune response predisposing infants to more severe RSV infection compared to adults., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Supplemental feeding can increase the overall health of animals but also can have variable effects on how animals defend themselves against parasites. However, the spatiotemporal effects of food supplementation on host-parasite interactions remain poorly understood, likely because large-scale, coordinated efforts to investigate them are difficult. Here, we introduce the Nest Parasite Community Science Project, which is a community-based science project that coordinates studies with bird nest box 'stewards' from the public and scientific community. This project was established to understand broad ecological patterns between hosts and their parasites. The goal of this study was to determine the effect of food supplementation on eastern bluebirds (Sialia sialis) and their nest parasite community across the geographic range of the bluebirds from 2018 to 2021. We received 674 nests from 69 stewards in 26 states in the eastern United States. Nest box stewards reported whether or not they provided mealworms or suet near nesting bluebirds, then they followed the nesting success of the birds (number of eggs laid and hatched, proportion that hatched, number and proportion of nestlings that successfully fledged). We then identified and quantified parasites in the nests. Overall, we found that food supplementation increased fledging success. The most common nest parasite taxon was the parasitic blow fly (Protocalliphora sialia), but a few nests contained fleas (Ceratophyllus idius, C. gallinae and Orchopeas leucopus) and mites (Dermanyssus spp. and Ornithonyssus spp.). Blow flies were primarily found at northern latitudes, where food supplementation affected blow fly prevalence. However, the direction of this effect varied substantially in direction and magnitude across years. More stewards fed bluebirds at southern latitudes than at northern latitudes, which contradicts the findings of other community-based science projects. Overall, food supplementation of birds was associated with increased host fitness but did not appear to play a consistent role in defence against these parasites across all years. Our study demonstrates the importance of coordinated studies across years and locations to understand the effects of environmental heterogeneity, including human-based food supplementation, on host-parasite dynamics., (© 2024 The Author(s). Journal of Animal Ecology © 2024 British Ecological Society.)

During the COVID-19 vaccination rollout from March 2021- December 2022, the Centers for Disease Control and Prevention funded 110 primary and 1051 subrecipient partners at the national, state, local, and community-based level to improve COVID-19 vaccination access, confidence, demand, delivery, and equity in the United States. The partners implemented evidence-based strategies among racial and ethnic minority populations, rural populations, older adults, people with disabilities, people with chronic illness, people experiencing homelessness, and other groups disproportionately impacted by COVID-19. CDC also expanded existing partnerships with healthcare professional societies and other core public health partners, as well as developed innovative partnerships with organizations new to vaccination, including museums and libraries. Partners brought COVID-19 vaccine education into farm fields, local fairs, churches, community centers, barber and beauty shops, and, when possible, partnered with local healthcare providers to administer COVID-19 vaccines. Inclusive, hyper-localized outreach through partnerships with community-based organizations, faith-based organizations, vaccination providers, and local health departments was critical to increasing COVID-19 vaccine access and building a broad network of trusted messengers that promoted vaccine confidence. Data from monthly and quarterly REDCap reports and monthly partner calls showed that through these partnerships, more than 295,000 community-level spokespersons were trained as trusted messengers and more than 2.1 million COVID-19 vaccinations were administered at new or existing vaccination sites. More than 535,035 healthcare personnel were reached through outreach strategies. Quality improvement interventions were implemented in healthcare systems, long-term care settings, and community health centers resulting in changes to the clinical workflow to incorporate COVID-19 vaccine assessments, recommendations, and administration or referrals into routine office visits. Funded partners' activities improved COVID-19 vaccine access and addressed community concerns among racial and ethnic minority groups, as well as among people with barriers to vaccination due to chronic illness or disability, older age, lower income, or other factors., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jane R. Nilson reports a relationship with Astrazeneca (AZN), Amcor (AMCR), and Organon (OGN) and Mutual fund Eventide Healthcare and Life Fund that includes: equity or stocks. Sara Adelsberg, Theresa Bailey, Alexa Frank, and Claire Perkins: CDC has contracted with Deloitte Consulting, LLP, since December 2019 to support CDC’s Immunization Services Division in developing, standing up, and implementing a comprehensive, multi-faceted program focused on reducing racial and ethnic disparities in adult immunization. Deloitte Consulting, LLP, is a large organization that receives funding from many organizations and agencies. CDC funded a number of activities implemented by Deloitte and others. These authors do not have any reason to believe that any activities beyond those included in this support have any material relationship to this manuscript. Elizabeth Sobczyk: serves on an advisory committee for Sanofi Pasteur related to pertussis, separate from her time with AMDA. Julie Zajac: served on the Cooperative Extension System’s Health Innovation Task Force from March 2020 to March 2022. Since December 2022, she has served on the Extension Foundation’s Health Leadership Committee., (Published by Elsevier Ltd.)

Respiratory syncytial virus (RSV) is a common cause of respiratory infections, causing significant morbidity and mortality, especially in young children. Why RSV infection in children is more severe as compared to healthy adults is not fully understood. In the present study, we infect both pediatric and adult human nose organoid-air liquid interface (HNO-ALIs) cell lines with two contemporary RSV isolates and demonstrate how they differ in virus replication, induction of the epithelial cytokine response, cell injury, and remodeling. Pediatric HNO-ALIs were more susceptible to early RSV replication, elicited a greater overall cytokine response, demonstrated enhanced mucous production, and manifested greater cellular damage compared to their adult counterparts. Adult HNO-ALIs displayed enhanced mucus production and robust cytokine response that was well controlled by superior regulatory cytokine response and possibly resulted in lower cellular damage than in pediatric lines. Taken together, our data suggest substantial differences in how pediatric and adult upper respiratory tract epithelium responds to RSV infection. These differences in epithelial cellular response can lead to poor mucociliary clearance and predispose infants to a worse respiratory outcome of RSV infection., Competing Interests: Conflict of interest: The authors declare no conflicts of interest.

Vertebrates confronted with challenging environments often experience an increase in circulating glucocorticoids, which result in morphological, physiological and behavioral changes that promote survival. However, chronically elevated glucocorticoids can suppress immunity, which may increase susceptibility to disease. Since the introduction of avian malaria to Hawaii a century ago, low-elevation populations of Hawaii Amakihi (Chlorodrepanis virens) have undergone strong selection by avian malaria and evolved increased resilience (the ability to recover from infection), while populations at high elevation with few vectors have not undergone selection and remain susceptible. We investigated how experimentally elevated corticosterone affects the ability of high- and low-elevation male Amakihi to cope with avian malaria by measuring innate immunity, hematocrit and malaria parasitemia. Corticosterone implants resulted in a decrease in hematocrit in high- and low-elevation birds but no changes to circulating natural antibodies or leukocytes. Overall, leukocyte count was higher in low- than in high-elevation birds. Malaria infections were detected in a subset of low-elevation birds. Infected individuals with corticosterone implants experienced a significant increase in circulating malaria parasites while untreated infected birds did not. Our results suggest that Amakihi innate immunity measured by natural antibodies and leukocytes is not sensitive to changes in corticosterone, and that high circulating corticosterone may reduce the ability of Amakihi to cope with infection via its effects on hematocrit and malaria parasite load. Understanding how glucocorticoids influence a host's ability to cope with introduced diseases provides new insight into the conservation of animals threatened by novel pathogens., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

(1) Background: Arboviruses of medical and veterinary significance have been identified on all seven continents, with every human and animal population at risk for exposure. Like arboviruses, chronic neurodegenerative diseases, like Alzheimer's and Parkinson's disease, are found wherever there are humans. Significant differences in baseline gene and protein expression have been determined between human-induced pluripotent stem cell lines derived from non-Parkinson's disease individuals and from individuals with Parkinson's disease. It was hypothesized that these inherent differences could impact cerebral organoid responses to viral infection. (2) Methods: In this study, cerebral organoids from a non-Parkinson's and Parkinson's patient were infected with Chikungunya virus and observed for two weeks. (3) Results: Parkinson's organoids lost mass and exhibited a differential antiviral response different from non-Parkinson's organoids. Neurotransmission data from both infected non-Parkinson's and Parkinson's organoids had dysregulation of IL-1, IL-10, and IL-6. These cytokines are associated with mood and could be contributing to persistent depression seen in patients following CHIKV infection. Both organoid types had increased expression of CXCL10, which is linked to demyelination. (4) Conclusions: The differential antiviral response of Parkinson's organoids compared with non-Parkinson's organoids highlights the need for more research in neurotropic infections in a neurologically compromised host.

Glucocorticoids, androgens, and prolactin regulate metabolism and reproduction, but they also play critical roles in immunomodulation. Since the introduction of avian malaria to Hawaii a century ago, low elevation populations of the Hawaii Amakihi (Chlorodrepanis virens) that have experienced strong selection by avian malaria have evolved increased resilience (the ability to recover from infection), while high elevation populations that have undergone weak selection remain less resilient. We investigated how variation in malaria selection has affected corticosterone, testosterone, and prolactin hormone levels in Amakihi during the breeding season. We predicted that baseline corticosterone and testosterone (which have immunosuppressive functions) would be reduced in low elevation and malaria-infected birds, while stress-induced corticosterone and prolactin (which have immunostimulatory functions) would be greater in low elevation and malaria-infected birds. As predicted, prolactin was significantly higher in malaria-infected than uninfected females (although more robust sample sizes would help to confirm this relationship), while testosterone trended higher in malaria-infected than uninfected males and, surprisingly, neither baseline nor stress-induced CORT varied with malaria infection. Contrary to our predictions, stress-induced corticosterone was significantly lower in low than high elevation birds while testosterone in males and prolactin in females did not vary by elevation, suggesting that Amakihi hormone modulation across elevation is determined by variables other than disease selection (e.g., timing of breeding, energetic challenges). Our results shed new light on relationships between introduced disease and hormone modulation, and they raise new questions that could be explored in experimental settings., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Zika virus (ZIKV) is a flavivirus that originated in Africa but emerged in Latin America in 2015. In this region, other flaviviruses such as Dengue (DENV), West Nile, and Yellow Fever virus (YFV) also circulate, allowing for possible antigenic cross-reactivity to impact viral infections and immune responses. Studies have found antibody-mediated enhancement between DENV and ZIKV, but the impact of YFV antibodies on ZIKV infection has not been fully explored. ZIKV infections cause congenital syndromes, such as microcephaly, necessitating further research into ZIKV vertical transmission through the placental barrier. Recent advancements in biomedical engineering have generated co-culture methods that allow for the in vitro recapitulation of the maternal-fetal interface. This study utilized a transwell assay, which was a co-culture model utilizing human placental syncytiotrophoblasts, fetal umbilical cells, and a differentiating embryoid body, to replicate the maternal-fetal axis. To determine if cross-reactive YFV vaccine antibodies impacted the pathogenesis of ZIKV across the maternal-fetal axis, syncytiotrophoblasts were inoculated with ZIKV or ZIKV incubated with YFV vaccine antisera, and the viral load was measured 72 h post-inoculation. Here, we report that BeWo and HUVEC cells were permissive to ZIKV and that the impact of YFV post-vaccination antibodies on ZIKV replication was cell line-dependent. Embryoid bodies were also permissive to ZIKV, and the presence of YFV antibodies collected 4-14 months post-vaccination reduced ZIKV infection when placental cells were present. However, when directly infected with ZIKV, the embryoid bodies displayed significantly increased viral loads in the presence of YFV antiserum taken 30 days post-vaccination. The data show that each of the cell lines and EBs have a unique response to ZIKV complexed with post-vaccination serum, suggesting there may be cell-specific mechanisms that impact congenital ZIKV infections. Since ZIKV infections can cause severe congenital syndromes, it is crucial to understand any potential enhancement or protection offered from cross-reactive, post-vaccination antibodies.

Historically, investigations of how organismal investments in immunity fluctuate in response to environmental and physiological changes have focused on seasonally breeding organisms that confine reproduction to seasons with relatively unchallenging environmental conditions and abundant resources. The red crossbill, Loxia curvirostra , is a songbird that can breed opportunistically if conifer seeds are abundant, on both short, cold, and long, warm days, providing an ideal system to investigate environmental and reproductive effects on immunity. In this study, we measured inter- and intra-annual variation in complement, natural antibodies, PIT54 and leucocytes in crossbills across four summers (2010-2013) and multiple seasons within 1 year (summer 2011-spring 2012). Overall, we observed substantial changes in crossbill immune investment among summers, with interannual variation driven largely by food resources, while variation across multiple seasons within a single cone year was less pronounced and lacked a dominant predictor of immune investment. However, we found weak evidence that physiological processes (e.g. reproductive condition, moult) or abiotic factors (e.g. temperature, precipitation) affect immune investment. Collectively, this study suggests that a reproductively flexible organism may be able to invest in both reproduction and survival-related processes, potentially by exploiting rich patches with abundant resources. More broadly, these results emphasize the need for more longitudinal studies of trade-offs associated with immune investment.

Introduction: The Orthopaedic In-Training Examination (OITE) assesses orthopaedic resident knowledge over 275 multiple-choice questions.Since the first publication examining the contents of the pathology section was published over ten years ago, the pathology content has been renamed (oncology) and revamped. As the overall extent of these alterations is currently unknown, the efficacy of current orthopaedic oncology educational practices for optimal OITE performance should be questioned. To determine how the oncology (pathology) material has changed, we compared the following characteristics from previous examinations (2002 to 2006) to current examinations (2012 to 2016): (1) What are the average number of oncology questions being asked? (2) What are the specific imaging modalities presented for examinee interpretation? (3) Which pathologic diagnoses are commonly examined? (4) What is the pattern of taxonomic question classifications?, Methods: The 2012 to 2016 OITE study guides were reviewed, and each oncology question was categorized into one of the following: benign or malignant, imaging modality grouping, common pathologic diagnosis, question type, and taxonomic classification. The aforementioned information was extrapolated from the previous pathology publication published in 2010 to create the previous examination cohort (2002 to 2006). The current examination characteristics were then compared with those of the previous examinations., Results: The current number of oncology OITE questions significantly decreased from previous years (27.2 versus 21.2; P = 0.015). Current examinations displayed a significant increase in testing the interpretation of diagnostic imaging modalities compared with previous examinations (78.3% versus 55.8%; P < 0.001). The current examinations examined a wide spectrum of pathologic diagnoses, including previously untested pathologies. The number of taxonomy 1 questions on current examinations significantly decreased (36.8% versus 24.5%; P = 0.032), whereas the number of taxonomy 3 questions significantly increased from previous examinations (48.1% versus 32.4%; P = 0.032)., Discussion: This study demonstrated that the nature of the orthopaedic oncology (pathology) section has changed over the past 10 years. Although the overall number of pathology-related questions decreased, the difficulty level of these questions increased, demanding a higher level of knowledge and critical thinking. A formal orthopaedic oncology rotation may be the best method to educate and improve OITE oncology performance., Level of Evidence: Prognostic study, level III.

Background: The opioid epidemic has spurred investigations for nonopioid options, yet limited research persists on medical marijuana's (MMJ) efficacy in managing cancer-related symptoms. Objective: We sought to characterize MMJ's role on symptomatic relief and opioid consumption in the oncologic population. Design: Retrospective chart review of MMJ-certified oncology patients was performed. Divided patients into MMJ use [MMJ(+)] versus no use [MMJ(-)], and Edmonton Symptom Assessment System (ESAS)-reported pain cohorts: "mild-moderate" versus "severe." Measurements: Medical records were reviewed for ESAS, to measure physical and emotional symptoms, and opiate consumption, converted into morphine milligram equivalents (MME). Minimal clinically important differences were determined. Wilcoxon signed-rank tests determined statistical significance between MMJ-certification and most recent palliative care visit. Results: Identified 232 patients [95/232 MMJ(-); 137/232 MMJ(+)]. Pain, physical and total ESAS significantly improved for total MMJ(-) and MMJ(+); however, only MMJ(+) significantly improved emotional ESAS. MMJ(-) opioid consumption increased by 23% (97.5-120 mg/day MME, p  = 0.004), while it remained constant (45-45 mg/day MME, p  = 0.522) in MMJ(+). Physical and total ESAS improved in mild-moderate-MMJ(-) and MMJ(+). Pain and emotional symptoms worsened in MMJ(-); while MMJ(+)'s pain remained unchanged and emotional symptoms improved. MMJ(-) opioid consumption increased by 29% (90-126 mg/day MME, p  = 0.012); while MMJ(+)'s decreased by 33% (45-30 mg/day MME, p  = 0.935). Pain, physical, emotional, and total ESAS scores improved in severe-MMJ(-) and MMJ(+); opioid consumption reduced by 22% in MMJ(-) (135-106 mg/day MME, p  = 0.124) and 33% in MMJ(+) (90-60 mg/day MME, p  = 0.421). Conclusions: MMJ(+) improved oncology patients' ESAS scores despite opioid dose reductions and should be considered a viable adjuvant therapy for palliative management.

Chikungunya virus (CHIKV) is an alphavirus that causes febrile illness punctuated by severe polyarthralgia. After the emergence of CHIKV in the Western Hemisphere, multiple reports of congenital infections were published that documented neurological complications, cardiac defects, respiratory distress, and miscarriage. The Western Hemisphere is endemic to several alphaviruses, and whether antigenic cross-reactivity can impact the course of infection has not been explored. Recent advances in biomedical engineering have produced cell co-culture models that replicate the cellular interface at the maternal fetal axis. We employed a trans-well assay to determine if cross-reactive antibodies affected the movement and replication of CHIKV across placental cells and into an embryoid body. The data showed that antibodies to Venezuelan equine encephalitis virus significantly reduced CHIKV viral load in embryoid bodies. The data highlighted the fact that viral pathogenesis can be cell-specific and that exploiting antigenic cross-reactivity could be an avenue for reducing the impact of congenital CHIKV infections.

Proper diet and nutrition are essential for maintaining the health of captive birds, but specific nutritional requirements can vary by species. Our knowledge of avian nutrition is predominantly based on data collected from gallinaceous birds, which is the primary basis for the dietary recommendations for companion birds, such as budgerigars ( Melopsittacus undulatus ) and other psittacine birds, potentially leading to a higher risk of malnutrition. In the wild, budgerigars eat predominantly Australian grass seed of the Astrebla genus, which may not be similar to the commercially available food fed to captive budgerigars, both in nutrient content and in their physiologic effects. In this study, we examined the relationship between diet type and immune function by separating 36 budgerigars into 3 dietary treatments: 1) Roudybush formulated pellet diet (Roudybush BirdFood Inc, Woodland, CA, USA), 2) Kaytee Forti-Diet Pro Health seed mix (Kaytee Products Inc, Chilton, WI, USA), and 3) a natural seed diet containing fresh canary grass, flax, nyger, oat groats, and white millet seeds. We monitored body weight, measured the microbial killing ability of whole blood by Escherichia coli and Candida albicans , and collected blood smears to assess white blood cell counts during a period of 8 weeks. Overall, we observed no significant effects of the 3 different diets on bird microbial killing ability or on white blood cell counts, suggesting similar health outcomes for budgerigars that consume mixed seed and those that receive pellet-based diets during this relatively short-term study.

The objective was to investigate the effects of novel policing techniques on hospital-observed incidence, healthcare utilization, mortality and costs associated with gun violence, from the perspective of a level-1 trauma center. An eight-year retrospective review evaluating the clinical and financial effects of gunshot wound (GSW) encounters between January 1st, 2010 and December 31st, 2017. Individuals who presented to the emergency department (Level-1 trauma center in Camden, NJ) between January 1, 2010 and December 31, 2017 with GSW (995 encounters) were included; however, patients with incomplete financial or medical record data were excluded (55 encounters). Patients were subdivided into two cohorts: before and after changes in policing tactics (May 1st, 2013). 940 total firearm-related encounters were included in the study. Following the policing changes, the hospital-observed quarterly incidence of GSW encounters decreased by 22% post-policing changes, 44.3 to 34.6 (p = 0.038). Average quarterly days spent in-house for GSW treatment decreased 220.7 to 151.3 (31%) days. Hospital observed mortality increased from 13.5% of presentations to 17.3% of presentations (p = 0.106). Total cost savings associated with the policing change was roughly $254,000 per quarter (p = 0.023). In areas susceptible to high rates of gun violence, similar novel policing tactics could significantly decrease hospital-observed incidence, costs and healthcare utilization demanded by firearm-related injury., (© 2019 The Authors.)

While parasite infection can have substantial fitness consequences in organisms, the predictors of parasite prevalence and intensity are often complex and vary depending on the host species. Here, we examined correlates of Haemoproteus (a common malaria parasite) prevalence and intensity in an opportunistically breeding songbird, the red crossbill (Loxia curvirostra). Specifically, we quantified Haemoproteus prevalence and intensity in crossbills caught in the Grand Teton National Park from 2010 to 2013. We found that parasite prevalence varies seasonally and across years, with the highest number of infected individuals occurring in the summer, although there was variation across summers sampled, and that prevalence was positively related to annual mean cone crop sizes (a measure of crossbill food abundance) and daily ambient temperature (a correlate of vector abundance). Parasite intensity was significantly and positively related to one measure of innate immunity, leucocyte counts per blood volume. Finally, neither crossbill age, ecomorph, nor sex had significant effects on parasite infection intensity; however, parasite prevalence did significantly vary among ecomorph and age classes. These results support the interpretation that a combination of physiological (specifically immune activity) and environmental factors affects parasite prevalence and infection intensity in this opportunistically breeding avian species.

An organism's investment in immune function often varies seasonally but understanding of how fluctuations in environmental conditions directly modulate investment remains limited. This experiment investigated how changes in photoperiod and food availability affect investment in constitutive innate immunity and the acute phase response induced by lipopolysaccharide (LPS) injections in captive red crossbills ( Loxia curvirostra ). Crossbills are reproductively flexible songbirds that specialize on an unpredictably available food resource and display temporal variation in immunity in the wild. Birds were separated into four treatments and exposed to long or short day lengths for 6 weeks before continuing on an ad libitum diet or experiencing a 20% food reduction for 10 days. Birds were un-injected or injected with LPS both before and after diet change. Innate immunity was quantified throughout the experiment to assess effects of photoperiod, food availability and their interactions on hemolysis-hemagglutination, haptoglobin, bacterial killing ability and leukocyte counts. Overall, increasing day length significantly increased both bacterial killing ability and leukocyte counts. Surprisingly, food restriction had little effect on the immune parameters, potentially owing to the 'low-cost' environment of captivity and suggesting that investment in innate immunity is prioritized and maintained whenever possible. LPS injections induced stereotypical sickness behaviors and increased bacterial killing ability in short day birds and complement activity (hemolysis) both before and after food restriction. These results demonstrate robust seasonal modulation of immune investment and an ability to maintain innate immunity in the face of limited resources in these temporally flexible songbirds., (© 2017. Published by The Company of Biologists Ltd.)

Mutator phenotypes create genetic diversity that fuels tumor evolution. DNA polymerase (Pol) ε mediates leading strand DNA replication. Proofreading defects in this enzyme drive a number of human malignancies. Here, using budding yeast, we show that mutator variants of Pol ε depend on damage uninducible (Dun)1, an S-phase checkpoint kinase that maintains dNTP levels during a normal cell cycle and up-regulates dNTP synthesis upon checkpoint activation. Deletion of DUN1 (dun1Δ) suppresses the mutator phenotype of pol2-4 (encoding Pol ε proofreading deficiency) and is synthetically lethal with pol2-M644G (encoding altered Pol ε base selectivity). Although pol2-4 cells cycle normally, pol2-M644G cells progress slowly through S-phase. The pol2-M644G cells tolerate deletions of mediator of the replication checkpoint (MRC) 1 (mrc1Δ) and radiation sensitive (Rad) 9 (rad9Δ), which encode mediators of checkpoint responses to replication stress and DNA damage, respectively. The pol2-M644G mutator phenotype is partially suppressed by mrc1Δ but not rad9Δ; neither deletion suppresses the pol2-4 mutator phenotype. Thus, checkpoint activation augments the Dun1 effect on replication fidelity but is not required for it. Deletions of genes encoding key Dun1 targets that negatively regulate dNTP synthesis, suppress the dun1Δ pol2-M644G synthetic lethality and restore the mutator phenotype of pol2-4 in dun1Δ cells. DUN1 pol2-M644G cells have constitutively high dNTP levels, consistent with checkpoint activation. In contrast, pol2-4 and POL2 cells have similar dNTP levels, which decline in the absence of Dun1 and rise in the absence of the negative regulators of dNTP synthesis. Thus, dNTP pool levels correlate with Pol ε mutator severity, suggesting that treatments targeting dNTP pools could modulate mutator phenotypes for therapy.

Mutator phenotypes accelerate the evolutionary process of neoplastic transformation. Historically, the measurement of mutation rates has relied on scoring the occurrence of rare mutations in target genes in large populations of cells. Averaging mutation rates over large cell populations assumes that new mutations arise at a constant rate during each cell division. If the mutation rate is not constant, an expanding mutator population may contain subclones with widely divergent rates of evolution. Here, we report mutation rate measurements of individual cell divisions of mutator yeast deficient in DNA polymerase ε proofreading and base-base mismatch repair. Our data are best fit by a model in which cells can assume one of two distinct mutator states, with mutation rates that differ by an order of magnitude. In error-prone cell divisions, mutations occurred on the same chromosome more frequently than expected by chance, often in DNA with similar predicted replication timing, consistent with a spatiotemporal dimension to the hypermutator state. Mapping of mutations onto predicted replicons revealed that mutations were enriched in the first half of the replicon as well as near termination zones. Taken together, our findings show that individual genome replication events exhibit an unexpected volatility that may deepen our understanding of the evolution of mutator-driven malignancies.

Background: PET scanning has been shown in randomized trials to reduce the frequency of surgery without cure among patients with potentially resectable non-small cell lung cancer (NSCLC). We examined whether more frequent use of PET scanning at the facility level improves survival among patients with NSCLC in real-world practice., Methods: In this prospective cohort study of 622 US veterans with newly diagnosed NSCLC, we compared groups defined by the frequency of PET scan use measured at the facility level and categorized as low (<25%), medium (25%-60%), or high (>60%)., Results: The median age of the sample was 69 years. Ninety-eight percent were men, 36% were Hispanic or nonwhite, and 54% had moderate or severe comorbidities. At low-, medium-, and high-use facilities, PET scan was performed in 13%, 40%, and 72% of patients, respectively (P<.0001). Baseline characteristics were similar across groups, including clinical stage based on CT scanning. More frequent use of PET scanning was associated with more frequent invasive staging (P<.001) and nonsignificant improvements in downstaging (P=.13) and surgery without cure (P=.12). After a median of 352 days of follow-up, 22% of the sample was still alive, including 22% at low- and medium-use facilities and 20% at high-use facilities. After adjustment and compared with patients at low-use facilities, the hazard of death was greater for patients at high-use facilities (adjusted hazard ratio [HR], 1.35; 95% CI, 1.05-1.74) but not different for patients at medium-use facilities (adjusted HR, 1.14; 95% CI, 0.88-1.46)., Conclusions: In this study of veterans with NSCLC, markedly greater use of PET scanning at the facility level was associated with more frequent use of invasive staging and possible improvements in downstaging and surgery without cure, but greater use of PET scanning was not associated with better survival.

Genetic defects in DNA polymerase accuracy, proofreading, or mismatch repair (MMR) induce mutator phenotypes that accelerate adaptation of microbes and tumor cells. Certain combinations of mutator alleles synergistically increase mutation rates to levels that drive extinction of haploid cells. The maximum tolerated mutation rate of diploid cells is unknown. Here, we define the threshold for replication error-induced extinction (EEX) of diploid Saccharomyces cerevisiae. Double-mutant pol3 alleles that carry mutations for defective DNA polymerase-δ proofreading (pol3-01) and accuracy (pol3-L612M or pol3-L612G) induce strong mutator phenotypes in heterozygous diploids (POL3/pol3-01,L612M or POL3/pol3-01,L612G). Both pol3-01,L612M and pol3-01,L612G alleles are lethal in the homozygous state; cells with pol3-01,L612M divide up to 10 times before arresting at random stages in the cell cycle. Antimutator eex mutations in the pol3 alleles suppress this lethality (pol3-01,L612M,eex or pol3-01,L612G,eex). MMR defects synergize with pol3-01,L612M,eex and pol3-01,L612G,eex alleles, increasing mutation rates and impairing growth. Conversely, inactivation of the Dun1 S-phase checkpoint kinase suppresses strong pol3-01,L612M,eex and pol3-01,L612G,eex mutator phenotypes as well as the lethal pol3-01,L612M phenotype. Our results reveal that the lethal error threshold in diploids is 10 times higher than in haploids and likely determined by homozygous inactivation of essential genes. Pronounced loss of fitness occurs at mutation rates well below the lethal threshold, suggesting that mutator-driven cancers may be susceptible to drugs that exacerbate replication errors.

Context: The Closing the Quality Gap series from the Agency for Healthcare Research and Quality summarizes evidence for eight high-priority health care topics: outcomes used in disability research, bundled payment programs, public reporting initiatives, health care disparities, palliative care, the patient-centered medical home, prevention of health care-associated infections, and medication adherence., Objective: To distill evidence from this series and provide insight into the "state of the science" of quality improvement (QI)., Methods: We provided common guidance for topic development and qualitatively synthesized evidence from the series topic reports to identify cross-topic themes, challenges, and evidence gaps as related to QI practice and science., Results: Among topics that examined effectiveness of QI interventions, we found improvement in some outcomes but not others. Implementation context and potential harms from QI activities were not widely evaluated or reported, although market factors appeared important for incentive-based QI strategies. Patient-focused and systems-focused strategies were generally more effective than clinician-focused strategies, although the latter approach improved clinician adherence to infection prevention strategies. Audit and feedback appeared better for targeting professionals and organizations, but not patients. Topic reviewers observed heterogeneity in outcomes used for QI evaluations, weaknesses in study design, and incomplete reporting., Conclusions: Synthesizing evidence across topics provided insight into the state of the QI field for practitioners and researchers. To facilitate future evidence synthesis, consensus is needed around a smaller set of outcomes for use in QI evaluations and a framework and lexicon to describe QI interventions more broadly, in alignment with needs of decision makers responsible for improving quality.

Background: Care coordination has increasingly been recognized as an important aspect of high-quality health care delivery. Robust measures of coordination processes will be essential tools to evaluate, guide and support efforts to understand and improve coordination, yet little agreement exists among stakeholders about how to best measure care coordination. We aimed to review and characterize existing measures of care coordination processes and identify areas of high and low density to guide future measure development., Methods: We conducted a systematic review of measures published in MEDLINE through April 2012 and identified from additional key sources and informants. We characterized included measures with respect to the aspects of coordination measured (domain), measurement perspective (patient/family, health care professional, system representative), applicable settings and patient populations (by age and condition), and data used (survey, chart review, administrative claims)., Results: Among the 96 included measure instruments, most relied on survey methods (88%) and measured aspects of communication (93%), in particular the transfer of information (81%). Few measured changing coordination needs (11%). Nearly half (49%) of instruments mapped to the patient/family perspective; 29% to the system representative and 27% to the health care professionals perspective. Few instruments were applicable to settings other than primary care (58%), inpatient facilities (25%), and outpatient specialty care (22%)., Conclusions: New measures are needed that evaluate changing coordination needs, coordination as perceived by health care professionals, coordination in the home health setting, and for patients at the end of life.

Background: Timeliness is an important dimension of health care quality. It is unclear whether timeliness improves clinical outcomes in patients with lung cancer., Methods: This study systematically reviewed studies that described timeliness of care, examined associations between timeliness and clinical outcomes or tested an intervention to improve timeliness of care in patients with lung cancer. English language studies published between 1 January 1995 and 1 June 2007 were included. Two reviewers independently abstracted data on study methods, population, sample size, relevant time intervals and outcomes., Results: 49 studies were identified that reported at least one time interval in lung cancer care, 18 studies that examined the association between timeliness and clinical outcomes and 8 studies that described interventions aimed at improving timeliness. Most studies were performed in European Union member countries, including 24 studies performed in Great Britain and Ireland. Median times to diagnosis (range 8-60 days) and times to treatment (range 30-84 days) often exceeded published recommendations. Three studies found that timely care was associated with better survival, eight found no association and four reported better survival in patients who received less timely care. Interventions that improved timeliness included nurse-led care coordination, multidisciplinary meetings via teleconference and a standardised expedited "two-stop" diagnostic process., Conclusions: Times to diagnosis and treatment of lung cancer are often longer than recommended. Factors associated with timeliness have been incompletely examined, and it remains unclear whether more timely care improves outcomes.

Introduction: By providing timely care at all steps along the continuum of lung cancer care, providers may be able to limit disease progression before treatment and possibly improve clinical outcomes. This study examines the timeliness of key events in the process of care between initial radiograph and first treatment., Methods: Dates of key events were extracted from the medical records of 2463 veterans receiving lung cancer care at 133 Department of Veterans Affairs (VA) facilities. After reviewing their site's abstraction results, facility leaders completed a survey on their perceptions of their local processes of lung cancer care., Results: Median time from first radiography to first treatment was 71 days. The longest intermediate time interval examined was between first treatment referral and first treatment (median = 12 days). Time from first to last diagnostic test was most variable (interquartile range = 0-27 days). We found a significant trend indicating that the time interval from first radiograph to treatment was shorter for patients with more advanced disease. This effect was also significant within six of the seven intermediate time intervals we examined. Survey responses indicated that the chart review process stimulated improvement activity., Conclusions: Although patients with earlier stage disease benefit more from treatment, they do not proceed as quickly through the continuum of care as patients with more advanced disease. By measuring variability in timeliness of care at multiple steps in the lung cancer care process, facilities may identify opportunities for improvement.

Background: Timeliness is an important dimension of quality of care for patients with lung cancer., Methods: We reviewed the records of consecutive patients in whom non-small cell lung cancer (NSCLC) had been diagnosed between January 1, 2002, and December 31, 2003, at the Veterans Affairs Palo Alto Health Care System. We used multivariable statistical methods to identify independent predictors of timely care and examined the effect of timeliness on survival., Results: We identified 129 veterans with NSCLC (mean age, 67 years; 98% men; 83% white), most of whom had adenocarcinoma (51%) or squamous cell carcinoma (30%). A minority of patients (18%) presented with a solitary pulmonary nodule (SPN). The median time from the initial suspicion of cancer to treatment was 84 days (interquartile range, 38 to 153 days). Independent predictors of treatment within 84 days included hospitalization within 7 days (odds ratio [OR], 8.2; 95% confidence interval [CI], 2.9 to 23), tumor size of > 3.0 cm (OR, 4.8; 95% CI, 1.8 to 12.4), the presence of additional chest radiographic abnormalities (OR, 3.0; 95% CI, 1.1 to 8.5), and the presence of one or more symptoms suggesting metastasis (OR, 2.6; 95% CI, 1.1 to 6.2). More timely care was not associated with better survival time (adjusted hazard ratio, 1.6; 95% CI, 1.3 to 1.9). However, in patients with SPNs, there was a trend toward better survival time when the time to treatment was < 84 days., Conclusions: The time to treatment for patients with NSCLC was often longer than recommended. Patients with larger tumors, symptoms, and other chest radiographic abnormalities receive more timely care. In patients with malignant SPNs, survival may be better when treatment is initiated promptly.

Introduction: Little is known about the natural history of malignant solitary pulmonary nodules (SPN). Experts' beliefs may help fill these knowledge gaps and explain variation in clinical practices., Methods: Using a modified Delphi process, we surveyed a group of lung cancer experts about tumor growth, disease progression, and prognosis in patients with malignant SPN. After completing the first survey, experts were given the opportunity during a second survey to revise their responses in light of their peers' beliefs., Results: The response rate was 100% (14 of 14) for both surveys. There was consensus that disease progression depends on the tumor growth rate, that survival for patients with untreated lung cancer is approximated by a declining exponential function, and that treatment is delayed by approximately 1 tumor volume doubling time (TVDT) in patients who undergo a period of "watchful waiting." Just over half of experts (8 of 14) agreed that lung cancer progresses in three steps (from local to regional to distant disease), whereas 43% (6 of 14) preferred a 2-step model (from local to systemic disease). Likewise, 64% of experts (9 of 14) believed that malignant nodules grow exponentially, whereas 36% (5 of 14) believed that growth is slower than exponential. Experts' estimates of the risk of disease progression during a period of observation lasting 1 TVDT varied from 1 to 50%. Estimates of 5-year survival for patients in whom diagnosis and treatment were delayed by 1 TVDT varied between 40% and 80%., Conclusions: There is substantial variability in experts' beliefs about the natural history of untreated, malignant SPN. Different beliefs may be partly responsible for variation in management practices.

Background: Effective strategies for managing patients with solitary pulmonary nodules (SPN) depend critically on the pre-test probability of malignancy., Objective: To validate two previously developed models that estimate the probability that an indeterminate SPN is malignant, based on clinical characteristics and radiographic findings., Methods: Data on age, smoking and cancer history, nodule size, location and spiculation were collected retrospectively from the medical records of 151 veterans (145 men, 6 women; age range 39-87 years) with an SPN measuring 7-30 mm (inclusive) and a final diagnosis established by histopathology or 2-year follow-up. Each patient's final diagnosis was compared with the probability of malignancy predicted by two models: one developed by investigators at the Mayo Clinic and the other developed from patients enrolled in a VA Cooperative Study. The accuracy of each model was assessed by calculating areas under the receiver operating characteristic (ROC) curve and the models were calibrated by comparing predicted and observed rates of malignancy., Results: The area under the ROC curve for the Mayo Clinic model (0.80; 95% CI 0.72 to 0.88) was higher than that of the VA model (0.73; 95% CI 0.64 to 0.82), but this difference was not statistically significant (Delta = 0.07; 95% CI -0.03 to 0.16). Calibration curves showed that the probability of malignancy was underestimated by the Mayo Clinic model and overestimated by the VA model., Conclusions: Two existing prediction models are sufficiently accurate to guide decisions about the selection and interpretation of subsequent diagnostic tests in patients with SPNs, although clinicians should also consider the prevalence of malignancy in their practice setting when choosing a model.

A series of oxygen and/or nitrogen substituted 2-(aminomethyl)phenols was synthesized and tested orally in rats for saluretic and diuretic effects. Intravenous dog data are included as supplementary material to demonstrate diuretic responses, or lack thereof, in a second species. In general, substitution on nitrogen with groups other than lower alkyl or substitution on nitrogen and/or oxygen with groups resistant to hydrolysis substantially diminished or ablated saluretic effects.

A series of 2-(aminomethyl)phenols was synthesized and tested in rats and dogs for saluretic and diuretic activity. A number of these compounds exhibit a high order of activity on iv or po administration. The most active compounds belong to a subseries of 4-alkyl-6-halo derivatives of which 2, 2-(aminomethyl)-4-(1,1-dimethylethyl)-6-iodophenol, is the most active. Compound 2 also possesses significant antihypertensive activity, an adjunctive pharmacological parameter which distinguishes 2 from the other compounds prepared in this series. In addition, 2 displays both topical saluretic and antiinflammatory activities.

The synthesis of a number of 3,4-dihydrospiro-2H-1,3-benzoxazines and their corresponding benzoxazinium salts are reported. The saluretic effects displayed by these N,O-spiroannulated 2-(aminomethyl)phenols appear to be, in part, inversely related to their respective in vivo rates of hydrolysis. Good antihypertensive effects are found only in spirobenzoxazinium 22. Thus, a combination of spiroannulation and quaternization on 2 to produce 22 leads to a loss of saluretic effects with maintenance of antihypertensive effects and, thereby, serves to separate these pharmacological properties.

The discovery of the (acryloylaryloxy)acetic acids as a new class of potent diuretics prompted the investigation of related bicyclic compounds. Annelated analogues of the parent series, the (2-alkyl- and 2,2-dialkyl-1-oxo-5-indanyloxy)acetic acids, were the subjects of this study. Those compounds, unlike the monocyclic parent compound, lacked the double bond adjacent to the carbonyl group. More importantly, they possessed both saluretic and uricosuric properties. The optimal single 2-substituents for maximal saluretic and uricosuric activity were determined. In general, better activity was observed when a second 2-alkyl substituent (especially methyl) was present in the molecule. Replacement of the carboxy substituent by 5-tetrazolyl generally resulted in a reduction in activity.

A series of modified 2-(aminomethyl)phenols was synthesized and tested orally in rats for saluretic and diuretic effects. Intravenous dog data are included as supplementary material to show that the diuretic responses, or lack thereof, may be obtained in a second species. Reorientation of the 2-(aminomethyl) group either meta or para to the hydroxyl substituent resulted in loss of diuretic effects. Similarly, replacement of either the phenolic hydroxyl or the aminomethyl group with other functional moieties substantially diminished saluretic effects.

A series of [(2-nitro-1-alkenyl)aryloxy]acetic acids was synthesized and tested in dogs for saluretic and diuretic activity. A number of these compounds exhibit a high order of activity on iv or po administration; representative of these is (E)-[2,3-dichloro-4-(2-nitropropenyl)phenoxy]acetic acid (5). The most highly active compounds are qualitatively similar in action to [2,3-dichloro-4-(2-methylenebutyryl)phenoxylacetic acid (ethacrynic acid) in causing a prompt increase in the excretion of water and of sodium and chloride ions in approximately equimolar amounts but are three to five times as potent. Potassium ion excretion is increased but less markedly than sodium excretion.

A number of bicyclic ring-fused analogues of 2-(aminomethyl)phenol were synthesized and tested orally in rats and intravenously in dogs for saluretic and diuretic effects. Of the 15 alicylic, aromatic, and heterocyclic ring-fused compounds tested, only 2-(aminomethyl)-4-chloro-1-naphthalenol hydrochloride (2) and 7-(aminomethyl)-6-hydroxy-5,8-dimethyl-1,2,3,4-tetrahydronaphthalene hydrochloride (6) displayed a high order of activity.