Measurement of Complement Activation via Plasma-Soluble C5b-9 Comparison with Terminal Complement Complex Staining in a Series of Kidney Biopsies.

INTRODUCTION: With the emergence of therapeutic complement inhibitors, there is a need to identify patients with complement-driven inflammation. C5b-9 is the terminal product of the three complement pathways and therefore a marker of total complement activation. We present a pilot study which aims to assess whether plasma soluble C5b-9 (sC5b-9) correlates with terminal complement complex (TCC) staining in kidney tissue. The secondary aim was to assess the utility of plasma sC5b-9 as part of routine workup in kidney patients undergoing kidney biopsy. METHODS: Thirty-seven patients undergoing kidney biopsy had plasma sC5b-9 and TCC staining on kidney tissue performed. Additional blood markers including creatinine, haemoglobin, CRP, factor H, factor I, and midkine levels were also taken. These parameters were correlated with the histological diagnoses. Patients were divided into a diseased group (n = 31) and a control group (n = 6) consisting of transplanted kidneys with minor or no changes. Of the biopsies in the control group, 50% were performed as per protocol, and the other 50% were performed due to clinical need. RESULTS: There was no correlation found between plasma sC5b-9 and TCC kidney staining. Elevated sC5b-9 levels were found in a heterogeneous group of patients but were associated with higher CRP and lower haemoglobin levels. Overall, there was more TCC kidney staining in the diseased group compared with the control group, and a trend was observed of diabetic, primary membranous nephropathy, and amyloidosis patients having more intense glomerular and peritubular/interstitial staining. CONCLUSION: Plasma sC5b-9 as a marker of total complement activation does not correlate with TCC kidney staining. This discordance suggests that plasma sC5b-9 and TCC staining are distinct markers of disease. TCC staining reflects chronicity and tissue deposition of complement over time. Conversely, plasma sC5b-9 concentrations change rapidly and reflect systemic complement activation. Complement activation was present in a heterogeneous group of kidney disease, indicating the underlying role of complement in many disorders.

Development and validation of a risk score to identify children at risk of life-threatening asthma.

OBJECTIVE: To develop and validate a prediction risk score for identification of children at risk of developing life-threatening asthma (LTA). METHODS: Our study utilized existing medical records and retrospective analysis to develop and validate a risk score. The study population included children aged 2-17 years, admitted with a primary diagnosis of asthma, to Sydney Children's Hospital between 2011-2016. Children admitted in the intensive care unit with asthma at risk of LTA (cases) and those admitted into general ward (comparison group), were randomly divided into a derivation and a validation cohort. Candidate predictors from derivation cohort were selected through multivariable regression, which were used to estimate each child's risk of developing LTA in the validation cohort. Predictive performance of the risk score was evaluated by the area under the receiver operating characteristic curve (AUROC) and Hosmer-Lemeshow goodness-of-fit test. RESULTS: The study population comprised of 1171 children; 586 in the derivation and 585 in the validation cohort. Four independent candidate variables from derivation cohort (age at admission, socioeconomic status, a family history of asthma/atopy and previous asthma hospitalizations) were retained in the predictive model (AUROC 0.759; 95% CI, 0.694-0.823), with a sensitivity of 78.5% and specificity of 46.6%. CONCLUSIONS: Our risk algorithm based on routinely collected clinical data may be used to develop a user-friendly risk score for early identification and monitoring of children at risk of developing LTA.

A Randomized Trial to Improve Adherence to Follow-up Eye Examinations Among People With Glaucoma.

INTRODUCTION: Appointment nonadherence is common among people with glaucoma, making it difficult for eye care providers to monitor glaucoma progression. Our objective was to determine whether the use of patient navigators, in conjunction with social worker support, could increase adherence to recommended follow-up eye appointments. METHODS: A randomized, controlled trial evaluated the effectiveness of an intervention that used patient navigators and social workers to improve patient adherence to follow-up eye care compared with usual care. Participants with glaucoma and other eye diseases (N = 344) were identified at primary care clinics in community settings through telemedicine screening of imaging and then randomized to enhanced intervention (EI) or usual care (UC). Data on participants' visits with local ophthalmologists were collected for up to 3 years from randomization. Groups were compared for timely attendance at the first visit with the local ophthalmologist and adherence to recommended follow-up visits. RESULTS: Timely attendance at the first visit was higher for EI than UC (74.4% vs 39.0%; average relative risk [aRR] = 1.85; 95% CI, 1.51-2.28; P < .001). Rates of adherence to recommended annual follow-up during year 1 were 18.6% in the EI group and 8.1% in the usual care group (aRR = 2.08; 95% CI, 1.14-3.76; P = .02). The aRR across years 2 and 3 was 3.92 (95% CI, 1.24-12.43; P = .02). CONCLUSION: An intervention using patient navigators and social workers doubled the rate of adherence to annual recommended follow-up eye care compared with usual care in community settings, and was effective at increasing connections with local ophthalmologists. Interventions to further improve long-term adherence are needed.

Role of technology in improving knowledge and confidence in asthma management in school staff.

Objective: To investigate the effectiveness of technology enabled learning in improving asthma first aid knowledge and self-confidence in providing asthma first aid to children in staff within a school setting. Study Design: A prospective randomized parallel study using a pre and post test design was conducted across Metropolitan schools of New South Wales (NSW), Australia. School staff in selected schools were randomly assigned to receive first aid asthma management training via a self-directed multimedia eBook learning resource or standard face-to-face training. Staff completed a 14 item validated Asthma First Aid Knowledge Questionnaire and a 4 item, 10-point Likert-scale asthma management self-confidence questionnaire immediately pre and post training. Results: 148 school staff from 46 schools were recruited with a total of 59 (78%) staff completing the eBook training and 62 (86%) completing face-to-face training. The mean asthma first aid knowledge score and self-confidence score in managing asthma increased significantly (p < 0.0001) in the eBook training group post training. There was no significant difference in the increase in the mean scores post training between the eBook and face-to-face training groups (p = 0.11). Conclusion: Asthma management knowledge and self-confidence increased in school staff following the eBook training. In school settings where human resources for health education are limited, technology enabled learning may be substituted to provide a self-directed approach to asthma first aid management training.

Lipid signaling and fat storage in the dark-eyed junco.

Seasonal hyperphagia and fattening promote survivorship in migratory and wintering birds, but reduced adiposity may be more advantageous during the breeding season. Factors such as photoperiod, temperature, and food predictability are known environmental determinants of fat storage, but the underlying neuroendocrine mechanisms are less clear. Endocannabinoids and other lipid signaling molecules regulate multiple aspects of energy balance including appetite and lipid metabolism. However, these functions have been established primarily in mammals; thus the role of lipid signals in avian fat storage remains largely undefined. Here we examined relationships between endocannabinoid signaling and individual variation in fat storage in captive white-winged juncos (Junco hyemalis aikeni) following a transition to long-day photoperiods. We report that levels of the endocannabinoid 2-arachidonoylglycerol (2-AG), but not anandamide (AEA), in furcular and abdominal fat depots correlate negatively with fat mass. Hindbrain mRNA expression of CB1 endocannabinoid receptors also correlates negatively with levels of fat, demonstrating that fatter animals experience less central and peripheral endocannabinoid signaling when in breeding condition. Concentrations of the anorexigenic lipid, oleoylethanolamide (OEA), also inversely relate to adiposity. These findings demonstrate unique and significant relationships between adiposity and lipid signaling molecules in the brain and periphery, thereby suggesting a potential role for lipid signals in mediating adaptive levels of fat storage.

Differential effects of stress on microglial cell activation in male and female medial prefrontal cortex.

Susceptibility to stress-linked psychological disorders, including post-traumatic stress disorder and depression, differs between men and women. Dysfunction of medial prefrontal cortex (mPFC) has been implicated in many of these disorders. Chronic stress affects mPFC in a sex-dependent manner, differentially remodeling dendritic morphology and disrupting prefrontally mediated behaviors in males and females. Chronic restraint stress induces microglial activation, reflected in altered microglial morphology and immune factor expression, in mPFC in male rats. Unstressed females exhibit increased microglial ramification in several brain regions compared to males, suggesting both heightened basal activation and a potential for sex-dependent effects of stress on microglial activation. Therefore, we assessed microglial density and ramification in the prelimbic region of mPFC, and immune-associated genes in dorsal mPFC in male and female rats following acute or chronic restraint stress. Control rats were left unstressed. On the final day of restraint, brains were collected for either qPCR or visualization of microglia using Iba-1 immunohistochemistry. Microglia in mPFC were classified as ramified, primed, reactive, or amoeboid, and counted stereologically. Expression of microglia-associated genes (MHCII, CD40, IL6, CX3CL1, and CX3CR1) was also assessed using qPCR. Unstressed females showed a greater proportion of primed to ramified microglia relative to males, alongside heightened CX3CL1-CX3CR1 expression. Acute and chronic restraint stress reduced the proportion of primed to ramified microglia and microglial CD40 expression in females, but did not significantly alter microglial activation in males. This sex difference in microglial activation could contribute to the differential effects of stress on mPFC structure and function in males versus females.

Divergence along the gonadal steroidogenic pathway: Implications for hormone-mediated phenotypic evolution.

Across a range of taxa, hormones regulate suites of traits that influence survival and reproductive success; however, the mechanisms by which hormone-mediated traits evolve are still unclear. We hypothesized that phenotypic divergence might follow from differential regulation of genes encoding key steps in hormone biosynthesis and thus the rate of hormone production. We tested this hypothesis in relation to the steroid hormone testosterone by comparing two subspecies of junco (Junco hyemalis) in the wild and in captivity. These subspecies have diverged over the last 10-15kyears in multiple testosterone-mediated traits, including aggression, ornamentation, and body size. We show that variation in gonadal gene expression along the steroid biosynthetic pathway predicts phenotypic divergence within and among subspecies, and that the more androgenized subspecies exhibits a more prolonged time-course of elevated testosterone following exogenous stimulation. Our results point to specific genes that fulfill key conditions for phenotypic evolution because they vary functionally in their expression among individuals and between populations, and they map onto population variation in phenotype in a common garden. Our findings therefore build an important bridge between hormones, genes, and phenotypic evolution.

The prevalence of unique SNPs in the renin-angiotensin system highlights the need for pharmacogenetics in Indigenous Australians.

Genetic differences between ethnic populations affect susceptibility to disease and efficacy of drugs. This study examined and compared the prevalence of single nucleotide polymorphisms (SNPs) in genes of the renin-angiotensin system (RAS) in a desert community of Indigenous Australians and in non-Indigenous Australians. The polymorphisms were angiotensinogen, AGT G-217A (rs5049); AGT G+174A (rs4762); Angiotensin II type 1 receptor, AGTR1 A+1166C (rs5186); angiotensin converting enzyme, ACE A-240T (rs4291), ACE T-93C (rs4292); renin, REN T+1142C (rs5706). They were measured using allelic discrimination assays. The prevalence of REN T+1142C SNP was similar in the two populations; 99% were homozygous for the T allele. All other SNPs were differently distributed between the two populations (P < 0.0001). In non-Indigenous Australians, the A allele at position 204 of ACE rs4291 was prevalent (61.8%) whereas in the Indigenous Australians the A allele was less prevalent (28%). For rs4292, the C allele had a prevalence of 37.9% in non-Indigenous Australians but in Indigenous Australians the prevalence was only 1%. No Indigenous individuals were homozygous for the C allele of AGTR1 (rs5186). Thus the prevalence of RAS SNPs in this Indigenous Australian desert community was different from non-Indigenous Australians as was the prevalence of cytokine SNPs (as shown in a previous study). These differences may affect susceptibility to chronic renal and cardiovascular disease and may alter the efficacy of drugs used to inhibit the RAS. These studies highlight the need to study the pharmacogenetics of drug absorption, distribution, metabolism and excretion in Indigenous Australians for safe prescribing guidelines.

Examining sources of variation in HPG axis function among individuals and populations of the dark-eyed junco.

Gonadal steroids are important mediators of traits relevant to fitness, and thus may be targets of selection. However, more knowledge is needed about sources of variation along the endocrine axes that may contribute to functional variation in steroid levels. In a controlled captive environment, we studied males of two closely related subspecies of the dark-eyed junco (Junco hyemalis) that differ in testosterone-related phenotype, asking whether they also differ in testosterone (T), and assessing the contribution of the sequential links of the hypothalamic-pituitary-gonadal axis. When males of both subspecies were challenged with gonadotropin-releasing hormone (GnRH), they were similar in circulating luteinizing hormone (LH) and T responses. When challenged with exogenous LH, they again produced levels of T similar to one another, and to the levels produced in response to GnRH. However, the smaller, less ornamented, and less aggressive subspecies had greater abundance of mRNA for LH receptor in the testes and for androgen receptor in the rostral hypothalamus, suggesting potential differences in regulatory feedback. We suggest that circulating hormone levels may be less prone to evolutionary change than the responsiveness of individual hormone targets. Among individuals, T titers were highly repeatable whether males were challenged with GnRH or with LH, but LH produced in response to GnRH did not covary with T produced in response to LH. Testis mass, but not LH receptor transcript abundance, predicted individual variation in T responses. These data implicate the gonad, but not the pituitary, as an important source of individual variation in T production.

Autism spectrum disorder phenotypes and prenatal exposure to methylmercury.

BACKGROUND: There continues to be public concern that mercury exposure and autism spectrum disorder (ASD) may be associated. The primary source of exposure to organic mercury in humans is to methylmercury from fish consumption. We evaluated the association between prenatal methylmercury exposure and ASD phenotype in children and adolescents in the Republic of Seychelles, where fish consumption is high. METHODS: We administered the Social Communication Questionnaire to parents of a cohort of 1784 children, adolescents, and young adults. The Social Responsiveness Scale was administered to teachers of 537 cohort subjects at about 10 years of age. Prenatal exposure to methylmercury was measured in maternal hair samples collected at or near the time of birth. Multivariable regression models evaluated the relationship between prenatal methylmercury exposure and ASD phenotypic scores, adjusting for relevant covariates. RESULTS: The mean prenatal methylmercury exposure for subjects in the analysis was 8.4 ppm (standard deviation [SD] = 5.7). The mean Social Communication Questionnaire score was 8.0 (SD = 4.4). The mean prenatal methylmercury exposure for subjects with Social Responsiveness Scale scores was 6.7 ppm (SD = 4.4) and the mean Social Responsiveness Scale score was 57.6 (SD = 26.8). No consistent association between prenatal methylmercury exposure and ASD screening instrument was found, using linear and nonlinear regression analyses. CONCLUSIONS: Prenatal exposure to methylmercury was not associated with ASD phenotypic behaviors in our cohort of high fish consumers. Our findings contribute to the growing literature suggesting that exposure to methylmercury does not play an important role in the development of ASD phenotypic behavior.

Sources of variation in HPG axis reactivity and individually consistent elevation of sex steroids in a female songbird.

Understanding sources of individual differences in steroid hormone production has important implications for the evolution of reproductive and social behaviors. In females in particular, little is known about the mechanistic sources of these individual differences, despite established linkages between sex steroids and a variety of fitness-related traits. Using captive female dark-eyed juncos (Junco hyemalis) from two subspecies, we asked how variation in different components of the hypothalamo-pituitary-gonadal (HPG) axis related to variation in testosterone production among females, and we compared females to males in multiple components of the HPG axis. We demonstrated consistent individual differences in testosterone elevation in response to challenges with luteinizing hormone (LH) and gonadotropin-releasing hormone (GnRH). These hormone challenges led to more LH production but less testosterone production in females than males, and the sexes differed in some but not all measures of sensitivity to hormones along the HPG axis. Similar to findings in males, variation in testosterone production among females was not related to variation in LH production, gonadal LH-receptor mRNA abundance, or hypothalamic abundance of androgen receptor mRNA or aromatase mRNA. Rather, the primary source of individual variation in circulating steroids appears to the gonad, a conclusion further supported by positive correlations between testosterone and estradiol production. Unlike males, females did not differ by subspecies in any of the endocrine parameters that we assessed, suggesting some degree of independent evolution between the two sexes. Our results highlight the sources of physiological variation that may underlie the evolution of hormone-mediated phenotypes in females.

Driver Mutation Variant Allele Frequency in Circulating Tumor DNA and Association with Clinical Outcome in Patients with Non-Small Cell Lung Cancer and EGFR- and KRAS-Mutated Tumors.

Clinical implementation of mutational analysis for next-generation sequencing-based assays has largely been of a binary nature, with pathogenic mutations being reported as either positive or negative. Actionability on the continuous output of variant allele frequency (VAF) has not been well characterized in the clinical setting, thus limiting its use. In this study, analytical validity and performance of the short variant VAF based on a next-generation sequencing-based liquid biopsy assay, FoundationOne Liquid CDx, were evaluated through assessment of precision, analytical accuracy, limit of blank, and limit of detection. Analytical validation of VAF values measured by using FoundationOne Liquid CDx supports that these values are accurate, precise, robust, and linear with the true VAF value. The association of allele frequency of clinically relevant short variants in circulating-free DNA and the association with overall survival for patients using real-world data were also assessed. The results of the association analysis indicate that VAF of the predictive biomarker mutation negatively correlates with overall survival of patients with non-small cell lung cancer.

Impact of integrated care coordination on pediatric asthma hospital presentations.

Introduction: Frequent asthma attacks in children result in unscheduled hospital presentations. Patient centered care coordination can reduce asthma hospital presentations. In 2016, The Sydney Children's Hospitals Network launched the Asthma Follow up Integrated Care Initiative with the aim to reduce pediatric asthma emergency department (ED) presentations by 50% through developing and testing an integrated model of care led by care coordinators (CCs). Methods: The integrated model of care was developed by a multidisciplinary team at Sydney Children's Hospital Randwick (SCH,R) and implemented in two phases: Phase I and Phase II. Children aged 2-16 years who presented ≥4 times to the ED of the SCH,R in the preceding 12 months were enrolled in Phase I and those who had ≥4 ED presentations and ≥1 hospital admissions with asthma attack were enrolled in Phase II. Phase I included a suite of interventions delivered by CCs including encouraging parents/carers to schedule follow-up visits with GP post-discharge, ensuring parents/carers are provided with standard asthma resource pack, offering referrals to asthma education sessions, sending a letter to the child's GP advising of the child's recent hospital presentation and coordinating asthma education webinar for GPs. In addition, in Phase II CCs sent text messages to parents/carers reminding them to follow-up with the child's GP. We compared the change in ED visits and hospital admissions at baseline (6 months pre-enrolment) and at 6-and 12-months post-enrolment in the program. Results: During December 2016-January 2021, 160 children (99 in Phase I and 61 in Phase II) were enrolled. Compared to baseline at 6- and 12-months post-enrolment, the proportion of children requiring ≥1 asthma ED presentations reduced by 43 and 61% in Phase I and 41 and 66% in Phase II. Similarly, the proportion of children requiring ≥1 asthma hospital admissions at 6- and 12-months post-enrolment reduced by 40 and 47% in Phase I and 62 and 69% in Phase II. Conclusion: Our results support that care coordinator led integrated model of asthma care which enables integration of acute and primary care services and provides families with asthma resources and education can reduce asthma hospital presentations in children.

Clinical and analytical validation of FoundationOne®CDx, a comprehensive genomic profiling assay for solid tumors.

FoundationOne®CDx (F1CDx) is a United States (US) Food and Drug Administration (FDA)-approved companion diagnostic test to identify patients who may benefit from treatment in accordance with the approved therapeutic product labeling for 28 drug therapies. F1CDx utilizes next-generation sequencing (NGS)-based comprehensive genomic profiling (CGP) technology to examine 324 cancer genes in solid tumors. F1CDx reports known and likely pathogenic short variants (SVs), copy number alterations (CNAs), and select rearrangements, as well as complex biomarkers including tumor mutational burden (TMB) and microsatellite instability (MSI), in addition to genomic loss of heterozygosity (gLOH) in ovarian cancer. CGP services can reduce the complexity of biomarker testing, enabling precision medicine to improve treatment decision-making and outcomes for cancer patients, but only if test results are reliable, accurate, and validated clinically and analytically to the highest standard available. The analyses presented herein demonstrate the extensive analytical and clinical validation supporting the F1CDx initial and subsequent FDA approvals to ensure high sensitivity, specificity, and reliability of the data reported. The analytical validation included several in-depth evaluations of F1CDx assay performance including limit of detection (LoD), limit of blank (LoB), precision, and orthogonal concordance for SVs (including base substitutions [SUBs] and insertions/deletions [INDELs]), CNAs (including amplifications and homozygous deletions), genomic rearrangements, and select complex biomarkers. The assay validation of >30,000 test results comprises a considerable and increasing body of evidence that supports the clinical utility of F1CDx to match patients with solid tumors to targeted therapies or immunotherapies based on their tumor's genomic alterations and biomarkers. F1CDx meets the clinical needs of providers and patients to receive guideline-based biomarker testing, helping them keep pace with a rapidly evolving field of medicine.

Response to exogenous kisspeptin varies according to sex and reproductive condition in Siberian hamsters (Phodopus sungorus).

Most animals experience marked changes in reproductive status across development that are regulated by changes in the hypothalamo-pituitary-gonadal (HPG) axis. The upstream mechanisms regulating this axis remain less well understood. The neuropeptide kisspeptin serves as a positive regulator of reproduction; the precise actions of kisspeptin on the HPG axis in animals of differing developmental and seasonal reproductive states, however, remain unresolved. Further, sex differences in response to kisspeptin have not been fully explored. In Experiment 1, we investigated whether sensitivity to a broad range of kisspeptin doses differed in adult male and female Siberian hamsters held on reproductively inhibitory or stimulatory photoperiods. In Experiment 2, we asked whether the response to kisspeptin differed across stages of reproductive development. Males and females displayed elevated luteinizing hormone (LH) in response to kisspeptin; however, the sexes differed in this response, with males showing greater LH responses to kisspeptin than females. Hamsters responded to kisspeptin across all stages of reproductive development, although the magnitude of this response differed between animals of differental ages and between the sexes. Males showed significant increases in LH at an earlier developmental age than females; females also showed blunted LH responses during early adulthood whereas males remained relatively constant in their response to kisspeptin. These findings suggest that reproductively active and inactive hamsters are responsive to kisspeptin, but that the sexes differ in their responsiveness. Collectively, these data provide further insight into the basic actions of kisspeptin in the regulation of reproduction and provide a potential mechanism for the regulation of differential reproductive responses between the sexes.

Assessment of Variation in Care Following Hospital Discharge for Children with Acute Asthma.

PURPOSE: To evaluate potential variation in care management pathways following hospital discharge for children with asthma in New South Wales, Australia. METHODS: A cross-sectional web-based survey was conducted in emergency departments (EDs) and paediatric units of public hospitals with more than five paediatric beds within New South Wales, Australia, between July 2018 and March 2019. Nursing and medical staff in EDs and paediatric units who had cared for children aged under 18 years with asthma in the preceding 12 months were invited to participate in this study. Outcome measures included use of clinical practice guidelines and asthma action plan (AAP); advice on post-hospitalization follow-up; provision of asthma education for parents/carers; availability of community-based asthma services; communication with schools/childcare services. RESULTS: A total of 502 participants (236 nursing and 266 medical staff, response rate=22%) from 37 hospitals were included. Overall, the use of AAP was not universal (median=90%; IQR=81-96%) with significant difference across local health districts (LHDs) (88.6%, 95% CI=85.4-91.3) and between EDs and paediatric wards (p=9.4×10-9); and a range of asthma clinical practice guidelines were used. Post-hospitalization follow-up within 2-3 days was recommended by 70% of the respondents, but only 8% reported that hospitals had a system in place to ensure follow-up compliance. Formal asthma education sessions (27% respondents) were seldom provided to parents/carers during hospital stays, especially in EDs (14% respondents). Less than 50% of the respondents were aware of any asthma community services for children and only 4% reported that schools/childcare services were notified about the child's hospital admission for an asthma flare up. CONCLUSION: There are marked variations in the post-hospitalization asthma care and community management for children in NSW. An integrated standardized model of care may improve health outcomes in children with asthma.

Nest survival of Seaside Sparrows (Ammospiza maritima) in the wake of the Deepwater Horizon oil spill.

In 2010, the Deepwater Horizon oil spill released an estimated 4.9 million barrels of oil into the Gulf of Mexico, damaging coastal ecosystems. Seaside Sparrows (Ammospiza maritima)-a year-round resident of Gulf Coast salt marshes-were exposed to oil, as shown by published isotopic and molecular analyses, but fitness consequences have not been clarified. We monitored nests around two bays in Plaquemines Parish, Louisiana, USA from 2012-2017 to assess possible impacts on the nesting biology of Seaside Sparrows. A majority of nests failed (76% of known-fate nests, N = 252 nests, 3521 exposure-days) during our study, and predation was the main cause of nest failure (~91% of failed nests). Logistic exposure analysis revealed that daily nest survival rate: (1) was greater at nests with denser vegetation at nest height, (2) was higher in the more sheltered bay we studied, (3) decreased over the course of the breeding season in each year, and (4) was not correlated with either sediment polycyclic aromatic hydrocarbon concentrations or estimated predator abundance during the years for which we had those data. Although the Deepwater Horizon spill impacted other aspects of Seaside Sparrow ecology, we found no definitive effect of initial oiling or oiled sediment on nest survival during 2012-2017. Because predation was the overwhelming cause of nest failure in our study, additional work on these communities is needed to fully understand demographic and ecological impacts of storms, oil spills, other pollutants, and sea-level rise on Seaside Sparrows and their predators.

Community-based interventions for childhood asthma using comprehensive approaches: a systematic review and meta-analysis.

OBJECTIVE: We conducted a systematic review and meta-analysis to determine the effectiveness of comprehensive community-based interventions with ≥ 2 components in improving asthma outcomes in children. METHODS: A systematic search of Medline, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Excerpta Medica Database (EMBASE), Cochrane Library and hand search of reference collections were conducted to identify any research articles published in English between 2000 and 2019. All studies reporting community-based asthma interventions with ≥ 2 components (e.g., asthma self-management education, home environmental assessment or care coordination etc.) for children aged ≤ 18 years were included. Meta-analyses were performed using random-effects model to estimate pooled odds ratio (OR) with 95% confidence intervals (CIs). RESULTS: Of the 2352 studies identified, 21 studies were included in the final analysis: 19 pre-post interventions, one randomised controlled trial (RCT) and one retrospective study. Comprehensive asthma programs with multicomponent interventions were associated with significant reduction in asthma-related Emergency Department (ED) visits (OR = 0.26; 95% CI 0.20-0.35), hospitalizations (OR = 0.24; 95% CI 0.15-0.38), number of days (mean difference = - 2.58; 95% CI - 3.00 to - 2.17) and nights with asthma symptoms (mean difference = - 2.14; 95% CI - 2.94 to - 1.34), use of short-acting asthma medications/bronchodilators (BD) (OR = 0.28; 95% CI 0.16-0.51), and increase use of asthma action plan (AAP) (OR = 8.87; 95% CI 3.85-20.45). CONCLUSION: Community-based asthma care using more comprehensive approaches may improve childhood asthma management and reduce asthma related health care utilization.

Long-term persistence of wildlife populations in a pastoral area.

Facilitating coexistence between people and wildlife is a major conservation challenge in East Africa. Some conservation models aim to balance the needs of people and wildlife, but the effectiveness of these models is rarely assessed. Using a case-study approach, we assessed the ecological performance of a pastoral area in northern Tanzania (Manyara Ranch) and established a long-term wildlife population monitoring program (carried out intermittently from 2003 to 2008 and regularly from 2011 to 2019) embedded in a distance sampling framework. By comparing density estimates of the road transect-based long-term monitoring to estimates derived from systematically distributed transects, we found that the bias associated with nonrandom placement of transects was nonsignificant. Overall, cattle and sheep and goat reached the greatest densities and several wildlife species occurred at densities similar (zebra, wildebeest, waterbuck, Kirk's dik-dik) or possibly even greater (giraffe, eland, lesser kudu, Grant's gazelle, Thomson's gazelle) than in adjacent national parks in the same ecosystem. Generalized linear mixed models suggested that most wildlife species (8 out of 14) reached greatest densities during the dry season, that wildlife population densities either remained constant or increased over the 17-year period, and that herbivorous livestock species remained constant, while domestic dog population decreased over time. Cross-species correlations did not provide evidence for interference competition between grazing or mixed livestock species and wildlife species but indicate possible negative relationships between domestic dog and warthog populations. Overall, wildlife and livestock populations in Manyara Ranch appear to coexist over the 17-year span. Most likely, this is facilitated by existing connectivity to adjacent protected areas, effective anti-poaching efforts, spatio-temporal grazing restrictions, favorable environmental conditions of the ranch, and spatial heterogeneity of surface water and habitats. This long-term case study illustrates the potential of rangelands to simultaneously support wildlife conservation and human livelihood goals if livestock grazing is restricted in space, time, and numbers.

Clinical and analytical validation of FoundationOne Liquid CDx, a novel 324-Gene cfDNA-based comprehensive genomic profiling assay for cancers of solid tumor origin.

As availability of precision therapies expands, a well-validated circulating cell-free DNA (cfDNA)-based comprehensive genomic profiling assay has the potential to provide considerable value as a complement to tissue-based testing to ensure potentially life-extending therapies are administered to patients most likely to benefit. Additional data supporting the clinical validity of cfDNA-based testing is necessary to inform optimal use of these assays in the clinic. The FoundationOne®Liquid CDx assay is a pan-cancer cfDNA-based comprehensive genomic profiling assay that was recently approved by FDA. Validation studies included >7,500 tests and >30,000 unique variants across >300 genes and >30 cancer types. Clinical validity results across multiple tumor types are presented. Additionally, results demonstrated a 95% limit of detection of 0.40% variant allele fraction for select substitutions and insertions/deletions, 0.37% variant allele fraction for select rearrangements, 21.7% tumor fraction for copy number amplifications, and 30.4% TF for copy number losses. The limit of detection for microsatellite instability and blood tumor mutational burden were also determined. The false positive variant rate was 0.013% (approximately 1 in 8,000). Reproducibility of variant calling was 99.59%. In comparison with an orthogonal method, an overall positive percent agreement of 96.3% and negative percent agreement of >99.9% was observed. These study results demonstrate that FoundationOne Liquid CDx accurately and reproducibly detects the major types of genomic alterations in addition to complex biomarkers such as microsatellite instability, blood tumor mutational burden, and tumor fraction. Critically, clinical validity data is presented across multiple cancer types.