Pregnancy Planning and its Association with Autism Spectrum Disorder: Findings from the Study to Explore Early Development.

OBJECTIVES: To examine associations between pregnancy planning and autism spectrum disorder (ASD) in offspring. METHODS: The Study to Explore Early Development (SEED), a multi-site case-control study, enrolled preschool-aged children with ASD, other DDs, and from the general population (POP). Some children with DDs had ASD symptoms but did not meet the ASD case definition. We examined associations between mother's report of trying to get pregnant (pregnancy planning) and (1) ASD and (2) ASD symptomatology (ASD group, plus DD with ASD symptoms group combined) (each vs. POP group). We computed odds ratios adjusted for demographic, maternal, health, and perinatal health factors (aORs) via logistic regression. Due to differential associations by race-ethnicity, final analyses were stratified by race-ethnicity. RESULTS: Pregnancy planning was reported by 66.4%, 64.8%, and 76.6% of non-Hispanic White (NHW) mothers in the ASD, ASD symptomatology, and POP groups, respectively. Among NHW mother-child pairs, pregnancy planning was inversely associated with ASD (aOR = 0.71 [95% confidence interval 0.56-0.91]) and ASD symptomatology (aOR = 0.67 [0.54-0.84]). Pregnancy planning was much less common among non-Hispanic Black mothers (28-32% depending on study group) and Hispanic mothers (49-56%) and was not associated with ASD or ASD symptomatology in these two race-ethnicity groups. CONCLUSION: Pregnancy planning was inversely associated with ASD and ASD symptomatology in NHW mother-child pairs. The findings were not explained by several adverse maternal or perinatal health factors. The associations observed in NHW mother-child pairs did not extend to other race-ethnicity groups, for whom pregnancy planning was lower overall.

First Report of Neofabraea actinidiae causing a Cranberry Fruit Rot in Oregon.

Cranberry (Vaccinium macrocarpon, L.) is a commercial small fruit that is native to North America. Oregon ranks fourth in cranberry production in the U.S.A. with 1052 Ha of cranberry beds and annual production of 23,590 metric tonnes (USDA NASS 2021). Cranberry fruit rot diseases are caused by a complex of 15 fungal pathogens belonging to 10 genera (Polashock et al. 2017). In fruit rot surveys of 'Stevens' cranberry beds in Coos and Curry Counties, Oregon, berries were collected before harvest and sorted by symptoms (e.g. softening, shriveling, or discoloration). Cranberries with field rot symptoms were surface-disinfested and lesion margin tissue placed on V8 agar. Cultures were incubated at room temperature and outgrowing fungi were transferred twice onto fresh V8 agar to obtain single isolates. Storage rots that developed on asymptomatic cranberries held at 4°C for 8 weeks were processed similarly. Since 2017, we periodically isolated Neofabraea actinidiae, which is not a member of the cranberry fruit rot complex, from rotted cranberries (Polashock et al. 2017). In 2022, N. actinidiae was isolated from 22% of 45 cranberries collected from an organically managed farm and developed storage rot and from 6% of 50 storage-rot cranberries from three conventionally managed farms. Symptoms associated with N. actinidiae on 'Stevens' cranberries often include softening and brown tissue surrounded by a yellow-colored ring. On V8 agar, N. actinidiae grew as compact white circular colonies with dense aerial hyphae near the center and accompanied by a red pigment in the agar. Pink-colored mucoidal irregular conidiomata often developed on the colony after 3 weeks. Conidia were hyaline, aseptate, and ellipsoidal to fusiform ranging from 7.5 to 12.6 µm long X 3.5 to 5.6 µm wide (n=100). Genomic DNA was extracted from N. actinidiae isolates from cranberries in 2017 and 2022. ß-tubulin and the ITS 5/4 region were amplified and sequenced with primers Bt-T2m-Up/Bt-LEV-Lo1 and ITS5/ITS4 using conditions of de Jong et al. (2001) and White et al. (1990), respectively. Sequences were deposited in NCBI Genbank (Accessions: OR606303, OR606305, OR606306, & OR606309 for ITS; OR610314, OR610316, OR610317, & OR610320 for ß-tubulin). BlastN analysis of ß-tubulin (695 bp) and ITS (489-490 bp) had a 99.6 to 99.8% and 99.8 to 100% identity, respectively, to Neofabraea actinidiae (CBS 121403) (Accession numbers: KR859285 ß-tubulin and KR859079 ITS). Phylogenetic analysis of concatenated sequences using Tamura-Nei neighbor-joining (Tamura et al. 2004) confirmed identity of cranberry isolates as N. actinidiae. Koch's Postulates were confirmed with four N. actinidiae isolates from cranberry. Agar or hyphal plugs were placed in a 3 mm wound on the side of six surface-disinfested, asymptomatic berries and incubated in a moist chamber at 20°C for 15 days or 4°C for 55 days. Similar symptoms developed on each berry inoculated with N. actinidiae, but not agar alone. The fungus was recovered from symptomatic tissues and identity confirmed by colony morphology. N. actinidiae causes a ripe rot and storage rot in kiwifruit and is one of the species causing Bull's Eye Rot of pome fruits (Tyson et al. 2019). Cryptosporiopsis actinidiae (anamorph) was isolated from cranberries roots in British Columbia, CA, but considered unlikely to be the causal agent of dieback disease of cranberry vines (Sabaratnam et al. 2009). We have demonstrated that N. actinidiae causes a cranberry fruit rot in beds and in storage. Its prevalence, associated fruit rot symptoms, and disease incidence will continue to be monitored.

Prenatal ultrasound use and risk of autism spectrum disorder: Findings from the case-control Study to Explore Early Development.

BACKGROUND: Studies evaluating the association between prenatal ultrasounds and autism spectrum disorder (ASD) have largely produced negative results. Concern remains due to the rising identification of children with ASD and ultrasound use. OBJECTIVE: To evaluate the association between prenatal ultrasound use and ASD. METHODS: We used data from the Study to Explore Early Development, a multisite case-control study of preschool-aged children with ASD implemented during 2007-2012. We recruited cases from children receiving developmental disability services and randomly selected population controls from birth records. ASD case status was based on in-person standardised assessments. We stratified analyses by pre-existing maternal medical conditions and pregnancy complications associated with increased ultrasound use (ultrasound indications) and used logistic regression to model case status by increasing ultrasound counts. For pregnancies with medical record data on ultrasound timing, we conducted supplementary tests to model associations by trimester of exposure. RESULTS: Among 1524 singleton pregnancies, ultrasound indications were more common for ASD cases than controls; respectively, for each group, no indications were reported for 45.1% and 54.2% of pregnancies, while ≥2 indications were reported for 26.1% and 18.4% of pregnancies. The percentage of pregnancies with multiple ultrasounds varied by case status and the presence of ultrasound indications. However, stratified regression models showed no association between increasing ultrasound counts and case status, either for pregnancies without (aOR 1.01, 95% CI 0.92, 1.11) or with ultrasound indications (aOR 1.01, 95% CI 0.95, 1.08). Trimester-specific analyses using medical record data showed no association in any individual trimester. CONCLUSIONS: We found no evidence that prenatal ultrasound use increases ASD risk. Study strengths included gold-standard assessments for ASD case classification, comparison of cases with controls, and a stratified sample to account for conditions associated both with increased prenatal ultrasound use and ASD.

Reasons for participation in a child development study: Are cases with developmental diagnoses different from controls?

BACKGROUND: Current knowledge about parental reasons for allowing child participation in research comes mainly from clinical trials. Fewer data exist on parents' motivations to enrol children in observational studies. OBJECTIVES: Describe reasons parents of preschoolers gave for participating in the Study to Explore Early Development (SEED), a US multi-site study of autism spectrum disorder (ASD) and other developmental delays or disorders (DD), and explore reasons given by child diagnostic and behavioural characteristics at enrolment. METHODS: We included families of children, age 2-5 years, participating in SEED (n = 5696) during 2007-2016. We assigned children to groups based on characteristics at enrolment: previously diagnosed ASD; suspected ASD; non-ASD DD; and population controls (POP). During a study interview, we asked parents their reasons for participating. Two coders independently coded responses and resolved discrepancies via consensus. We fit binary mixed-effects models to evaluate associations of each reason with group and demographics, using POP as reference. RESULTS: Participants gave 1-5 reasons for participation (mean = 1.7, SD = 0.7). Altruism (48.3%), ASD research interest (47.4%) and perceived personal benefit (26.9%) were most common. Two novel reasons were knowing someone outside the household with the study conditions (peripheral relationship; 14.1%) and desire to contribute to a specified result (1.4%). Odds of reporting interest in ASD research were higher among diagnosed ASD participants (odds ratio [OR] 2.89, 95% confidence interval [CI] 2.49-3.35). Perceived personal benefit had higher odds among diagnosed (OR 1.92, 95% CI 1.61-2.29) or suspected ASD (OR 3.67, 95% CI 2.99-4.50) and non-ASD DD (OR 1.80, 95% CI 1.50-2.16) participants. Peripheral relationship with ASD/DD had lower odds among all case groups. CONCLUSIONS: We identified meaningful differences between groups in parent-reported reasons for participation. Differences demonstrate an opportunity for future studies to tailor recruitment materials and increase the perceived benefit for specific prospective participants.

Taxonomic Reclassification of the Fungal Pathogen Causing Dry Berry Disease of Caneberries into the Division Ascomycota as Monilinia rubi.

As molecular genetic techniques improve and sequence data becomes available for more fungal species, taxonomic classifications historically based upon growth morphology alone are being revisited and occasionally reclassified. Herein, we present such an instance for the fungal pathogen that causes dry berry disease of caneberries. The organism was previously described as the basidiomycete fungus Rhizoctonia rubi based upon the pathogen's production of Rhizoctonia-like angular branching hyphae. Utilizing molecular genetic techniques unavailable when the pathogen was first characterized in 1959, three housekeeping gene regions (ITS, ß-tubulin, and G3PDH) were sequenced across 13 contemporary dry berry isolates, as well as the original 1959 R. rubi type strain, CBS382.59. The resulting neighbor-joining, maximum likelihood, and Bayesian phylogenies for single and multilocus sequences provide strong evidence that the dry berry pathogen was misclassified. This data, in addition to revisiting in vivo macroscopic and microscopic growth morphology, again comparing contemporary dry berry isolates to the CBS382.59 type strain, suggests that the causal organism is a new species within the genus Monilinia that we propose be classified as Monilinia rubi. A transition from designation as a basidiomycete fungus to an ascomycete fungus could have implications on chemical management decisions, as well as the assumptions made about cell structure and the pathogen's putative life cycle.

A Novel Signaling Pathway Connects Thiamine Biosynthesis, Bacterial Respiration, and Production of the Exopolysaccharide Amylovoran in Erwinia amylovora.

Erwinia amylovora is a plant pathogen causing necrotrophic fire blight disease of apple, pear, and other rosaceous plants. This bacterium colonizes host vascular tissues via the production of exopolysaccharides (EPSs) including amylovoran. It is well-established that the nearly ubiquitous plasmid pEA29 of E. amylovora is an essential virulence factor, but the underlying mechanism remains uncharacterized. Here, we demonstrated that pEA29 was required for E. amylovora to produce amylovoran and to form a biofilm, and this regulation was dependent on the thiamine biosynthesis operon thiOSGF. We then conducted carbohydrate and genetic analyses demonstrating that the thiamine-mediated effect on amylovoran production was indirect, as cells lacking thiOSGF produced an EPS that did not contain glucuronic acid, one of the key components of amylovoran, whereas the transcriptional activity and RNA levels of the amylovoran biosynthesis genes were not altered. Alternatively, addition of exogenous thiamine restored amylovoran production in the pEA29-cured strain of E. amylovora and positively impacted amylovoran production in a dose-dependent manner. Individual deletion of several chromosomal thiamine biosynthesis genes also affected amylovoran production, implying that a complete thiamine biosynthesis pathway is required for the thiamine-mediated effect on amylovoran production in E. amylovora. Finally, we determined that an imbalanced tricarboxylic acid cycle negatively affected amylovoran production, which was restored by addition of exogenous thiamine or overexpression of the thiOSGF operon. In summary, our report revealed a novel signaling pathway that impacts E. amylovora virulence in which thiamine biosynthesis enhances bacterial respiration that provides energetic requirements for the biosynthesis of EPS amylovoran.[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Association Between Midpregnancy Polyunsaturated Fatty Acid Levels and Offspring Autism Spectrum Disorder in a California Population-Based Case-Control Study.

Polyunsaturated fatty acids (PUFAs) are critical for brain development and have been linked with neurodevelopmental outcomes. We conducted a population-based case-control study in California to examine the association between PUFAs measured in midpregnancy serum samples and autism spectrum disorder (ASD) in offspring. ASD cases (n = 499) were identified through the California Department of Developmental Services and matched to live-birth population controls (n = 502) on birth month, year (2010 or 2011), and sex. Logistic regression models were used to examine crude and adjusted associations. In secondary analyses, we examined ASD with and without co-occurring intellectual disability (ID; n = 67 and n = 432, respectively) and effect modification by sex and ethnicity. No clear patterns emerged, though there was a modest inverse association with the top quartile of linoleic acid level (highest quartile vs. lowest: adjusted odds ratio = 0.74, 95% confidence interval: 0.49, 1.11; P for trend = 0.10). Lower levels of total and ω-3 PUFAs were associated with ASD with ID (lowest decile of total PUFAs vs. deciles 4-7: adjusted odds ratio = 2.78, 95% confidence interval: 1.13, 6.82) but not ASD without ID. We did not observe evidence of effect modification by the factors examined. These findings do not suggest a strong association between midpregnancy PUFA levels and ASD. In further work, researchers should consider associations with ASD with ID and in other time windows.

Coccidioidomycosis outbreak among inmate wildland firefighters: California, 2017.

BACKGROUND: In California, state prison inmates are employed to fight wildfires, which involves performing soil-disrupting work. Wildfires have become more common, including areas where Coccidioides, the soil-dwelling fungus that causes coccidioidomycosis, proliferates. However, work practices that place wildland firefighters at risk for coccidioidomycosis have not been investigated. METHODS: On August 17, 2017, the California Department of Public Health was notified of a cluster of coccidioidomycosis cases among Wildfire A inmate wildland firefighters. We collected data through medical record abstraction from suspected case-patients and mailed a survey assessing potential job task risk factors to Wildfire A inmate firefighters. We described respondent characteristics and conducted a retrospective case-control investigation to assess coccidioidomycosis risk factors. RESULTS: Among 198 inmate firefighters who worked on Wildfire A, 112 (57%) completed the survey. Of 10 case-patients (four clinical and six laboratory-confirmed), two were hospitalized. In the case-control analysis of 71 inmate firefighters, frequently cutting fire lines with a McLeod tool (odds ratio [OR]: 5.5; 95% confidence interval [CI]: 1.1-37.2) and being in a dust cloud or storm (OR: 4.3; 95% CI: 1.1-17.4) were associated with illness. Two of 112 inmate firefighters reported receiving coccidioidomycosis training; none reported wearing respiratory protection on this wildfire. CONCLUSIONS: Wildland firefighters who use hand tools and work in dusty conditions where Coccidioides proliferates are at risk for coccidioidomycosis. Agencies that employ them should provide training about coccidioidomycosis and risk reduction, limit dust exposure, and implement respiratory protection programs that specify where respirator use is feasible and appropriate.

Repeated Phenotypic Evolution by Different Genetic Routes in Pseudomonas fluorescens SBW25.

Repeated evolution of functionally similar phenotypes is observed throughout the tree of life. The extent to which the underlying genetics are conserved remains an area of considerable interest. Previously, we reported the evolution of colony switching in two independent lineages of Pseudomonas fluorescens SBW25. The phenotypic and genotypic bases of colony switching in the first lineage (Line 1) have been described elsewhere. Here, we deconstruct the evolution of colony switching in the second lineage (Line 6). We show that, as for Line 1, Line 6 colony switching results from an increase in the expression of a colanic acid-like polymer (CAP). At the genetic level, nine mutations occur in Line 6. Only one of these-a nonsynonymous point mutation in the housekeeping sigma factor rpoD-is required for colony switching. In contrast, the genetic basis of colony switching in Line 1 is a mutation in the metabolic gene carB. A molecular model has recently been proposed whereby the carB mutation increases capsulation by redressing the intracellular balance of positive (ribosomes) and negative (RsmAE/CsrA) regulators of a positive feedback loop in capsule expression. We show that Line 6 colony switching is consistent with this model; the rpoD mutation generates an increase in ribosomal gene expression, and ultimately an increase in CAP expression.

Ribosome Provisioning Activates a Bistable Switch Coupled to Fast Exit from Stationary Phase.

Observations of bacteria at the single-cell level have revealed many instances of phenotypic heterogeneity within otherwise clonal populations, but the selective causes, molecular bases, and broader ecological relevance remain poorly understood. In an earlier experiment in which the bacterium Pseudomonas fluorescens SBW25 was propagated under a selective regime that mimicked the host immune response, a genotype evolved that stochastically switched between capsulation states. The genetic cause was a mutation in carB that decreased the pyrimidine pool (and growth rate), lowering the activation threshold of a preexisting but hitherto unrecognized phenotypic switch. Genetic components surrounding bifurcation of UTP flux toward DNA/RNA or UDP-glucose (a precursor of colanic acid forming the capsules) were implicated as key components. Extending these molecular analyses-and based on a combination of genetics, transcriptomics, biochemistry, and mathematical modeling-we show that pyrimidine limitation triggers an increase in ribosome biosynthesis and that switching is caused by competition between ribosomes and CsrA/RsmA proteins for the mRNA transcript of a positively autoregulated activator of colanic acid biosynthesis. We additionally show that in the ancestral bacterium the switch is part of a program that determines stochastic entry into a semiquiescent capsulated state, ensures that such cells are provisioned with excess ribosomes, and enables provisioned cells to exit rapidly from stationary phase under permissive conditions.

Early Life Exposure to Air Pollution and Autism Spectrum Disorder: Findings from a Multisite Case-Control Study.

BACKGROUND: Epidemiologic studies have reported associations between prenatal and early postnatal air pollution exposure and autism spectrum disorder (ASD); however, findings differ by pollutant and developmental window. OBJECTIVES: We examined associations between early life exposure to particulate matter ≤2.5 µm in diameter (PM2.5) and ozone in association with ASD across multiple US regions. METHODS: Our study participants included 674 children with confirmed ASD and 855 population controls from the Study to Explore Early Development, a multi-site case-control study of children born from 2003 to 2006 in the United States. We used a satellite-based model to assign air pollutant exposure averages during several critical periods of neurodevelopment: 3 months before pregnancy; each trimester of pregnancy; the entire pregnancy; and the first year of life. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for study site, maternal age, maternal education, maternal race/ethnicity, maternal smoking, and month and year of birth. RESULTS: The air pollution-ASD associations appeared to vary by exposure time period. Ozone exposure during the third trimester was associated with ASD, with an OR of 1.2 (95% CI: 1.1, 1.4) per 6.6 ppb increase in ozone. We additionally observed a positive association with PM2.5 exposure during the first year of life (OR = 1.3 [95% CI: 1.0, 1.6] per 1.6 µg/m increase in PM2.5). CONCLUSIONS: Our study corroborates previous findings of a positive association between early life air pollution exposure and ASD, and identifies a potential critical window of exposure during the late prenatal and early postnatal periods.

A pilot study of an integrated mental health, social and medical model for diabetes care in an inner-city setting: Three Dimensions for Diabetes (3DFD).

AIMS: We examined the effectiveness of a service innovation, Three Dimensions for Diabetes (3DFD), that consisted of a referral to an integrated mental health, social care and diabetes treatment model, compared with usual care in improving biomedical and health economic outcomes. METHODS: Using a non-randomized control design, the 3DFD model was offered in two inner-city boroughs in London, UK, where diabetes health professionals could refer adult residents with diabetes, suboptimal glycaemic control [HbA1c ≥ 75 mmol/mol (≥ 9.0%)] and mental health and/or social problems. In the usual care group, there was no referral pathway and anonymized data on individuals with HbA1c ≥ 75 mmol/mol (≥ 9.0%) were collected from primary care records. Change in HbA1c from baseline to 12 months was the primary outcome, and change in healthcare costs and biomedical variables were secondary outcomes. RESULTS: 3DFD participants had worse glycaemic control and higher healthcare costs than control participants at baseline. 3DFD participants had greater improvement in glycaemic control compared with control participants [-14 mmol/mol (-1.3%) vs. -6 mmol/mol (-0.6%) respectively, P < 0.001], adjusted for confounding. Total follow-up healthcare costs remained higher in the 3DFD group compared with the control group (mean difference £1715, 95% confidence intervals 591 to 2811), adjusted for confounding. The incremental cost-effectiveness ratio was £398 per mmol/mol unit decrease in HbA1c , indicating the 3DFD intervention was more effective and costed more than usual care. CONCLUSIONS: A biomedical, psychological and social criteria-based referral system for identifying and managing high-cost and high-risk individuals with poor glycaemic control can lead to improved health in all three dimensions.

Pilot Randomized Trial of a Pharmacy Intervention for Older Adults with Cancer.

BACKGROUND: Oncology clinicians often struggle with managing medications and vaccinations in older adults with cancer. We sought to demonstrate the feasibility and preliminary efficacy of integrating pharmacists into the care of older adults with cancer to enhance medication management and vaccination administration. METHODS: We randomly assigned patients aged ≥65 years with breast, gastrointestinal, or lung cancer receiving first-line chemotherapy to the pharmacy intervention or usual care. Patients assigned to the intervention met with a pharmacist once during their second or third chemotherapy infusion. We obtained information about patients' medications and vaccinations via patient report and from the electronic health record (EHR) at baseline and week 4. We determined the number of discrepant (difference between patient report and EHR) and potentially inappropriate (Beers Criteria assessed by nonintervention pharmacists blinded to group assignment) medications. We defined the intervention as feasible if >75% of patients enrolled in the study and received the pharmacist visit. RESULTS: From January 17, 2017, to October 27, 2017, we enrolled and randomized 60 patients (80.1% of patients approached). Among those assigned to the intervention, 96.6% received the pharmacist visit. At week 4, intervention patients had higher rates of acquiring vaccinations for pneumonia (27.6% vs. 0.0%, p = .002) and influenza (27.6% vs. 0.0%, p = .002) compared with usual care. Intervention patients had fewer discrepant (5.82 vs. 8.07, p = .094) and potentially inappropriate (3.46 vs. 4.80, p = .069) medications at week 4, although differences were not significant. CONCLUSION: Integrating pharmacists into the care of older adults with cancer is feasible with encouraging preliminary efficacy for enhancing medication management and improving vaccination rates. IMPLICATIONS FOR PRACTICE: Results of this study showed the feasibility, acceptability, and preliminary efficacy of an intervention integrating pharmacists into the care of older adults with cancer. Notably, patients assigned to the intervention had fewer discrepant medications and were more likely to acquire vaccinations for pneumonia and influenza. Importantly, this work represents the first randomized controlled trial involving the integration of pharmacists into the outpatient oncologic care of older adults with cancer. In the future, a larger randomized trial is needed to demonstrate the efficacy of this care model to enhance medication management and improve vaccination outcomes for older patients with cancer.

Prenatal Exposure to Endocrine-disrupting Chemicals in Relation to Autism Spectrum Disorder and Intellectual Disability.

BACKGROUND: Exposure to endocrine disruptors is unavoidable. Many such compounds are suspected to impact neurologic development of children, but most studies conducted have considered effects of individual chemicals in isolation. Because exposures co-occur, it is important to consider their health impacts in a single regression framework. METHODS: We applied Bayesian statistical tools (including shared mean and mixture priors for 25 unique chemicals) to study independent associations of endocrine disruptor biomarkers with autism spectrum disorder (ASD) (n = 491) and intellectual disability (n = 155), compared with 373 general population controls, in the Early Markers for Autism study. We measured biomarkers in maternal serum collected and stored from midpregnancy and considered them individually or as a class (i.e., summed polychlorinated biphenyls). We adjusted all models for original matching factors (child sex and month and year of birth), maternal age, maternal race/ethnicity, parity, and maternal education at the time samples were collected. We estimated the change in the odds of ASD or intellectual disability per 1 SD increase in the z-score of measured biomarker concentration for each chemical. RESULTS: Odds of ASD and intellectual disability did not change with increasing concentration for any specific endocrine disruptor. The effect estimates for each chemical were centered on or near an odds ratio of 1.00 in both models where we applied a shared mean or a mixture prior. CONCLUSION: Our mixtures analyses do not suggest an independent relationship with ASD or intellectual disability with any of the 25 chemicals examined together in this mixtures analysis.

Longitudinal study of age of menarche in association with childhood concentrations of persistent organic pollutants.

BACKGROUND: Age at female puberty is associated with adult morbidities, including breast cancer and diabetes. Hormonally active chemicals are suspected of altering pubertal timing. We examined whether persistent organic pollutants (POPs) are associated with age at menarche in a longitudinal study. METHODS: We analyzed data for females enrolled at age 6-8 years in the Breast Cancer and Environment Research Program from California and Ohio. Participants were followed annually 2004-2013 and provided serum (mean age 7.8 years) for measurement of polychlorinated biphenyl (PCB), organochlorine pesticide (OCP), and polybrominated diphenyl ether (PBDE) concentrations. Age of menarche was assigned based on parental and participant reported dates and ages of menarche. Adjusted hazard ratios (aHRs) for menarchal onset were calculated with Cox proportional regression. Body mass index (BMI), potentially on the causal pathway, was added to parallel analyses. RESULTS: Age of menarche was later with higher summed PCB levels (median 11.9 years in quartile 1 [Q1] versus 12.7 in quartile 4 [Q4]) and OCP levels (12.1 years versus 12.4, respectively). When adjusting for all covariates except BMI, higher POP concentrations were associated with later age at menarche (Q4 versus Q1 aHRs: PBDEs 0.75 [95% CI 0.58, 0.97], PCBs 0.67 [95% CI 0.5, 0.89], and OCPs 0.66 [95% CI 0.50, 0.89]). Additional adjustment for BMI attenuated aHRs; PCB aHR approached the null. CONCLUSION: Findings revealed later onset of menarche with higher concentrations of certain POPs, possibly through an association with BMI. Altered pubertal timing may have long lasting effects on reproductive health and disease risk, so continued attention is important for understanding the biological processes affected by hormonally active chemicals.

Arginase-1 expressing microglia in close proximity to motor neurons were increased early in disease progression in canine degenerative myelopathy, a model of amyotrophic lateral sclerosis.

Toxicity within superoxide dismutase-1 (SOD1)-associated familial amyotrophic lateral sclerosis (ALS) is non-cell autonomous with direct contribution from microglia. Microglia exhibit variable expression of neuroprotective and neurotoxic molecules throughout disease progression. The mechanisms regulating microglial phenotype within ALS are not well understood. This work presents a first study to examine the specific microglial phenotypic response in close association to motor neurons in a naturally occurring disease model of ALS, canine degenerative myelopathy (DM). Microglia closely associated with motor neurons were increased in all stages of DM progression, although only DM Late reached statistical significance. Furthermore, the number of arginase-1 expressing microglia per motor neuron were significantly increased in early stages of DM, whereas the number of inducible nitric oxide synthase (iNOS)-expressing microglia per motor neuron was indistinguishable from aged controls at all stages of disease. Fractalkine, a chemotactic molecule for microglia, was expressed in motor neurons, and the fractalkine receptor was specifically localized to microglia. However, we found no correlation between microglial response and lumbar spinal cord fractalkine levels. Taken together, these data suggest that arginase-1-expressing microglia are recruited to the motor neuron early in DM disease through a fractalkine-independent mechanism.

Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy.

Canine degenerative myelopathy (DM) is a naturally occurring neurodegenerative disease with similarities to some forms of amyotrophic lateral sclerosis (ALS). Most dogs that develop DM are homozygous for a common superoxide dismutase 1 gene (SOD1) mutation. However, not all dogs homozygous for this mutation develop disease. We performed a genome-wide association analysis in the Pembroke Welsh Corgi (PWC) breed comparing DM-affected and -unaffected dogs homozygous for the SOD1 mutation. The analysis revealed a modifier locus on canine chromosome 25. A haplotype within the SP110 nuclear body protein (SP110) was present in 40% of affected compared with 4% of unaffected dogs (P = 1.5 × 10(-5)), and was associated with increased probability of developing DM (P = 4.8 × 10(-6)) and earlier onset of disease (P = 1.7 × 10(-5)). SP110 is a nuclear body protein involved in the regulation of gene transcription. Our findings suggest that variations in SP110-mediated gene transcription may underlie, at least in part, the variability in risk for developing DM among PWCs that are homozygous for the disease-related SOD1 mutation. Further studies are warranted to clarify the effect of this modifier across dog breeds.

Critically ill patients' experiences of nursing care in the intensive care unit.

BACKGROUND: Understanding critically ill patients' experiences of nursing care is an important aspect that can improve quality of care in the intensive care unit. AIM: To elicit critically ill patients' experiences of nursing care in the adult intensive care units. DESIGN: A qualitative descriptive design was utilized. METHODS: Sixteen patients who had a predicted mortality risk of above 50% within the first 24 h of admission to the intensive care unit and had been discharged to the ward were purposively selected. The study was conducted at three academic affiliated, tertiary/quaternary specialist hospitals in South Africa. Individual semi-structured interviews were conducted with the selected participants until a point of data saturation was reached. Data were analysed using a conventional content analysis technique (Hsieh and Shannon, 2005). Lincoln and Guba's criteria for ensuring the trustworthiness of qualitative research were applied. FINDINGS: Four major themes emerged: 'being in someone's shoes', 'communication', 'presence' and 'religion and spirituality'. CONCLUSIONS: Even though some participants' responses reflected 'good' nursing care, the majority of the participants had negative experiences in relation to the nursing care they received while admitted in the selected intensive care units. RELEVANCE TO CLINICAL PRACTICE: This study demonstrates critically ill patients' voices and preferences of intensive nursing care and describes some issues that require not only nurses' but also managerial improvements and interventions in order to ensure quality care and, eventually, patients' satisfaction with intensive nursing care.

Demographic and Operational Factors Predicting Study Completion in a Multisite Case-Control Study of Preschool Children.

Participant attrition can limit inferences drawn from study results and inflate research costs. We examined factors associated with completion of the Study to Explore Early Development (2007-2011), a multiple-component, case-control study of risk factors for autism spectrum disorder in preschoolers, conducted in California, Colorado, Georgia, Maryland, North Carolina, and Pennsylvania. Participants (n = 3,769) were asked to complete phone interviews, questionnaires, an in-person evaluation, and biologic sampling. We examined whether participant demographic and administrative factors predicted completion using mixed-effects logistic regression models. Completion of individual key study components was generally 70% or higher. However, 58% of families completed all per-protocol data elements (defined a priori as key study components). Per-protocol completion differed according to mother's age, race, educational level, driving distance to clinic, number of contact attempts to enroll, and number of telephone numbers provided (all P < 0.05). Case status was not associated with completion, despite additional data collection for case-confirmation. Analysis of a subset that completed an early interview revealed no differences in completion by household factors of income, primary language spoken, number of adults, or number of children with chronic conditions. Differences in completion by race and education were notable and need to be carefully considered in developing future recruitment and completion strategies.

Bistability in a metabolic network underpins the de novo evolution of colony switching in Pseudomonas fluorescens.

Phenotype switching is commonly observed in nature. This prevalence has allowed the elucidation of a number of underlying molecular mechanisms. However, little is known about how phenotypic switches arise and function in their early evolutionary stages. The first opportunity to provide empirical insight was delivered by an experiment in which populations of the bacterium Pseudomonas fluorescens SBW25 evolved, de novo, the ability to switch between two colony phenotypes. Here we unravel the molecular mechanism behind colony switching, revealing how a single nucleotide change in a gene enmeshed in central metabolism (carB) generates such a striking phenotype. We show that colony switching is underpinned by ON/OFF expression of capsules consisting of a colanic acid-like polymer. We use molecular genetics, biochemical analyses, and experimental evolution to establish that capsule switching results from perturbation of the pyrimidine biosynthetic pathway. Of central importance is a bifurcation point at which uracil triphosphate is partitioned towards either nucleotide metabolism or polymer production. This bifurcation marks a cell-fate decision point whereby cells with relatively high pyrimidine levels favour nucleotide metabolism (capsule OFF), while cells with lower pyrimidine levels divert resources towards polymer biosynthesis (capsule ON). This decision point is present and functional in the wild-type strain. Finally, we present a simple mathematical model demonstrating that the molecular components of the decision point are capable of producing switching. Despite its simple mutational cause, the connection between genotype and phenotype is complex and multidimensional, offering a rare glimpse of how noise in regulatory networks can provide opportunity for evolution.