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Background: Poor nutrition has been associated with impaired immunity and accelerated disease progression in HIV- infected children. The aim of this study was to quantify the levels of nutrient intake in HIV-infected children and compare these to standard recommendations. Methods: We surveyed HIV-infected Tanzanian children enrolled in a pediatric care program that provided routine nutritional counseling and vitamin supplementation. We obtained anthropometric measurements and determined 24-hour macronutrient and micronutrient intakes and food insecurity. Values were compared to recommended nutrient intakes based on age and gender. Results: We interviewed 48 pairs of children and their caregiver(s). The age of the child ranged from 2-14 years; median age 6 and 60% female. The median weight-for-height z-score for children ≤ 5 years was 0.69 and BMI-for-age z-scores for children >5 was -0.84. Macronutrient evaluation showed that 29 (60%) children were deficient in dietary intake of energy; deficiency was more common in older children (p=0.004). Micronutrient evaluation shows that over half of study subjects were deficient in dietary intake of vitamin A, vitamin D, vitamin E, thiamine, riboflavin, niacin, folate, vitamin B12, and calcium. Food insecurity was reported by 20 (58%) caregivers. Conclusions and Public Health Implications: The diets of many HIV-infected children at a specialized treatment center in Tanzania do not meet recommended levels of macro- and micro nutrients. Food insecurity was a contributory factor. Enhanced dietary counseling and provision of macro- and micro-nutrient supplements will be necessary to achieve optimal nutrition for most HIV-infected children in resource-poor regions. Keywords: HIV • Tanzania • Children • Energy Intake • Food Insecurity • Micronutrients Copyright © 2014 Modlin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ObjectivesDefinitive sample sizes for clinical trials in rare diseases are usually infeasible. Bayesian methodology can be used to maximise what is learnt from clinical trials in these circumstances. We elicited expert prior opinion for a future Bayesian randomised controlled trial for a rare inflammatory paediatric disease, polyarteritis nodosa (MYPAN, Mycophenolate mofetil for polyarteritis nodosa).MethodsA Bayesian prior elicitation meeting was convened. Opinion was sought on the probability that a patient in the MYPAN trial treated with cyclophosphamide would achieve disease remission within 6-months, and on the relative efficacies of mycophenolate mofetil and cyclophosphamide. Expert opinion was combined with previously unseen data from a recently completed randomised controlled trial in ANCA associated vasculitis.ResultsA pan-European group of fifteen experts participated in the elicitation meeting. Consensus expert prior opinion was that the most likely rates of disease remission within 6 months on cyclophosphamide or mycophenolate mofetil were 74% and 71%, respectively. This prior opinion will now be taken forward and will be modified to formulate a Bayesian posterior opinion once the MYPAN trial data from 40 patients randomised 1:1 to either CYC or MMF become available.ConclusionsWe suggest that the methodological template we propose could be applied to trial design for other rare diseases.

We examined how emergency department (ED) visits for potentially preventable, mental health, and other diagnoses were related to same-day access and provider continuity in primary care using administrative data from 71,296 patients in 22 VHA clinics over a three-year period. ED visits were categorized as non-emergent; primary care treatable; preventable; not preventable; or mental health-related. We conducted multi-level regression models adjusted for patient and clinic factors. More same-day access significantly predicted fewer non-emergent and primary care treatable ED visits while continuity was not significantly related to any type of ED visit. Neither measure was related to ED visits for mental health problems.

Daily gridded precipitation data are needed for investigating spatiotemporal variability of precipitation, including extremes; however, uncertainties related to daily precipitation products are large. Here, we compare a range of precipitation grids for Australia. These datasets include products derived solely from in situ observations (interpolated datasets) and two products that combine both remote sensed data and in situ observations. We find that all precipitation grids have similar climatologies for annual aggregated precipitation totals and annual maximum precipitation. The temporal correlations of daily precipitation values are higher between the interpolated datasets, but the correlations between the most widely used interpolated product (AWAP) and the two remotely sensed products (TRMM and GPCP) are still reasonable. Our results, however, point to distinct structural uncertainties between those datasets gridding in situ observations and those datasets deriving precipitation estimates primarily from satellite measurements. All datasets analysed agree well for low to moderate daily precipitation amounts up to about 20 mm but diverge at upper quantiles, indicating that substantial uncertainty exists in gridded precipitation extremes over Australia.

Tonotopy is a fundamental organizational feature of the auditory system. Sounds are encoded by the spatial and temporal patterns of electrical activity in spiral ganglion neurons (SGNs) and are transmitted via tonotopically ordered processes from the cochlea through the eighth nerve to the cochlear nuclei. Upon reaching the brainstem, SGN axons bifurcate in a stereotyped pattern, innervating target neurons in the anteroventral cochlear nucleus (aVCN) with one branch and in the posteroventral and dorsal cochlear nuclei (pVCN and DCN) with the other. Each branch is tonotopically organized, thereby distributing acoustic information systematically along multiple parallel pathways for processing in the brainstem. In mice with a mutation in the receptor guanylyl cyclase Npr2, this spatial organization is disrupted. Peripheral SGN processes appear normal, but central SGN processes fail to bifurcate and are disorganized as they exit the auditory nerve. Within the cochlear nuclei, the tonotopic organization of the SGN terminal arbors is blurred and the aVCN is underinnervated with a reduced convergence of SGN inputs onto target neurons. The tonotopy of circuitry within the cochlear nuclei is also degraded, as revealed by changes in the topographic mapping of tuberculoventral cell projections from DCN to VCN. Nonetheless, Npr2 mutant SGN axons are able to transmit acoustic information with normal sensitivity and timing, as revealed by auditory brainstem responses and electrophysiological recordings from VCN neurons. Although most features of signal transmission are normal, intermittent failures were observed in responses to trains of shocks, likely due to a failure in action potential conduction at branch points in Npr2 mutant afferent fibers. Our results show that Npr2 is necessary for the precise spatial organization typical of central auditory circuits, but that signals are still transmitted with normal timing, and that mutant mice can hear even with these deficits.

This study sought to examine the relationship between self-reported time and distance to the nearest retail grocery store, healthy and unhealthy food consumption, and objectively measured body mass index. We conducted a survey with 1,503 racially diverse, low-income residents at five public health centers in Los Angeles County. Most participants reported shopping at a supermarket (86.7%) and driving (59.9%) to their usual source for groceries. Over half reported living less than a mile from (58.9%) and traveling five minutes or less to reach (50.3%) the nearest grocery store. In the multivariable regression models, neither self-reported distance nor time to the nearest grocery store was consistently associated with fruit and vegetable intake, sugar-sweetened beverage consumption, or body mass index. Results suggest the need to consider access and quality as well as urban planning and transportation, when examining the relationship between the retail food environment and health outcomes.

It has long been hypothesized that climate can modify both the pattern and magnitude of erosion in mountainous landscapes, thereby controlling morphology, rates of deformation, and potentially modulating global carbon and nutrient cycles through weathering feedbacks. Although conceptually appealing, geologic evidence for a direct climatic control on erosion has remained ambiguous owing to a lack of high-resolution, long-term terrestrial records and suitable field sites. Here we provide direct terrestrial field evidence for long-term synchrony between erosion rates and Milankovitch-driven, 400-kyr eccentricity cycles using a Plio-Pleistocene cosmogenic radionuclide paleo-erosion rate record from the southern Central Andes. The observed climate-erosion coupling across multiple orbital cycles, when combined with results from the intermediate complexity climate model CLIMBER-2, are consistent with the hypothesis that relatively modest fluctuations in precipitation can cause synchronous and nonlinear responses in erosion rates as landscapes adjust to ever-evolving hydrologic boundary conditions imposed by oscillating climate regimes.

ObjectivesAchieving widespread vaccine acceptance across various employment sectors is key to a successful public health response to COVID-19, but little is known about factors influencing vaccine acceptance among essential non-health care workers. We examined factors influencing vaccine acceptance among a sample of essential non-health care workers in California.MethodsWe conducted a survey in early spring 2021 at 2 corporations in Los Angeles County, California, to identify and describe factors influencing vaccine acceptance and the ability of incentives to increase this acceptance. We used modified Poisson regression analysis to estimate adjusted prevalence ratios and a best-subset selection algorithm to identify the strongest factors influencing vaccine acceptance.ResultsOf 678 workers who completed the survey, 450 were unvaccinated. Among unvaccinated participants, having trust in information about the vaccine from public health experts, having ≥1 chronic health condition related to COVID-19 severity, being Asian, and perceiving risk for COVID-19 were factors that most influenced vaccine acceptance. Most (271 of 296, 91.6%) participants who had trust in information from public health experts and 30.6% (30 of 98) of participants who did not have trust in information from public health experts said that they would accept the vaccine. Seventeen of 24 (70.8%) vaccine-hesitant workers who had trust in information from public health experts and 12 of 72 (16.7%) vaccine-hesitant workers who did not have trust in this information said that they would be more likely to accept the vaccine if an incentive were offered.ConclusionsEfforts to increase vaccine coverage at workplaces should focus on improving trust in the vaccine and increasing public awareness that the vaccine is free.

Telehealth is a promising modality for Part C early intervention (EI), services typically implemented face-to-face in home and community settings. Barriers to telehealth in EI reported prior to COVID-19 included lack of training and access to reliable internet. The abrupt telehealth shift at the onset of the pandemic did not permit a phased adoption approach. This mixed-methods study aimed to characterize perspectives of service changes resulting from the telehealth transition. Providers (n = 39) and caregivers (n = 11) completed surveys about perceptions towards the telehealth switch. All providers indicated at least one aspect of services had changed. Approximately half of caregivers reported satisfaction with services decreased and half that satisfaction remained the same. Implications for telehealth in EI beyond the pandemic are discussed., Author(s): Alice Bravo [sup.1] , Lisa V. Ibañez [sup.2] , Sabine Scott [sup.2] , Catherine Dick [sup.2] , Pascale Carpentier [sup.2] , Wendy L. Stone [sup.2] Author Affiliations: (1) https://ror.org/00cvxb145, [...]

Current methods to study angiogenesis in cancer growth and development can be difficult and costly, requiring extensive use of in vivo methodologies. Here, we utilized an in vitro adipocyte derived stem cell and endothelial colony forming cell (ADSC/ECFC) co-culture system to investigate the effect of lentiviral-driven shRNA knockdown of target genes compared to a non-targeting shRNA control on cord formation using High Content Imaging. Cord formation was significantly reduced following knockdown of the VEGF receptor VEGFR2 in VEGF-driven cord formation and the FGF receptor FGFR1 in basic FGF (bFGF)-driven cord formation. In addition, cord formation was significantly reduced following knockdown of the transcription factor forkhead box protein O1 (FOXO1), a protein with known positive effects on angiogenesis and blood vessel stabilization in VEGF- and bFGF-driven cord formation. Lentiviral shRNA also demonstrated utility for stable knockdown of VEGFR2 and FOXO1 in ECFCs, allowing for interrogation of protein knockdown effects on in vivo neoangiogenesis in a Matrigel plug assay. In addition to interrogating the effect of gene knockdown in endothelial cells, we utilized lentiviral shRNA to knockdown specificity protein 1 (SP1), a transcription factor involved in the expression of VEGF, in U-87 MG tumor cells to demonstrate the ability to analyze angiogenesis in vitro in a tumor-driven transwell cord formation system and in tumor angiogenesis in vivo. A significant reduction in tumor-driven cord formation, VEGF secretion, and in vivo tumor angiogenesis was observed upon SP1 knockdown. Therefore, evaluation of target gene knockdown effects in the in vitro co-culture cord formation assay in the ADSC/ECFC co-culture, ECFCs alone, and in tumor cells translated directly to in vivo results, indicating the in vitro method as a robust, cost-effective and efficient in vitro surrogate assay to investigate target gene involvement in endothelial or tumor cell function in angiogenesis.

Information flow through neural circuits is determined by the nature of the synapses linking the subtypes of neurons. How neurons acquire features distinct to each synapse remains unknown. We show that the transcription factor Mafb drives the formation of auditory ribbon synapses, which are specialized for rapid transmission from hair cells to spiral ganglion neurons (SGNs). Mafb acts in SGNs to drive differentiation of the large postsynaptic density (PSD) characteristic of the ribbon synapse. In Mafb mutant mice, SGNs fail to develop normal PSDs, leading to reduced synapse number and impaired auditory responses. Conversely, increased Mafb accelerates synaptogenesis. Moreover, Mafb is responsible for executing one branch of the SGN differentiation program orchestrated by the Gata3 transcriptional network. Remarkably, restoration of Mafb rescues the synapse defect in Gata3 mutants. Hence, Mafb is a powerful regulator of cell-type specific features of auditory synaptogenesis that offers a new entry point for treating hearing loss.

When the axons that carry signals to muscles are growing, they rely on help from Frizzled3—a protein that is known to perform a number of other important functions in cells—to reach their final destination.

Lrig proteins are conserved transmembrane proteins that modulate a variety of signaling pathways from worm to humans. In mammals, there are three family members - Lrig1, Lrig2, and Lrig3--that are defined by closely related extracellular domains with a similar arrangement of leucine rich repeats and immunoglobulin domains. However, the intracellular domains show little homology. Lrig1 inhibits EGF signaling through internalization and degradation of ErbB receptors. Although Lrig3 can also bind ErbB receptors in vitro, it is unclear whether Lrig2 and Lrig3 exhibit similar functions to Lrig1. To gain insights into Lrig gene functions in vivo, we compared the expression and function of the Lrigs in the inner ear, which offers a sensitive system for detecting effects on morphogenesis and function. We find that all three family members are expressed in the inner ear throughout development, with Lrig1 and Lrig3 restricted to subsets of cells and Lrig2 expressed more broadly. Lrig1 and Lrig3 overlap prominently in the developing vestibular apparatus and simultaneous removal of both genes disrupts inner ear morphogenesis. This suggests that these two family members act redundantly in the otic epithelium. In contrast, although Lrig1 and Lrig2 are frequently co-expressed, Lrig1(-/-);Lrig2(-/-) double mutant ears show no enhanced structural abnormalities. At later stages, Lrig1 expression is sustained in non-sensory tissues, whereas Lrig2 levels are enhanced in neurons and sensory epithelia. Consistent with these distinct expression patterns, Lrig1 and Lrig2 mutant mice exhibit different forms of impaired auditory responsiveness. Notably, Lrig1(-/-);Lrig2(-/-) double mutant mice display vestibular deficits and suffer from a more severe auditory defect that is accompanied by a cochlear innervation phenotype not present in single mutants. Thus, Lrig genes appear to act both redundantly and independently, with Lrig2 emerging as the most functionally distinct family member.

OBJECTIVE: The dearth of age-appropriate formulations of many medicines for children poses a major challenge to pediatric therapeutic practice, adherence, and health care delivery worldwide. We provide information on current administration practices of pediatric medicines and describe key stakeholder preferences for new formulation characteristics. PATIENTS AND METHODS: We surveyed children aged 6-12 years, parents/caregivers over age 18 with children under age 12, and healthcare workers in 10 regions of Tanzania to determine current pediatric medicine prescription and administration practices as well as preferences for new formulations. Analyses were stratified by setting, pediatric age group, parent/caregiver education, and healthcare worker cadre. RESULTS: Complete data were available for 206 children, 202 parents/caregivers, and 202 healthcare workers. Swallowing oral solid dosage forms whole or crushing/dissolving them and mixing with water were the two most frequently reported methods of administration. Children frequently reported disliking medication taste, and many had vomited doses. Healthcare workers reported medicine availability most significantly influences prescribing practices. Most parents/caregivers and children prefer sweet-tasting medicine. Parents/caregivers and healthcare workers prefer oral liquid dosage forms for young children, and had similar thresholds for the maximum number of oral solid dosage forms children at different ages can take. CONCLUSIONS: There are many impediments to acceptable and accurate administration of medicines to children. Current practices are associated with poor tolerability and the potential for under- or over-dosing. Children, parents/caregivers, and healthcare workers in Tanzania have clear preferences for tastes and formulations, which should inform the development, manufacturing, and marketing of pediatric medications for resource-limited settings.

Experiments utilizing the Looptail mutant mouse, which harbors a missense mutation in the vangl2 gene, have been essential for studies of planar polarity and linking the function of the core planar cell polarity proteins to other developmental signals. Originally described as having dominant phenotypic traits, the molecular interactions underlying the Looptail mutant phenotype are unclear because Vangl2 protein levels are significantly reduced or absent from mutant tissues. Here we introduce a vangl2 knockout mouse and directly compare the severity of the knockout and Looptail mutant phenotypes by intercrossing the two lines and assaying the planar polarity of inner ear hair cells. Overall the vangl2 knockout phenotype is milder than the phenotype of compound mutants carrying both the Looptail and vangl2 knockout alleles. In compound mutants a greater number of hair cells are affected and changes in the orientation of individual hair cells are greater when quantified. We further demonstrate in a heterologous cell system that the protein encoded by the Looptail mutation (Vangl2(S464N)) disrupts delivery of Vangl1 and Vangl2 proteins to the cell surface as a result of oligomer formation between Vangl1 and Vangl2(S464N), or Vangl2 and Vangl2(S464N), coupled to the intracellular retention of Vangl2(S464N). As a result, Vangl1 protein is missing from the apical cell surface of vestibular hair cells in Looptail mutants, but is retained at the apical cell surface of hair cells in vangl2 knockouts. Similarly the distribution of Prickle-like2, a putative Vangl2 interacting protein, is differentially affected in the two mutant lines. In summary, we provide evidence for a direct physical interaction between Vangl1 and Vangl2 through a combination of in vitro and in vivo approaches and propose that this interaction underlies the dominant phenotypic traits associated with the Looptail mutation.

The vestibular apparatus of the vertebrate inner ear uses three fluid-filled semicircular canals to sense angular acceleration of the head. Malformation of these canals disrupts the sense of balance and frequently causes circling behavior in mice. The Epistatic circler (Ecl) is a complex mutant derived from wildtype SWR/J and C57L/J mice. Ecl circling has been shown to result from the epistatic interaction of an SWR-derived locus on chromosome 14 and a C57L-derived locus on chromosome 4, but the causative genes have not been previously identified.We developed a mouse chromosome substitution strain (CSS-14) that carries an SWR/J chromosome 14 on a C57BL/10J genetic background and, like Ecl, exhibits circling behavior due to lateral semicircular canal malformation. We utilized CSS-14 to identify the chromosome 14 Ecl gene by positional cloning. Our candidate interval is located upstream of bone morphogenetic protein 4 (Bmp4) and contains an inner ear-specific, long non-coding RNA that we have designated Rubie (RNA upstream of Bmp4 expressed in inner ear). Rubie is spliced and polyadenylated, and is expressed in developing semicircular canals. However, we discovered that the SWR/J allele of Rubie is disrupted by an intronic endogenous retrovirus that causes aberrant splicing and premature polyadenylation of the transcript. Rubie lies in the conserved gene desert upstream of Bmp4, within a region previously shown to be important for inner ear expression of Bmp4. We found that the expression patterns of Bmp4 and Rubie are nearly identical in developing inner ears.Based on these results and previous studies showing that Bmp4 is essential for proper vestibular development, we propose that Rubie is the gene mutated in Ecl mice, that it is involved in regulating inner ear expression of Bmp4, and that aberrant Bmp4 expression contributes to the Ecl phenotype.

BackgroundIntegrated care for comorbid depression and chronic medical disease improved physical and mental health outcomes in randomized controlled trials. The Veterans Health Administration (VA) implemented Primary Care-Mental Health Integration (PC-MHI) across all primary care clinics nationally to increase access to mental/behavioral health treatment, alongside physical health management.ObjectiveTo examine whether widespread, pragmatic PC-MHI implementation was associated with improved care quality for chronic medical diseases.Design, setting, and participantsThis retrospective cohort study included 828,050 primary care patients with at least one quality metric among 396 VA clinics providing PC-MHI services between October 2013 and September 2016.Main measure(s)For outcome measures, chart abstractors rated whether diabetes and cardiovascular quality metrics were met for patients at each clinic as part of VA's established quality reporting program. The explanatory variable was the proportion of primary care patients seen by integrated mental health specialists in each clinic annually. Multilevel logistic regression models examined associations between clinic PC-MHI proportion and patient-level quality metrics, adjusting for regional, patient, and time-level effects and clinic and patient characteristics.Key resultsMedian proportion of patients seen in PC-MHI per clinic was 6.4% (IQR=4.7-8.7%). Nineteen percent of patients with diabetes had poor glycemic control (hemoglobin A1c >9%). Five percent had severely elevated blood pressure (>160/100 mmHg). Each two-fold increase in clinic PC-MHI proportion was associated with 2% lower adjusted odds of poor glycemic control (95% CI=0.96-0.99; p=0.046) in diabetes. While there was no association with quality for patients diagnosed with hypertension, patients without diagnosed hypertension had 5% (CI=0.92-0.99; p=0.046) lower adjusted odds of having elevated blood pressures.Conclusions and relevancePrimary care clinics where integrated mental health care reached a greater proportion of patients achieved modest albeit statistically significant gains in key chronic care quality metrics, providing optimism about the expected effects of large-scale PC-MHI implementation on physical health.

The Lrig genes encode a family of transmembrane proteins that have been implicated in tumorigenesis, psoriasis, neural crest development, and complex tissue morphogenesis. Whether these diverse phenotypes reflect a single underlying cellular mechanism is not known. However, Lrig proteins contain evolutionarily conserved ectodomains harboring both leucine-rich repeats and immunoglobulin domains, suggesting an ability to bind to common partners. Previous studies revealed that Lrig1 binds to and inhibits members of the ErbB family of receptor tyrosine kinases by inducing receptor internalization and degradation. In addition, other receptor tyrosine kinase binding partners have been identified for both Lrig1 and Lrig3, leaving open the question of whether defective ErbB signaling is responsible for the observed mouse phenotypes.Here, we report that Lrig3, like Lrig1, is able to interact with ErbB receptors in vitro. We examined the in vivo significance of these interactions in the inner ear, where Lrig3 controls semicircular canal formation by determining the timing and extent of Netrin1 expression in the otic vesicle epithelium. We find that ErbB2 and ErbB3 are present in the early otic epithelium, and that Lrig3 acts cell-autonomously here, as would be predicted if Lrig3 regulates ErbB2/B3 activity. However, inhibition of ErbB activation in the chick otic vesicle has no detectable effect on Netrin gene expression or canal morphogenesis.Our results suggest that although both Lrig1 and Lrig3 can interact with ErbB receptors in vitro, modulation of Neuregulin signaling is unlikely to contribute to Lrig3-dependent processes of inner ear morphogenesis. These results highlight the similar binding properties of Lrig1 and Lrig3 and underscore the need to determine how these two family members bind to and regulate different receptors to affect diverse aspects of cell behavior in vivo.

This study examined the feasibility of implementing the Screening Tool for Autism in Toddlers, an interactive Level-2 screen for autism spectrum disorder, within Part C Early Intervention settings. Participants included 69 Early Intervention providers (M age = 43.3 years, 93.7% females, 92.4% Whites) from nine programs who attended a one-day Screening Tool for Autism in Toddlers training workshop. Half of the providers reported using the Screening Tool for Autism in Toddlers, and reported it to be feasible and effective. Regardless of Screening Tool for Autism in Toddlers use, providers reported increased knowledge about recognizing the early signs of autism spectrum disorder following the workshop. Provider-reported self-efficacy regarding skills related to autism spectrum disorder screening increased significantly from baseline to the 18-month follow-up. Providers also described the facilitators (e.g. promotes communication with families) and barriers (e.g. certification process), that influenced their adoption. Results highlight the potential use of the Screening Tool for Autism in Toddlers within Early Intervention settings to identify autism spectrum disorder, and suggest an implementation model in which specific providers serve as a screening "point-person," rather than expecting it to be used by all providers. Future research should aim to identify characteristics of agencies or providers that might facilitate Screening Tool for Autism in Toddlers use, as well as specific implementation plans and strategies that might promote long-term sustainability of Level-2 screening practices.

ImportanceIn 2016, the US Preventive Services Task Force newly recommended universal screening for depression, with the expectation that screening would be associated with appropriate treatment. Few studies have been able to assess the population-based trajectory from screening to receipt of follow-up and treatment for individuals with depression.ObjectiveTo examine adherence to guidelines for follow-up and treatment among primary care patients who newly screened positive for depression in the Veterans Health Administration (VA).Design, setting, and participantsThis retrospective cohort study used VA electronic data to identify patients who newly screened positive for depression on the 2-item Patient Health Questionnaire at 82 primary care VA clinics in California, Arizona, and New Mexico between October 1, 2015, and September 30, 2019. Data analysis was performed from December 2020 to August 2021.Main outcomes and measuresReceipt of guideline-concordant care for screen-positive patients who were determined by clinicians as having depression was assessed. Timely follow-up (within 84 days of screening) was defined as receiving 3 or more mental health specialty visits, 3 or more psychotherapy visits, or 3 or more primary care visits with a depression diagnosis according to the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. Completing at least minimal treatment (within 12 months) was defined as having 60 days or more of antidepressant prescriptions filled, 4 or more mental health specialty visits, or 3 or more psychotherapy visits.ResultsThe final cohort included 607 730 veterans (mean [SD] age, 59.4 [18.2] years; 546 516 men [89.9%]; 339 811 non-Hispanic White [55.9%]); 8%, or 82 998 of 997 185 person-years, newly screened positive for depression. Clinicians identified fewer than half with depression (15 155 patients), of whom 32% (5034 of 15 650 person-years) met treatment guidelines for timely follow-up and 77% (12 026 of 15 650 person-years) completed at least minimal treatment. Younger age (odds ratio, 0.990; 95% CI, 0.986-0.993; P

ObjectiveWe recently demonstrated that relative to consensus-based methods, actuarial methods may improve diagnostic accuracy across the continuum of cognitively normal (CN), mild cognitive impairment (MCI), and dementia in the overall National Alzheimer's Coordinating Center (NACC) cohort. However, the generalizability and comparative utility of current methods of diagnosing MCI and dementia due to Alzheimer's disease and related disorders (ADRD) are significantly understudied in non-Hispanic Black (NHB) older adults. Thus, we extended our previous investigation to more specifically explore the utility of consensus-based and actuarial diagnostic methods in NHB older adults.Method: We compared baseline consensus and actuarial diagnostic rates, and associations of ratings of functioning with neuropsychological performance and diagnostic outcomes, in NHB (n = 963) and non-Hispanic White (NHW; n = 4577) older adults in the NACC cohort.Results: 60.0% of the NHB subsample, versus 29.2% of the NHW subsample, included participants who met actuarial criteria for MCI despite being classified as CN or impaired-not-MCI per consensus. Additionally, associations between ratings of functioning and neuropsychological performance were less consistent in NHB participants than in NHW participants.Conclusions: Our results provide evidence of differential degrees of association between reported functioning and neuropsychological performance in NHB and NHW older adults, which may contribute to racial group differences in diagnostic rates, and prompt consideration of the strengths and weaknesses of consensus-based and actuarial diagnostic approaches in assessing neurocognitive functioning in NHB older adults.

Parizek M, Douglas TEL, Novotna K, Kromka A, Brady MA, Renzing A, Voss E, Jarosova M, Palatinus L, Tesarek P, Ryparova P, Lisa V, dos Santos AM, Bacakova L. Nanofibrous poly (lactide-co-glycolide) membranes loaded with diamond nanoparticles as promising substrates for bone tissue engineering. Int J Nanomedicine. 2012;7:1931–1951. Dr PH Warnke was mistakenly removed from the list of authors of this paper. The correct citation is as follows:Parizek M, Douglas TEL, Novotna K, Kromka A, Brady MA, Renzing A, Voss E, Jarosova M, Palatinus L, Tesarek P, Ryparova P, Lisa V, dos Santos AM, Warnke PH, Bacakova L. Nanofibrous poly (lactide-co-glycolide) membranes loaded with diamond nanoparticles as promising substrates for bone tissue engineering. Int J Nanomedicine. 2012;7:1931–1951. Dr Warnke’s affiliations are:Department of Oral and Maxillofacial Surgery, University of Kiel, Germany; and Clem Jones Research Centre for Stem Cells and Tissue Regenerative Therapies, Bond University, Gold Coast, QLD, Australia.

Determining the time of emergence of climates altered from their natural state by anthropogenic influences can help inform the development of adaptation and mitigation strategies to climate change. Previous studies have examined the time of emergence of climate averages. However, at the global scale, the emergence of changes in extreme events, which have the greatest societal impacts, has not been investigated before. Based on state-of-the-art climate models, we show that temperature extremes generally emerge slightly later from their quasi-natural climate state than seasonal means, due to greater variability in extremes. Nevertheless, according to model evidence, both hot and cold extremes have already emerged across many areas. Remarkably, even precipitation extremes that have very large variability are projected to emerge in the coming decades in Northern Hemisphere winters associated with a wettening trend. Based on our findings we expect local temperature and precipitation extremes to already differ significantly from their previous quasi-natural state at many locations or to do so in the near future. Our findings have implications for climate impacts and detection and attribution studies assessing observed changes in regional climate extremes by showing whether they will likely find a fingerprint of anthropogenic climate change.

ObjectiveGiven that several non-cognitive factors can contribute to difficulties with everyday functioning, examining the extent to which cognition is associated with brain-related changes in everyday functioning is critical to accurate characterization of cognitive disorders. In this study, we examined neuropsychological correlates of the shared variance between everyday functioning and pathological indicators of cognitive aging using MRI brain volumetrics.Participants and methodsParticipants were 600 adults aged 55 and older without dementia [432 cognitively normal; 168 mild cognitive impairment (MCI)] from the National Alzheimer's Coordinating Center cohort who underwent neuropsychological testing, informant-rated everyday functioning, and brain MRI scanning at baseline. The shared variance between everyday functioning and brain volumetrics (i.e., hippocampal volume, white matter hyperintensity volume) was extracted using the predicted value from multiple regression. The shared variance was used as an indicator of pathological everyday functional impairment. The residual variance from the regression analysis was used to examine functional reserve.ResultsLarger white matter hyperintensity volumes (p = 0.002) and smaller hippocampal volumes (p

BackgroundGiven persistent gaps in coordination of care for medically complex primary care patients, efficient strategies are needed to promote better care coordination.ObjectiveThe Coordination Toolkit and Coaching project compared two toolkit-based strategies of differing intensity to improve care coordination at VA primary care clinics.DesignMulti-site, cluster-randomized QI initiative.ParticipantsTwelve VA primary care clinics matched in 6 pairs.InterventionsWe used a computer-generated allocation sequence to randomize clinics within each pair to two implementation strategies. Active control clinics received an online toolkit with evidence-based tools and QI coaching manual. Intervention clinics received the online toolkit plus weekly assistance from a distance coach for 12 months.Main measuresWe quantified patient experience of general care coordination using the Health Care System Hassles Scale (primary outcome) mailed at baseline and 12-month follow-up to serial cross-sectional patient samples. We measured the difference-in-difference (DiD) in clinic-level-predicted mean counts of hassles between coached and non-coached clinics, adjusting for clustering and patient characteristics using zero-inflated negative binomial regression and bootstrapping to obtain 95% confidence intervals. Other measures included care coordination QI projects attempted, tools adopted, and patient-reported exposure to projects.Key resultsN = 2,484 (49%) patients completed baseline surveys and 2,481 (48%) completed follow-ups. Six coached clinics versus five non-coached clinics attempted QI projects. All coached clinics versus two non-coached clinics attempted more than one project or projects that were multifaceted (i.e., involving multiple components addressing a common goal). Five coached versus three non-coached clinics used 1-2 toolkit tools. Both the coached and non-coached clinics experienced pre-post reductions in hassle counts over the study period (- 0.42 (- 0.76, - 0.08) non-coached; - 0.40 (- 0.75, - 0.06) coached). However, the DiD (0.02 (- 0.47, 0.50)) was not statistically significant; coaching did not improve patient experience of care coordination relative to the toolkit alone.ConclusionAlthough coached clinics attempted more or more complex QI projects and used more tools than non-coached clinics, coaching provided no additional benefit versus the online toolkit alone in patient-reported outcomes.Trial registrationClinicalTrials.gov identifier: NCT03063294.

Family-centered care represents a collaborative partnership between caregivers and service providers, and is associated with positive caregiver and child outcomes. This approach may be especially important for caregivers with early concerns about autism, as service providers are often the gateway to appropriately-specialized intervention. Perceptions of family-centered care received from primary care providers (PCPs) and Part C Early Intervention (EI) providers were rated by two groups of caregivers: those concerned about autism (n = 37) and those concerned about another developmental problem (n = 22), using the Measure of Processes of Care (MPOC-20). Ratings did not differ across caregiver groups, but both groups rated EI providers significantly higher than PCPs, which may reflect systems-level differences between primary care and EI.

Health services made many changes quickly in response to the SARS-CoV-2 pandemic. Many more are being made. Some changes were already evaluated, and there are rigorous research methods and frameworks for evaluating their local implementation and effectiveness. But how useful are these methods for evaluating changes where evidence of effectiveness is uncertain, or which need adaptation in a rapidly changing situation? Has implementation science provided implementers with tools for effective implementation of changes that need to be made quickly in response to the demands of the pandemic? This perspectives article describes how parts of the research and practitioner communities can use and develop a combination of implementation and improvement to enable faster and more effective change in the future, especially where evidence of local effectiveness is limited. We draw on previous reviews about the advantages and disadvantages of combining these two domains of knowledge and practice. We describe a generic digitally assisted rapid cycle testing (DA-RCT) approach that combines elements of each in order to better describe a change, monitor outcomes, and make adjustments to the change when implemented in a dynamic environment.

Background and objectivesGiven prior work demonstrating that mild cognitive impairment (MCI) can be empirically differentiated into meaningful cognitive subtypes, we applied actuarial methods to comprehensive neuropsychological data from the University of California San Diego Alzheimer's Disease Research Center (ADRC) in order to identify cognitive subgroups within ADRC participants without dementia and to examine cognitive, biomarker, and neuropathologic trajectories.MethodsCluster analysis was performed on baseline neuropsychological data (n = 738; mean age 71.8). Survival analysis examined progression to dementia (mean follow-up 5.9 years). CSF Alzheimer disease (AD) biomarker status and neuropathologic findings at follow-up were examined in a subset with available data.ResultsFive clusters were identified: optimal cognitively normal (CN; n = 130) with above-average cognition, typical CN (n = 204) with average cognition, nonamnestic MCI (naMCI; n = 104), amnestic MCI (aMCI; n = 216), and mixed MCI (mMCI; n = 84). Progression to dementia differed across MCI subtypes (mMCI > aMCI > naMCI), with the mMCI group demonstrating the highest rate of CSF biomarker positivity and AD pathology at autopsy. Actuarial methods classified 29.5% more of the sample with MCI and outperformed consensus diagnoses in capturing those who had abnormal biomarkers, progressed to dementia, or had AD pathology at autopsy.DiscussionWe identified subtypes of MCI and CN with differing cognitive profiles, clinical outcomes, CSF AD biomarkers, and neuropathologic findings over more than 10 years of follow-up. Results demonstrate that actuarial methods produce reliable cognitive phenotypes, with data from a subset suggesting unique biological and neuropathologic signatures. Findings indicate that data-driven algorithms enhance diagnostic sensitivity relative to consensus diagnosis for identifying older adults at risk for cognitive decline.