Prospective Association of Parenting Stress with Later Child Behavior Problems in Early Childhood Autism.

PURPOSE: Autistic children are reported to display higher levels of externalizing and internalizing behaviors than neurotypical children, and their parents report more stress than parents of neurotypical children. It is unclear whether child behavior difficulties contribute to increased parenting stress, whether parenting stress contributes to child behavior difficulties, or whether the relationship may be bidirectional. METHODS: We investigated prospective bidirectional associations between parenting stress and child externalizing and internalizing behaviors when autistic children were aged on average 3.5, 4.5, and 5.5 years. Data collected at these three timepoints were examined across two panels: Time 1 to Time 2 (n = 38 parent-child dyads) and Time 2 to Time 3 (n = 27 dyads). RESULTS: Across Time 1 to Time 2, early parenting stress was significantly associated with later child externalizing behavior, and cross-lagged panel analysis supported a uni- rather than a bidirectional association between these factors. There was some evidence of a bidirectional association between parenting stress and child internalizing behavior, though this was non-significant when the strong stability of child internalizing behavior was statistically controlled. In contrast, across Time 2 to Time 3, there were no significant prospective associations found between variables, highlighting the importance of considering the impact of parenting stress early in the course of childhood autism. CONCLUSION: Our results add to research indicating that support targeting parent characteristics, especially parenting stress, could ameliorate subsequent outcomes for both parents and children.

Rapidly Enlarging Parotid Mass in a Person Living with HIV: A Case of Multiple Myeloma with Extramedullary Plasmacytoma.

BACKGROUND The differential diagnosis for a parotid mass is broad, including infectious, autoimmune, and neoplastic etiologies. In people with HIV, regardless of viral suppression or immune status, neoplastic causes are more common. This report describes the evaluation of a woman with a large parotid mass, with an ultimate diagnosis of multiple myeloma with extramedullary plasmacytoma. CASE REPORT A 51-year-old woman with HIV infection presented with headache, weight loss, and right facial mass that was present for 5 years but more rapidly enlarging in the prior year. CD4 count was 234 cells/mL, and HIV RNA was 10 810 copies/mL. Physical examination was significant for a large deforming right-sided facial mass, decreased sensation in the V1 and V2 distributions, and right-sided ophthalmoplegia and ptosis. MRI and PET/CT scan confirmed a metabolically active large parotid mass with extension into the cavernous sinus. An IgG kappa monoclonal spike was present on serum protein electrophoresis. Incisional biopsy of the facial mass showed atypical lymphoid cells with plasmablastic and plasmacytic morphology with a high mitotic rate and proliferation index. She was diagnosed with R-ISS stage II IgG kappa multiple myeloma with extramedullary plasmacytoma, and initiated on chemotherapy, radiation, and antiretroviral therapy. CONCLUSIONS A rapidly enlarging parotid mass should prompt timely evaluation and biopsy for definitive diagnosis, particularly in immunocompromised patients, including people with HIV. Extramedullary plasmacytomas have a more aggressive disease process in people with HIV and are associated with high-risk multiple myeloma and progression, as seen in this patient.

Recommendation-making in the emergency department: A qualitative study of how Canadian emergency physicians guide treatment decisions about resuscitation in critically ill patients.

Study Objective: Emergency physicians are frequently responsible for making time-sensitive decisions around the provision of life-sustaining treatment. These decisions can involve goals of care or code status discussion, which will often substantially alter a patient's care pathway. A central part of these conversations that has received relatively little attention are recommendations for care. By proposing a best course of action or treatment via a recommendation, a clinician can ensure that their patients receive care that is concordant with their values. The objective of this study is to explore emergency physicians' attitudes toward recommendations about resuscitation in critically ill patients in the emergency department (ED). Methods: We recruited Canadian emergency physicians via multiple recruitment strategies to ensure maximum variation sampling. Semi-structured qualitative interviews were conducted until thematic saturation occurred. Participants were asked about their perspectives and experiences with respect to recommendation-making in critically ill patients and to identify areas for improvement in this process in the ED. We used a qualitative descriptive approach and thematic analysis to identify themes around recommendation-making in the ED for critically ill patients. Results: Sixteen emergency physicians agreed to participate. We identified four themes and multiple subthemes. Major themes included identification of the roles and responsibilities of the emergency physician (EP) with respect to making a recommendation, the logistics or process of making a recommendation, barriers to making a recommendation, and how to improve recommendation-making and goals of care conversations in the ED. Conclusion: Emergency physicians provided a range of perspectives on the role of recommendation-making in critically ill patients in the ED. Several barriers to the inclusion of a recommendation were identified and many physicians provided ideas on how to improve goals of care conversations, the recommendation-making process, and ensure that critically ill patients receive care that is concordant with their values.

Parent-identified barriers to accessing exposure therapy: A qualitative study using process mapping.

Background: Youth with anxiety and obsessive-compulsive disorder (OCD) rarely access exposure therapy, an evidence-based treatment. Known barriers include transportation, waitlists, and provider availability. Efforts to improve access to exposure require an understanding of the process that families take to find therapists, yet no prior studies have examined parents' perspectives of the steps involved. Methods: Parents of children who have received exposure therapy for anxiety and/or OCD (N = 23) were recruited from a hospital-based specialty anxiety clinic where the majority of their children previously received exposure. Recruitment was ongoing until thematic saturation was reached. Parents completed questionnaires and attended an online focus group during which they were asked to describe each step they took-from recognizing their child needed treatment to beginning exposure. A process map was created and shown in real-time, edited for clarity, and emailed to parents for member checking. Authors analyzed process maps to identify common themes. Results: Several themes emerged, as visually represented in a final process map. Participants identified a "search-outreach" loop, in which they repeated the cycle of looking for therapists, contacting them, and being unable to schedule an appointment due to factors such as cost, waitlists, and travel time. Parents often did not know about exposure and reported feeling guilty about their lack of knowledge and inability to find a suitable provider. Parents reported frustration that medical providers did not often know about exposure and sometimes dismissed parents' concerns. Participants emphasized the difficulty of navigating the mental health system; many reported that it took years to find an exposure therapist, and that the search was sometimes stalled due to fluctuating symptoms. Conclusion: A common thread among identified barriers was the amount of burden placed on parents to find treatment with limited support, and the resultant feelings of isolation and guilt. Findings point to several directions for future research, such as the development of parent support groups for navigating the mental health system; enhancing coordination of care between medical and mental health providers; and streamlining referral processes.

Imaging of Brain Structural and Functional Effects in People With Human Immunodeficiency Virus.

Before the introduction of antiretroviral therapy, human immunodeficiency virus (HIV) infection was often accompanied by central nervous system (CNS) opportunistic infections and HIV encephalopathy marked by profound structural and functional alterations detectable with neuroimaging. Treatment with antiretroviral therapy nearly eliminated CNS opportunistic infections, while neuropsychiatric impairment and peripheral nerve and organ damage have persisted among virally suppressed people with HIV (PWH), suggesting ongoing brain injury. Neuroimaging research must use methods sensitive for detecting subtle HIV-associated brain structural and functional abnormalities, while allowing for adjustments for potential confounders, such as age, sex, substance use, hepatitis C coinfection, cardiovascular risk, and others. Here, we review existing and emerging neuroimaging tools that demonstrated promise in detecting markers of HIV-associated brain pathology and explore strategies to study the impact of potential confounding factors on these brain measures. We emphasize neuroimaging approaches that may be used in parallel to gather complementary information, allowing efficient detection and interpretation of altered brain structure and function associated with suboptimal clinical outcomes among virally suppressed PWH. We examine the advantages of each imaging modality and systematic approaches in study design and analysis. We also consider advantages of combining experimental and statistical control techniques to improve sensitivity and specificity of biotype identification and explore the costs and benefits of aggregating data from multiple studies to achieve larger sample sizes, enabling use of emerging methods for combining and analyzing large, multifaceted data sets. Many of the topics addressed in this article were discussed at the National Institute of Mental Health meeting "Biotypes of CNS Complications in People Living with HIV," held in October 2021, and are part of ongoing research initiatives to define the role of neuroimaging in emerging alternative approaches to identifying biotypes of CNS complications in PWH. An outcome of these considerations may be the development of a common neuroimaging protocol available for researchers to use in future studies examining neurological changes in the brains of PWH.

Small-molecule screen reveals pathways that regulate C4 secretion in stem cell-derived astrocytes.

In the brain, the complement system plays a crucial role in the immune response and in synaptic elimination during normal development and disease. Here, we sought to identify pathways that modulate the production of complement component 4 (C4), recently associated with an increased risk of schizophrenia. To design a disease-relevant assay, we first developed a rapid and robust 3D protocol capable of producing large numbers of astrocytes from pluripotent cells. Transcriptional profiling of these astrocytes confirmed the homogeneity of this population of dorsal fetal-like astrocytes. Using a novel ELISA-based small-molecule screen, we identified epigenetic regulators, as well as inhibitors of intracellular signaling pathways, able to modulate C4 secretion from astrocytes. We then built a connectivity map to predict and validate additional key regulatory pathways, including one involving c-Jun-kinase. This work provides a foundation for developing therapies for CNS diseases involving the complement cascade.

Trajectory of Change in Parental Accommodation and Its Relation to Symptom Severity and Impairment in Pediatric OCD.

Family accommodation (FA) has been shown to relate to poorer treatment outcomes in pediatric obsessive compulsive disorder (OCD), yet few studies have examined the trajectory of change in FA throughout treatment and its relation to treatment outcomes. This study examined change in FA in relation to change in symptom severity and impairment in 63 youth receiving a family-based intervention for early-onset OCD. FA, symptom severity and functional impairment were assessed at baseline, week 5, week 9, and post-treatment (week 14). Results suggested that changes in FA in the beginning stages of treatment preceded global symptom improvement (but not OCD specific improvement) whereas changes in functional impairment preceded changes in FA. In the latter half of treatment, changes in FA preceded improvement in global and OCD specific symptom severity as well as functional impairment. These findings highlight the importance of reducing FA, especially in the later stages of treatment, in order to optimize treatment outcomes in early-onset OCD.

Effects of SARS-CoV-2 Infection on Attention, Memory, and Sensorimotor Performance.

Background: Recovery after SARS-CoV-2 infection is extremely variable, with some individuals recovering quickly, and others experiencing persistent long-term symptoms or developing new symptoms after the acute phase of infection, including fatigue, poor concentration, impaired attention, or memory deficits. Many existing studies reporting cognitive deficits associated with SARS-CoV-2 infection are limited by the exclusive use of self-reported measures or a lack of adequate comparison groups. Methods: Forty-five participants, ages 18-70, (11 Long-COVID, 14 COVID, and 20 No-COVID) underwent behavioral testing with the NIH Toolbox Neuro-Quality of Life survey and selected psychometric tests, including a flanker interference task and the d2 Test of Attention. Results: We found greater self-reported anxiety, apathy, fatigue, emotional dyscontrol, sleep disturbance and cognitive dysfunction in COVID compared No-COVID groups. After categorizing COVID patients according to self-reported concentration problems, we observed declining performance patterns in multiple attention measures across No-COVID controls, COVID and Long-COVID groups. COVID participants, compared to No-COVID controls, exhibited worse performance on NIH Toolbox assessments, including the Eriksen Flanker, Nine-Hole Pegboard and Auditory Verbal Learning tests. Conclusion: This study provides convergent evidence that previous SARS-CoV-2 infection is associated with impairments in sustained attention, processing speed, self-reported fatigue and concentration. The finding that some patients have cognitive and visuomotor dysfunction in the absence of self-reported problems suggests that SARS-CoV-2 infection can have unexpected and persistent subclinical consequences.

Identifying barriers and facilitators to palliative care integration in the management of hospitalized patients with COVID-19: A qualitative study.

BACKGROUND: Palliative care is well suited to support patients hospitalized with COVID-19, but integration into care has been variable and generally poor. AIM: To understand barriers and facilitators of palliative care integration for hospitalized patients with COVID-19. METHODS: Internists, Intensivists and palliative care physicians completed semi-structured interviews about their experiences providing care to patients with COVID-19. Results were analysed using thematic analysis. RESULTS: Twenty-three physicians (13 specialist palliative care, five intensivists, five general internists) were interviewed; mean ± SD age was 42 ± 11 years and 61% were female. Six thematic categories were described including: patient and family factors, palliative care knowledge, primary provider factors, COVID-19 specific factors, palliative care service factors, and leadership and culture factors. Patient and family factors included patient prognosis, characteristics that implied prognosis (i.e., age, etc.), and goals of care. Palliative care knowledge included confidence in primary palliative care skills, misperception that COVID-19 is not a 'palliative diagnosis', and the need to choose quantity or quality of life in COVID-19 management. Primary provider factors included available time, attitude, and reimbursement. COVID-19 specific factors were COVID-19 as an impetus to act, uncertain illness trajectory, treatments and outcomes, and infection control measures. Palliative care service factors were accessibility, adaptability, and previous successful relationships. Leadership and culture factors included government-mandated support, presence at COVID planning tables, and institutional and unit culture. CONCLUSION: The study findings highlight the need for leadership support for formal integrated models of palliative care for patients with COVID-19, a palliative care role in pandemic planning, and educational initiatives with primary palliative care providers.

Rapid deployment of a virtual simulation curriculum to prepare for critical care triage during the COVID-19 pandemic.

BACKGROUND: During the COVID-19 pandemic in Ontario, Canada, an Emergency Standard of Care for Major Surge was created to establish a uniform process for the "triage" of finite critical care resources. This proposed departure from usual clinical care highlighted the need for an educational tool to prepare physicians for making and communicating difficult triage decisions. We created a just-in-time, virtual, simulation-based curriculum and evaluated its impact for our group of academic Emergency Physicians. METHODS: Our curriculum was developed and evaluated following Stufflebeam's Context-Input-Process-Product model. Our virtual simulation sessions, delivered online using Microsoft Teams, addressed a range of clinical scenarios involving decisions about critical care prioritization (i.e., Triage). Simulation participants completed a pre-course multiple-choice knowledge test and rating scales pertaining to their attitudes about using the Emergency Standard of Care protocol before and 2-4 weeks after participating. Qualitative feedback about the curriculum was solicited through surveys. RESULTS: Nine virtual simulation sessions were delivered over 3 weeks, reaching a total of 47 attending emergency physicians (74% of our active department members). Overall, our intervention led to a 36% (95% CI 22.9-48.3%) improvement in participants' self-rated comfort and attitudes in navigating triage decisions and communicating with patients at the end of life. Scores on the knowledge test improved by 13% (95% CI 0.4-25.6%). 95% of participants provided highly favorable ratings of the course content and similarly indicated that the session was likely or very likely to change their practice. The curriculum has since been adopted at multiple sites around the province. CONCLUSION: Our novel virtual simulation curriculum facilitated rapid dissemination of the Emergency Standard of Care for Major Surge to our group of Emergency Physicians despite COVID-19-related constraints on gathering. The active learning afforded by this method improved physician confidence and knowledge with these difficult protocols.

RéSUMé: CONTEXTE: Au cours de la pandémie de COVID-19 en Ontario, au Canada, une norme de soins d'urgence pour les poussées majeures a été créée afin d'établir un processus uniforme pour le " triage " des ressources limitées en soins intensifs. Cette proposition d'écart par rapport aux soins cliniques habituels a mis en évidence la nécessité d'un outil éducatif pour préparer les médecins à prendre et à communiquer des décisions de triage difficiles. Nous avons créé un programme d'études virtuel, juste à temps, basé sur la simulation et avons évalué son impact sur notre groupe de médecins urgentistes universitaires. MéTHODES: Notre programme d'études a été développé et évalué selon le modèle Contexte-Intrant-Processus-Produit de Stufflebeam. Nos sessions de simulation virtuelle, réalisées en ligne à l'aide de Microsoft Teams, ont abordé une série de scénarios cliniques impliquant des décisions sur la priorisation des soins intensifs (c.-à-d. le triage). Les participants à la simulation ont rempli un test de connaissances à choix multiples avant le cours et des échelles d'évaluation concernant leurs attitudes à l'égard de l'utilisation du protocole de soins d'urgence standard avant et deux à quatre semaines après leur participation. Des commentaires qualitatifs sur le programme ont été sollicités par le biais d'enquêtes. RéSULTATS: Neuf sessions de simulation virtuelle ont été dispensées sur trois semaines, touchant au total 47 médecins urgentistes titulaires (74 % des membres actifs de notre service). Dans l'ensemble, notre intervention a conduit à une amélioration de 36 % (IC 95 % 22,9-48,3 %) de l'auto-évaluation du confort et des attitudes des participants en matière de décisions de triage et de communication avec les patients en fin de vie. Les scores au test de connaissances se sont améliorés de 13% (IC 95% 0,4-25,6%). 95 % des participants ont donné une évaluation très favorable du contenu du cours et ont également indiqué que la session était susceptible ou très susceptible de modifier leur pratique. Le programme d'études a depuis été adopté à plusieurs endroits dans la province. CONCLUSION: Notre nouveau programme de simulation virtuelle a facilité la diffusion rapide des normes de soins d'urgence en cas de crise majeure à notre groupe d'urgentistes, malgré les contraintes de rassemblement liées au COVID-19. L'apprentissage actif que permet cette méthode a amélioré la confiance et les connaissances des médecins concernant ces protocoles difficiles.

GWAS and genomic prediction of milk urea nitrogen in Australian and New Zealand dairy cattle.

BACKGROUND: Urinary nitrogen leakage is an environmental concern in dairy cattle. Selection for reduced urinary nitrogen leakage may be done using indicator traits such as milk urea nitrogen (MUN). The result of a previous study indicated that the genetic correlation between MUN in Australia (AUS) and MUN in New Zealand (NZL) was only low to moderate (between 0.14 and 0.58). In this context, an alternative is to select sequence variants based on genome-wide association studies (GWAS) with a view to improve genomic prediction accuracies. A GWAS can also be used to detect quantitative trait loci (QTL) associated with MUN. Therefore, our objectives were to perform within-country GWAS and a meta-GWAS for MUN using records from up to 33,873 dairy cows and imputed whole-genome sequence data, to compare QTL detected in the GWAS for MUN in AUS and NZL, and to use sequence variants selected from the meta-GWAS to improve the prediction accuracy for MUN based on a joint AUS-NZL reference set. RESULTS: Using the meta-GWAS, we detected 14 QTL for MUN, located on chromosomes 1, 6, 11, 14, 19, 22, 26 and the X chromosome. The three most significant QTL encompassed the casein genes on chromosome 6, PAEP on chromosome 11 and DGAT1 on chromosome 14. We selected 50,000 sequence variants that had the same direction of effect for MUN in AUS and MUN in NZL and that were most significant in the meta-analysis for the GWAS. The selected sequence variants yielded a genetic correlation between MUN in AUS and MUN in NZL of 0.95 and substantially increased prediction accuracy in both countries. CONCLUSIONS: Our results demonstrate how the sharing of data between two countries can increase the power of a GWAS and increase the accuracy of genomic prediction using a multi-country reference population and sequence variants selected based on a meta-GWAS.

Lesion location may attenuate response to strategy training in acute stroke.

BACKGROUND: Strategy training, a rehabilitation intervention, reduces disability and improves functional skills associated with goal-directed behavior. Stroke lesions impacting selected ventromedial regions of interest associated with initiation of goal-directed behavior may attenuate intervention response. If so, strategy training may not be optimal for people with stroke lesions in these regions. OBJECTIVE: To examine whether ventromedial regions of interest attenuate changes in disability status attributed to strategy training. DESIGN: Secondary analysis of data from two randomized controlled clinical trials. SETTING: Inpatient stroke rehabilitation. PARTICIPANTS: People with acute stroke diagnosis and available diagnostic studies enrolled in inpatient rehabilitation randomized controlled studies between 2009 and 2017. INTERVENTION: Participants were randomized to strategy training or a control condition in addition to the usual care during inpatient rehabilitation. MAIN OUTCOME MEASURES: Diagnostic magnetic resonance imaging studies were retrieved from electronic medical records, and stroke lesion location was characterized by a neuroradiologist. Intervention response was defined by Functional Independence Measure change scores of 22 points or greater. RESULTS: Only 186 of 275 participants had diagnostic studies available; 13 patients showed no apparent lesion on their diagnostic study. Among 173 cases, 156 had complete data at discharge (strategy training n = 71, control n = 85). Twenty-five cases had a lesion within a region of interest (strategy training n = 14, control n = 11). Intervention response was attenuated in the strategy training group for those with lesions in regions of interest [χ2 (1, n = 71) = 4.60, P = .03], but not for those in the control group [Fisher exact test, n = 85, P = .19). CONCLUSIONS: Lesions in the ventromedial regions of interest may attenuate response to strategy training.

MULTI-DOMAIN LEARNING BY META-LEARNING: TAKING OPTIMAL STEPS IN MULTI-DOMAIN LOSS LANDSCAPES BY INNER-LOOP LEARNING.

We consider a model-agnostic solution to the problem of Multi-Domain Learning (MDL) for multi-modal applications. Many existing MDL techniques are model-dependent solutions which explicitly require nontrivial architectural changes to construct domain-specific modules. Thus, properly applying these MDL techniques for new problems with well-established models, e.g. U-Net for semantic segmentation, may demand various low-level implementation efforts. In this paper, given emerging multi-modal data (e.g., various structural neuroimaging modalities), we aim to enable MDL purely algorithmically so that widely used neural networks can trivially achieve MDL in a model-independent manner. To this end, we consider a weighted loss function and extend it to an effective procedure by employing techniques from the recently active area of learning-to-learn (meta-learning). Specifically, we take inner-loop gradient steps to dynamically estimate posterior distributions over the hyperparameters of our loss function. Thus, our method is model-agnostic, requiring no additional model parameters and no network architecture changes; instead, only a few efficient algorithmic modifications are needed to improve performance in MDL. We demonstrate our solution to a fitting problem in medical imaging, specifically, in the automatic segmentation of white matter hyperintensity (WMH). We look at two neuroimaging modalities (T1-MR and FLAIR) with complementary information fitting for our problem.

ROBUST WHITE MATTER HYPERINTENSITY SEGMENTATION ON UNSEEN DOMAIN.

Typical machine learning frameworks heavily rely on an underlying assumption that training and test data follow the same distribution. In medical imaging which increasingly begun acquiring datasets from multiple sites or scanners, this identical distribution assumption often fails to hold due to systematic variability induced by site or scanner dependent factors. Therefore, we cannot simply expect a model trained on a given dataset to consistently work well, or generalize, on a dataset from another distribution. In this work, we address this problem, investigating the application of machine learning models to unseen medical imaging data. Specifically, we consider the challenging case of Domain Generalization (DG) where we train a model without any knowledge about the testing distribution. That is, we train on samples from a set of distributions (sources) and test on samples from a new, unseen distribution (target). We focus on the task of white matter hyperintensity (WMH) prediction using the multi-site WMH Segmentation Challenge dataset and our local in-house dataset. We identify how two mechanically distinct DG approaches, namely domain adversarial learning and mix-up, have theoretical synergy. Then, we show drastic improvements of WMH prediction on an unseen target domain.

A multi-scanner neuroimaging data harmonization using RAVEL and ComBat.

Modern neuroimaging studies frequently combine data collected from multiple scanners and experimental conditions. Such data often contain substantial technical variability associated with image intensity scale (image intensity scales are not the same in different images) and scanner effects (images obtained from different scanners contain substantial technical biases). Here we evaluate and compare results of data analysis methods without any data transformation (RAW), with intensity normalization using RAVEL, with regional harmonization methods using ComBat, and a combination of RAVEL and ComBat. Methods are evaluated on a unique sample of 16 study participants who were scanned on both 1.5T and 3T scanners a few months apart. Neuroradiological evaluation was conducted for 7 different regions of interest (ROI's) pertinent to Alzheimer's disease (AD). Cortical measures and results indicate that: (1) RAVEL substantially improved the reproducibility of image intensities; (2) ComBat is preferred over RAVEL and the RAVEL-ComBat combination in terms of regional level harmonization due to more consistent harmonization across subjects and image-derived measures; (3) RAVEL and ComBat substantially reduced bias compared to analysis of RAW images, but RAVEL also resulted in larger variance; and (4) the larger root mean square deviation (RMSD) of RAVEL compared to ComBat is due mainly to its larger variance.

Chlamydia Treatment Practices and Time to Treatment in Massachusetts: Directly Observed Therapy Versus Pharmacy Prescriptions.

BACKGROUND: Directly observed therapy (DOT) is recommended for the treatment of chlamydia, however pharmacy prescriptions are frequently used. Adherence to DOT and the association between treatment method and time to treatment is unknown. METHODS: We conducted a retrospective review of a randomized 2% of laboratory-confirmed chlamydia infections reported to the Massachusetts Department of Public Health from January 1, 2019 to May 31, 2019. Clinicians and pharmacies were contacted to ascertain treatment methods and timing. We assessed frequency of DOT and pharmacy prescriptions in the treatment of chlamydia infection in Massachusetts. We used log rank test to compare time to treatment initiation for patients receiving DOT versus pharmacy prescriptions. Data were stratified according to whether treatment was empiric or laboratory-driven. KEY RESULTS: We ascertained full outcomes for 199 patients. Eighty patients received DOT and 119 patients received pharmacy prescriptions. DOT was more common among those receiving empiric treatment and pharmacy prescriptions were more common among those receiving laboratory-driven treatment. The median time to treatment was 1.5 days for patients treated with DOT and 3 days for those treated with pharmacy prescriptions. For both groups, the median time to treatment for empiric therapy was 0 days and for laboratory-driven therapy was 4 days. The differences in time to treatment were not statistically significant. CONCLUSIONS: Pharmacy prescriptions are frequently used for the treatment of chlamydia in Massachusetts. We did not observe a significant difference in the time to treatment between DOT and pharmacy prescriptions.

Glycolysis Inhibition Induces Functional and Metabolic Exhaustion of CD4+ T Cells in Type 1 Diabetes.

In Type 1 Diabetes (T1D), CD4+ T cells initiate autoimmune attack of pancreatic islet ß cells. Importantly, bioenergetic programs dictate T cell function, with specific pathways required for progression through the T cell lifecycle. During activation, CD4+ T cells undergo metabolic reprogramming to the less efficient aerobic glycolysis, similarly to highly proliferative cancer cells. In an effort to limit tumor growth in cancer, use of glycolytic inhibitors have been successfully employed in preclinical and clinical studies. This strategy has also been utilized to suppress T cell responses in autoimmune diseases like Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), and Rheumatoid Arthritis (RA). However, modulating T cell metabolism in the context of T1D has remained an understudied therapeutic opportunity. In this study, we utilized the small molecule PFK15, a competitive inhibitor of the rate limiting glycolysis enzyme 6-phosphofructo-2-kinase/fructose-2,6- biphosphatase 3 (PFKFB3). Our results confirmed PFK15 inhibited glycolysis utilization by diabetogenic CD4+ T cells and reduced T cell responses to ß cell antigen in vitro. In an adoptive transfer model of T1D, PFK15 treatment delayed diabetes onset, with 57% of animals remaining euglycemic at the end of the study period. Protection was due to induction of a hyporesponsive T cell phenotype, characterized by increased and sustained expression of the checkpoint molecules PD-1 and LAG-3 and downstream functional and metabolic exhaustion. Glycolysis inhibition terminally exhausted diabetogenic CD4+ T cells, which was irreversible through restimulation or checkpoint blockade in vitro and in vivo. In sum, our results demonstrate a novel therapeutic strategy to control aberrant T cell responses by exploiting the metabolic reprogramming of these cells during T1D. Moreover, the data presented here highlight a key role for nutrient availability in fueling T cell function and has implications in our understanding of T cell biology in chronic infection, cancer, and autoimmunity.

Genome-wide fine-mapping identifies pleiotropic and functional variants that predict many traits across global cattle populations.

The difficulty in finding causative mutations has hampered their use in genomic prediction. Here, we present a methodology to fine-map potentially causal variants genome-wide by integrating the functional, evolutionary and pleiotropic information of variants using GWAS, variant clustering and Bayesian mixture models. Our analysis of 17 million sequence variants in 44,000+ Australian dairy cattle for 34 traits suggests, on average, one pleiotropic QTL existing in each 50 kb chromosome-segment. We selected a set of 80k variants representing potentially causal variants within each chromosome segment to develop a bovine XT-50K genotyping array. The custom array contains many pleiotropic variants with biological functions, including splicing QTLs and variants at conserved sites across 100 vertebrate species. This biology-informed custom array outperformed the standard array in predicting genetic value of multiple traits across populations in independent datasets of 90,000+ dairy cattle from the USA, Australia and New Zealand.

The mediating role of child-teacher dependency in the association between early mother-child attachment and behavior problems in middle childhood.

This study examines child-teacher dependency in preschool as a pathway through which mother-child attachment is associated with children's behavior problems across middle childhood. Data include direct assessments of attachment security and styles, teacher reports of child-teacher dependency, and maternal reports of behavior problems from the NICHD SECCYD (N = 769 children). Children with more secure attachments at 24 months were less likely to exhibit child-teacher dependency at 54 months. Children with ambivalent, controlling, or insecure/other attachments at 36 months had higher levels of child-teacher dependency at 54 months. Results from multi-level models showed that child-teacher dependency at 54 months was associated with higher levels of internalizing, but not externalizing, behavior problems across middle childhood. Child-teacher dependency partially mediated the association between insecure/other mother-child attachment and internalizing behaviors in middle childhood. Supporting preschool teachers to reduce child-teacher dependency may help ameliorate risk for internalizing behaviors posed by insecure/other attachment.

Differential Effects of AIDS and Chronic Human Immunodeficiency Virus Infection on Gray Matter Volume.

BACKGROUND: Age, human immunodeficiency virus (HIV) infection, illicit drug use, and central nervous system (CNS) opportunistic infections can affect brain structure, with the striatum being particularly sensitive to HIV effects. Nevertheless, the impact of non-CNS AIDS-defining illness (ADI) on brain structure has been less investigated. We examined ADI and HIV effects on brain volume. METHODS: In a cross-sectional study, including 95 virally suppressed seropositive and 84 demographically matched, seronegative participants, we examined serostatus and ADI effects. Cortical and subcortical gray matter volume (GMV) regions of interest were estimated with computational neuroanatomy techniques applied to high-resolution, T1-weighted magnetic resonance imaging data. Linear regression was used to model HIV serostatus and ADI effects on global and regional GMV, adjusting for age, sex, CD4 nadir, drug use, and total intracranial volume. RESULTS: While HIV serostatus was associated with lower striatal volume (B = -.59 [95% confidence interval {CI}, -1.08 to -.10]), co-occurring ADI was independently associated with lower striatal volume (B = -.73 [95% CI, -1.36 to -.09]). ADI was also associated with lower global (B = -19.35 [95% CI, -32.42 to -6.29]) and regional GMV. CONCLUSIONS: While HIV infection is associated with a localized effect on striatal structure, having a prior ADI is a strong predictor of smaller global and regional GMV. The lack of interaction between HIV serostatus or ADI with age suggests that chronic HIV infection and ADI have independent effects on brain structure, without associated accelerated lower volume with age. ADI history should be incorporated into statistical adjustments in HIV neuroimaging analysis. These findings also lend support to current HIV treatment guidelines urging prompt antiretroviral therapy initiation after HIV diagnosis.