Search

A single dose of psilocybin, a psychedelic that acutely causes distortions of space-time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials1-4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus5-8. It remains unclear how human brain network changes relate to subjective and lasting effects of psychedelics. Here we tracked individual-specific brain changes with longitudinal precision functional mapping (roughly 18 magnetic resonance imaging visits per participant). Healthy adults were tracked before, during and for 3 weeks after high-dose psilocybin (25 mg) and methylphenidate (40 mg), and brought back for an additional psilocybin dose 6-12 months later. Psilocybin massively disrupted functional connectivity (FC) in cortex and subcortex, acutely causing more than threefold greater change than methylphenidate. These FC changes were driven by brain desynchronization across spatial scales (areal, global), which dissolved network distinctions by reducing correlations within and anticorrelations between networks. Psilocybin-driven FC changes were strongest in the default mode network, which is connected to the anterior hippocampus and is thought to create our sense of space, time and self. Individual differences in FC changes were strongly linked to the subjective psychedelic experience. Performing a perceptual task reduced psilocybin-driven FC changes. Psilocybin caused persistent decrease in FC between the anterior hippocampus and default mode network, lasting for weeks. Persistent reduction of hippocampal-default mode network connectivity may represent a neuroanatomical and mechanistic correlate of the proplasticity and therapeutic effects of psychedelics.

Regular exercise promotes whole-body health and prevents disease, but the underlying molecular mechanisms are incompletely understood1-3. Here, the Molecular Transducers of Physical Activity Consortium4 profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome and immunome in whole blood, plasma and 18 solid tissues in male and female Rattus norvegicus over eight weeks of endurance exercise training. The resulting data compendium encompasses 9,466 assays across 19 tissues, 25 molecular platforms and 4 training time points. Thousands of shared and tissue-specific molecular alterations were identified, with sex differences found in multiple tissues. Temporal multi-omic and multi-tissue analyses revealed expansive biological insights into the adaptive responses to endurance training, including widespread regulation of immune, metabolic, stress response and mitochondrial pathways. Many changes were relevant to human health, including non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health and tissue injury and recovery. The data and analyses presented in this study will serve as valuable resources for understanding and exploring the multi-tissue molecular effects of endurance training and are provided in a public repository ( https://motrpac-data.org/ ).

Health-related social needs are prevalent among cancer patients; associated with substantial negative health consequences; and drive pervasive inequities in cancer incidence, severity, treatment choices and decisions, and outcomes. To address the lack of clinical trial evidence to guide health-related social needs interventions among cancer patients, the National Cancer Institute Cancer Care Delivery Research Steering Committee convened experts to participate in a clinical trials planning meeting with the goal of designing studies to screen for and address health-related social needs among cancer patients. In this commentary, we discuss the rationale for, and challenges of, designing and testing health-related social needs interventions in alignment with the National Academy of Sciences, Engineering, and Medicine 5As framework. Evidence for food, housing, utilities, interpersonal safety, and transportation health-related social needs interventions is analyzed. Evidence regarding health-related social needs and delivery of health-related social needs interventions differs in maturity and applicability to cancer context, with transportation problems having the most maturity and interpersonal safety the least. We offer practical recommendations for health-related social needs interventions among cancer patients and the caregivers, families, and friends who support their health-related social needs. Cross-cutting (ie, health-related social needs agnostic) recommendations include leveraging navigation (eg, people, technology) to identify, refer, and deliver health-related social needs interventions; addressing health-related social needs through multilevel interventions; and recognizing that health-related social needs are states, not traits, that fluctuate over time. Health-related social needs-specific interventions are recommended, and pros and cons of addressing more than one health-related social needs concurrently are characterized. Considerations for collaborating with community partners are highlighted. The need for careful planning, strong partners, and funding is stressed. Finally, we outline a future research agenda to address evidence gaps.

IntroductionWhite matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-β1-42 (Aβ42)-positive status.MethodsIndividual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume.ResultsVRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p-FDR

9p21.3 locus polymorphisms have the strongest correlation with coronary artery disease, but as a noncoding locus, disease connection is enigmatic. The lncRNA ANRIL found in 9p21.3 may regulate vascular smooth muscle cell (VSMC) phenotype to contribute to disease risk. We observed significant heterogeneity in induced pluripotent stem cell-derived VSMCs from patients homozygous for risk versus isogenic knockout or nonrisk haplotypes. Subpopulations of risk haplotype cells exhibited variable morphology, proliferation, contraction, and adhesion. When sorted by adhesion, risk VSMCs parsed into synthetic and contractile subpopulations, i.e., weakly adherent and strongly adherent, respectively. Of note, >90% of differentially expressed genes coregulated by haplotype and adhesion and were associated with Rho GTPases, i.e., contractility. Weakly adherent subpopulations expressed more short isoforms of ANRIL, and when overexpressed in knockout cells, ANRIL suppressed adhesion, contractility, and αSMA expression. These data suggest that variable lncRNA penetrance may drive mixed functional outcomes that confound pathology.

BackgroundCoronavirus disease 2019 (COVID-19) convalescent plasma (CCP) reduces hospitalizations among outpatients treated early after symptom onset. It is unknown whether CCP reduces time to symptom resolution among outpatients.MethodsWe evaluated symptom resolution at day 14 by trial arm using an adjusted subdistribution hazard model, with hospitalization as a competing risk. We also assessed the prevalence of symptom clusters at day 14 between treatments. Clusters were defined based on biologic clustering, impact on ability to work, and an algorithm.ResultsAmong 1070 outpatients followed up after transfusion, 381 of 538 (70.8%) receiving CCP and 381 of 532 (71.6%) receiving control plasma were still symptomatic (P = .78) at day 14. Associations between CCP and symptom resolution by day 14 did not differ significantly from those in controls after adjustment for baseline characteristics (adjusted subdistribution hazard ratio, 0.99; P = .62). The most common cluster consisted of cough, fatigue, shortness of breath, and headache and was found in 308 (57.2%) and 325 (61.1%) of CCP and control plasma recipients, respectively (P = .16).ConclusionsIn this trial of outpatients with early COVID-19, CCP was not associated with faster resolution of symptoms compared with control. Overall, there were no differences by treatment in the prevalence of each symptom or symptom clusters at day 14.Clinical trials registrationNCT04373460.

Motor cortex (M1) has been thought to form a continuous somatotopic homunculus extending down the precentral gyrus from foot to face representations1,2, despite evidence for concentric functional zones3 and maps of complex actions4. Here, using precision functional magnetic resonance imaging (fMRI) methods, we find that the classic homunculus is interrupted by regions with distinct connectivity, structure and function, alternating with effector-specific (foot, hand and mouth) areas. These inter-effector regions exhibit decreased cortical thickness and strong functional connectivity to each other, as well as to the cingulo-opercular network (CON), critical for action5 and physiological control6, arousal7, errors8 and pain9. This interdigitation of action control-linked and motor effector regions was verified in the three largest fMRI datasets. Macaque and pediatric (newborn, infant and child) precision fMRI suggested cross-species homologues and developmental precursors of the inter-effector system. A battery of motor and action fMRI tasks documented concentric effector somatotopies, separated by the CON-linked inter-effector regions. The inter-effectors lacked movement specificity and co-activated during action planning (coordination of hands and feet) and axial body movement (such as of the abdomen or eyebrows). These results, together with previous studies demonstrating stimulation-evoked complex actions4 and connectivity to internal organs10 such as the adrenal medulla, suggest that M1 is punctuated by a system for whole-body action planning, the somato-cognitive action network (SCAN). In M1, two parallel systems intertwine, forming an integrate-isolate pattern: effector-specific regions (foot, hand and mouth) for isolating fine motor control and the SCAN for integrating goals, physiology and body movement.

During childhood, neural systems supporting high-level cognitive processes undergo periods of rapid growth and refinement, which rely on the successful coordination of activation across the brain. Some coordination occurs via cortical hubs-brain regions that coactivate with functional networks other than their own. Adult cortical hubs map into three distinct profiles, but less is known about hub categories during development, when critical improvement in cognition occurs. We identify four distinct hub categories in a large youth sample (n = 567, ages 8.5-17.2), each exhibiting more diverse connectivity profiles than adults. Youth hubs integrating control-sensory processing split into two distinct categories (visual control and auditory/motor control), whereas adult hubs unite under one. This split suggests a need for segregating sensory stimuli while functional networks are experiencing rapid development. Functional coactivation strength for youth control-processing hubs are associated with task performance, suggesting a specialized role in routing sensory information to and from the brain's control system.

Functional MRI (fMRI) data acquired using echo-planar imaging (EPI) are highly distorted by magnetic field inhomogeneities. Distortion and differences in image contrast between EPI and T1-weighted and T2-weighted (T1w/T2w) images makes their alignment a challenge. Typically, field map data are used to correct EPI distortions. Alignments achieved with field maps can vary greatly and depends on the quality of field map data. However, many public datasets lack field map data entirely. Additionally, reliable field map data is often difficult to acquire in high-motion pediatric or developmental cohorts. To address this, we developed Synth, a software package for distortion correction and cross-modal image registration that does not require field map data. Synth combines information from T1w and T2w anatomical images to construct an idealized undistorted synthetic image with similar contrast properties to EPI data. This synthetic image acts as an effective reference for individual-specific distortion correction. Using pediatric (ABCD: Adolescent Brain Cognitive Development) and adult (MSC: Midnight Scan Club; HCP: Human Connectome Project) data, we demonstrate that Synth performs comparably to field map distortion correction approaches, and often outperforms them. Field map-less distortion correction with Synth allows accurate and precise registration of fMRI data with missing or corrupted field map information.

BackgroundThe efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent plasma (CCP) for preventing infection in exposed, uninfected individuals is unknown. CCP might prevent infection when administered before symptoms or laboratory evidence of infection.MethodsThis double-blinded, phase 2 randomized, controlled trial (RCT) compared the efficacy and safety of prophylactic high titer (≥1:320 by Euroimmun ELISA) CCP with standard plasma. Asymptomatic participants aged ≥18 years with close contact exposure to a person with confirmed coronavirus disease 2019 (COVID-19) in the previous 120 hours and negative SARS-CoV-2 test within 24 hours before transfusion were eligible. The primary outcome was new SARS-CoV-2 infection.ResultsIn total, 180 participants were enrolled; 87 were assigned to CCP and 93 to control plasma, and 170 transfused at 19 sites across the United States from June 2020 to March 2021. Two were excluded for screening SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) positivity. Of the remaining 168 participants, 12/81 (14.8%) CCP and 13/87 (14.9%) control recipients developed SARS-CoV-2 infection; 6 (7.4%) CCP and 7 (8%) control recipients developed COVID-19 (infection with symptoms). There were no COVID-19-related hospitalizations in CCP and 2 in control recipients. Efficacy by restricted mean infection free time (RMIFT) by 28 days for all SARS-CoV-2 infections (25.3 vs 25.2 days; P = .49) and COVID-19 (26.3 vs 25.9 days; P = .35) was similar for both groups.ConclusionsAdministration of high-titer CCP as post-exposure prophylaxis, although appearing safe, did not prevent SARS-CoV-2 infection.Clinical trials registrationNCT04323800.

IntroductionDespite the pressing need for primary care-based suicide prevention initiatives and growing acknowledgement of recruitment difficulties and Institutional Review Board (IRB) challenges in suicide research, we are aware of no illustrative examples describing how IRB decisions in the design of a primary care trial can compound recruitment challenges.MethodsThe CDC-funded trial (NCT02986113) of Men and Providers Preventing Suicide aimed to examine the effects of a tailored computer program encourage men with suicidal thoughts (n = 304, ages 35-64) to discuss suicide with a primary care clinician and accept treatment. Before a visit, participants viewed MAPS or a non-tailored control video. Post-visit, both arms were offered telephone collaborative care, as mandated by the institutional review board (IRB). We previously showed that exposure to MAPs led to improvements in communication about suicide in a primary care visit. In this paper, we report data on the study's primary outcome, suicide preparatory behaviors.ResultsAfter screening nearly 4100 men, 48 enrolled. Recruitment challenges, which were exacerabted by an IRB mandate narrowing post-intervention patient management differences between trial arms, limited detection of the effects of MAPS on suicide preparatory behaviors.ConclusionsWhile primary care settings are key sites for suicide prevention trials, issues such as recruitment difficulties and overly restrictive IRB requirements may limit their utility. Methodological innovation to improve recruitment and ethical guidance to inform IRB decision-making are needed.

PurposeTo determine the dose-dependent risk of systemic corticosteroids (SCs) and the risk of other immunosuppressive therapies on coronavirus disease 2019 (COVID-19) infection, hospitalization, and death in patients with noninfectious uveitis (NIU).DesignA retrospective cohort study from January 20, 2020, to December 31, 2020 (an era before widespread COVID-19 vaccination), using the Optum Labs Data Warehouse, a US national de-identified claims database.ParticipantsPatients who had at least 1 NIU diagnosis from January 1, 2017.MethodsUnadjusted and adjusted hazard ratios (HRs) were estimated for each variable and COVID-19 outcome using Cox proportional hazards models, with time-updated dichotomous indicators for outpatient immunosuppressive medication exposure. To assess the dose-dependent effect of SC exposure, the average daily dose of prednisone over the exposed interval was included in the adjusted models as a continuous variable, in addition to the dichotomous variable.Main outcome measuresIncidence rates of COVID-19 infection, COVID-19-related hospitalization, and COVID-19-related in-hospital death.ResultsThis study included 52 286 NIU patients of whom 12 000 (23.0%) were exposed to immunosuppressive medications during the risk period. In adjusted models, exposure to SCs was associated with increased risk of COVID-19 infection (HR, 2.66; 95% confidence interval [CI], 2.19-3.24; P < 0.001), hospitalization (HR, 3.26; 95% CI, 2.46-4.33; P < 0.001), and in-hospital death (HR, 1.99; 95% CI, 0.93-4.27; P = 0.08). Furthermore, incremental increases in the dosage of SCs were associated with a greater risk for these outcomes. Although tumor necrosis factor-α (TNF-α) inhibitors were associated with an increased risk of infection (HR, 1.48; 95% CI, 1.08-2.04; P = 0.02), other immunosuppressive treatments did not increase the risk of COVID-19 infection, hospitalization, or death.ConclusionsThis study from an era before widespread COVID-19 vaccination demonstrates that outpatient SC exposure is associated with greater risk of COVID-19 infection and severe outcomes in patients with NIU. Future studies should evaluate the impact of immunosuppression in vaccinated NIU patients. Limiting exposure to SCs and use of alternative therapies may be warranted.

DescriptionCoronavirus disease 2019 convalescent plasma (CCP) has emerged as a potential treatment of COVID-19. However, meta-analysis data and recommendations are limited. The Association for the Advancement of Blood and Biotherapies (AABB) developed clinical practice guidelines for the appropriate use of CCP.MethodsThese guidelines are based on 2 living systematic reviews of randomized controlled trials (RCTs) evaluating CCP from 1 January 2019 to 26 January 2022. There were 33 RCTs assessing 21 916 participants. The results were summarized using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method. An expert panel reviewed the data using the GRADE framework to formulate recommendations.Recommendation 1 (outpatient)The AABB suggests CCP transfusion in addition to the usual standard of care for outpatients with COVID-19 who are at high risk for disease progression (weak recommendation, moderate-certainty evidence).Recommendation 2 (inpatient)The AABB recommends against CCP transfusion for unselected hospitalized persons with moderate or severe disease (strong recommendation, high-certainty evidence). This recommendation does not apply to immunosuppressed patients or those who lack antibodies against SARS-CoV-2.Recommendation 3 (inpatient)The AABB suggests CCP transfusion in addition to the usual standard of care for hospitalized patients with COVID-19 who do not have SARS-CoV-2 antibodies detected at admission (weak recommendation, low-certainty evidence).Recommendation 4 (inpatient)The AABB suggests CCP transfusion in addition to the usual standard of care for hospitalized patients with COVID-19 and preexisting immunosuppression (weak recommendation, low-certainty evidence).Recommendation 5 (prophylaxis)The AABB suggests against prophylactic CCP transfusion for uninfected persons with close contact exposure to a person with COVID-19 (weak recommendation, low-certainty evidence).Good clinical practice statementCCP is most effective when transfused with high neutralizing titers to infected patients early after symptom onset.

Diffusion imaging aims to non-invasively characterize the anatomy and integrity of the brain's white matter fibers. We evaluated the accuracy and reliability of commonly used diffusion imaging methods as a function of data quantity and analysis method, using both simulations and highly sampled individual-specific data (927-1442 diffusion weighted images [DWIs] per individual). Diffusion imaging methods that allow for crossing fibers (FSL's BedpostX [BPX], DSI Studio's Constant Solid Angle Q-Ball Imaging [CSA-QBI], MRtrix3's Constrained Spherical Deconvolution [CSD]) estimated excess fibers when insufficient data were present and/or when the data did not match the model priors. To reduce such overfitting, we developed a novel Bayesian Multi-tensor Model-selection (BaMM) method and applied it to the popular ball-and-stick model used in BedpostX within the FSL software package. BaMM was robust to overfitting and showed high reliability and the relatively best crossing-fiber accuracy with increasing amounts of diffusion data. Thus, sufficient data and an overfitting resistant analysis method enhance precision diffusion imaging. For potential clinical applications of diffusion imaging, such as neurosurgical planning and deep brain stimulation (DBS), the quantities of data required to achieve diffusion imaging reliability are lower than those needed for functional MRI.

BackgroundPolyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (Covid-19). The efficacy of this plasma in preventing serious complications in outpatients with recent-onset Covid-19 is uncertain.MethodsIn this multicenter, double-blind, randomized, controlled trial, we evaluated the efficacy and safety of Covid-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization. The primary outcome was Covid-19-related hospitalization within 28 days after transfusion.ResultsParticipants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomization, and 1181 received a transfusion. In the prespecified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P = 0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with Covid-19 who were hospitalized were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalized.ConclusionsIn participants with Covid-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progression leading to hospitalization. (Funded by the Department of Defense and others; CSSC-004 ClinicalTrials.gov number, NCT04373460.).

Convalescent plasma, collected from donors who have recovered from a pathogen of interest, has been used to treat infectious diseases, particularly in times of outbreak, when alternative therapies were unavailable. The COVID-19 pandemic revived interest in the use of convalescent plasma. Large observational studies and clinical trials that were executed during the pandemic provided insight into how to use convalescent plasma, whereby high levels of antibodies against the pathogen of interest and administration early within the time course of the disease are critical for optimal therapeutic effect. Several studies have shown outpatient administration of COVID-19 convalescent plasma (CCP) to be both safe and effective, preventing clinical progression in patients when administered within the first week of COVID-19. The United States Food and Drug Administration expanded its emergency use authorization (EUA) to allow for the administration of CCP in an outpatient setting in December 2021, at least for immunocompromised patients or those on immunosuppressive therapy. Outpatient transfusion of CCP and infusion of monoclonal antibody therapies for a highly transmissible infectious disease introduces nuanced challenges related to infection prevention. Drawing on our experiences with the clinical and research use of CCP, we describe the logistical considerations and workflow spanning procurement of qualified products, infrastructure, staffing, transfusion, and associated management of adverse events. The purpose of this description is to facilitate the efforts of others intent on establishing outpatient transfusion programs for CCP and other antibody-based therapies.

PurposeTo assess the potential of a transfer learning strategy leveraging radiologist supervision to enhance convolutional neural network-based (CNN) localization of pneumonia on radiographs and to further assess the prognostic value of CNN severity quantification on patients evaluated for COVID-19 pneumonia, for whom severity on the presenting radiograph is a known predictor of mortality and intubation.Materials and methodsWe obtained an initial CNN previously trained to localize pneumonia along with 25,684 radiographs used for its training. We additionally curated 1466 radiographs from patients who had a computed tomography (CT) performed on the same day. Regional likelihoods of pneumonia were then annotated by cardiothoracic radiologists, referencing these CTs. Combining data, a preexisting CNN was fine-tuned using transfer learning. Whole-image and regional performance of the updated CNN was assessed using receiver-operating characteristic area under the curve and Dice. Finally, the value of CNN measurements was assessed with survival analysis on 203 patients with COVID-19 and compared against modified radiographic assessment of lung edema (mRALE) score.ResultsPneumonia detection area under the curve improved on both internal (0.756 to 0.841) and external (0.864 to 0.876) validation data. Dice overlap also improved, particularly in the lung bases (R: 0.121 to 0.433, L: 0.111 to 0.486). There was strong correlation between radiologist mRALE score and CNN fractional area of involvement (ρ=0.85). Survival analysis showed similar, strong prognostic ability of the CNN and mRALE for mortality, likelihood of intubation, and duration of hospitalization among patients with COVID-19.ConclusionsRadiologist-supervised transfer learning can enhance the ability of CNNs to localize and quantify the severity of disease. Closed-loop systems incorporating radiologists may be beneficial for continued improvement of artificial intelligence algorithms.

Background Four-dimensional (4D) flow MRI has the potential to provide hemodynamic insights for a variety of abdominopelvic vascular diseases, but its clinical utility is currently impaired by background phase error, which can be challenging to correct. Purpose To assess the feasibility of using deep learning to automatically perform image-based background phase error correction in 4D flow MRI and to compare its effectiveness relative to manual image-based correction. Materials and Methods A convenience sample of 139 abdominopelvic 4D flow MRI acquisitions performed between January 2016 and July 2020 was retrospectively collected. Manual phase error correction was performed using dedicated imaging software and served as the reference standard. After reserving 40 examinations for testing, the remaining examinations were randomly divided into training (86% [85 of 99]) and validation (14% [14 of 99]) data sets to train a multichannel three-dimensional U-Net convolutional neural network. Flow measurements were obtained for the infrarenal aorta, common iliac arteries, common iliac veins, and inferior vena cava. Statistical analyses included Pearson correlation, Bland-Altman analysis, and F tests with Bonferroni correction. Results A total of 139 patients (mean age, 47 years ± 14 [standard deviation]; 108 women) were included. Inflow-outflow correlation improved after manual correction (ρ = 0.94, P < .001) compared with that before correction (ρ = 0.50, P < .001). Automated correction showed similar results (ρ = 0.91, P < .001) and demonstrated very strong correlation with manual correction (ρ = 0.98, P < .001). Both correction methods reduced inflow-outflow variance, improving mean difference from -0.14 L/min (95% limits of agreement: -1.61, 1.32) (uncorrected) to 0.05 L/min (95% limits of agreement: -0.32, 0.42) (manually corrected) and 0.05 L/min (95% limits of agreement: -0.38, 0.49) (automatically corrected). There was no significant difference in inflow-outflow variance between manual and automated correction methods (P = .10). Conclusion Deep learning automated phase error correction reduced inflow-outflow bias and variance of volumetric flow measurements in four-dimensional flow MRI, achieving results comparable with manual image-based phase error correction. © RSNA, 2021 See also the editorial by Roldán-Alzate and Grist in this issue.

PurposeTo identify if noninfectious uveitis (NIU) is associated with a greater risk of Coronavirus Disease 2019 (COVID-19) infection, hospitalization, and death.DesignA retrospective cohort study from January 20, 2020 to December 31, 2020, using a national claims-based database.ParticipantsEnrollees who had continuous enrollment with both medical and pharmacy coverage for 3 years before January 20, 2020. Patients with an NIU diagnosis within 3 years of the start of the study were included in the NIU cohort. Those with infectious uveitis codes or new NIU diagnoses during the risk period were excluded.MethodsCox proportional hazard models were used to identify unadjusted hazard ratios (HRs) and adjusted HRs for all covariates for each outcome measure. Adjusted models accounted for patient demographics, health status, and immunosuppressive medication use during the risk period.Main outcome measuresRates of COVID-19 infection, COVID-19-related hospitalization, and COVID-19-related in-hospital death identified with International Classification of Disease 10th revision codes.ResultsThis study included 5 806 227 patients, of whom 29 869 (0.5%) had a diagnosis of NIU. On unadjusted analysis, patients with NIU had a higher rate of COVID-19 infection (5.7% vs. 4.5%, P < 0.001), COVID-19-related hospitalization (1.2% vs. 0.6%, P < 0.001), and COVID-19-related death (0.3% vs. 0.1%, P < 0.001). However, in adjusted models, NIU was not associated with a greater risk of COVID-19 infection (HR, 1.05; 95% confidence interval [CI], 1.00-1.10; P = 0.04), hospitalization (HR, 0.98; 95% CI, 0.88-1.09; P = 0.67), or death (HR, 0.90, 95% CI, 0.72-1.13, P = 0.37). Use of systemic corticosteroids was significantly associated with a higher risk of COVID-19 infection, hospitalization, and death.ConclusionsPatients with NIU were significantly more likely to be infected with COVID-19 and experience severe disease outcomes. However, this association was due to the demographics, comorbidities, and medications of patients with NIU, rather than NIU alone. Patients using systemic corticosteroids were significantly more likely to be infected with COVID-19 and were at greater risk of hospitalization and in-hospital death. Additional investigation is necessary to identify the impact of corticosteroid exposure on COVID-19-related outcomes.

Suicide among young people is an increasingly prevalent and devastating public health crisis around the world. To reduce the rate of suicide, it is important to identify factors that can help us better predict suicidal ideation and behaviors. Adolescent temperament (effortful control, negative emotionality, positive emotionality) may be a source of risk and resilience for the onset of suicidal ideation, plans, and attempts. The present study uses longitudinal data from a large, community sample of Mexican-origin youth (N = 674), assessed annually from age 12 to 21, to examine how temperament is associated with the onset of suicidal ideation and behaviors during adolescence and young adulthood. Results indicate that higher levels of effortful control (activation control, inhibitory control, attention) are associated with decreased probability of experiencing the onset of suicidal ideation, plans, and attempts, whereas higher levels of negative emotionality (particularly aggression, frustration, and depressed mood) are associated with increased probability of experiencing the onset of suicidal ideation and behaviors. Positive emotionality (surgency, affiliation) was not associated with the onset of suicidal ideation and behaviors. Supplemental analyses showed conceptually similar findings for the Big Five, with Conscientiousness associated with decreased risk, Neuroticism associated with increased risk, and the other three dimensions showing largely null results. The findings did not vary significantly for boys and girls or for youth born in the U.S. versus Mexico. Overall, these findings suggest that adolescent temperament serves as both a protective factor (via effortful control/Conscientiousness) and a risk factor (via negative emotionality/Neuroticism) for suicidal ideation and behaviors in Mexican-origin youth. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

BackgroundThe risk of severe coronavirus disease 2019 (COVID-19) varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immunologic resilience (IR).ObjectiveWe sought to examine whether deficits in IR that antedate or are induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection independently predict COVID-19 mortality.MethodsIR levels were quantified with 2 novel metrics: immune health grades (IHG-I [best] to IHG-IV) to gauge CD8+ and CD4+ T-cell count equilibrium, and blood gene expression signatures. IR metrics were examined in a prospective COVID-19 cohort (n = 522); primary outcome was 30-day mortality. Associations of IR metrics with outcomes in non-COVID-19 cohorts (n = 13,461) provided the framework for linking pre-COVID-19 IR status to IR during COVID-19, as well as to COVID-19 outcomes.ResultsIHG-I, tracking high-grade equilibrium between CD8+ and CD4+ T-cell counts, was the most common grade (73%) among healthy adults, particularly in females. SARS-CoV-2 infection was associated with underrepresentation of IHG-I (21%) versus overrepresentation (77%) of IHG-II or IHG-IV, especially in males versus females (P < .01). Presentation with IHG-I was associated with 88% lower mortality, after controlling for age and sex; reduced risk of hospitalization and respiratory failure; lower plasma IL-6 levels; rapid clearance of nasopharyngeal SARS-CoV-2 burden; and gene expression signatures correlating with survival that signify immunocompetence and controlled inflammation. In non-COVID-19 cohorts, IR-preserving metrics were associated with resistance to progressive influenza or HIV infection, as well as lower 9-year mortality in the Framingham Heart Study, especially in females.ConclusionsPreservation of immunocompetence with controlled inflammation during antigenic challenges is a hallmark of IR and associates with longevity and AIDS resistance. Independent of age, a male-biased proclivity to degrade IR before and/or during SARS-CoV-2 infection predisposes to severe COVID-19.

The hippocampus is critically important for a diverse range of cognitive processes, such as episodic memory, prospective memory, affective processing, and spatial navigation. Using individual-specific precision functional mapping of resting-state functional MRI data, we found the anterior hippocampus (head and body) to be preferentially functionally connected to the default mode network (DMN), as expected. The hippocampal tail, however, was strongly preferentially functionally connected to the parietal memory network (PMN), which supports goal-oriented cognition and stimulus recognition. This anterior-posterior dichotomy of resting-state functional connectivity was well-matched by differences in task deactivations and anatomical segmentations of the hippocampus. Task deactivations were localized to the hippocampal head and body (DMN), relatively sparing the tail (PMN). The functional dichotomization of the hippocampus into anterior DMN-connected and posterior PMN-connected parcels suggests parallel but distinct circuits between the hippocampus and medial parietal cortex for self- versus goal-oriented processing.

Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = -0.111 to -0.068, FDR corrected P values

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen's d = -0.11, p = 0.0055). The tapetum connects the left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.

Global change is leading to warming, acidification, and oxygen loss in the ocean. In the Southern California Bight, an eastern boundary upwelling system, these stressors are exacerbated by the localized discharge of anthropogenically enhanced nutrients from a coastal population of 23 million people. Here, we use simulations with a high-resolution, physical-biogeochemical model to quantify the link between terrestrial and atmospheric nutrients, organic matter, and carbon inputs and biogeochemical change in the coastal waters of the Southern California Bight. The model is forced by large-scale climatic drivers and a reconstruction of local inputs via rivers, wastewater outfalls, and atmospheric deposition; it captures the fine scales of ocean circulation along the shelf; and it is validated against a large collection of physical and biogeochemical observations. Local land-based and atmospheric inputs, enhanced by anthropogenic sources, drive a 79% increase in phytoplankton biomass, a 23% increase in primary production, and a nearly 44% increase in subsurface respiration rates along the coast in summer, reshaping the biogeochemistry of the Southern California Bight. Seasonal reductions in subsurface oxygen, pH, and aragonite saturation state, by up to 50 mmol m-3, 0.09, and 0.47, respectively, rival or exceed the global open-ocean oxygen loss and acidification since the preindustrial period. The biological effects of these changes on local fisheries, proliferation of harmful algal blooms, water clarity, and submerged aquatic vegetation have yet to be fully explored.

The MORDOR study, a masked, community-level randomized clinical trial conducted in Niger, Malawi and Tanzania (2015 to 2017), showed that biannual administration of single-dose azithromycin to preschool children reduced all-cause mortality. We sought to evaluate its impact on causes of death in children aged 1-59 months in Tanzania. A random sampling of 614 communities was conducted in Kilosa District, Tanzania, with simple random assignment of communities to receive either azithromycin or placebo. In these communities, a census was carried out every 6 months and children aged 1-59 months received biannual (every 6 months), single-dose azithromycin (~20mg/kg) or placebo depending on community assignment, over a 2-year period. Mortality was determined at the time of the biannual census. For child deaths, a verbal autopsy was performed to ascertain the cause using a standardized diagnostic classification. A total of 190- (0.58 /100 person-years) and 200 deaths (0.59/100 person-years) were reported in the azithromycin and placebo arms, respectively. Malaria, pneumonia and diarrhea, accounted for 71% and 68% of deaths in the respective arms. Overall, the mortality was not different by treatment arm, nor were the distribution of causes of death after adjusting for community clustering. The cause-specific mortality for diarrhea/pneumonia was no different over time. In children aged 1-5 months, 32 deaths occurred in the placebo arm and 25 deaths occurred in the azithromycin arm; 20 (62.5%) deaths in the placebo- and 10 (40%) in the azithromycin arm were attributed to diarrhea or pneumonia. Neither differences in the number of deaths nor the diarrhea/pneumonia attribution was statistically significant after adjusting for community clustering. In conclusion, azithromycin was not associated with a significant decline in deaths by specific causes compared to placebo. The non-significant lower rates of diarrhea or pneumonia in children

Viral infection and pathogenesis is mediated by host protein-viral protein complexes that are important targets for therapeutic intervention as they are potentially less prone to development of drug resistance. We have identified human, recombinant antibodies (Fabs) from a phage display library that bind to three HIV-host complexes. We used these Fabs to 1) stabilize the complexes for structural studies; and 2) facilitate characterization of the function of these complexes. Specifically, we generated recombinant Fabs to Vif-CBF-β-ELOB-ELOC (VCBC); ESCRT-I complex and AP2-complex. For each complex we measured binding affinities with KD values of Fabs ranging from 12-419 nM and performed negative stain electron microscopy (nsEM) to obtain low-resolution structures of the HIV-Fab complexes. Select Fabs were converted to scFvs to allow them to fold intracellularly and perturb HIV-host protein complex assembly without affecting other pathways. To identify these recombinant Fabs, we developed a rapid screening pipeline that uses quantitative ELISAs and nsEM to establish whether the Fabs have overlapping or independent epitopes. This pipeline approach is generally applicable to other particularly challenging antigens that are refractory to immunization strategies for antibody generation including multi-protein complexes providing specific, reproducible, and renewable antibody reagents for research and clinical applications. The curated antibodies described here are available to the scientific community for further structural and functional studies on these critical HIV host-factor proteins.

The Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance study showed that administration of biannual, single-dose azithromycin to preschool children reduces mortality. We sought to evaluate its impact on azithromycin resistance. Thirty randomly selected communities in Kilosa district, Tanzania, were randomized to receive 6-monthly single-dose azithromycin (∼20 mg/kg) versus placebo treatment of children aged 1-59 months. From each community, 40 children (aged 1-59 months) were randomly selected at baseline, 12 and 24 months. Isolation and resistance testing of Streptococcus pneumoniae and Escherichia coli were evaluated using nasopharyngeal and rectal swabs, respectively. The carriage prevalence and the proportion of azithromycin-resistant isolates were determined using disk diffusion. At baseline, the characteristics of the randomly selected children were similar by treatment arms. Both at baseline and in annual cross-sectional surveys, rates of S. pneumoniae and E. coli isolation between treatment arms were similar. The proportions of azithromycin-resistant S. pneumoniae isolates in the children in communities treated with azithromycin versus placebo at baseline, 12 months, and 24 months were 26.5% (18.1%; P = 0.26), 26.8% (16.5%; P = 0.29), and 13.4% (17.0%; P = 0.57), respectively. The proportions of azithromycin-resistant E. coli isolates at baseline, 12 months, and 24 months in the azithromycin (versus placebo) arms were 14.9% (18.9%; P = 0.16), 21.5% (16.6%; P = 0.10), and 14.9% (14.7%; P = 0.95), respectively. Over the 24 months, the mean treatment coverage for the azithromycin and placebo was 76.9% and 74.8%, respectively (P = 0.49). Biannual administration of single-dose azithromycin to children did not appear to result in excess azithromycin resistance in S. pneumoniae and E. coli isolates over 24 months of follow-up.

A cluster-randomized clinical trial showed that biannual single-dose azithromycin reduced mortality in preschool children; we sought to determine the effect on anemia. A simple random sample of 30 communities from Kilosa district, Tanzania, were themselves randomized to receive either 6-monthly treatment of children aged 1-59 months with single-dose azithromycin or placebo. From each community, 40 preschool children were randomly selected at baseline, 12 months, and 24 months. At surveys, the children underwent hemoglobin testing; WHO definitions for anemia were applied. After adjusting for community clustering, the prevalence of anemia was not significantly different by treatment assignment at baseline, 12 months, and 24 months. In each of the cross-sectional surveys, anemia prevalence was associated with younger age; the odds of being anemic was highest in those aged < 12 months. There was also a general decrease in the prevalence of anemia during the study. Although azithromycin was not shown to affect anemia, significantly, the study highlights burden of anemia in rural, African communities.

A growing number of optogenetic tools have been developed to reversibly control binding between two engineered protein domains. In contrast, relatively few tools confer light-switchable binding to a generic target protein of interest. Such a capability would offer substantial advantages, enabling photoswitchable binding to endogenous target proteins in cells or light-based protein purification in vitro. Here, we report the development of opto-nanobodies (OptoNBs), a versatile class of chimeric photoswitchable proteins whose binding to proteins of interest can be enhanced or inhibited upon blue light illumination. We find that OptoNBs are suitable for a range of applications including reversibly binding to endogenous intracellular targets, modulating signaling pathway activity, and controlling binding to purified protein targets in vitro. This work represents a step towards programmable photoswitchable regulation of a wide variety of target proteins.

Background Cardiac MRI is limited by long acquisition times, yet faster acquisition of smaller-matrix images reduces spatial detail. Deep learning (DL) might enable both faster acquisition and higher spatial detail via super-resolution. Purpose To explore the feasibility of using DL to enhance spatial detail from small-matrix MRI acquisitions and evaluate its performance against that of conventional image upscaling methods. Materials and Methods Short-axis cine cardiac MRI examinations performed between January 2012 and December 2018 at one institution were retrospectively collected for algorithm development and testing. Convolutional neural networks (CNNs), a form of DL, were trained to perform super resolution in image space by using synthetically generated low-resolution data. There were 70%, 20%, and 10% of examinations allocated to training, validation, and test sets, respectively. CNNs were compared against bicubic interpolation and Fourier-based zero padding by calculating the structural similarity index (SSIM) between high-resolution ground truth and each upscaling method. Means and standard deviations of the SSIM were reported, and statistical significance was determined by using the Wilcoxon signed-rank test. For evaluation of clinical performance, left ventricular volumes were measured, and statistical significance was determined by using the paired Student t test. Results For CNN training and retrospective analysis, 400 MRI scans from 367 patients (mean age, 48 years ± 18; 214 men) were included. All CNNs outperformed zero padding and bicubic interpolation at upsampling factors from two to 64 (P < .001). CNNs outperformed zero padding on more than 99.2% of slices (9828 of 9907). In addition, 10 patients (mean age, 51 years ± 22; seven men) were prospectively recruited for super-resolution MRI. Super-resolved low-resolution images yielded left ventricular volumes comparable to those from full-resolution images (P > .05), and super-resolved full-resolution images appeared to further enhance anatomic detail. Conclusion Deep learning outperformed conventional upscaling methods and recovered high-frequency spatial information. Although training was performed only on short-axis cardiac MRI examinations, the proposed strategy appeared to improve quality in other imaging planes. © RSNA, 2020 Online supplemental material is available for this article.

Despite thousands of neuroprotectants demonstrating promise in preclinical trials, a neuroprotective therapeutic has yet to be approved for the treatment of acute brain injuries such as stroke or traumatic brain injury. Developing a more detailed understanding of models and populations demonstrating "neurological resilience" in spite of brain injury can give us important insights into new translational therapies. Resilience is the process of active adaptation to a stressor. In the context of neuroprotection, models of preconditioning and unique animal models of extreme physiology (such as hibernating species) reliably demonstrate resilience in the laboratory setting. In the clinical setting, resilience is observed in young patients and can be found in those with specific genetic polymorphisms. These important examples of resilience can help transform and extend the current neuroprotective framework from simply countering the injurious cascade into one that anticipates, monitors, and optimizes patients' physiological responses from the time of injury throughout the process of recovery. This review summarizes the underpinnings of key adaptations common to models of resilience and how this understanding can be applied to new neuroprotective approaches.

The western blacklegged tick, Ixodes pacificus, an important vector in the western United States of two zoonotic spirochetes: Borrelia burgdorferi (also called Borreliella burgdorferi), causing Lyme disease, and Borrelia miyamotoi, causing a relapsing fever-type illness. Human cases of Lyme disease are well-documented in California, with increased risk in the north coastal areas and western slopes of the Sierra Nevada range. Despite the established presence of B. miyamotoi in the human-biting I. pacificus tick in California, clinical cases with this spirochete have not been well studied. To assess exposure to B. burgdorferi and B. miyamotoi in California, and to address the hypothesis that B. miyamotoi exposure in humans is similar in geographic range to B. burgdorferi, 1,700 blood donor sera from California were tested for antibodies to both pathogens. Sampling was from high endemic and low endemic counties for Lyme disease in California. All sera were screened using the C6 ELISA. All C6 positive and equivocal samples and nine randomly chosen C6 negative samples were further analyzed for B. burgdorferi antibody using IgG western blot and a modified two ELISA test system and for B. miyamotoi antibody using the GlpQ ELISA and B. miyamotoi whole cell sonicate western blot. Of the 1,700 samples tested in series, eight tested positive for antibodies to B. burgdorferi (0.47%, Exact 95% CI: 0.20, 0.93) and two tested positive for antibodies to B. miyamotoi (0.12%, Exact 95% CI: 0.01, 0.42). There was no statistically significant difference in seroprevalence for either pathogen between high and low Lyme disease endemic counties. Our results confirm a low frequency of Lyme disease and an even lower frequency of B. miyamotoi exposure among adult blood donors in California; however, our findings reinforce public health messaging that there is risk of infection by these emerging diseases in the state.

BackgroundThe MORDOR study, a cluster randomized clinical trial, showed that single-dose azithromycin (20 mg/kg) administered biannually for 2 years to preschool children reduced mortality; a study was conducted to determine its effect on clinical symptomatic episodes of malaria as a potential mechanism for mortality benefit.MethodsA randomized control trial (RCT) was conducted, whereby 30 randomly selected communities in Kilosa District, Tanzania were randomized to receive 6-monthly treatment of children ages 1-59 months with single-dose azithromycin (20 mg/kg) vs. placebo. A prospective cohort study was nested within the RCT: children, aged 1 to 35 months at baseline, were randomly selected in each community and evaluated at 6-monthly intervals for 2 years. At each visit, the children were assessed for recent or ongoing fever and anti-malarial treatment; a rapid diagnostic test (RDT) for malaria was performed. The two major outcomes of interest were prevalence of RDT positivity and clinical malaria. The latter was defined as RDT-positivity with fever at time of evaluation and/or reported fever in the 3 days prior to evaluation. Methods that account for correlations at community level and within individuals over time were used to evaluate associations.ResultsAt baseline, the prevalence rates in the children in the azithromycin and placebo arms were 17.6% vs. 15.5% for RDT positivity (p = 0.76) and 6.1% vs. 4.3% (p = 0.56) for clinical malaria. There was a decline in both RDT-positivity and clinical malaria over time in both arms. The difference by treatment assignment was not significant for clinical malaria; it was significant for RDT-positivity with greater odds of decline in the placebo arm (p = 0.01).ConclusionsLack of evidence for a significant difference in the prevalence of clinical malaria in children at any visit following treatment suggests that the effect of single-dose azithromycin on malaria is at best transient and limited in scope. Chance overrepresentation of non-seasonal transmission in the communities in the azithromycin arm may account for higher rates of RDT-positivity and less decline over time. Trial registration Clinicaltrials.gov NCT02047981.

Mass drug administration (MDA) for trachoma control using azithromycin has generated concern for the development of resistant organisms. However, the contribution from azithromycin available in local pharmacies has not been studied. In Kilosa district, Tanzania, MDA stopped over 4 years ago, and this study sought to determine the availability of azithromycin in local pharmacies and correlate it with azithromycin resistance in children born after MDA. A cross-sectional survey was conducted in 644 randomly selected hamlets in Kilosa district, in which the presence of a pharmacy and the availability of azithromycin and erythromycin were determined. In 30 randomly selected hamlets, a random sample of 60 children less than 5 years were tested for azithromycin-resistant Streptococcus pneumoniae (Spn) and Escherichia coli (Ec), from nasopharyngeal and rectal swabs, based on disk diffusion criteria. Only 26.6% of hamlets had a pharmacy. Azithromycin and erythromycin were available in 30.8% and 89.1% of pharmacies closest to the hamlets, respectively. In the 30 communities tested for resistance, the overall prevalence of azithromycin-resistant Spn isolates was 14%. Six of seven (87%) hamlets where azithromycin was available had resistant Spn, compared with 14 of 23 (61%) hamlets without availability. Similarly, six of seven (87%) hamlets where azithromycin was available had resistant Ec isolates compared with 21 of 23 (70%) hamlets without availability. However, the differences were not statistically significant (P = 0.46 and 0.49, respectively). The availability of azithromycin in pharmacies in the district was limited, and a strong correlation with azithromycin-resistant Spn or Ec was not observed.

BackgroundObstetric hemorrhage (OH) and access to peripartum blood transfusion remains a global health challenge. The rates of peripartum transfusion in South Africa exceed those in high-income countries despite comparable rates of OH. We sought to evaluate factors associated with peripartum transfusion.Study design and methodsA case-control study was conducted at four large South African hospitals. Transfused peripartum women (cases) and nontransfused controls were stratum matched 1:2 by hospital and delivery date. Data on obstetric, transfusion, and human immunodeficiency virus (HIV) history were abstracted from medical records. Blood was obtained for laboratory evaluation. We calculated unadjusted and adjusted odds ratios (ORs) for transfusion using logistic regression.ResultsA total of 1200 transfused cases and 2434 controls were evaluated. Antepartum hemorrhage (OR, 197.95; 95% confidence interval [CI], 104.27-375.78), hemorrhage with vaginal delivery (OR, 136.46; 95% CI, 75.87-245.18), prenatal anemia (OR, 22.76; 95% CI, 12.34-41.93 for prenatal hemoglobin level

PurposeTo develop a rapid segmentation-free method to visualize and compute wall shear stress (WSS) throughout the aorta using 4D Flow MRI data. WSS is the drag force-per-area the vessel endothelium exerts on luminal blood; abnormal levels of WSS are associated with cardiovascular pathologies. Previous methods for computing WSS are bottlenecked by labor-intensive manual segmentation of vessel boundaries. A rapid automated segmentation-free method for computing WSS is presented.Theory and methodsShear stress is the dot-product of the viscous stress tensor and the inward normal vector. The inward normal vectors are approximated as the gradient of fluid speed at every voxel. Subsequently, a 4D map of shear stress is computed as the partial derivatives of velocity with respect to the inward normal vectors. We highlight the shear stress near the wall by fusing visualization with edge-emphasized anatomical data.ResultsAs a proof-of-concept, four cases with aortic pathologies are presented. Visualization allows for rapid localization of pathologic WSS. Subsequent analysis of these pathological regions enables quantification of WSS. Average WSS during peak systole measures approximately 50-60 cPa in nonpathological regions of the aorta and is elevated in regions of stenosis, coarctation, and dissection. WSS is reduced in regions of aneurysm.ConclusionA volumetric technique for calculation and visualization of WSS from 4D Flow MRI data is presented. Traditional labor-intensive methods for WSS rely on explicit manual segmentation of vessel boundaries before visualization. This automated volumetric strategy for visualization and quantification of WSS may facilitate its clinical translation.

Few studies have evaluated the effectiveness of Zika virus (ZIKV) public health educational campaigns. Following a ZIKV educational campaign in Roatán, Honduras (October 2016), a survey was administered (March-May 2017) to residents (N = 348) and health-care professionals ([HCPs]; N = 44) to evaluate ZIKV knowledge, attitudes, and preventive practices, with attention to sexual health. Knowledge scores were calculated and mapped using participants' home locations. The knowledge scores between HCPs and residents were significantly different (mean 17 versus 11; P < 0.001). Only 6% of residents and 14% of HCPs knew that ZIKV was sexually transmissible. Few reported abstinence (2.6% residents; 9.4% HCPs) or condom use (1.6% residents; 12.5% HCPs) to prevent ZIKV infection. Of all subjects, 15.6% were pregnant or had a pregnant partner in the past year; 57.6% expressed concern over ZIKV. Mapping demonstrated spatial heterogeneity in knowledge. The findings suggest a need for improved public health messaging in ZIKV-affected areas.

Mass administration of azithromycin (MDA) is integral to trachoma control. Recent studies suggest that MDA may increase drug-resistant pathogens, yet findings from prior studies suggest little long-term impact on resistance. This disparity may be linked to differences in pre-MDA community-level resistance patterns. We describe carriage prevalence and antibiotic resistance patterns for Streptococcus pneumoniae (Spn) (nasopharyngeal swab collection), Staphylococcus aureus (SA) (nasopharyngeal swabs), and Escherichia coli (EC) (rectal swabs) in 1,047 children ages 1-59 months in a district with MDA cessation 4 years ago. Antibiotic susceptibility was evaluated by disk diffusion and Etest. The carriage rates for Spn, SA, and EC were 43.5% (455/1,047), 13.2% (138/1,047), and 61.7% (646/1,047), respectively. Resistance to AZM was observed in 14.3%, 29.0%, and 16.6% of the Spn, SA, and EC isolates, respectively. Spn resistance was variable (0-67%) by hamlet. Future analyses will assess the influence of pre-MDA antibiotic resistance patterns on those observed following MDA.

Among 397,640 first-time blood donors screened in South Africa during 2012-2015, HIV prevalence was 1.13%, hepatitis B virus prevalence 0.66%, and hepatitis C virus prevalence 0.03%. Findings of note were a high HIV prevalence in Mpumalanga Province and the near absence of hepatitis C virus nationwide.

BackgroundThe robustness of ChIP-seq datasets is highly dependent upon the antibodies used. Currently, polyclonal antibodies are the standard despite several limitations: They are non-renewable, vary in performance between lots and need to be validated with each new lot. In contrast, monoclonal antibody lots are renewable and provide consistent performance. To increase ChIP-seq standardization, we investigated whether monoclonal antibodies could replace polyclonal antibodies. We compared monoclonal antibodies that target five key histone modifications (H3K4me1, H3K4me3, H3K9me3, H3K27ac and H3K27me3) to their polyclonal counterparts in both human and mouse cells.ResultsOverall performance was highly similar for four monoclonal/polyclonal pairs, including when we used two distinct lots of the same monoclonal antibody. In contrast, the binding patterns for H3K27ac differed substantially between polyclonal and monoclonal antibodies. However, this was most likely due to the distinct immunogen used rather than the clonality of the antibody.ConclusionsAltogether, we found that monoclonal antibodies as a class perform equivalently to polyclonal antibodies for the detection of histone post-translational modifications in both human and mouse. Accordingly, we recommend the use of monoclonal antibodies in ChIP-seq experiments.

BackgroundFalse-positive infectious transfusion screening results remain a challenge with continued loss of both donors and blood products. We sought to identify associations between donor demographic characteristics (age, race, sex, education, first-time donor status) and testing false positive for viruses during routine blood donation screening. In addition the study assessed the prevalence of high-risk behaviors in false-positive donors.Study design and methodsBlood Systems, Inc. donors with allogeneic donations between January 1, 2011, and December 31, 2012, were compared in a case-control study. Those with a false-positive donation for one of four viruses (human immunodeficiency virus [HIV], human T-lymphotropic virus [HTLV], hepatitis B virus [HBV], and hepatitis C virus [HCV]) were included as cases. Those with negative test results were controls. For a subset of cases, infectious risk factors were evaluated.ResultsBlack race and Hispanic ethnicity were associated with HCV and HTLV false-positive results. Male sex and lower education were associated with HCV false positivity, and age 25 to 44 was associated with HTLV false positivity. First-time donors were more likely to be HCV false positive although less likely to be HBV and HTLV false positive. No significant associations between donor demographics and HIV false positivity were observed. A questionnaire for false-positive donors showed low levels of high-risk behaviors.ConclusionDemographic associations with HCV and HTLV false-positive results overlap with those of true infection. While true infection is unlikely given current testing algorithms and risk factor evaluation, the findings suggest nonrandom association. Further investigation into biologic mechanisms is warranted.

BackgroundGlobally, as in South Africa, obstetric hemorrhage (OH) remains a leading cause of maternal mortality and morbidity. Although blood transfusion is critical to OH management, the incidence and predictors of transfusion as well as their relation to human immunodeficiency virus (HIV) infection are poorly described.Study design and methodsA cross-sectional study was conducted of all peripartum patients at four major hospitals in South Africa (April to July 2012). Comprehensive clinical data were collected on patients who sustained OH and/or were transfused. Logistic regression was used to model risk factors for OH and transfusion.ResultsA total of 15,725 peripartum women were evaluated, of whom 3969 (25.2%) were HIV positive. Overall, 387 (2.5%) women sustained OH and 438 (2.8%) received transfusions, including 213 (1.4%) women with both OH and transfusion. There was no significant difference in OH incidence between HIV-positive (2.8%) and HIV-negative (2.3%) patients (adjusted odds ratio [OR], 0.95; 95% confidence interval [CI], 0.72-1.25). In contrast, the incidence of blood transfusion was significantly higher in HIV-positive (3.7%) than in HIV-negative (2.4%) patients (adjusted OR, 1.52; 95% CI, 1.14-2.03). Other risk factors for transfusion included OH, low prenatal hemoglobin, the treating hospital, lack of prenatal care, and gestational age of not more than 34 weeks.ConclusionIn the South African obstetric setting, the incidence of peripartum blood transfusion is significantly higher than in the United States and other high-income countries while OH incidence is similar. While OH and prenatal anemia are major predictors of transfusion, HIV infection is a common and independent contributing factor.

BackgroundThe Medical Priority Dispatch System (MPDS) is a commonly used computer-based emergency medical dispatch (EMD) system that is widely used to prioritize 9-1-1 calls and optimize resource allocation. There are five major priority classes used to dispatch 9-1-1 calls in the San Francisco System; Alpha codes are the lowest priority (lowest expected acuity) and Echo are the highest priority.ObjectiveWe sought to determine which MPDS dispatch codes are associated with high prehospital nontransport rates (NTRs).MethodsAll unique MPDS call categories from 2009 in a highly urbanized, two-tier advanced life support (ALS) system were sorted according to highest NTRs. There are many reasons for nontransport, such as "gone on arrival," and "patient denied transport." Those categories with greater than 100 annual calls were further evaluated. MPDS groups that included multiple categories with NTRs exceeding 25% were then identified and each category was analyzed. Results. EMS responded to a total of 81,437 calls in 2009, of which 18,851 were not transported by EMS. The majority of the NTRs were found among "cardiac/ respiratory arrest/death," "assault/sexual assaults," "unknown problem/man down," "traffic/transportation accidents," and "unconscious/fainting." "Cardiac or respiratory arrest/death -obvious death" (9B1) had the highest overall nontransport rate, 99.25% (1/134), most likely due to declaration of death. "Unknown problem -man down -medical alert notification" had the second highest NTR, 67.22% (138/421). However, Echo priority codes had the highest overall nontransport rates (45.45%) and Charlie had the lowest (13.84%).ConclusionsThe nontransport rates of individual MPDS categories vary considerably and should be considered in any system design. We identified 52 unique call categories to have a 25% or greater NTR, 18 of which exceeded 40%. The majority of NTRs occurred among the "cardiac/respiratory arrest/death," "assault/sexual assaults," "unknown problem/man down," "traffic/transportation accidents," and "unconscious/fainting" categories. The higher the priority code within each subset (AB vs. CDE), the less likely the patient was to be transported. Charlie priority codes had a lower NTR than Delta, and Delta was lower than Echo. Charlie codes were therefore the strongest predictors of hospital transport, while Echo codes (highest priority) were those with the highest nontransport rates and were the worst predictors of hospital transport in the emergent subset.

BackgroundIn December 2010, a case of West Nile virus (WNV) encephalitis occurring in a kidney recipient shortly after organ transplantation was identified.MethodsA public health investigation was initiated to determine the likely route of transmission, detect potential WNV infections among recipients from the same organ donor, and remove any potentially infected blood products or tissues. Available serum, cerebrospinal fluid, and urine samples from the organ donor and recipients were tested for WNV infection by nucleic acid testing and serology.ResultsTwo additional recipients from the same organ donor were identified, their clinical and exposure histories were reviewed, and samples were obtained. WNV RNA was retrospectively detected in the organ donor's serum. After transplantation, the left kidney recipient had serologic and molecular evidence of WNV infection and the right kidney recipient had prolonged but clinically inapparent WNV viremia. The liver recipient showed no clinical signs of infection but had flavivirus IgG antibodies; however, insufficient samples were available to determine the timing of infection. No remaining infectious products or tissues were identified.ConclusionsClinicians should suspect WNV as a cause of encephalitis in organ transplant recipients and report cases to public health departments for prompt investigation of the source of infection. Increased use of molecular testing and retaining pretransplantation sera may improve the ability to detect and diagnose transplant-associated WNV infection in organ transplant recipients.

Blood safety remains an important public health concern in Africa where lack of availability or provision of unsafe blood adversely impacts morbidity and mortality in the region. In recognition of this shortfall, the World Health Organization (WHO) established a goal of regional blood safety by 2012 through improved "organization and management, blood donor recruitment and collection, testing of donor blood as well as appropriate clinical use of blood" (Tagny et al: Transfusion. 2008;48:1256-1261; Tapko et al: Status of Blood Safety in the WHO African Region: Report of the 2006 Survey http://www.afro.who.int/en/divisions-a-programmes/dsd/health-technologies-a-laboratories.html. Brazzaville, Republic of Congo: WHO Regional Office for Africa; 2006). Although there has been substantial progress toward meeting these objectives, there are continued obstacles to both development and sustainability. In a setting where transfusion oversight is still being improved, transfusion-transmitted infections are of real concern. The high prevalence of some transfusion-transmissible agents such as hepatitis B virus and HIV in the general population means that some infected blood units escape detection by even well-performed laboratory testing, resulting in potential downstream transmission to patients. The spectrum of transfusion-transmitted infection include conventional as well as exotic pathogens, many of which are endemic to the region, thereby imparting ongoing challenges to recruitment and testing strategies.