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To understand the roles of acute-phase viral dynamics and host immune responses in post-acute sequelae of SARS-CoV-2 infection (PASC), we enrolled 136 participants within 5 days of their first positive SARS-CoV-2 real-time PCR test. Participants self-collected up to 21 nasal specimens within the first 28 days post-symptom onset; interviewer-administered questionnaires and blood samples were collected at enrollment, days 9, 14, 21, 28, and month 4 and 8 post-symptom onset. Defining PASC as the presence of any COVID-associated symptom at their 4-month visit, we compared viral markers (quantity and duration of nasal viral RNA load, infectious viral load, and plasma N-antigen level) and host immune markers (IL-6, IL-10, TNF-α, IFN-α, IFN-γ, MCP, IP-10, and Spike IgG) over the acute period. Compared to those who fully recovered, those reporting PASC demonstrated significantly higher maximum levels of SARS-CoV-2 RNA and N-antigen, burden of RNA and infectious viral shedding, and lower Spike-specific IgG levels within 9 days post-illness onset. No significant differences were identified among a panel of host immune markers. Our results suggest early viral dynamics and the associated host immune responses play a role in the pathogenesis of PASC, highlighting the importance of understanding early biological markers in the natural history of PASC.

BACKGROUNDThe presence and reactivation of chronic viral infections, such as EBV, CMV, and HIV, have been proposed as potential contributors to long COVID (LC), but studies in well-characterized postacute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited.METHODSIn a cohort of 280 adults with prior SARS-CoV-2 infection, we assessed the presence and types of LC symptoms and prior medical history (including COVID-19 history and HIV status) and performed serological testing for EBV and CMV using a commercial laboratory. We used covariate-adjusted binary logistic regression models to identify independent associations between variables and LC symptoms.RESULTSWe observed that LC symptoms, such as fatigue and neurocognitive dysfunction, at a median of 4 months following initial diagnosis were independently associated with serological evidence suggesting recent EBV reactivation (early antigen-diffuse IgG positivity) or high nuclear antigen (EBNA) IgG levels but not with ongoing EBV viremia. Serological evidence suggesting recent EBV reactivation (early antigen-diffuse IgG positivity) was most strongly associated with fatigue (OR = 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR = 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR = 0.52).CONCLUSIONOverall, these findings suggest differential effects of chronic viral coinfections on the likelihood of developing LC and association with distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted.TRIAL REGISTRATIONLong-term Impact of Infection with Novel Coronavirus; ClinicalTrials.gov NCT04362150.FUNDINGThis work was supported by NIH/National Institute of Allergy and Infectious Diseases grants (3R01AI141003-03S1, R01AI158013, and K24AI145806); the Zuckerberg San Francisco General Hospital Department of Medicine and Division of HIV, Infectious Diseases, and Global Medicine; and the UCSF-Bay Area Center for AIDS Research (P30-AI027763).

INTRODUCTION: Medications to treat opioid use disorder (MOUD) during pregnancy and in the postpartum period remain underutilized. A need exists to enhance our understanding of modifiable factors, facilitators, and barriers to MOUD utilization and adherence in the perinatal period to improve maternal and child outcomes. METHODS: The study conducted semi-structured qualitative interviews with recently pregnant people with opioid use disorder (OUD) to explore experiences as a pregnant and/or parenting person with OUD, perceptions of enabling factors and barriers to treatment utilization, incentivizing factors for maintaining adherence, and acceptability of ongoing supports to sustain treatment adherence. The study team used constant comparative methods to analyze transcripts and develop the codebook. The team double coded the transcripts, with an overall kappa coefficient of 0.88. RESULTS: The study team interviewed twenty-six women on average 10.1 months after delivery. All women had some prior experience using MOUD. Four unique themes emerged as barriers to medication utilization and adherence in the perinatal period: 1) Lack of agency and autonomy surrounding medication decisions because pregnancy or parenting status affected treatment adherence; 2) Hesitancy to use MOUD to minimize risk of newborn withdrawal; 3) Concern about increased scrutiny and potential loss of custody due to mandated child protective services reporting for opioid-exposure at delivery in Massachusetts; and 4) Perception that treatment environments, particularly methadone clinics, did not provide gender-responsive or equitable care, and standardized, inflexible visit regulations were particularly difficult to comply with in the early postpartum period. CONCLUSIONS: Women with OUD experienced a double bind when making perinatal treatment decisions, describing pressure to use MOUD with negative consequences after delivery. Key areas for possible intervention emerged from interviews. These areas include improving uptake of shared decision-making to increase patient autonomy and agency, particularly among those in the earliest stages of recovery during pregnancy; ongoing education around perinatal MOUD safety and efficacy; detangling MOUD and neonatal withdrawal signs from mandated child protective services reporting; and improving gender-responsive and equitable care in substance use disorder treatment programs, including incorporating the utilization of home visiting services for dosing assessments and administration in the early postpartum period.

The prospect of eradicating malaria continues to be challenging in the face of increasing parasite resistance to antimalarial drugs so that novel antimalarials active against asexual, sexual, and liver-stage malaria parasites are urgently needed. In addition, new antimalarials need to be affordable and available to those most in need and, bearing in mind climate change, should ideally be sustainable. The West African climbing shrub Cryptolepis sanguinolenta is used traditionally for the treatment of malaria; its principal alkaloid, cryptolepine (1), has been shown to have antimalarial properties, and the synthetic analogue 2,7-dibromocryptolepine (2) is of interest as a lead toward new antimalarial agents. Cryptolepine (1) was isolated using a two-step Soxhlet extraction of C. sanguinolenta roots, followed by crystallization (yield 0.8% calculated as a base with respect to the dried roots). Semi-synthetic 7-bromo- (3), 7, 9-dibromo- (4), 7-iodo- (5), and 7, 9-dibromocryptolepine (6) were obtained in excellent yields by reaction of 1 with N-bromo- or N-iodosuccinimide in trifluoroacetic acid as a solvent. All compounds were active against Plasmodia in vitro, but 6 showed the most selective profile with respect to Hep G2 cells: P. falciparum (chloroquine-resistant strain K1), IC50 = 0.25 µM, SI = 113; late stage, gametocytes, IC50 = 2.2 µM, SI = 13; liver stage, P. berghei sporozoites IC50 = 6.13 µM, SI = 4.6. Compounds 3-6 were also active against the emerging zoonotic species P. knowlesi with 5 being the most potent (IC50 = 0.11 µM). In addition, 3-6 potently inhibited T. brucei in vitro at nM concentrations and good selectivity with 6 again being the most selective (IC50 = 59 nM, SI = 478). These compounds were also cytotoxic to wild-type ovarian cancer cells as well as adriamycin-resistant and, except for 5, cisplatin-resistant ovarian cancer cells. In an acute oral toxicity test in mice, 3-6 did not exhibit toxic effects at doses of up to 100 mg/kg/dose × 3 consecutive days. This study demonstrates that C. sanguinolenta may be utilized as a sustainable source of novel compounds that may lead to the development of novel agents for the treatment of malaria, African trypanosomiasis, and cancer.

ObjectiveTo examine the extent to which colloquial phrases used to describe opioid-exposed mother-infant dyads affects attitudes toward mothers with opioid use disorder (OUD) to assess the role stigmatizing language may have on the care of mothers with OUD.MethodsWe employed a randomized, cross-sectional, case vignette of an opioid-exposed dyad, varying on 2 factors: (1) language to describe newborn ("substance-exposed newborn" vs "addicted baby") and (2) type of maternal opioid use (injection heroin vs nonmedical use of prescription opioids). Participants were recruited using an online survey platform. Substance-related stigma, punitive-blaming, and supportive scales were constructed to assess attitudes. Two-way analyses of variance were conducted to determine mean scale differences by vignette. Posthoc analyses assessed individual item-level differences.ResultsAmong 1227 respondents, we found a small statistical difference between language and opioid type factors for the supportive scale only (F = 4.31, η2 = .004, P = 0.038), with greater agreement with supportive statements when describing injection heroin use, compared to prescription opioid use, for the "substance-exposed newborn" vignette only. In posthoc analyses, greater than 85% of respondents agreed the mother was "responsible for her opioid use," her "addiction was caused by poor choices," and that she "put her baby in danger."ConclusionsWe found no major differences in attitudes regardless of vignette received. Overall, respondents supported opportunities for maternal recovery yet blamed women, describing mothers as culpable for causing harm to their newborn, showcasing internally conflicting views. These views could contribute to ongoing stigma and avoidance of care among pregnant women with OUD.

BackgroundThe postpartum year is a vulnerable period for women with opioid use disorder, with increased rates of fatal and nonfatal overdose; however, data on the continuation of medications for opioid use disorder on a population level are limited.ObjectiveThis study aimed to examine the effect of discontinuing methadone and buprenorphine in women with opioid use disorder in the year following delivery and determine the extent to which maternal and infant characteristics are associated with time to discontinuation of medications for opioid use disorder.Study designThis population-based retrospective cohort study used linked administrative data of 211,096 deliveries in Massachusetts between 2011 and 2014 to examine the adherence to medications for opioid use disorder. Individuals receiving medications for opioid use disorder after delivery were included in the study. Here, demographic, psychosocial, prenatal, and delivery characteristics are described. Kaplan-Meier survival analysis and Cox regression modeling were used to examine factors associated with medication discontinuation.ResultsA total of 2314 women who received medications for opioid use disorder at delivery were included in our study. Overall, 1484 women (64.1%) continued receiving medications for opioid use disorder for a full 12 months following delivery. The rate of continued medication use varied from 34% if women started on medications for opioid use disorder the month before delivery to 80% if the medications were used throughout pregnancy. Kaplan-Meier survival curves differed by maternal race and ethnicity (the 12-month continuation probability was .65 for White non-Hispanic women and .51 for non-White women; P

PURPOSE: The purpose of this study was to characterize the phenotypic spectrum of ophthalmic findings in patients with Alagille syndrome. METHODS: We conducted a retrospective, observational, multicenter, study on 46 eyes of 23 subjects with Alagille syndrome. We reviewed systemic and ophthalmologic data extracted from medical records, color fundus photography, fundus autofluorescence, optical coherence tomography, visual fields, electrophysiological assessments, and molecular genetic findings. RESULTS: Cardiovascular abnormalities were found in 83% of all cases (of those, 74% had cardiac murmur), whereas 61% had a positive history of hepatobiliary issues, and musculoskeletal anomalies were present in 61% of all patients. Dysmorphic facies were present in 16 patients, with a broad forehead being the most frequent feature. Ocular symptoms were found in 91%, with peripheral vision loss being the most frequent complaint. Median (range) Snellen visual acuity of all eyes was 20/25 (20/20 to hand motion [HM]). Anterior segment abnormalities were present in 74% of the patients; of those, posterior embryotoxon was the most frequent finding. Abnormalities of the optic disc were found in 52%, and peripheral retinal abnormalities were the most frequent ocular finding in this series, found in 96% of all patients. Fifteen JAG1 mutations were identified in 16 individuals; of those, 6 were novel. CONCLUSIONS: This study reports a cohort of patients with Alagille syndrome in which peripheral chorioretinal changes were more frequent than posterior embryotoxon, the most frequent ocular finding according to a number of previous studies. We propose that these peripheral chorioretinal changes are a new hallmark to help diagnose this syndrome.

As the SARS-CoV-2 pandemic continues, reports have demonstrated neurologic sequelae following COVID-19 recovery. Mechanisms to explain long-term neurological sequelae are unknown and need to be identified. Plasma from 24 individuals recovering from COVID-19 at 1 to 3 months after initial infection were collected for cytokine and antibody levels and neuronal-enriched extracellular vesicle (nEV) protein cargo analyses. Plasma cytokine IL-4 was increased in all COVID-19 participants. Volunteers with self-reported neurological problems (nCoV, n = 8) had a positive correlation of IL6 with age or severity of the sequalae, at least one co-morbidity and increased SARS-CoV-2 antibody compared to those COVID-19 individuals without neurological issues (CoV, n = 16). Protein markers of neuronal dysfunction including amyloid beta, neurofilament light, neurogranin, total tau, and p-T181-tau were all significantly increased in the nEVs of all participants recovering from COVID-19 compared to historic controls. This study suggests ongoing peripheral and neuroinflammation after COVID-19 infection that may influence neurological sequelae by altering nEV proteins. Individuals recovering from COVID-19 may have occult neural damage while those with demonstrative neurological symptoms additionally had more severe infection. Longitudinal studies to monitor plasma biomarkers and nEV cargo are warranted to assess persistent neurodegeneration and systemic effects.

Digital health coaching is an intervention for type 2 diabetes mellitus (T2DM) that has potential to improve the quality of care for patients. Previous research has established the efficacy of digital interventions for behavior change. This pilot study addresses a research gap in finding effective and accessible behavioral interventions for under-resourced individuals with T2DM. We examined the impact of Healthy at Home, a 12-week phone and SMS-based (short message service) digital health coaching program, on insulin resistance which is an upstream marker for T2DM progression. We compared this intervention to usual diabetic care in a family medicine residency clinic in a randomized controlled trial. Digital health coaching significantly improved participants calculated Homeostatic Model Assessment for Insulin Resistance (HOMA2-IR) by -0.9 ± 0.4 compared with the control group (p = 0.029). This significance remained after controlling for years diagnosed with T2DM, enrollment in Medicaid, access to food, baseline stage of change, and race (p = 0.027). Increasing access to digital health coaching may lead to more effective control of diabetes for under-resourced patients. This study demonstrates the potential to implement a personalized, scalable, and effective digital health intervention to treat and manage T2DM through a lifestyle and behavioral approach to improve clinical outcomes (http://clinicaltrials.gov, NCT04872647).

The role of the Adventure Sports Coach (ASC) has recently become the focus of academic interest. Although research emerging from the field is beginning to diversify, the majority is limited in terms of sampling and methodology. The current study broadened the participant base by providing a demographic analysis of ASCs. An online survey of 504 participants captured key demographics, 'coaching category' and 'coaching level'. Chi-square analysis investigated differences between genders. ASCs were predominantly male, relatively young, well-educated and well qualified. Despite many coaches holding high-level awards, their main practice was coaching beginners. A marked asymmetry existed between genders, with two-thirds of the sample being male. Female coaches were younger, less well qualified, and significantly under-represented in the higher coaching echelons. The lack of female coaches, and their clear under-representation in higher coaching categories is concerning. Recruitment, retention, and development of female ASCs is therefore a priority.

BackgroundOur understanding of the different effects of targeted versus nontargeted violence on Ebola virus (EBOV) transmission in Democratic Republic of the Congo (DRC) is limited.MethodsWe used time-series data of case counts to compare individuals in Ebola-affected health zones in DRC, April 2018-August 2019. Exposure was number of violent events per health zone, categorized into Ebola-targeted or Ebola-untargeted, and into civilian-induced, (para)military/political, or protests. Outcome was estimated daily reproduction number (Rt) by health zone. We fit linear time-series regression to model the relationship.ResultsAverage Rt was 1.06 (95% confidence interval [CI], 1.02-1.11). A mean of 2.92 violent events resulted in cumulative absolute increase in Rt of 0.10 (95% CI, .05-.15). More violent events increased EBOV transmission (P = .03). Considering violent events in the 95th percentile over a 21-day interval and its relative impact on Rt, Ebola-targeted events corresponded to Rt of 1.52 (95% CI, 1.30-1.74), while civilian-induced events corresponded to Rt of 1.43 (95% CI, 1.21-1.35). Untargeted events corresponded to Rt of 1.18 (95% CI, 1.02-1.35); among these, militia/political or ville morte events increased transmission.ConclusionsEbola-targeted violence, primarily driven by civilian-induced events, had the largest impact on EBOV transmission.

BackgroundOur understanding of the different effects of targeted versus nontargeted violence on Ebola virus (EBOV) transmission in Democratic Republic of the Congo (DRC) is limited.MethodsWe used time-series data of case counts to compare individuals in Ebola-affected health zones in DRC, April 2018-August 2019. Exposure was number of violent events per health zone, categorized into Ebola-targeted or Ebola-untargeted, and into civilian-induced, (para)military/political, or protests. Outcome was estimated daily reproduction number (Rt) by health zone. We fit linear time-series regression to model the relationship.ResultsAverage Rt was 1.06 (95% confidence interval [CI], 1.02-1.11). A mean of 2.92 violent events resulted in cumulative absolute increase in Rt of 0.10 (95% CI, .05-.15). More violent events increased EBOV transmission (P = .03). Considering violent events in the 95th percentile over a 21-day interval and its relative impact on Rt, Ebola-targeted events corresponded to Rt of 1.52 (95% CI, 1.30-1.74), while civilian-induced events corresponded to Rt of 1.43 (95% CI, 1.21-1.35). Untargeted events corresponded to Rt of 1.18 (95% CI, 1.02-1.35); among these, militia/political or ville morte events increased transmission.ConclusionsEbola-targeted violence, primarily driven by civilian-induced events, had the largest impact on EBOV transmission.

Elimination of an infectious disease requires subcritical transmission, or a reproductive number less than one, and can be assessed with cross-sectional surveys conducted by neglected tropical disease programs. Here, we assess the distribution of onchocerciasis prevalence taken from surveys across sub-Saharan Africa before the initiation of ivermectin in mass drug administrations. Pre-intervention nodular palpation cross-sectional surveys were available from 15 countries in the Expanded Special Project for Elimination of Neglected Tropical Diseases (ESPEN) database. We determined whether the distribution of the prevalence over communities in an area was consistent with a geometric distribution, which previous studies have suggested indicates a subcritical disease. If not, we fitted a negative binominal distribution (hypothetically supercritical) or a mixture of two distributions: geometric (hypothetically subcritical) and Poisson (hypothetically supercritical). The overall distribution of community-level onchocerciasis prevalence estimates from the ESPEN dataset from 2005 to 2014 was not consistent with a geometric distribution. By contrast, data from several countries and parts of countries were consistent with the geometric distribution, for example, some areas within Nigeria and Angola. Even if the geometric distribution suggested pre-intervention subcriticality in more localized geographical areas, our model using pooled survey data of all geographic areas suggests that the entire pre-intervention prevalence does not fit a geometric distribution. Further work will be required to confirm the significance of a geometric distribution for onchocerciasis.

We sought to replicate and expand upon previous work demonstrating antenatal TTC9B and HP1BP3 gene DNA methylation is prospectively predictive of postpartum depression (PPD) with ~80% accuracy. In a preterm birth study from Emory, Illumina MethylEPIC microarray derived 1st but not 3rd trimester biomarker models predicted 3rd trimester Edinburgh Postnatal Depression Scale (EPDS) scores ≥ 13 with an AUC=0.8 (95% CI: 0.63-0.8). Bisulfite pyrosequencing derived biomarker methylation was generated using bisulfite pyrosequencing across all trimesters in a pregnancy cohort at UC Irvine and in 3rd trimester from an independent Johns Hopkins pregnancy cohort. A support vector machine model incorporating 3rd trimester EPDS scores, TTC9B, and HP1BP3 methylation status predicted 4 week to 6 week postpartum EPDS ≥ 13 from 3rd trimester blood in the UC Irvine cohort (AUC=0.78, 95% CI: 0.64-0.78) and from the Johns Hopkins cohort (AUC=0.84, 95% CI: 0.72-0.97), both independent of previous psychiatric diagnosis. Technical replicate predictions in a subset of the Johns Hopkins cohort exhibited strong cross experiment correlation. This study confirms the PPD prediction model has the potential to be developed into a clinical tool enabling the identification of pregnant women at future risk of PPD who may benefit from clinical intervention.