Lack of disease during chronic human cytomegalovirus (CMV) infection depends on the maintenance of a high-frequency CMV-specific T cell response. The composition of the T cell receptor (TCR) ...repertoire underlying this response remains poorly characterised, especially within African populations in which CMV is endemic from infancy. Here we focus on the immunodominant CD8+ T cell response to the immediate-early 2 (IE-2)-derived epitope NEGVKAAW (NW8) restricted by HLA-B*44:03, a highly prevalent response in African populations, which in some subjects represents >10% of the circulating CD8+ T cells. Using pMHC multimer staining and sorting of NW8-specific T cells, the TCR repertoire raised against NW8 was characterised here using high-throughput sequencing in 20 HLA-B*44:03 subjects. We found that the CD8+ T cell repertoire raised in response to NW8 was highly skewed and featured preferential use of a restricted set of V and J gene segments. Furthermore, as often seen in immunity against ancient viruses like CMV and Epstein-Barr virus (EBV), the response was strongly dominated by identical TCR sequences shared by multiple individuals, or "public" TCRs. Finally, we describe a pair "superdominant" TCR clonotypes, which were germline or nearly germline-encoded and produced at remarkably high frequencies in certain individuals, with a single CMV-specific clonotype representing up to 17% of all CD8+ T cells. Given the magnitude of the NW8 response, we propose that this major skewing of CMV-specific immunity leads to massive perturbations in the overall TCR repertoire in HLA-B*44:03 individuals.
Abstract
Background
Early HIV diagnosis allows combination antiretroviral therapy (cART) initiation in the first days of life following in utero (IU) infection. The impact of early cART initiation on ...infant viral reservoir size in the setting of high-frequency cART nonadherence is unknown.
Methods
Peripheral blood total HIV DNA from 164 early treated (day 0–21 of life) IU HIV-infected South African infants was measured using droplet digital PCR at birth and following suppressive cART. We evaluated the impact of cART initiation timing on HIV reservoir size and decay, and on the risk of subsequent plasma viremia in cART-suppressed infants.
Results
Baseline HIV DNA (median 2.8 log10 copies/million peripheral blood mononuclear cells, range 0.7–4.8) did not correlate with age at cART initiation (0–21 days) but instead with maternal antenatal cART use. In 98 infants with plasma viral suppression on cART, HIV DNA half-life was 28 days. However, the probability of maintenance of plasma aviremia was low (0.46 at 12 months) and not influenced by HIV DNA load. Unexpectedly, longer time to viral suppression was associated with protection against subsequent viral rebound.
Conclusions
With effective prophylaxis against mother-to-child transmission, cART initiation timing in the first 3 weeks of life is not critical to reservoir size.
Peripheral blood HIV DNA levels from 164 South African in utero HIV-infected infants showed that with antiretroviral mother-to-child transmission prophylaxis, combination antiretroviral therapy initiation timing in the first 3 weeks of life does not significantly influence latent HIV reservoir size.
Parent-led, home-based education, or homeschooling, has grown rapidly over recent decades with participation rates increasing more than 100-fold to now nearly one in 25 students nationwide in the ...United States. However, the research base has not grown correspondingly, and homeschoolers remain understudied. We systematically surveyed a population of homeschooling families (N = 881 responses) who had reported homeschooling a high-ability student to learn more about their characteristics and perceptions. Specifically, we report a mixed-methods analysis of the survey responses addressing whether and why these parents would or would not consider returning their child to a traditional school setting. Respondents were predominantly mothers who reported a high level of formal education and who were primarily responsible for implementing homeschooling with their child. Qualitative thematic analysis of open-ended responses yielded five main themes: preference, academics, concerns about future educational opportunities, satisfaction, and well-being. Findings both support and extend prior research with this population.
The need for a clinically accessible method with the ability to match protein activity within heterogeneous tissues is currently unmet by existing technologies. Our proteomics sample preparation ...platform, named microPOTS (Microdroplet Processing in One pot for Trace Samples), can be used to measure relative protein abundance in micron-scale samples alongside the spatial location of each measurement, thereby tying biologically interesting proteins and pathways to distinct regions. However, given the smaller pixel/voxel number and amount of tissue measured, standard mass spectrometric analysis pipelines have proven inadequate. Here we describe how existing computational approaches can be adapted to focus on the specific biological questions asked in spatial proteomics experiments. We apply this approach to present an unbiased characterization of the human islet microenvironment comprising the entire complex array of cell types involved while maintaining spatial information and the degree of the islet’s sphere of influence. We identify specific functional activity unique to the pancreatic islet cells and demonstrate how far their signature can be detected in the adjacent tissue. Our results show that we can distinguish pancreatic islet cells from the neighboring exocrine tissue environment, recapitulate known biological functions of islet cells, and identify a spatial gradient in the expression of RNA processing proteins within the islet microenvironment.
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•We used our microPOTS platform to carry out deep proteome imaging of the human pancreatic islet and its surrounding microenvironment with seven biological replicates.•Our analysis yielded the identification and quantification of over 6000 proteins from ∼50,000 μm2 tissue area samples.•Differential expression analysis identified biological pathways uniquely active in islet cells, and biological network interrogation identified additional relevant proteins.•Rank-based statistics enables the characterization of gradients that occur across the individual tissue images.
We applied our Microdroplet Processing in One pot for Trace Samples (microPOTS) TMT platform to study the pancreatic islet microenvironment in the human pancreas. With this approach, we were able to quantify over 6000 proteins from seven different regions within the same patient. Here we describe enhancements to existing computational approaches to extract functional hypotheses from this first-of-its-kind dataset. In addition to recapitulating known functions of the islet, we are also able to identify specific immune and RNA processing activities with spatial heterogeneity in expression.
We report the detection of a transiting hot Neptune exoplanet orbiting TOI-824 (SCR J1448-5735), a nearby (d = 64 pc) K4V star, using data from the Transiting Exoplanet Survey Satellite. The newly ...discovered planet has a radius Rp = 2.93 0.20 and an orbital period of 1.393 days. Radial velocity measurements using the Planet Finder Spectrograph and the High Accuracy Radial velocity Planet Searcher spectrograph confirm the existence of the planet, and we estimate its mass to be 18.47 1.84 . The planet's mean density is = 4.03 , making it more than twice as dense as Neptune. TOI-824 b's high equilibrium temperature makes the planet likely to have a cloud-free atmosphere, and thus it is an excellent candidate for follow-up atmospheric studies. The detectability of TOI-824 b's atmosphere from both ground and space is promising and could lead to the detailed characterization of the most irradiated small planet at the edge of the hot Neptune desert that has retained its atmosphere to date.
Abstract
Background
Injection drug use (IDU) following treatment for hepatitis C virus (HCV) infection may lead to reinfection, particularly if access to harm reduction services is suboptimal. This ...study assessed HCV reinfection risk following direct-acting antiviral therapy within Australian prisons that had opioid agonist therapy (OAT) programs but did not have needle and syringe programs (NSPs).
Methods
The Surveillance and Treatment of Prisoners With Hepatitis C (SToP-C) study enrolled people incarcerated in 4 prisons between 2014 and 2019. Participants treated for HCV were followed every 3–6 months to identify reinfection (confirmed by sequencing). Reinfection incidence and associated factors were evaluated.
Results
Among 388 participants receiving treatment, 161 had available posttreatment follow-up and were included in analysis (92% male; median age, 33 years; 67% IDU in prison; median follow-up 9 months). Among those with recent (in the past month) IDU (n = 71), 90% had receptive needle/syringe sharing. During 145 person-years (PY) of follow-up, 18 cases of reinfection were identified. Reinfection incidence was 12.5/100 PY (95% confidence interval CI: 7.9–19.8) overall, increasing to 28.7/100 PY (95% CI: 16.3–50.6) among those with recent IDU and needle/syringe sharing. In adjusted analysis, recent IDU with needle/syringe sharing was associated with increased reinfection risk (adjusted hazard ratio aHR, 4.74 95% CI: 1.33–16.80; P = .016) and longer HCV testing interval with decreased risk (ie, chance of detection; aHR, 0.41 per each month increase 95% CI: .26–.64; P < .001).
Conclusions
A high rate of HCV reinfection was observed within prison. Posttreatment surveillance and retreatment are essential to limit the impact of reinfection. High-coverage OAT and NSPs should be considered within prisons.
Clinical Trials Registration
NCT02064049
A high reinfection incidence (13/100 person-years PY) was observed among people treated for hepatitis C virus in prison. Risk was highest in those with injection drug use and receptive needle/syringe sharing (29/100 PY). Increased access to harm reduction in prisons is needed.
HER2-targeted therapy dramatically improves outcomes in early breast cancer. Here we report the results of two HER2-targeted combinations in the neoadjuvant I-SPY2 phase 2 adaptive platform trial for ...early breast cancer at high risk of recurrence: ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel, trastuzumab and pertuzumab (THP). Eligible women have >2.5 cm clinical stage II/III HER2
breast cancer, adaptively randomized to T-DM1/P, THP, or a common control arm of paclitaxel/trastuzumab (TH), followed by doxorubicin/cyclophosphamide, then surgery. Both T-DM1/P and THP arms 'graduate' in all subtypes: predicted pCR rates are 63%, 72% and 33% for T-DM1/P (n = 52), THP (n = 45) and TH (n = 31) respectively. Toxicity burden is similar between arms. Degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens are associated with response to both T-DM1/P and THP and can further identify highly responsive HER2
tumors to HER2-directed therapy. This may help identify patients who can safely de-escalate cytotoxic chemotherapy without compromising excellent outcome.
•Amidst COVID-19, successes included virtual didactics, camaraderie, and flexibility.•Amidst COVID-19, challenges include PPE, scheduling, case volume, and burnout.•There is a clear need for ...thoughtful pandemic institutional planning and policies.•Surgery residencies must ensure balanced training, with a focus on wellness.
As the COVID-19 pandemic dynamically changes our society, it is important to consider how the pandemic has affected the training and wellness of surgical residents. Using a qualitative study of national focus groups with general surgery residents, we aim to identify common themes surrounding their personal, clinical, and educational experiences that could be used to inform practice and policy for future pandemics and disasters.
Six 90-minute focus groups were conducted by a trained qualitative researcher who elicited responses on six predetermined topics. De-identified transcripts and audio recordings were later analyzed by two independent researchers who organized responses to each topic into themes.
Focus groups were conducted virtually and anonymously.
General surgery residents were recruited from across the country. Demographic information of potential participants was coded, and subjects were randomly selected to ensure a diverse group of participants.
The impact of the COVID-19 pandemic on residents’ clinical, educational, and personal experiences varied depending on the institutional response of the program and the burden of COVID-19 cases geographically. Many successes were identified: the use of telehealth and virtual didactics, an increased sense of camaraderie amongst residents, and flexibility in scheduling. Many challenges were also identified: uncertainty at work regarding personal protective equipment and scheduling, decreased case volume and educational opportunities, and emotional trauma and burnout associated with the pandemic.
These data gathered from our qualitative study highlight a clear, urgent need for thoughtful institutional planning and policies for the remainder of this and future pandemics. Residency programs must ensure a balanced training program for surgical residents as they attempt to master the skills of their craft while also serving as employed health care providers in a pandemic. Furthermore, a focus on wellness, in addition to clinical competency and education, is vital to resident resilience and success in a pandemic setting.
•The OUD prevalence among primary care patients in 6 health systems was 1.0 %.•For patients with OUD, the prevalence of treatment with buprenorphine was 21.0 %.•Patients with poorest health and ...greatest acute care use had the lowest treatment.•System changes are needed to increase treatment of OUD in primary care patients.
The U.S. experienced nearly 48,000 opioid overdose deaths in 2017. Treatment of opioid use disorder (OUD) with buprenorphine is a recommended part of primary care, yet little is known about current U.S. practices in this setting. This observational study reports the prevalence of documented OUD and OUD treatment with buprenorphine among primary care patients in six large health systems.
Adults with ≥2 primary care visits during a three-year period (10/1/2013-9/30/2016) in six health systems were included. Data were obtained from electronic health record and claims data, with measures, assessed over the three-year period, including indicators for documented OUD from ICD 9 and 10 codes and OUD treatment with buprenorphine. The prevalence of OUD treatment was adjusted for age, gender, race/ethnicity, and health system.
Among 1,368,604 primary care patients, 13,942 (1.0 %) had documented OUD, and among these, 21.0 % had OUD treatment with buprenorphine. For those with documented OUD, the adjusted prevalence of OUD treatment with buprenorphine varied across demographic and clinical subgroups. OUD treatment was lower among patients who were older, women, Black/African American and Hispanic (compared to white), non-commercially insured, and those with non-cancer pain, mental health disorders, greater comorbidity, and more opioid prescriptions, emergency department visits or hospitalizations.
Among primary care patients in six health systems, one in five with an OUD were treated with buprenorphine, with disparities across demographic and clinical characteristics. Less buprenorphine treatment among those with greater acute care utilization highlights an opportunity for systems-level changes to increase OUD treatment.
The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide ...association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.
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