The increasing incidence of hepatitis C virus (HCV) infections underscores the need for an effective vaccine. Successful vaccines to other viruses generally depend on a long-lasting humoral response. ...However, data on the half-life of HCV-specific responses are lacking. Here we study archived sera and mononuclear cells that were prospectively collected up to 18 years after cure of chronic HCV infection to determine the role of HCV antigen in maintaining neutralizing antibody and B cell responses. We show that HCV-neutralizing activity decreases rapidly in potency and breadth after curative treatment. In contrast, HCV-specific memory B cells persist, and display a restored resting phenotype, normalized chemokine receptor expression and preserved ability to differentiate into antibody-secreting cells. The short half-life of HCV-neutralizing activity is consistent with a lack of long-lived plasma cells. The persistence of HCV-specific memory B cells and the reduced inflammation after cure provide an opportunity for vaccination to induce protective immunity against re-infection.
Development of a prophylactic hepatitis C virus (HCV) vaccine will require accurate and reproducible measurement of neutralizing breadth of vaccine-induced antibodies. Currently available HCV panels ...may not adequately represent the genetic and antigenic diversity of circulating HCV strains, and the lack of standardization of these panels makes it difficult to compare neutralization results obtained in different studies. Here, we describe the selection and validation of a genetically and antigenically diverse reference panel of 15 HCV pseudoparticles (HCVpps) for neutralization assays.
We chose 75 envelope (E1E2) clones to maximize representation of natural polymorphisms observed in circulating HCV isolates, and 65 of these clones generated functional HCVpps. Neutralization sensitivity of these HCVpps varied widely. HCVpps clustered into 15 distinct groups based on patterns of relative sensitivity to 7 broadly neutralizing monoclonal antibodies. We used these data to select a final panel of 15 antigenically representative HCVpps.
Both the 65 and 15 HCVpp panels span 4 tiers of neutralization sensitivity, and neutralizing breadth measurements for 7 broadly neutralizing monoclonal antibodies were nearly equivalent using either panel. Differences in neutralization sensitivity between HCVpps were independent of genetic distances between E1E2 clones.
Neutralizing breadth of HCV antibodies should be defined using viruses spanning multiple tiers of neutralization sensitivity rather than panels selected solely for genetic diversity. We propose that this multitier reference panel could be adopted as a standard for the measurement of neutralizing antibody potency and breadth, facilitating meaningful comparisons of neutralization results from vaccine studies in different laboratories.
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A panel of hepatitis C virus pseudoparticles with 4 tiers of antibody resistance was developed. These pseudoparticles can be used to measure neutralizing breadth of antibodies induced by candidate vaccines.
The HIV Organ Policy Equity Act legalizes organ procurement from donors with HIV (HIV D+). A prior survey of Organ Procurement Organizations (OPOs) estimated >2000 HIV D+ referrals/year; however, ...only 30-35 HIV D+/year have had organs procured. Given this gap, we sought to understand HIV D+ referrals and procurements in practice.
We prospectively collected data on all OPO-reported HIV D+ referrals, including reasons for nonprocurement. We evaluated trends and compared HIV D+ characteristics by procurement status using regression, chi-squared tests, and Wilcoxon rank-sum tests.
From December 23, 2015 to May 31, 2021, there were 710 HIV D+ referrals from 49 OPOs, of which 171 (24%) had organs procured. HIV D+ referrals increased from 7 to 15 per month (
< 0.001), and the procurement rate increased from 10% to 39% (
< 0.001). Compared with HIV D+ without procurement, HIV D+ with procurement were younger (median age 36 versus 50 y), more commonly White (46% versus 36%), and more often had trauma-related deaths (29% versus 8%) (all
< 0.001). Nonprocurement was attributed to medical reasons in 63% of cases, of which 36% were AIDS-defining infections and 64% were HIV-unrelated, commonly due to organ failure (36%), high neurologic function (31%), and cancer (14%). Nonprocurement was attributed to nonmedical reasons in 26% of cases, commonly due to no authorization (42%), no waitlist candidates (21%), or no transplant center interest (20%).
In the early years of the HIV Organ Policy Equity Act, actual HIV D+ referrals were much lower than prior estimates; however, the numbers and procurement rates increased over time. Nonprocurement was attributed to both medical and nonmedical issues, and addressing these issues could increase organ availability.
Closed-loop control (CLC) has been shown to improve glucose time in range and other glucose metrics; however, randomized trials >3 months comparing CLC with sensor-augmented pump (SAP) therapy are ...limited. We recently reported glucose control outcomes from the 6-month international Diabetes Closed-Loop (iDCL) trial; we now report patient-reported outcomes (PROs) in this iDCL trial.
Participants were randomized 2:1 to CLC (
= 112) versus SAP (
= 56) and completed questionnaires, including Hypoglycemia Fear Survey, Diabetes Distress Scale (DDS), Hypoglycemia Awareness, Hypoglycemia Confidence, Hyperglycemia Avoidance, and Positive Expectancies of CLC (INSPIRE) at baseline, 3, and 6 months. CLC participants also completed Diabetes Technology Expectations and Acceptance and System Usability Scale (SUS).
The Hypoglycemia Fear Survey Behavior subscale improved significantly after 6 months of CLC compared with SAP. DDS did not differ except for powerless subscale scores, which worsened at 3 months in SAP. Whereas Hypoglycemia Awareness and Hyperglycemia Avoidance did not differ between groups, CLC participants showed a tendency toward improved confidence in managing hypoglycemia. The INSPIRE questionnaire showed favorable scores in the CLC group for teens and parents, with a similar trend for adults. At baseline and 6 months, CLC participants had high positive expectations for the device with Diabetes Technology Acceptance and SUS showing high benefit and low burden scores.
CLC improved some PROs compared with SAP. Participants reported high benefit and low burden with CLC. Clinical Trial Identifier: NCT03563313.
•Nfe2 is involved in erythropoiesis in zebrafish.•Nfe2 is a novel regulator of pro-oxidant induced oxidative stress.•Embryos mount a molecularly unique oxidative stress response compared to ...larvae.•Nfe2 regulates a wide-variety of genes beyond erythropoiesis.
Development is a complex and well-defined process characterized by rapid cell proliferation and apoptosis. At this stage in life, a developmentally young organism is more sensitive to toxicants as compared to an adult. In response to pro-oxidant exposure, members of the Cap’n’Collar (CNC) basic leucine zipper (b-ZIP) transcription factor family (including Nfe2 and Nfe2-related factors, Nrfs) activate the expression of genes whose protein products contribute to reduced toxicity. Here, we studied the role of the CNC protein, Nfe2, in the developmental response to pro-oxidant exposure in the zebrafish (Danio rerio). Following acute waterborne exposures to diquat or tert-buytlhydroperoxide (tBOOH) at one of three developmental stages, wildtype (WT) and nfe2 knockout (KO) embryos and larvae were morphologically scored and their transcriptomes sequenced. Early in development, KO animals suffered from hypochromia that was made more severe through exposure to pro-oxidants; this phenotype in the KO may be linked to decreased expression of alas2, a gene involved in heme synthesis. WT and KO eleutheroembryos and larvae were phenotypically equally affected by exposure to pro-oxidants, where tBOOH caused more pronounced phenotypes as compared to diquat. Comparing diquat and tBOOH exposed embryos relative to the WT untreated control, a greater number of genes were up-regulated in the tBOOH condition as compared to diquat (tBOOH: 304 vs diquat: 148), including those commonly found to be differentially regulated in the vertebrate oxidative stress response (OSR) (e.g. hsp70.2, txn1, and gsr). When comparing WT and KO across all treatments and times, there were 1170 genes that were differentially expressed, of which 33 are known targets of the Nrf proteins Nrf1 and Nrf2. More specifically, in animals exposed to pro-oxidants a total of 968 genes were differentially expressed between WT and KO across developmental time, representing pathways involved in coagulation, embryonic organ development, body fluid level regulation, erythrocyte differentiation, and oxidation-reduction, amongst others. The greatest number of genes that changed in expression between WT and KO occurred in animals exposed to diquat at 2h post fertilization (hpf). Across time and treatment, there were six genes (dhx40, cfap70, dnajb9b, slc35f4, spi-c, and gpr19) that were significantly up-regulated in KO compared to WT and four genes (fhad1, cyp4v7, nlrp12, and slc16a6a) that were significantly down-regulated. None of these genes have been previously identified as targets of Nfe2 or the Nrf family. These results demonstrate that the zebrafish Nfe2 may be a regulator of both primitive erythropoiesis and the OSR during development.
Despite prolific efforts to characterize the antibody response to human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) mono-infections, the response to chronic co-infection with ...these two ever-evolving viruses is poorly understood. Here, we investigate the antibody repertoire of a chronically HIV-1/HCV co-infected individual using linking B cell receptor to antigen specificity through sequencing (LIBRA-seq). We identify five HIV-1/HCV cross-reactive antibodies demonstrating binding and functional cross-reactivity between HIV-1 and HCV envelope glycoproteins. All five antibodies show exceptional HCV neutralization breadth and effector functions against both HIV-1 and HCV. One antibody, mAb688, also cross-reacts with influenza and coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We examine the development of these antibodies using next-generation sequencing analysis and lineage tracing and find that somatic hypermutation established and enhanced this reactivity. These antibodies provide a potential future direction for therapeutic and vaccine development against current and emerging infectious diseases. More broadly, chronic co-infection represents a complex immunological challenge that can provide insights into the fundamental rules that underly antibody-antigen specificity.
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•LIBRA-seq is applied to characterize antibody responses to HIV-1/HCV co-infection•A diverse set of functional HIV-1/HCV cross-reactive antibodies are identified•A glycan-directed antibody exhibits exceptionally broad anti-viral recognition•Antibody somatic hypermutation is a major determinant for HIV-1/HCV cross-reactivity
Pilewski et al. uses LIBRA-seq to identify multiple, functional HIV-1/HCV cross-reactive antibodies with diverse epitope specificities. This study identifies a glycan-reactive, broadly anti-viral antibody recognizing the NTD of SARS-CoV-2, in addition to antigens from multiple other viruses. The authors further show that somatic hypermutation both establishes and enhances HIV-1/HCV cross-reactivity.
Since the 20th century, health care institutions have used morbidity and mortality conferences (MMCs) as a forum to discuss complicated cases and fatalities to capitalize on lessons learned. Medical ...technology, health care processes, and the teams who provide care have evolved over time, but the format of the MMC has remained relatively unchanged. The present article outlines 5 key areas for improvement within the MMC along with prescriptive and actionable recommendations for mitigating these challenges. This work incorporates the contributions of numerous researchers and practitioners from the educational, training, debrief, and health care fields. With the best practices and lessons learned from various domains in mind, we recommend optimizing the MMC by (1) encouraging a culture that leverages expertise from multiple sources, (2) allocating ample time for innovative thinking, (3) using a global approach that considers individual, team, and system-level factors, (4) leveraging learnings from errors as well as near misses, and (5) promoting communication, innovative thinking, and actionable planning. The 5 evidence-based recommendations herein serve to ensure that MMCs are structured learning events that promote, encourage, and support safe, reliable care. Furthermore, the outlined recommendations seek to capitalize upon the MMC's opportunity to engage early discovery as well as proactive risk assessment and action-oriented solutions.
Medical students need to understand core neuroscience principles as a foundation for their required clinical experiences in neurology. In fact, they need a solid neuroscience foundation for their ...clinical experiences in all other medical disciplines also because the nervous system plays such a critical role in the function of every organ system. Because of the rapid pace of neuroscience discoveries, it is unrealistic to expect students to master the entire field. It is also unnecessary, as students can expect to have ready access to electronic reference sources no matter where they practice. In the preclerkship phase of medical school, the focus should be on providing students with the foundational knowledge to use those resources effectively and interpret them correctly. This article describes an organizational framework for teaching the essential neuroscience background needed by all physicians. This is particularly germane at a time when many medical schools are reassessing traditional practices and instituting curricular changes such as competency-based approaches, earlier clinical immersion, and increased emphasis on active learning. This article reviews factors that should be considered when developing the preclerkship neuroscience curriculum, including goals and objectives for the curriculum, the general topics to include, teaching and assessment methodology, who should direct the course, and the areas of expertise of faculty who might be enlisted as teachers or content experts. These guidelines were developed by a work group of experienced educators appointed by the Undergraduate Education Subcommittee (UES) of the American Academy of Neurology (AAN). They were then successively reviewed, edited, and approved by the entire UES, the AAN Education Committee, and the AAN Board of Directors.
Data are limited on the need for and benefits of pump setting optimization with automated insulin delivery. We examined clinical management of a closed-loop control (CLC) system and its relationship ...to glycemic outcomes.
We analyzed personal parameter adjustments in 168 participants in a 6-month multicenter trial of CLC with Control-IQ versus sensor-augmented pump (SAP) therapy. Preset parameters (BR = basal rates, CF = correction factors, CR = carbohydrate ratios) were optimized at randomization, 2 and 13 weeks, for safety issues, participant concerns, or initiation by participants' usual diabetes care team. Time in range (TIR 70-180 mg/dL) was compared in the week before and after parameter changes.
In 607 encounters for parameter changes, there were fewer adjustments for CLC than SAP (3.4 vs. 4.1/participant). Adjustments involved BR (CLC 69%, SAP 80%), CR (CLC 68%, SAP 50%), CF (CLC 44%, SAP 41%), and overnight parameters (CLC 62%, SAP 75%). TIR before and after adjustments was 71.2% and 71.3% for CLC and 61.0% and 62.9% for SAP. The highest baseline HbA
CLC subgroup had the largest TIR improvement (51.2% vs. 57.7%). When a CR was made more aggressive in the CLC group, postprandial time >180 mg/dL was 43.1% before the change and 36.0% after the change. The median postprandial time <70 mg/dL before making CR less aggressive was 1.8%, and after the change was 0.7%.
No difference in TIR was detected with parameter changes overall, but they may have an effect in higher HbA
subgroups or following user-directed boluses, suggesting that changes may matter more in suboptimal control or during discrete periods of the day. Clinical Trials Registration number: NCT03563313.
Human capital is typically an organization's most valuable asset; however, hiring and retaining talented employees is a costly enterprise. Investing in employees with training and development to ...provide them with a competent, competitive edge is one way to retain employees and mitigate turnover. To truly reap the benefits of training, organizations must commit to securing the acquired competencies and training sustainment to ameliorate decay. Without such commitment, there is substantial deterioration in knowledge, skills, and attitudes (KSAs) following training. Despite the importance of training sustainment, little instruction and direction are available to assist practitioners in mitigating decay. Consequently, the purpose of this article is to provide practitioners with scientifically grounded guidance by offering 14 assumptions about training sustainment. We organize these assumptions into four tenets: (a) creating a mandate to sustain trained KSAs, (b) championing sustainment of trained KSAs, (c) empowering employees to use trained KSAs, and (d) evaluating sustainment success.
What's It Mean? Implications for Consulting Psychology
Consulting inherently entails one of an organizations' most valuable assets-human capital. The retention, though, of human capital is contingent upon training and development. The longevity of training relies on concerted efforts related to training sustainment. This article provides four tenets to provide guidance on maximizing training sustainment.
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