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Inadequate sleep is associated with all-cause mortality in the general population. Substance use has adverse effects on sleep, and insomnia symptoms are common among people with HIV. Therefore, persons who inject drugs may face a heightened risk of adverse outcomes from inadequate sleep. We evaluated the association of inadequate sleep with mortality among persons who inject drugs in a long-standing community cohort.

I. INTRODUCTION II. ARTIFICIAL INTELLIGENCE A. Intelligent Machines B. Rational Agents C. Assessing AI Agents III. INTERNATIONAL LAW AND CYBER OPERATIONS A. Cyberspace B. International Law C. Applying International Law [...]

In June 2022, the US Food and Drug Administration Center for Biologics Evaluation and Research held the 73rd meeting of the Cellular, Tissue, and Gene Therapies Advisory Committee for public discussion of regulatory expectations for xenotransplantation products. The members of a joint American Society of Transplant Surgeons/American Society of Transplantation committee on xenotransplantation compiled a meeting summary focusing on 7 topics believed to be key by the committee: (1) preclinical evidence supporting progression to a clinical trial, (2) porcine kidney function, (3) ethical aspects, (4) design of initial clinical trials, (5) infectious disease issues, (6) industry perspectives, and (7) regulatory oversight.

The article discusses tips in managing and investing trust property, particularly how trustees can avoid the pitfalls in assigning investment management functions. Also cited are the things a trustee should consider when developing an overall investment strategy like the general economic conditions and the potential effects of inflation or deflation, and the provisions of the Uniform Prudent Investor Act (UPIA).

HIV-1 remains a global health crisis1, highlighting the need to identify new targets for therapies. Here, given the disproportionate HIV-1 burden and marked human genome diversity in Africa2, we assessed the genetic determinants of control of set-point viral load in 3,879 people of African ancestries living with HIV-1 participating in the international collaboration for the genomics of HIV3. We identify a previously undescribed association signal on chromosome 1 where the peak variant associates with an approximately 0.3 log10-transformed copies per ml lower set-point viral load per minor allele copy and is specific to populations of African descent. The top associated variant is intergenic and lies between a long intergenic non-coding RNA (LINC00624) and the coding gene CHD1L, which encodes a helicase that is involved in DNA repair4. Infection assays in iPS cell-derived macrophages and other immortalized cell lines showed increased HIV-1 replication in CHD1L-knockdown and CHD1L-knockout cells. We provide evidence from population genetic studies that Africa-specific genetic variation near CHD1Lassociates with HIV replication in vivo. Although experimental studies suggest that CHD1L is able to limit HIV infection in some cell types in vitro, further investigation is required to understand the mechanisms underlying our observations, including any potential indirect effects of CHD1L on HIV spread in vivo that our cell-based assays cannot recapitulate.

The purpose of this study was to evaluate whether assessment of cell phenotypes using flow cytometry (FCM), combined with clinical data, could identify pulmonary infection immediately following thoracic trauma.

Porcine vascular endothelial cells (PECs) form a mechanistic centerpiece of xenograft rejection. Here, we determined that resting PECs release swine leukocyte antigen class I (SLA-I) but not swine leukocyte antigen class-II DR (SLA-DR) expressing extracellular vesicles (EVs) and investigated whether these EVs proficiently initiate xenoreactive T cell responses via direct xenorecognition and costimulation. Human T cells acquired SLA-I+EVs with or without direct contact to PECs, and these EVs colocalized with T cell receptors. Although interferon gamma-activated PECs released SLA-DR+EVs, the binding of SLA-DR+EVs to T cells was sparse. Human T cells demonstrated low levels of proliferation without direct contact to PECs, but marked T cell proliferation was induced following exposure to EVs. EV-induced proliferation proceeded independent of monocytes/macrophages, suggesting that EVs delivered both a T cell receptor signal and costimulation. Costimulation blockade targeting B7, CD40L, or CD11a significantly reduced T cell proliferation to PEC-derived EVs. These findings indicate that endothelial-derived EVs can directly initiate T cell-mediated immune responses, and suggest that inhibiting the release of SLA-I EVs from organ xenografts has the potential to modify the xenograft rejection. We propose a secondary-direct pathway for T cell activation via xenoantigen recognition/costimulation by endothelial-derived EVs.

The choice of deprivation index can influence conclusions drawn regarding the extent of deprivation within a community and the identification of the most deprived communities in the United States. This study aimed to determine the degree of correlation among deprivation indices commonly used to characterize transplant populations. We used a retrospective cohort consisting of adults listed for liver or kidney transplants between 2008 and 2018 to compare 4 deprivation indices: neighborhood deprivation index, social deprivation index (SDI), area deprivation index, and social vulnerability index. Pairwise correlation between deprivation indices by transplant referral regions was measured using Spearman correlations of population-weighted medians and upper quartiles. In total, 52 individual variables were used among the 4 deprivation indices with 25% overlap. For both organs, the correlation between the population-weighted 75th percentile of the deprivation indices by transplant referral region was highest between SDI and social vulnerability index (liver and kidney, 0.93) and lowest between area deprivation index and SDI (liver, 0.19 and kidney, 0.15). The choice of deprivation index affects the applicability of research findings across studies examining the relationship between social risk and clinical outcomes. Appropriate application of these measures to transplant populations requires careful index selection based on the intended use and included variable relevance.

ABSTRACTAmbient particulate matter (PM2.5) is an important component of natural and human-generated air pollution and a major contributor to the global burden of disease. Short-term effects of PM2.5exposure on respiratory illness have been described but most evidence arises from high pollution settings. We used case-crossover methods to estimate effects of outdoor PM2.5levels on emergency department (ED) presentations and hospital admissions for a range of acute respiratory illnesses and age groups in Melbourne, Australia from 2014–2019, with and without adjustment for other pollutants and weather conditions, using daily and one-week averaged lags. We estimated incidence rate ratios for a 10 μg/m3increase in 7-day average ambient PM2.5of 1.043 (95% confidence interval (CI): 1.000–1.089) on ED presentation and 1.013 (95% CI: 0.971–1.056) on hospital admissions for acute respiratory illnesses for patients of any age. We observed distinct temporal patterns in daily lag effect by disease. The largest effects on acute lower respiratory tract infection and asthma were observed in children. Ambient PM2.5levels rarely exceeded standards in place at the time. Although uncertainty around most point estimates was relatively wide, these findings are most compatible with adverse health effects of ambient PM2.5at levels below currently established Australian national standards.Implications: Understanding the health impacts of air pollution is important for setting air quality targets, as well as for informing robust health system planning. Adverse effects of exposure to outdoor fine particulate matter on human respiratory health have been consistently described. However, most studies have been done in higher-pollution settings. Further, many studies have assessed health effects in broad categories such as all-cause respiratory mortality or hospitalization, and thus lack the granularity to inform detailed health service planning. Our study aimed to estimate effects of outdoor fine particulate matter on emergency department (ED) presentations and hospital admissions for a range of acute respiratory illnesses and age groups in Melbourne, Australia, a city with relatively good air quality by international comparison. Our study estimated consistent effects on both ED presentations and hospital admissions compatible with distinct patterns of adverse health effects at levels at or below established Australian national (and many international) standards. These results will help to inform both air quality policy and public health policy in similar settings.

The article discusses about the Rule 10b5-1 plan, which can afford an insider exposed to material non-public information (MNPI) with an affirmative defense against claims of insider trading in the U.S. Topics discussed include non-judicial settlement agreement (NJSA) statute, stock qualified small business stock (QSBS) eligible for a special exclusion from capital gains tax on sale and Internal Revenue Code Section 1045 rollover of gain of QSBS.

Background Few long-term studies of hepatitis B virus (HBV) infection and hepatocellular carcinoma have focused on women. We used a nationwide cohort of reproductive-aged Taiwanese women to study relationships of HBV infection and parity with hepatocellular carcinoma risk. Methods Prenatal test results were available for hepatitis B surface antigen (HBsAg) and e antigen (HBeAg) in the National Hepatitis B Vaccination Registry from 1782401 pregnant women tested from October 1, 1983, through March 31, 2000. Data from the 306 women who were diagnosed with hepatocellular carcinoma were ascertained during 15901 722 person-years of follow-up through linkage with National Cancer Registry and National Death Certification Registry. We used Cox proportional hazards models to investigate the association of age and reproductive and serological parameters with the risk of hepatocellular carcinoma. Results Incidence rates for hepatocellular carcinoma were 0.55, 7.91, and 8.76 per 100000 person-years among women who were HBsAg negative (ie, noncarriers), HBsAg positive plus HBeAg negative, and HBsAg positive plus HBeAg positive, respectively (compared with noncarriers, for HBsAg-positive and HbeAg-positive women, age-adjusted hazard ratio [HR] for developing hepatocellular carcinoma = 17.31, 95% confidence interval [CI] = 12.08 to 24.81; and for HBsAg-negative plus HBeAg-positive women, HR = 13.94, 95% CI = 10.34 to 18.79). Incidence rates were 0.39, 3.10, and 9.01 per 100000 person-years, respectively, among persistent noncarriers, HBsAg-serocleared carriers, and persistent HBsAg carriers (compared with noncarriers, for HBsAg-serocleared carriers, age-adjusted HR = 7.95, 95% CI = 3.50 to 18.04; and for HBsAg persistence, HR = 23.13, 95% Cl = 14.23 to 37.61). Incidence rates were 2.04, 1.55, and 1.66 per 100000 person-years for women who had one, two, or three or more children, respectively (compared with one child, for two children, age- and HBsAg-adjusted HR = 0.68, 95% CI = 0.50 to 0.93; and for three or more children, HR = 0.63, 95% CI = 0.42 to 0.92). Conclusions The risk for hepatocellular carcinoma was statistically significantly higher among women with chronic or active HBV infections and among those with persistent HBV infection or who underwent HBsAg seroclearance during follow-up than among HBV-unexposed women. This risk decreased as parity increased, independent of HBsAg status and age.

Background: We sought to identify factors associated with newly detected human papillomavirus (HPV) infection in a high-risk cohort of injection drug using women in Baltimore, MD. Methods: We studied 146 HIV-infected and 73 HIV-uninfected female participants in a 5-year prospective HIV natural history study. We examined the association of sexual and nonsexual risk factors and newly detected type-specific HPV infection as determined by consensus PCR between consecutive visits. Results: Newly detected HPV was more common among HIV-infected versus HIV-uninfected women (30% and 6%, respectively; P 500, 200-500, and Conclusions: Newly detected HPV clearly increased with greater immunosuppression in HIV-infected injection drug users. Larger studies of HIV-uninfected and infected high-risk individuals are needed to clarify the independent associations of crack and marijuana use with new (or reactivated) HPV infection.

Diatoms in the Pseudo‐nitzschiagenus produce the neurotoxin domoic acid. Domoic acid bioaccumulates in shellfish, causing illness in humans and marine animals upon ingestion. In 2017, high domoic acid levels in shellfish meat closed shellfish harvest in Narragansett Bay, Rhode Island for the first and only time in history, although abundant Pseudo‐nitzschiahave been observed for over 60 years.To investigate whether an environmental factor altered endemic Pseudo‐nitzschiaphysiology or new domoic acid‐producing strain(s) were introduced to Narragansett Bay, we conducted weekly sampling from 2017 to 2019 and compared closure samples. Plankton‐associated domoic acid was quantified by LC‐MS/MS and Pseudo‐nitzschiaspp. were identified using a taxonomically improved high‐throughput rDNA sequencing approach. Comparison with environmental data revealed a detailed understanding of domoic acid dynamics and seasonal multi‐species assemblages. Plankton‐associated domoic acid was low throughout 2017–2019, but recurred in fall and early summer maxima. Fall domoic acid maxima contained known toxic species as well as a novel Pseudo‐nitzschiagenotype. Summer domoic acid maxima included fewer species but also known toxin producers.Most 2017 closure samples contained the particularly concerning toxic species, P. australis, which also appeared infrequently during 2017–2019. Recurring Pseudo‐nitzschiaassemblages were driven by seasonal temperature changes, and plankton‐associated domoic acid correlated with low dissolved inorganic nitrogen. Thus, the Narragansett Bay closures were likely caused by both resident assemblages that become toxic depending on nutrient status as well as the episodic introductions of toxic species from oceanographic and climatic shifts.

Health equity research in transplantation has largely relied on national data sources, yet the availability of social determinants of health (SDOH) data varies widely among these sources. We sought to characterize the extent to which national data sources contain SDOH data applicable to end‐stage organ disease (ESOD) and transplant patients. We reviewed 10 active national data sources based in the United States. For each data source, we examined patient inclusion criteria and explored strengths and limitations regarding SDOH data, using the National Institutes of Health PhenX toolkit of SDOH as a data collection instrument. Of the 28 SDOH variables reviewed, eight‐core demographic variables were included in ≥80% of the data sources, and seven variables that described elements of social status ranged between 30 and 60% inclusion. Variables regarding identity, healthcare access, and social need were poorly represented (≤20%) across the data sources, and five of these variables were included in none of the data sources. The results of our review highlight the need for improved SDOH data collection systems in ESOD and transplant patients via: enhanced inter‐registry collaboration, incorporation of standardized SDOH variables into existing data sources, and transplant center and consortium‐based investigation and innovation. This study reports the availability of social determinants of health data applicable to end‐stage organ disease and transplant patients within national sources, finds variability in detail and consistency of data inclusion, and offers strategies for improved data collection at the health system and national levels.

In a large multicenter prospectively collected database, the Surgical Critical Care Initiative's microRNA team characterize novel changes in microRNA expression in response to severe trauma. Systemic levels of microRNAs were associated with recovery complications. #microRNA

Objective: People who inject drugs are a population who are often unengaged with health care services. The objective of this study was to characterize COVID-19 vaccine hesitancy and uptake in a community-based sample of people who inject drugs in Baltimore, Maryland.Methods: The ALIVE study (AIDS Linked to the IntraVenous Experience) in Baltimore is a community-based cohort study of people with a history of injection drug use. From March 2 through June 28, 2021, 346 ALIVE participants completed a survey on substance use, structural determinants of health, and COVID-19 vaccine hesitancy. The exposure of interest was COVID-19 vaccine hesitancy, and the primary outcome was vaccination status as of June 30, 2021. We extracted data on the dates of vaccination from electronic medical records linked to study participants.Results: The median age of the sample was 60 years; most participants were male (66%) and non-Hispanic Black (87%). Most (55%) trusted the COVID-19 vaccine, and 68% had received ≥1 dose. After age standardization, survey participants were more likely than the Maryland general population to be unvaccinated (prevalence ratio = 1.20; 95% CI, 0.97-1.49; P= .10). Participants who somewhat trusted or did not trust the COVID-19 vaccine had 6-fold higher odds of being unvaccinated than participants who trusted the vaccine (odds ratio = 6.30; 95% CI, 3.74-10.60).Conclusion: Uptake of COVID-19 vaccine among people with a history of injection drug use was high. Attitudes and knowledge about vaccination were important predictors of vaccine uptake. Education and outreach efforts could be effective in reducing hesitancy and increasing vaccination in substance-using populations.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ajog.2005.02.064 Byline: Gary A. Burgoine (a), Samuel D. Van Kirk (b), Jillian Romm (a), Alison B. Edelman (a), Sig-Linda Jacobson (a), Jeffrey T. Jensen (a) Abstract: This study was undertaken to compare grief resolution after dilation and evacuation (D&E) or induction of labor (IOL) for second-trimester pregnancy termination. Author Affiliation: (a) Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR (b) Women's Healthcare Associates, Meridian Park Hospital, Tualatin, OR Article Note: (footnote) Presented as a poster at the 71st Annual Meeting of the Pacific Coast Obstetrical and Gynecological Society, October 19-24, 2004, Phoenix, Ariz.

Mitochondria released from injured cells activate endothelial cells (ECs), fostering inflammatory processes, including allograft rejection. The stimulator of interferon genes (STING) senses endogenous mitochondrial DNA, triggering innate immune activation via NF-κB signaling. Here, we show that exogenous mitochondria exposure induces EC STING-NF-κB activation, promoting EC/effector memory T cell adhesion, which is abrogated by NF-κB and STING inhibitors. STING activation in mitochondrion-activated ECs is independent of canonical cGMP-AMP synthetase sensing/signaling, but rather is mediated by interferon gamma-inducible factor 16 (IFI16) and can be inhibited by IFI16 inhibition. Internalized mitochondria undergo mitofusion and STING-dependent mitophagy, leading to selective sequestration of internalized mitochondria. The exposure of donor hearts to exogenous mitochondria activates murine heart ECs in vivo. Collectively, our results suggest that IFI16-STING-NF-κB signaling regulates exogenous mitochondrion-induced EC activation and mitophagy, and exogenous mitochondria foster T cell–mediated CoBRR. These data suggest a novel, donor-directed, therapeutic approach toward mitigating perioperative allograft immunogenicity.

Type 1 diabetes results from the immune-mediated destruction of the insulin-producing pancreatic β-cells, located in cell clusters called the islets of Langerhans (1,2). The field of islet transplantation recently emerged [...], We've established a nonhuman primate islet allotransplant model to address questions such as whether transplanting islets into the gut's arterial system would more safely and as effectively support long-term islet allograft survival compared with the traditional portal vein approach. We reasoned that islets make up

The article discusses factors to be considered by trustees and advisors with regards to environmental, social and governance (ESG) investing in the U.S. Topics discussed include the duties of trustees outside the prudent investor rule (PIR) which may affect their ESG investing, the trustee decision tree, and the different types of trustees including ESG-convicted trustee, ESG-willing trustee, ESG-persuaded trustee and ESG-compelled trustee.

Automated Guided Vehicles (AGVs) have the flexibility to meet the material handling requirements of asynchronous assembly lines. Furthermore, AGVs can select from among alternative paths in accordance with a prescribed lane selection rule, thereby facilitating the use of parallel server workstations. In this paper, motivated by our work in the automotive industry, several new lane selection rules are proposed. One of these, First Available Server/First Available Buffer/Balanced Work Content (FAS/FAB/BWC), is compared to two existing rules: Alternating Server, and First Available Server/First Available Buffer/Expected Completion Time (FAS/FAB/EC). Three performance measures - job throughput, workload balance among servers, and alteration of input job sequence - are employed. A SIMAN simulation model of a small, asynchronous parallel assembly line is used to study the impact on system performance of both the lane selection rule and the number of parallel servers. Interaction between these two factors is studied through ANOVA. A number of interesting findings are reported for results of the lane selection rules with respect to the three performance measures. Their interpretation is used to motivate further research.

IMPORTANCE: Persons with immune dysfunction have a higher risk for severe COVID-19 outcomes. However, these patients were largely excluded from SARS-CoV-2 vaccine clinical trials, creating a large evidence gap. OBJECTIVE: To identify the incidence rate and incidence rate ratio (IRR) for COVID-19 breakthrough infection after SARS-CoV-2 vaccination among persons with or without immune dysfunction. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study analyzed data from the National COVID Cohort Collaborative (N3C), a partnership that developed a secure, centralized electronic medical record–based repository of COVID-19 clinical data from academic medical centers across the US. Persons who received at least 1 dose of a SARS-CoV-2 vaccine between December 10, 2020, and September 16, 2021, were included in the sample. MAIN OUTCOMES AND MEASURES: Vaccination, COVID-19 diagnosis, immune dysfunction diagnoses (ie, HIV infection, multiple sclerosis, rheumatoid arthritis, solid organ transplant, and bone marrow transplantation), other comorbid conditions, and demographic data were accessed through the N3C Data Enclave. Breakthrough infection was defined as a COVID-19 infection that was contracted on or after the 14th day of vaccination, and the risk after full or partial vaccination was assessed for patients with or without immune dysfunction using Poisson regression with robust SEs. Poisson regression models were controlled for a study period (before or after [pre– or post–Delta variant] June 20, 2021), full vaccination status, COVID-19 infection before vaccination, demographic characteristics, geographic location, and comorbidity burden. RESULTS: A total of 664 722 patients in the N3C sample were included. These patients had a median (IQR) age of 51 (34-66) years and were predominantly women (n = 378 307 [56.9%]). Overall, the incidence rate for COVID-19 breakthrough infection was 5.0 per 1000 person-months among fully vaccinated persons but was higher after the Delta variant became the dominant SARS-CoV-2 strain (incidence rate before vs after June 20, 2021, 2.2 [95% CI, 2.2-2.2] vs 7.3 [95% CI, 7.3-7.4] per 1000 person-months). Compared with partial vaccination, full vaccination was associated with a 28% reduced risk for breakthrough infection (adjusted IRR [AIRR], 0.72; 95% CI, 0.68-0.76). People with a breakthrough infection after full vaccination were more likely to be older and women. People with HIV infection (AIRR, 1.33; 95% CI, 1.18-1.49), rheumatoid arthritis (AIRR, 1.20; 95% CI, 1.09-1.32), and solid organ transplant (AIRR, 2.16; 95% CI, 1.96-2.38) had a higher rate of breakthrough infection. CONCLUSIONS AND RELEVANCE: This cohort study found that full vaccination was associated with reduced risk of COVID-19 breakthrough infection, regardless of the immune status of patients. Despite full vaccination, persons with immune dysfunction had substantially higher risk for COVID-19 breakthrough infection than those without such a condition. For persons with immune dysfunction, continued use of nonpharmaceutical interventions (eg, mask wearing) and alternative vaccine strategies (eg, additional doses or immunogenicity testing) are recommended even after full vaccination.

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Evidence of whether people living with HIV are at elevated risk of adverse COVID-19 outcomes is inconclusive. We aimed to investigate this association using the population-based National COVID Cohort Collaborative (N3C) data in the USA.

Thymic output and homeostatic mature cell proliferation both influence T cell repopulation following depletional induction, though the relative contribution of each and their association with recipient age have not been well studied. We investigated the repopulating T cell kinetics in kidney transplant recipients who underwent alemtuzumab induction followed by belatacept/rapamycin-based immunosuppression over 36-month posttransplantation. We focused specifically on the correlation between repopulating T cell subsets and the age of patients. Substantial homeostatic Ki67-expressing T cell proliferation was seen posttransplantation. A repertoire enriched for naïve T (TNaïve) cells emerged posttransplantation. Analysis by generalized estimating equation linear models revealed a strong negative linear association between reconstituting TNaïvecells and advancing age. A relationship between age and persistence of effector memory cells was shown. We assessed thymic output and found an increase in the frequency of recent thymic emigrants (RTEs, CD4+CD31+) at 12-month posttransplantation. Patients under 30 years of age showed significantly higher levels of CD4+CD31+cells than patients over 55 years of age pre- and posttransplantation. IL-7 and autologous mature dendritic cells (mDCs) induced CD57–cell proliferation. In contrast, mDCs, but not IL-7, induced CD57+cell proliferation. This study establishes the relationship between age and thymic output during T cell homeostatic repopulation after alemtuzumab induction.

In the late twentieth century, the rise of the female suicide bomber phenomenon was prevalent in Chechnya, Lebanon and Sri Lanka. Arguably, in terms of academic engagement and visibility within the wider public consciousness, the first wave of Palestinian female suicide bombers during the second intifada (2000–05) encapsulates particular notoriety in relation to the perceived deviance of Palestinian female participation in political violence. Key to this construction is the role of news media as an agent of power. This article examines coverage of Palestinian female suicide bombers during the second intifada period within the scarcely examined medium of British terrestrial broadcast news media. This article determines the impact of individual journalists' gender in producing forms of discourse that delegitimize political agency. In particular, it shall establish if female journalistic voices are complicit in communicating intersectional gendered and Orientalist frameworks.

Despite extraordinary achievements in over the past 20 years, the field of transplantation remains hindered by relatively narrow metrics for success. Eudaimonia is an Aristotelian concept that refers to flourishing, or achieving the best conditions possible, in every sense. The vast amounts of patient data that are collected throughout the transplant care continuum, ranging from social determinants of health to genomic profiles and patient‐reported outcomes, afford us unprecedented opportunity to enhance our definition of success for our transplant patients. We must engage the technologies available for data integration and analysis and apply them in an insightful way, such that our clinical practice evolves beyond patient and graft survival and toward a more comprehensive state of wellness. The authors propose multidimensional data integration to inform the pursuit of a holistic definition of improved well‐being after transplantation.

Kidney transplant recipients administered belatacept‐based maintenance immunosuppression present with a more favorable metabolic profile, reduced incidence of de novo donor‐specific antibodies (DSAs), and improved renal function and long‐term patient/graft survival relative to individuals receiving calcineurin inhibitor (CNI)‐based immunosuppression. However, the rates and severity of acute rejection (AR) are greater with the approved belatacept‐based regimen than with CNI‐based immunosuppression. Although these early co‐stimulation blockade‐resistant rejections are typically steroid sensitive, the higher rate of cellular AR has led many transplant centers to adopt immunosuppressive regimens that differ from the approved label. This article summarizes the available data on these alternative de novo belatacept‐based maintenance regimens. Steroid‐sparing, belatacept‐based immunosuppression (following T cell–depleting induction therapy) has been shown to yield AR rates comparable to those seen with CNI‐based regimens. Concomitant treatment with belatacept plus a mammalian target of rapamycin inhibitor (mTORi; sirolimus or everolimus) has yielded AR rates ranging from 0 to 4%. Because the optimal induction agent and number of induction doses; blood levels of mTORi; and dose, duration, and use of corticosteroids have yet to be determined, larger prospective clinical trials are needed to establish the optimal alternative belatacept‐based regimen for minimizing early cellular AR occurrence. Kirk et al. discuss available data on alternative de novo belatacept‐based immunosuppression regimens in place of the approved belatacept regimen to reduce acute rejection rates in kidney transplant recipients.

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Chemical screening libraries often feature natural product extracts (NPEs) due to the intriguing biological activities they possess and the structural diversity found in their individual components. A research project originally designed to create an extract library of every specimen in the University of Rhode Island (URI) Heber W. Youngken Jr. Medicinal Garden soon turned into a laboratory-based teaching project in which upper-division undergraduate students generated and analyzed extracts in an academic minisemester project. Additionally, motivated upper-division undergraduates carried out independent research isolating biologically active molecules. Hands-on laboratory activities enhanced students’ knowledge of methodologies and workflows associated with extract analysis and biological evaluation of botanical extracts. The synergy of the laboratory course with the independent study contributed to workforce preparation and library generation.

Depletional induction using antithymocyte globulin (ATG) reduces rates of acute rejection in adult kidney transplant recipients, yet little is known about its effects in children. Using a longitudinal cohort of 103 patients in the Immune Development in Pediatric Transplant (IMPACT) study, we compared T cell phenotypes after ATG or non‐ATG induction. We examined the effects of ATG on the early clinical outcomes of alloimmune events (development of de novo donor specific antibody and/or biopsy proven rejection) and infection events (viremia/viral infections). Long‐term patient and graft outcomes were examined using the Scientific Registry of Transplant Recipients. After ATG induction, although absolute counts of CD4 and CD8 T cells were lower, patients had higher percentages of CD4 and CD8 memory T cells with a concomitant decrease in frequency of naïve T cells compared to non‐ATG induction. In adjusted and unadjusted models, ATG induction was associated with increased early event‐free survival, with no difference in long‐term patient or allograft survival. Decreased CD4+naïve and increased CD4+effector memory T cell frequencies were associated with improved clinical outcomes. Though immunologic parameters are drastically altered with ATG induction, long‐term clinical benefits remain unclear in pediatric patients. The authors identify an association between antithymocyte globulin–based induction, an increase in memory and mature T cell phenotypes, and improved short‐term but not long‐term clinical outcomes for children undergoing kidney transplantation.

Kidney transplant outcomes are limited by toxicities associated with calcineurin inhibitors and steroids. This trial was conducted to determine whether a costimulation blockade (CoB)‐based regimen could achieve acceptable long‐term outcomes and graft survival could be maintained solely with CoB. Forty patients underwent alemtuzumab induction followed by belatacept and sirolimus maintenance therapy. Patients were offered weaning to belatacept monotherapy after 1 year and followed for 5 years. Five‐year patient and graft survival rates were 100% and 95%, respectively. Graft function remained stable with a mean estimated glomerular filtration rates of 67 ± 21 and 71 ± 19 at 36 and 60 months, respectively. There was no clinical rejection in the first year; subclinical rejection was detected by protocol biopsy in 4 patients. Twelve patients were successfully weaned to belatacept monotherapy. Cytomegalovirus and Epstein‐Barr virus reactivations were well controlled, but 9 patients experienced transient BK viremia during the first year. Alemtuzumab produced profound lymphopenia followed by gradual T cell and more rapid B cell reconstitution to a repertoire deviated toward naïve cells with increased regulatory T cells. This regimen effectively prevents allograft rejection without using steroids or calcineurin inhibitors, enriches for naïve cells susceptible to control with CoB, and permits control of rejection with belatacept monotherapy in selected patients. Excellent long‐term graft survival and renal function can be achieved using a calcineurin inhibitor–free and steroid‐free immunosuppression consisting of alemtuzumab induction followed by belatacept and rapamycin, a regimen which prevents costimulation blockade–resistant rejection and is permissive, in select patients, of minimization to once‐monthly belatacept infusions.