CD28-Selective Inhibition Prolongs Non-Human Primate Kidney Transplant Survival.

Costimulation blockade using belatacept results in improved renal function after kidney transplant as well as decreased likelihood of death/graft loss and reduced cardiovascular risk; however, higher rates and grades of acute rejection have prevented its widespread clinical adoption. Treatment with belatacept blocks both positive (CD28) and negative (CTLA-4) T cell signaling. CD28-selective therapies may offer improved potency by blocking CD28-mediated costimulation while leaving CTLA-4 mediated coinhibitory signals intact. Here we test a novel domain antibody directed at CD28 (anti-CD28 dAb (BMS-931699)) in a non-human primate kidney transplant model. Sixteen macaques underwent native nephrectomy and received life-sustaining renal allotransplantation from an MHC-mismatched donor. Animals were treated with belatacept alone, anti-CD28 dAb alone, or anti-CD28 dAb plus clinically relevant maintenance (MMF, Steroids) and induction therapy with either anti-IL-2R or T cell depletion. Treatment with anti-CD28 dAb extended survival compared to belatacept monotherapy (MST 187 vs. 29 days, p=0.07). The combination of anti-CD28 dAb and conventional immunosuppression further prolonged survival to MST ∼270 days. Animals maintained protective immunity with no significant infectious issues. These data demonstrate CD28-directed therapy is a safe and effective next-generation costimulatory blockade strategy with a demonstrated survival benefit and presumed advantage over belatacept by maintaining intact CTLA-4 coinhibitory signaling.

Should responder analyses be conducted on continuous outcomes?

Continuous outcomes are often dichotomized to classify trial subjects as responders or nonresponders, with the difference in rates of response between treatment and control defined as the "responder effect." In this article, we caution that dichotomization of continuous interval outcomes may not be best practice. Defining clinical benefit or harm for continuous interval outcomes as the difference between the means of treatment and control, that is, the "continuous treatment effect," we examine the case where treatment and control outcomes are normally distributed and differ only in location. For this case, continuous treatment effects may be considered clinically relevant if they exceed a prespecified minimum clinically important difference. In contrast, using minimum clinically important differences as dichotomization thresholds will not ensure clinically relevant responder effects. For example, in some situations, increasing the threshold may actually relax the criterion for effectiveness by increasing the calculated responder effect. Using responder effects to quantitatively assess benefit or risk of investigational drugs for continuous interval outcomes presents interpretational challenges. In particular, when the dichotomization threshold is halfway between the treatment and control outcome means, the responder effect is at a maximum with a magnitude monotonically related to the number of standard deviations between the mean outcomes of treatment and control. Large responder effect benefits may therefore reflect clinically unimportant continuous treatment effects amplified by small standard deviations, and small responder effect risks may reflect either clinically important continuous treatment effects minimized by large standard deviations, or selection of a dichotomization threshold not providing maximum responder effect.

Preventive Medicine Physicians' Role in Health Care Organizations' Pursuit of the Triple Aim.

CONTEXT: The Institute for Healthcare Improvement's Triple Aim is rooted in improving population health and therefore requires a focus on prevention as well as management of disease. Preventive medicine (PM) physicians are uniquely trained in clinical medicine as well as health care delivery and systems-based practice, thus potentially positioning them to lead population health and contribute to the Triple Aim. OBJECTIVE: The objectives of this study were to (1) describe PM physicians' contributions related to the Triple Aim and (2) describe PM physician satisfaction with these activities. DESIGN: A survey was administered to physicians graduating from a single Preventive Medicine Residency program between 1975 and 2015. Physicians were asked about work in 3 specific emerging areas that relate to the Triple Aim's focus on population health improvement: population health; health system transformation; and integration between primary care and public health. PM physicians were also asked about their job, career, and specialty satisfaction. RESULTS: Most respondents (74%) practiced population health, with the majority (63%) defining this as improving the health of the population at large versus for a defined clinical population (37%). Approximately half (59%) of PM physicians are involved in health system transformation leadership. Most respondents practice both public health and primary care, but only 32% report having had positions that involve integration of these activities. PM physicians reported high specialty satisfaction levels, particularly among those involved in population health and health care transformation. CONCLUSION: PM physicians already make substantial contributions to population health and lead work related to the Triple Aim. High satisfaction among PM physicians suggests that they can contribute to a stable and sustainable population health workforce.

Implementation of Evidence-Based Recommendations for Preventive Services in the Veterans Health Administration.

INTRODUCTION: The Veterans Health Administration (VHA) is the largest integrated health care system in the United States. To date, there has been scant research on how VHA adopts clinical preventive services guidelines and how U.S. Preventive Services Task Force recommendations factor into the process. METHODS: Researchers conducted semistructured interviews with eight VHA leaders to examine how they adopt, disseminate, and measure adherence to recommendations. Interviews were recorded, transcribed, and aggregated into a database to enable sorting and synthesis. Themes were identified across the key informant interviews. RESULTS: The development of VHA clinical prevention guidelines is coordinated by the National Center for Health Promotion and Disease Prevention. A VHA Advisory Committee discusses and votes to approve or disapprove each guideline. Several factors can impact the ability of a veterans affairs medical center to implement a guideline, such as local system capacity and priorities for quality improvement. Methods to promote implementation include electronic reminders, educational events, and a robust performance measurement system. CONCLUSIONS: Provision of evidence-based clinical preventive services is an important part of VHA's effort to provide high-quality care for Veterans. Recent achievements in lung cancer, colorectal cancer, and Hepatitis C screening highlight VHA's successful approach to implementation of preventive services guidance.

Alignment of Preventive Medicine Physicians' Residency Training With Professional Needs.

Preventive medicine (PM) physicians promote population-based approaches to health care with training that emphasizes public health, epidemiology, and policy. PM physicians use these skills in varied, often nonclinical, practice settings. PM career diversity challenges educators when designing residency curricula. Input from PM physicians about workforce environments is needed to ensure that residency requirements match skills needed post-residency. Graduates of one PM residency were sent a cross-sectional survey in 2016. Questions included professional experience, importance of 18 Accreditation Council for Graduate Medical Education sub-competencies and 13 leadership/management skills to current position, and residency training adequacy in those sub-competencies/skills. Responses were rated on 3-point Likert scales. Analyses were completed in 2017. Pearson's chi-square tests examined relationships between position type (academic/government) and perception of competencies' importance and training adequacy. Eighty PM physicians responded (46%): 44% worked in academia and 25% in federal/state/local government. Half (53%) were PM board certified. A total of 88% completed clinical residency prior to PM. Thirteen of 18 competencies were important to work, and respondents felt well trained in 16 of 18 competencies. Respondents did not feel well trained in emergency preparedness and surveillance systems during residency and their opinions about the importance of these sub-competencies varied based on where they worked. Respondents rated all 13 leadership/management skills as important, but reported inadequate residency training. In conclusion, respondents rated most Accreditation Council for Graduate Medical Education sub-competencies as important to current work and felt well trained, indicating good alignment between residency training and professional needs. Respondents also reported leadership/management training deficiencies. PM residencies might consider incorporating formal leadership training into curricula.

Long-term survival of pig-to-rhesus macaque renal xenografts is dependent on CD4 T cell depletion.

The shortage of available organs remains the greatest barrier to expanding access to transplant. Despite advances in genetic editing and immunosuppression, survival in experimental models of kidney xenotransplant has generally been limited to <100 days. We found that pretransplant selection of recipients with low titers of anti-pig antibodies significantly improved survival in a pig-to-rhesus macaque kidney transplant model (6 days vs median survival time 235 days). Immunosuppression included transient pan-T cell depletion and an anti-CD154-based maintenance regimen. Selective depletion of CD4+ T cells but not CD8+ T cells resulted in long-term survival (median survival time >400 days vs 6 days). These studies suggested that CD4+ T cells may have a more prominent role in xenograft rejection compared with CD8+ T cells. Although animals that received selective depletion of CD8+ T cells showed signs of early cellular rejection (marked CD4+ infiltrates), animals receiving selective CD4+ depletion exhibited normal biopsy results until late, when signs of chronic antibody rejection were present. In vitro study results suggested that rhesus CD4+ T cells required the presence of SLA class II to mount an effective proliferative response. The combination of low pretransplant anti-pig antibody and CD4 depletion resulted in consistent, long-term xenograft survival.

Screening for Intimate Partner Violence, Elder Abuse, and Abuse of Vulnerable Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Intimate partner violence (IPV), elder abuse, and abuse of vulnerable adults are common and result in adverse health outcomes. Objective: To review the evidence on screening and interventions for IPV, elder abuse, and abuse of vulnerable adults to inform the US Preventive Services Task Force. Data Sources: MEDLINE, Cochrane Library, EMBASE, and trial registries through October 4, 2017; references; experts; literature surveillance through August 1, 2018. Study Selection: English-language randomized clinical trials (RCTs), studies evaluating test accuracy, and cohort studies with a concurrent control group assessing harms. Data Extraction and Synthesis: Dual review of titles and abstracts, full-text articles, and study quality; qualitative synthesis of findings. Data were not pooled, primarily because of heterogeneity of populations, interventions, and outcomes. Main Outcomes and Measures: Abuse or neglect, morbidity caused by abuse, test accuracy, and harms. Results: Thirty studies were included (N = 14 959). Three RCTs (n = 3759) compared IPV screening with no screening; none found significant improvements in outcomes (eg, IPV or quality of life) over 3 to 18 months and 2 (n = 935) reported no harms of screening. Nine studies assessed tools to detect any past-year or current IPV in women; for past-year IPV (5 studies [n = 6331]), sensitivity of 5 tools ranged from 65% to 87% and specificity ranged from 80% to 95%. The accuracy of 5 tools (4 studies [n = 1795]) for detecting current abuse varied widely; sensitivity ranged from 46% to 94% and specificity ranged from 38% to 95%. Eleven RCTs (n = 6740) evaluated interventions for women with screen-detected IPV. Two enrolling pregnant women (n = 575) found significantly less IPV among women in the intervention group: 1 home visiting intervention (standardized mean difference [SMD], -0.34 [95% CI, -0.59 to -0.08]) and 1 behavioral counseling intervention for multiple risks (IPV, smoking, depression, tobacco exposure) (SMD, -0.40 [95% CI, -0.68 to -0.12]). No studies evaluated screening or interventions for elder abuse or abuse of vulnerable adults. One study assessing a screening tool for elder abuse had poor accuracy (sensitivity, 46% and specificity, 73% for detecting physical or verbal abuse). Conclusions and Relevance: Although available screening tools may reasonably identify women experiencing IPV, trials of IPV screening in adult women did not show a reduction in IPV or improvement in quality of life over 3 to 18 months. Limited evidence suggested that home visiting and behavioral counseling interventions that address multiple risk factors may lead to reduced IPV among pregnant or postpartum women. No studies assessed screening or treatment for elder abuse and abuse of vulnerable adults.

CD122 signaling in CD8+ memory T cells drives costimulation-independent rejection.

Interrupting T cell costimulatory signals as a strategy to control undesired immune responses, such as occur in autoimmunity or transplantation, has the potential to alleviate many of the unwanted side effects associated with current immunosuppressive therapies. Belatacept, a high-affinity version of CTLA4-Ig that blocks ligand ligation to CD28, has been approved for use in kidney transplant recipients. Despite the long-term benefits associated with its use, such as improved renal function and lower cardiovascular risk, a subset of patients treated with belatacept experience elevated rates of acute T cell-mediated rejection, tempering enthusiasm for its use. Here we demonstrate that costimulation-independent T cell alloreactivity relies on signaling through CD122, the shared IL-2 and IL-15 receptor ß-chain. Combined costimulatory and CD122 blockade improved survival of transplanted tissue in mice and nonhuman primates by controlling proliferation and effector function of CD8+ T cells. The high-affinity IL-2 receptor was dispensable for memory CD8+ T cell responses, whereas signaling through CD122 as a component of the high-affinity IL-15 receptor was critical for costimulation-independent memory CD8+ T cell recall, distinguishing specific roles for IL-2 and IL-15 in T cell activation. These studies outline a novel approach for clinical optimization of costimulatory blockade strategies in transplantation by targeting CD122.

Preventing T cell rejection of pig xenografts.

Xenotransplantation is a potential solution to the limited supply of donor organs. While early barriers to xenograft acceptance, such as hyperacute rejection, are now largely avoided through genetic engineering, the next frontier in successful xenograft survival will require prevention of T cell-mediated rejection. Most successful immunosuppressive regimens in xenotransplantation utilize T cell depletion with antibody therapy. Additionally, the use of T cell costimulatory blockade - specifically blockade of the CD40-CD154 pathway - shows promise with several reports of long-term xenograft survival. Additional therapies, such as transgenic expression of T cell coinhibitory molecules or transfer of immunomodulatory cells to promote tolerance, may be necessary to achieve reliable long-term xenograft acceptance. Further studies in pre-clinical models are essential in order to optimize these regimens prior to trials in patients.

Pre-transplant antibody screening and anti-CD154 costimulation blockade promote long-term xenograft survival in a pig-to-primate kidney transplant model.

Xenotransplantation has the potential to alleviate the organ shortage that prevents many patients with end-stage renal disease from enjoying the benefits of kidney transplantation. Despite significant advances in other models, pig-to-primate kidney xenotransplantation has met limited success. Preformed anti-pig antibodies are an important component of the xenogeneic immune response. To address this, we screened a cohort of 34 rhesus macaques for anti-pig antibody levels. We then selected animals with both low and high titers of anti-pig antibodies to proceed with kidney transplant from galactose-α1,3-galactose knockout/CD55 transgenic pig donors. All animals received T-cell depletion followed by maintenance therapy with costimulation blockade (either anti-CD154 mAb or belatacept), mycophenolate mofetil, and steroid. The animal with the high titer of anti-pig antibody rejected the kidney xenograft within the first week. Low-titer animals treated with anti-CD154 antibody, but not belatacept exhibited prolonged kidney xenograft survival (>133 and >126 vs. 14 and 21 days, respectively). Long-term surviving animals treated with the anti-CD154-based regimen continue to have normal kidney function and preserved renal architecture without evidence of rejection on biopsies sampled at day 100. This description of the longest reported survival of pig-to-non-human primate kidney xenotransplantation, now >125 days, provides promise for further study and potential clinical translation.

Team assessment of behaviour: a high stakes assessment with potential for poor implementation and impaired validity.

Team assessment of behaviour (TAB) is the multi-source feedback assessment of professional behaviours that all UK foundation doctors must engage in twice during their two-year programme. TAB can identify the few underperforming trainees and provide feedback to consolidate the good practice of most. For optimum validity, TAB must be undertaken by a range of assessors, as specified in the national UK Foundation Programme curriculum. This study reports an audit of invalid TAB submissions over a three-year cycle in the West Midlands' Foundation Programme. In 2010, large numbers of TABs were invalid, owing to an incorrect selection or number of assessors. Introduction of validity checking before sign-off greatly improved the numbers of valid assessments in 2011. This was partially sustained in 2012. Assurance of assessment validity is important to ensure delivery of appropriate constructive feedback and to allow early detection and remediation of signs of poor professional behaviours in foundation doctors.

Women, but not men, have prolonged QT interval if depressed after an acute coronary syndrome.

AIMS: Depression is a mortality risk marker for acute coronary syndrome (ACS) patients. We hypothesized that the QT interval, a predictor for risk of sudden cardiac death, was related to depressive symptoms in ACS. METHODS AND RESULTS: We performed an analysis of admission electrocardiograms from hospitalized patients with unstable angina or non-ST elevation myocardial infarction from two prospective observational studies of depression in ACS. Depressive symptoms were assessed with the Beck Depression Inventory (BDI), and depression was defined as BDI score ≥10, compared with <5. Patients with QRS duration ≥120 ms and/or who were prescribed antidepressants were excluded. QT intervals were adjusted for heart rate by two methods. Our analyses included 243 men (40.0% with BDI ≥10) and 139 women (62.0% with BDI ≥ 10). Among women, average QT corrected by Fridericia's method (QTcF) was 435.4 ± 26.6 ms in the depressed group, vs. 408.6 ± 24.3 ms in the non-depressed group (P< 0.01). However, among men, average QTcF was not significantly different between the depressed and non-depressed groups (415.4 ± 23.6 vs. 412.0 ± 25.8 ms, P= 0.29). In multivariable analyses that included hypertension, diabetes, ACS type, left ventricular ejection fraction <0.40, and use of QT-prolonging medication, there was a statistically significant interaction between depressive symptoms and gender (P< 0.001). CONCLUSIONS: In this ACS sample, prolongation of the QT interval was associated with depressive symptoms in women, but not in men. Further investigation of the mechanism of the relationship between depression and abnormal cardiac repolarization, particularly in women, is warranted to develop treatment strategies.