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An increasing number of patients older than 65 years are referred for and have access to organ transplantation, and an increasing number of older adults are donating organs. Although short-term outcomes are similar in older versus younger transplant recipients, older donor or recipient age is associated with inferior long-term outcomes. However, age is often a proxy for other factors that might predict poor outcomes more strongly and better identify patients at risk for adverse events. Approaches to transplantation in older adults vary across programs, but despite recent gains in access and the increased use of marginal organs, older patients remain less likely than other groups to receive a transplant, and those who do are highly selected. Moreover, few studies have addressed geriatric issues in transplant patient selection or management, or the implications on health span and disability when patients age to late life with a transplanted organ. This paper summarizes a recent trans-disciplinary workshop held by ASP, in collaboration with NHLBI, NIA, NIAID, NIDDK and AGS, to address issues related to kidney, liver, lung, or heart transplantation in older adults and to propose a research agenda in these areas.

BACKGROUND: Although vitamin deficiencies are rare in the United States, acute reductions in concentrations of plasma retinol (vitamin A) or alpha-tocopherol (vitamin E) have been associated with impaired immune responses in some clinical settings. OBJECTIVE: The objectives were to determine the plasma concentrations of retinol and alpha-tocopherol in patients undergoing dose-intensive therapy and hematopoietic stem cell transplant and to examine the association of plasma concentrations with clinical outcomes reflecting immunity. DESIGN: This was an observational trial of 120 consecutive recipients of hematopoietic stem cell transplant and a multivariate analysis of plasma vitamin concentrations, mucositis, infections in the first 30 d, and herpes zoster infections in the first year after hematopoietic stem cell transplant. RESULTS: Plasma retinol and alpha-tocopherol concentrations declined from baseline to day 7, typically recovering without specific replacement toward baseline by day 14. The severity of mucositis was a strong predictor of low plasma retinol on day 7 (P = 0.001). Eighty-two patients (68%) had at least one plasma retinol concentration < or = 1.05 micro mol/L, a concentration previously determined to be of immunologic significance, during the peritransplant period (day -8 to day 14). Men more frequently acquired herpes zoster than women, and men who developed hyporetinolemia (< or = 1.05 micro mol/L) had a significantly higher risk of herpes zoster (OR: 6.6; 95% CI: 1.5, 29.6). Plasma alpha-tocopherol was not associated with any clinical event measured in this study. CONCLUSION: Hyporetinolemia is common, particularly in subjects with severe mucositis, and is associated with an increased risk of herpes zoster infection in recipients of hematopoietic stem cell transplant. Additional investigations are required to determine whether these findings indicate a causal relation. Copyright © 2002 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Mesenteric panniculitis is a non-neoplastic condition involving inflammation and fibrosis of the small bowel mesentery. We describe a man in his 60s who presented with 3 months of febrile episodes, confusion and weight loss. The diagnosis of mesenteric panniculitis had been established 2 weeks prior based on an abdominal computerized tomography scan. Extensive diagnostic investigations during his hospitalisation were unrevealing, and the symptoms were ultimately attributed to the mesenteric panniculitis. The fevers resolved over several weeks, and no further episodes have occurred since discharge. This case suggests that mesenteric panniculitis merits consideration in the differential diagnosis of fever of unknown origin., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The learning health system (LHS) has emerged over the past 15 years as a concept for improving health care delivery. Core aspects of the LHS concept include: promoting improved patient care through organizational learning, innovation, and continuous quality improvement; identifying, critically assessing, and translating knowledge and evidence into improved practices; building new knowledge and evidence around how to improve health care and health outcomes; analyzing clinical data to support learning, knowledge generation, and improved patient care; and engaging clinicians, patients, and other stakeholders in processes of learning, knowledge generation, and translation. However, the literature has paid less attention to how these LHS aspects may integrate with the multiple missions of academic medical centers (AMCs). The authors define an academic learning health system (aLHS) as an LHS built around a robust academic community and central academic mission, and they propose 6 features that emphasize how an aLHS differs from an LHS. An aLHS capitalizes on embedded academic expertise in health system sciences; engages the full spectrum of translational investigation from mechanistic basic sciences to population health; builds pipelines of experts in LHS sciences and clinicians with fluency in practicing in an LHS; applies core LHS principles to the development of curricula and clinical rotations for medical students, housestaff, and other learners; disseminates knowledge more broadly to advance the evidence for clinical practice and health systems science methods; and addresses social determinants of health, creating community partnerships to mitigate disparities and improve health equity. As AMCs evolve, the authors expect that additional differentiating features and ways to operationalize the aLHS will be identified and hope this article stimulates further discussion around the intersection of the LHS concept and AMCs., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Association of American Medical Colleges.)

Background: Frailty is associated with numerous post-operative adverse outcomes in older adults. Current pre-operative frailty screening tools require additional data collection or objective assessments, adding expense and limiting large-scale implementation., Objective: To evaluate the association of an automated measure of frailty integrated within the Electronic Health Record (EHR) with post-operative outcomes for nonemergency surgeries., Design: Retrospective cohort study., Setting: Academic Medical Center., Participants: Patients 65 years or older that underwent nonemergency surgery with an inpatient stay 24 hours or more between October 8th, 2017 and June 1st, 2019., Exposures: Frailty as measured by a 54-item electronic frailty index (eFI)., Outcomes and Measurements: Inpatient length of stay, requirements for post-acute care, 30-day readmission, and 6-month all-cause mortality., Results: Of 4,831 unique patients (2,281 females (47.3%); mean (SD) age, 73.2 (5.9) years), 4,143 (85.7%) had sufficient EHR data to calculate the eFI, with 15.1% categorized as frail (eFI > 0.21) and 50.9% pre-frail (0.10 < eFI ≤ 0.21). For all outcomes, there was a generally a gradation of risk with higher eFI scores. For example, adjusting for age, sex, race/ethnicity, and American Society of Anesthesiologists class, and accounting for variability by service line, patients identified as frail based on the eFI, compared to fit patients, had greater needs for post-acute care (odds ratio (OR) = 1.68; 95% confidence interval (CI) = 1.36-2.08), higher rates of 30-day readmission (hazard ratio (HR) = 2.46; 95%CI = 1.72-3.52) and higher all-cause mortality (HR = 2.86; 95%CI = 1.84-4.44) over 6 months' follow-up., Conclusions: The eFI, an automated digital marker for frailty integrated within the EHR, can facilitate pre-operative frailty screening at scale., (© 2021 The American Geriatrics Society.)

Function and the independent performance of daily activities are of critical importance to older adults. Although function was once a domain of interest primarily limited to geriatricians, transdisciplinary research has demonstrated its value across the spectrum of medical and surgical care. Nonetheless, integrating a functional perspective into medical and surgical therapeutics has yet to be implemented consistently into clinical practice. This article summarizes the presentations and discussions from a workshop, "Embedding/Sustaining a Focus on Function in Specialty Research and Care," held on January 31 to February 1, 2019. The third in a series supported by the National Institute on Aging and the John A. Hartford Foundation, the workshop aimed to identify scientific gaps and recommend research strategies to advance the implementation of function in care of older adults. Transdisciplinary leaders discussed implementation of mobility programs and functional assessments, including comprehensive geriatric assessment; integrating cognitive and sensory functional assessments; the role of culture, environment, and community in incorporating function into research; innovative methods to better identify functional limitations, techniques, and interventions to facilitate functional gains; and the role of the health system in fostering integration of function. Workshop participants emphasized the importance of aligning goals and assessments and adopting a team science approach that includes clinicians and frontline staff in the planning, development, testing, and implementation of tools and initiatives. This article summarizes those discussions., (© 2020 The American Geriatrics Society.)

Background: Filming teaching sessions were reported in the medical literature in the 1980s and 1990s but appear to have been an underreported and/or underutilized teaching tool since that time. National faculty development programs, such as the Harvard Macy Institute (HMI) Program for Educators in Health Professions and the Stanford Faculty Development Center for Medical Teachers program, have attempted to bridge this gap in formal instruction in teaching skills through microteaching sessions involving videos for self- and peer-assessment and feedback., Objective: Current video-feedback faculty development initiatives are time intensive and impractical to implement broadly at an institutional level. Further, results of peer feedback have not been frequently reported in the literature at the institutional level. Our research aims to propose a convenient and effective process for incorporating video analysis into faculty devleopment programs., Design: Our work describes a novel technique using video-recorded, simulated teaching exercises to compile multi-dimensional feedback as an aid in faculty development programs that promote teaching-skill development. This research evaluated the effectiveness of a focused teaching practicum designed for faculty in multiple specialty departments with large numbers of older patients into a geriatrics-based faculty development program. Effectiveness of the practicum is evaluated using quantitative scoring and qualitative analysis of self-reflection as well as peer and trainee input., Results: VOTE sessions demonstrate an important exportable product which enable faculty to receive a detailed 360-degree assessment of their teaching., Conclusion: This intervention can be easily replicated and revised, as needed, to fit into the educational curriculum at other academic medical centers.

This article summarizes the presentations and discussions from a workshop, "Using Functional Assessment to Define Therapeutic Goals and Treatment," which took place on November 30 to December 1, 2017. This workshop brought together transdisciplinary leaders in the fields of function and disability and clinical investigators engaged in research on geriatric populations to outline opportunities and challenges for incorporating measures of function in clinical research. Topics addressed included reliable and clinically feasible measures of function and key domains of health (eg, musculoskeletal, cognitive, and sensory) that are most strongly associated with patients' perceptions of well-being, independence, and quality of life across a wide array of diseases and interventions. The workshop also focused on the importance of function in medical decision making to inform communications between specialty physicians and patients about prognosis and goals of care. Workshop participants called for more research on the role of function as a predictor of an intervention's effectiveness and an important treatment outcome. Such research would be facilitated by development of a core set of simple, short, functional measures that can be used by all specialties in the clinical setting to allow "big data" analytics and a pragmatic research. J Am Geriatr Soc 67:1782-1790, 2019., (© 2019 The American Geriatrics Society.)

Traditional clinical care models focus on the measurement and normalization of individual organ systems and de-emphasize aspects of health related to the integration of physiologic systems. Measures of physical, cognitive and sensory, and psychosocial or emotional function predict important health outcomes like death and disability independently from the severity of a specific disease, cumulative co-morbidity, or disease severity measures. A growing number of clinical scientists in several subspecialties are exploring the utility of functional assessment to predict complication risk, indicate stress resistance, inform disease screening approaches and risk factor interpretation, and evaluate care. Because a substantial number of older adults in the community have some form of functional limitation, integrating functional assessment into clinical medicine could have a large impact. Although interest in functional implications for health and disease management is growing, the science underlying functional capacity, functional limitation, physical frailty, and functional metrics is often siloed among different clinicians and researchers, with fragmented concepts and methods. On August 25-26, 2016, participants at a trans-disciplinary workshop, supported by the National Institute on Aging and the John A. Hartford Foundation, explored what is known about the pathways, contributors, and correlates of physical, cognitive, and sensory functional measures across conditions and disease states; considered social determinants and health disparities; identified knowledge gaps, and suggested priorities for future research. This article summarizes those discussions., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The Short Physical Performance Battery (SPPB) is a well regarded physical functioning assessment including balance, gait speed, and chair-stand tests. Its use has not been widely assessed in human immunodeficiency virus (HIV) care. We evaluated the feasibility of integrating the SPPB into care of aging people living with HIV (PLWH) and compared SPPB performance with aged HIV-uninfected individuals., Methods: We enrolled PLWH aged ≥50 at 3 HIV clinics and compared their SPPB scores and subscores with older HIV-uninfected adults in the Health, Aging, and Body Composition (Health ABC) study. We conducted regression analyses on age stratified by sex and adjusting for site, and we calculated percentage variance explained by age among PLWH and HIV-uninfected adults., Results: The SPPB was feasible to implement in clinical care and did not require licensed professionals; 176 PLWH completed it with a mean completion time of 7.0 minutes (standard deviation = 2.6). Overall mean SPPB score among PLWH was 10.3 (median 11.0, 25th percentile 9.0, 75th percentile 12.0). People living with HIV were younger than HIV-uninfected individuals (55 vs 74 years old). Mean SPPB scores and most subscores were similar among PLWH and older HIV-uninfected individuals despite the ~20-year age difference. Regression analyses of gait speed revealed similar slopes in PLWH and HIV-uninfected individuals; however, separate intercepts were needed for PLWH. Mean gait speeds were faster in older HIV-uninfected men and women (P < .01), yet relationships with age within PLWH and HIV uninfected were similar., Conclusions: The SPPB can be implemented into busy HIV clinics. Despite the ~20-year age difference, mean scores were similar among PLWH and older HIV-uninfected individuals, although gait speed was faster among HIV-uninfected individuals.

Although the field of frailty research has expanded rapidly, it is still a nascent concept within the clinical specialties. Frailty, conceptualized as greater vulnerability to stressors because of significant depletion of physiological reserves, predicts poorer outcomes in several medical specialties, including cardiology, human immunodeficiency virus care, and nephrology, and in the behavioral and social sciences. Lack of a consensus definition, proliferation of measurement tools, inadequate understanding of the biology of frailty, and lack of validated clinical algorithms for frail individuals hinders incorporation of frailty assessment and frailty research into the specialties. In 2015, the American Geriatrics Society, the National Institute on Aging (NIA), and the Alliance for Academic Internal Medicine held a conference for awardees of the NIA-sponsored Grants for Early Medical/Surgical Specialists Transition into Aging Research program to review the current state of knowledge regarding frailty in the subspecialties and to highlight examples of integrating frailty research into the medical specialties. Research questions to advance frailty research into specialty medicine are proposed., (© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.)

Historically, the medical subspecialties have not focused on the needs of older adults. This has changed with the implementation of initiatives to integrate geriatrics and aging research into the medical and surgical subspecialties and with the establishment of a home for internal medicine specialists within the annual American Geriatrics Society (AGS) meeting. With the support of AGS, other professional societies, philanthropies, and federal agencies, efforts to integrate geriatrics into the medical and surgical subspecialties have focused largely on training the next generation of physicians and researchers. They have engaged several subspecialties, which have followed parallel paths in integrating geriatrics and aging research. As a result of these combined efforts, there has been enormous progress in the integration of geriatrics and aging research into the medical and surgical subspecialties, and topics once considered to be geriatric concerns are becoming mainstream in medicine, but this integration remains a work in progress and will need to adapt to changes associated with healthcare reform., (© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.)

Clostridium difficile infection (CDI) is the most common cause of antibiotic-associated diarrhea and a significant burden on the health care system. Aging has been identified in the literature as a risk factor for CDI as well as adverse outcome from CDI. Although this effect of advanced age on CDI could be partially explained by clinical factors associated with aging, biologic factors are important. Innate immune system, responsible for immediate response to acute infections, plays a major role in CDI pathogenesis. Impairment in function of innate immunity with aging, demonstrated in other infection models, may lead to worse outcome with CDI. C. difficile toxin-specific antibody response protects the host against initial and recurrent infections as shown in observational studies and clinical trial. Effect of aging on antibody response to CDI has not been demonstrated, but the results from vaccine studies in other infections suggest a negative effect on humoral immunity from aging. Although intestinal microbiota from healthy people confers resistance to CDI by preventing C. difficile colonization, changes in composition of microbiota with aging may affect that resistance and increase risk for CDI. There are also age-associated changes in physiology, especially of the gastrointestinal tract, that may play a role in CDI risk and outcomes. In this review, we will first discuss the epidemiology of CDI in the elderly people, then the alteration in innate immunity, humoral response, and microbiota that increases susceptibility to CDI and severe disease and lastly, the physiological and functional changes that may modify outcomes of infection., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The prevalence of diabetes increases with age, driven in part by an absolute increase in incidence among adults aged 65 years and older. Individuals with diabetes are at higher risk for cardiovascular disease, and age strongly predicts cardiovascular complications. Inflammation and oxidative stress appear to play some role in the mechanisms underlying aging, diabetes, cardiovascular disease, and other complications of diabetes. However, the mechanisms underlying the age-associated increase in risk for diabetes and diabetes-related cardiovascular disease remain poorly understood. Moreover, because of the heterogeneity of the older population, a lack of understanding of the biology of aging, and inadequate study of the effects of treatments on traditional complications and geriatric conditions associated with diabetes, no consensus exists on the optimal interventions for older diabetic adults. The Association of Specialty Professors, along with the National Institute on Aging, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart, Lung, and Blood Institute, and the American Diabetes Association, held a workshop, summarized in this Perspective, to discuss current knowledge regarding diabetes and cardiovascular disease in older adults, identify gaps, and propose questions to guide future research., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Background: Antiretroviral therapy has reduced the incidence of adverse events and early mortality in HIV-infected persons. Despite these benefits, important comorbidities that increase with age (eg, diabetes, cardiovascular disease, cancer, liver disease, and neurocognitive impairment) are more prevalent in HIV-infected persons than in HIV-uninfected persons at every age, and geriatric syndromes such as falls and frailty occur earlier in HIV-infected persons. This raises a critical research question: Does HIV accelerate aging through pathways and mechanisms common to the aging process or is HIV simply an additional risk factor for a wide number of chronic conditions, thus accentuating aging?, Methods: Extensive literature review., Results: The purpose of this review is to briefly outline the evidence that age-related clinical syndromes are exacerbated by HIV, examine the ways in which HIV is similar, and dissimilar from natural aging, and assess the validity of HIV as a model of premature aging. Specific biomarkers of aging are limited in HIV-infected hosts and impacted by antiretroviral therapy, and a high rate of modifiable life style confounders (eg, smoking, substance abuse, alcohol) and coinfections (eg, hepatitis) in HIV-infected participants., Conclusions: There is a need for validated biomarkers of aging in the context of HIV. Despite these differences, welldesigned studies of HIV-infected participants are likely to provide new opportunities to better understand the mechanisms that lead to aging and age-related diseases., (© The Author 2013. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Patients in long-term care (LTC) are at increased risk for acquiring Clostridium difficile infection (CDI). We compared the characteristics and outcomes of matched cohorts with and without CDI in the LTC setting., Methods: Using a retrospective cohort design, demographic characteristics, Minimum Data Set (MDS 2.0) assessments (years 2007-2010), and pharmacy records of residents were analyzed. Residents were required to have a CDI diagnosis, ≥1 MDS 2.0 assessment ≤120 days pre- and post-index event, and receipt of metronidazole (MET) or vancomycin (VAN) within ±7 days of index date. Baseline characteristics were compared between cases and controls matched 1:3 on age, gender, and index year. Cox regression (CR) analysis evaluated the relationship between CDI status, and post-index mortality and hospitalization., Results: A total of 1145 CDI residents were matched with 3488 non-CDI residents. A second sample used propensity score methods. CDI vs. non-CDI residents had a higher baseline comorbidity burden (Charlson score: 3.0 ± 1.9 vs. 2.2 ± 1.8, respectively), and were more likely to have had a recent hospitalization (63% vs. 9%, respectively) and shorter mean pre-index continuous length of stay (cLOS) in the LTC (386.4 d ± 536.3 d vs. 568.3 d ± 567.4 d, respectively), all P < 0.0001. CR analyses of both samples indicated that CDI was strongly associated with shorter times to hospitalization and mortality (hazard ratio (HR) = 1.3, P = 0.023 and 2.2, P < 0.0001, respectively; propensity-matched group). Pre-index LTC cLOS also remained an important variable in the CR analysis and was the strongest predictor of post-index hospitalization and mortality (HR = 0.999 and 0.996, respectively, P < 0.0001), indicating that residents with longer pre-index LTC cLOS had longer times to post-index hospitalization and mortality. Our reliance on the MDS records for case identification was our chief limitation; misclassification was mitigated by our requirement to include CDI treatment as part of our inclusion criteria., Conclusions: Understanding factors that put LTC patients at risk for CDI can help guide better management and improvement of patient outcomes.

Background: Potent and safe adjuvants are needed to improve the efficacy of parenteral and mucosal vaccines. Cytokines, chemokines and growth factors have all proven to be effective immunomodulatory adjuvants when administered with a variety of antigens. We have previously evaluated the efficacy of membrane-anchored interleukins (IL) such as IL-2 and IL-4 co-presented as Cytokine-bearing Influenza Vaccines (CYT-IVACs) using a mouse model of influenza challenge., Findings: Here, we describe studies evaluating the parenteral and mucosal adjuvanticity of membrane-bound IL-12 and IL-23 CYT-IVACs in young adult mice. Mucosal immunization using IL-12 and IL-23 bearing whole influenza virus vaccine (WIV) was more effective at eliciting virus-specific nasal IgA and reducing viral lung burden following challenge compared to control WIV vaccinated animals. Both IL-12 and IL-23 bearing WIV elicited the highest anti-viral IgA levels in serum and nasal washes., Conclusions: This study highlights for the first time the mucosal adjuvant potential of IL-12 and IL-23 CYT-IVAC formulations in eliciting mucosal immune responses and reducing viral lung burden. The co-presentation of immunomodulators in direct context with viral antigen in whole inactivated viral vaccines may provide a means to significantly lower the dose of vaccine required for protection.

The population of the United States and most industrialized nations is undergoing rapid expansion of persons aged 65 years and older. This group experiences more illness, disability, and dependency than young adults and consumes the majority of heath care resources. This demographic change presents a number of challenges to current research infrastructure aimed at translating discoveries to improved human health. Key issues include the need to expand the workforce trained in aging research, development of specific resources and harmonization of measures and outcomes, and a culture change within the scientific community. In particular, complexity must be represented within research design and embraced as an important aspect of review panel critiques., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Influenza and its complications disproportionately affect the elderly, leading to high morbidity and mortality in this ever-increasing population. Despite widespread vaccination efforts, the current influenza vaccines are less effective in the elderly; hence newer vaccine strategies are needed to improve their efficacy in this age group. We have previously shown that co-presentation of cytokines on the surface of inactivated influenza virus particles affords better protection from lethal homotypic viral challenge in young adult mice than conventional non-adjuvanted whole inactivated vaccine. Here, we determined the efficacy of these vaccine formulations in Balb/c mice "aged" to 17 months ("aged mice") along with the addition of a membrane-bound interleukin-12 (IL-12) vaccine formulation. Our investigations found that a single low-dose intramuscular vaccination with inactivated whole influenza vaccine co-presenting IL-12 was sufficient to provide enhanced protection from subsequent influenza challenge as compared with non-adjuvanted whole inactivated vaccine. Our results indicate that incorporation of cytokines such as IL-12 in a membrane-bound formulation in whole inactivated vaccine may provide a means to lower the vaccine dose while eliciting enhanced protective responses in the elderly, an age group that responds poorly to current vaccination regimens.

The efficacy of different vaccines in protecting elderly individuals against Streptococcus pneumoniae infections is not clear. In the current study, aged mice (22-25 months old) exhibited significantly increased susceptibility to respiratory infection with serotype 3 S. pneumoniae relative to younger adult mice, regardless of whether mice were naive or immunized with native pneumococcal polysaccharide (PPS; Pneumovax23) or protein-PPS conjugate (Prevnar-13) vaccines. Nonetheless, Pneumovax-immunized aged mice developed limited bacteremia following respiratory challenge and exhibited significantly increased survival following systemic challenge relative to Prevnar-immune aged mice and young mice that had received either vaccine. This was explained by >10-fold increases in PPS-specific immunoglobulin G (IgG) levels in Pneumovax-immunized aged mice relative to other groups. Remarkably, PPS3-specific B-cell expansion, IgG switching, plasmablast differentiation, and spleen and bone marrow antibody-secreting cell frequencies were 10-fold higher in aged mice following Pneumovax immunization relative to young mice, due to significantly increased B-1b cell participation. In summary, this study highlights (1) the need to devise strategies to enhance respiratory immunity in aged populations, (2) the diverse responses young and aged populations generate to Pneumovax vs Prevnar vaccines, and (3) the potential value of exploiting B-1b cell responses in aged individuals for increased vaccine efficacy.

Individuals with HIV infection and two apolipoprotein L1 gene (APOL1) risk variants frequently develop nephropathy. Here we tested whether non-HIV viral infections influence nephropathy risk via interactions with APOL1 by assessing APOL1 genotypes and presence of urine JC and BK polyoma virus and plasma HHV6 and CMV by quantitative polymerase chain reaction. We analyzed 300 samples from unrelated and related first-degree relatives of African Americans with nondiabetic nephropathy using linear and nonlinear mixed models to account for familial relationships. The four groups evaluated were APOL1 zero/one versus two risk alleles, with or without nephropathy. Urine JCV and BKV were detected in 90 and 29 patients, respectively, whereas HHV6 and CMV were rare. Adjusting for family age at nephropathy, gender, and ancestry, presence of JCV genomic DNA in urine and APOL1 risk alleles were significantly negatively associated with elevated serum cystatin C, albuminuria (albumin-to-creatinine ratio over 30 mg/g), and kidney disease defined as an eGFR under 60 ml/min per 1.73 m(2) and/or albuminuria in an additive (APOL1 plus JCV) model. BK viruria was not associated with kidney disease. Thus, African Americans at increased risk for APOL1-associated nephropathy (two APOL1 risk variants) with JC viruria had a lower prevalence of kidney disease, suggesting that JCV interaction with APOL1 genotype may influence kidney disease risk.

Background: Nonhuman primates have similar shoulder anatomy and physiology compared to humans, and may represent a previously underutilized model for shoulder research. This study sought to identify naturally occurring bony and muscular degeneration in the shoulder of nonhuman primates and to assess relationships between structural and functional aspects of the shoulder and measures of physical function of the animals. We hypothesized that age-related degenerative changes in the shoulders of nonhuman primates would resemble those observed in aging humans., Methods: Middle-aged (n = 5; ages 9.4-11.8 years) and elderly (n = 6; ages 19.8-26.4 years) female vervet monkeys were studied for changes in mobility and shoulder function, and radiographic and histologic signs of age-related degeneration., Results: Four out of 6 (4/6) elderly animals had degenerative changes of the glenoid compared to 0/5 of the middle-aged animals (P = .005). Elderly animals had glenoid retroversion, decreased joint space, walked slower, and spent less time climbing and hanging than middle-aged vervets (P < .05). Physical mobility and shoulder function correlated with glenoid version angle (P < .05). Supraspinatus muscles of elderly animals were less dense (P = .001), had decreased fiber cross-sectional area (P < .001), but similar amounts of nuclear material (P = .085). Degenerative rotator cuff tears were not observed in any of the eleven animals., Discussion and Conclusion: The vervet monkey naturally undergoes age-related functional, radiographic and histological changes of the shoulder, and may qualify as an animal model for selected translational research of shoulder osteoarthritis., (Copyright © 2013 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Mosby, Inc. All rights reserved.)

Hepatitis B virus (HBV) vaccination is recommended for individuals with hepatitis C virus (HCV) infection given their shared risk factors and increased liver-related morbidity and mortality upon super-infection. Vaccine responses in this setting are often blunted, with poor response rates to HBV vaccinations in chronically HCV-infected individuals compared to healthy subjects. In this study, we investigated the role of T cell immunoglobulin mucin domain-3 (Tim-3)-mediated immune regulation in HBV vaccine responses during HCV infection. We found that Tim-3, a marker for T cell exhaustion, was over-expressed on monocytes, leading to a differential regulation of IL-12/IL-23 production which in turn TH17 cell accumulation, in HCV-infected HBV vaccine non-responders compared to HCV-infected HBV vaccine responders or healthy subjects (HS). Importantly, ex vivo blockade of Tim-3 signaling corrected the imbalance of IL-12/IL-23 as well as the IL-17 bias observed in HBV vaccine non-responders during HCV infection. These results suggest that Tim-3-mediated dysregulation of innate to adaptive immune responses is involved in HBV vaccine failure in individuals with chronic HCV infection, raising the possibility that blocking this negative signaling pathway might improve the success rate of HBV immunization in the setting of chronic viral infection., (Published by Elsevier Ltd.)

Objectives: To determine the effect of advancing age on the clinical outcomes of Clostridium difficile (CDI) treatment., Design: Regression modeling of results from two double-blind randomized multicenter studies on the treatment of primary and first recurrent cases of CDI to examine for effects of age and study drug on outcomes of cure (resolution of diarrhea), recurrence within 4 weeks of completing successful therapy, and cure without recurrence., Setting: Participants were randomized into studies in the United States, Canada, and Europe., Participants: Nine hundred ninety-nine individuals with toxin-positive CDI were randomized to receive vancomycin (125 mg 4 times daily) or fidaxomicin (200 mg twice daily) for 10 days., Measurements: The effect of advancing age in those aged 18 to 40 years and in 10-year increments thereafter was examined., Results: The model predicts a 17% lower clinical cure, 17% greater recurrence, and 13% lower sustained clinical response by advancing decade than in those younger than 40 (P < .01 each). Clinical cure was similar in the fidaxomicin and vancomycin treatment groups, although fidaxomicin was associated with a more than 50% lower relative risk for recurrence than vancomycin (P < .001). Multivariate regression modeling showed that risk factors accounting for poorer outcomes with advancing age include infection with the BI strain type, inpatient status, renal insufficiency, leukocytosis, hypoalbuminemia, and concomitant medication exposure., Conclusion: Measurable and progressive deterioration in CDI treatment outcomes occurred with advancing age in those aged 40 and older, highlighting the need for prevention and treatment strategies. Fidaxomicin treatment was associated with a 60% lower risk of recurrence than vancomycin after adjusting for age, concomitant antibiotics, and C. difficile strain., (© 2013, Copyright the Authors Journal compilation © 2013, The American Geriatrics Society.)

Vanishing bile duct syndrome (VBDS) is a group of rare disorders characterized by ductopenia, the progressive destruction and disappearance of intrahepatic bile ducts leading to cholestasis. Described in association with medications, autoimmune disorders, cancer, transplantation, and infections, the specific mechanisms of disease are not known. To date, only 4 cases of VBDS have been reported in human immunodeficiency virus (HIV) infected patients. We report 2 additional cases of HIV-associated VBDS and review the features common to the HIV-associated cases. Presentation includes hyperbilirubinemia, normal liver imaging, and negative viral and autoimmune hepatitis studies. In HIV-infected subjects, VBDS occurred at a range of CD4+ T-cell counts, in some cases following initiation or change in antiretroviral therapy. Lymphoma was associated with two cases; nevirapine, antibiotics, and viral co-infection were suggested as etiologies in the other cases. In HIV-positive patients with progressive cholestasis, early identification of VBDS and referral for transplantation may improve outcomes.

Background: Physical function declines, and markers of inflammation increase with advancing age, even in healthy persons. Microbial translocation (MT) is the systemic exposure to mucosal surface microbes/microbial products without overt bacteremia and has been described in a number of pathologic conditions. We hypothesized that markers of MT, soluble CD14 (sCD14) and lipopolysaccharide (LPS) binding protein (LBP), may be a source of chronic inflammation in older persons and be associated with poorer physical function., Methods: We assessed cross-sectional relationships among two plasma biomarkers of MT (sCD14 and LBP), physical function (hand grip strength, short physical performance battery [SPPB], gait speed, walking distance, and disability questionnaire), and biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), TNF-α soluble receptor 1 [TNFsR1]) in 59 older (60-89 years), healthy (no evidence of acute or chronic illness) men and women., Results: LBP was inversely correlated with SPPB score and grip strength (p = .02 and p < .01, respectively) and positively correlated with CRP (p = 0.04) after adjusting for age, gender, and body mass index. sCD14 correlated with IL-6 (p = .01), TNF-α (p = .05), and TNFsR1 (p < .0001). Furthermore, the correlations between LBP and SPPB and grip strength remained significant after adjusting for each inflammatory biomarker., Conclusions: In healthy older individuals, LBP, a surrogate marker of MT, is associated with worse physical function and inflammation. Additional study is needed to determine whether MT is a marker for or a cause of inflammation and the associated functional impairments.

Advancing age is accompanied by profound changes in immune function; some are induced by the loss of critical niches that support development of naïve cells (e.g. thymic involution), others by the intrinsic physiology of long-lived cells attempting to maintain homeostasis, still others by extrinsic effects such as oxidative stress or long-term exposure to antigen due to persistent viral infections. Once compensatory mechanisms can no longer maintain a youthful phenotype the end result is the immune senescent milieu - one characterized by chronic, low grade, systemic inflammation and impaired responses to immune challenge, particularly when encountering new antigens. This state is associated with progression of chronic illnesses like atherosclerosis and dementia, and an increased risk of acute illness, disability and death in older adults. The complex interaction between immune senescence and chronic illness provides an ideal landscape for translational research with the potential to greatly affect human health. However, current animal models and even human investigative strategies for immune senescence have marked limitations, and the reductionist paradigm itself may be poorly suited to meet these challenges. A new paradigm, one that embraces complexity as a core feature of research in older adults is required to address the critical health issues facing the burgeoning senior population, the group that consumes the majority of healthcare resources. In this review, we outline the major advantages and limitations of current models and offer suggestions for how to move forward., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Familial aggregation of non-diabetic end-stage renal disease (ESRD) is found in African Americans and variants in the apolipoprotein L1 gene (APOL1) contribute to this risk. To detect genetic associations with milder forms of nephropathy in the high-risk families, analyses were performed using generalized estimating equations to assess relationships between kidney disease phenotypes and APOL1 variants in 786 relatives of 470 families. Adjusting for familial correlations, 23.1, 46.7, and 30.2% of genotyped relatives possessed two, one, or no APOL1 risk variants, respectively. Relatives with two compared with one or no risk variants had statistically indistinguishable median systolic blood pressure, urine albumin to creatinine ratio, estimated glomerular filtration rate (GFR; MDRD equation), and serum cystatin C levels. After adjusting for age, gender, age at ESRD in families, and African ancestry, significant associations were detected between APOL1 with overt proteinuria and estimated GFR (CKD-EPI equation), with a trend toward significance for quantitative albuminuria. Thus, relatives of African Americans with non-diabetic ESRD are enriched for APOL1 risk variants. After adjustment, two APOL1 risk variants weakly predict mild forms of kidney disease. Second hits appear necessary for the initiation of APOL1-associated nephropathy.

Background: Chronic lymphocytic leukemia (CLL) patients are at high risk for acute respiratory illness (ARI)., Objective: We evaluated the safety and efficacy of a proprietary extract of Panax quinquefolius, CVT-E002, in reducing ARI., Methods: This was a double-blind, placebo-controlled, randomized trial of 293 subjects with early-stage, untreated CLL conducted January-March 2009., Results: ARI was common, occurring on about 10% of days during the study period. There were no significant differences of the 2 a priori primary end points: ARI days (8.5 ± 17.2 for CVT-E002 vs 6.8 ± 13.3 for placebo) and severe ARI days (2.9 ± 9.5 for CVT-E002 vs 2.6 ± 9.8 for placebo). However, 51% of CVT-E002 vs 56% of placebo recipients experienced at least 1 ARI (difference, -5%; 95% confidence interval [CI], -16% to 7%); more intense ARI occurred in 32% of CVT-E002 vs 39% of placebo recipients (difference, -7%; 95% CI, -18% to 4%), and symptom-specific evaluation showed reduced moderate to severe sore throat (P = .004) and a lower rate of grade ≥3 toxicities (P = .02) in CVT-E002 recipients. Greater seroconversion (4-fold increases in antibody titer) vs 9 common viral pathogens was documented in CVT-E002 recipients (16% vs 7%, P = .04)., Limitations: Serologic evaluation of antibody titers was not tied to a specific illness, but covered the entire study period., Conclusion: CVT-E002 was well tolerated. It did not reduce the number of ARI days or antibiotic use; however, there was a trend toward reduced rates of moderate to severe ARI and significantly less sore throat, suggesting that the increased rate of seroconversion most likely reflects CVT-E002-enhanced antibody responses., (Copyright © 2012 Elsevier Inc. All rights reserved.)

HIV risk behaviors, susceptibility to HIV acquisition, progression of disease after infection, and response to antiretroviral therapy all vary by age. In those living with HIV, current effective treatment has increased the median life expectancy to >70 years of age. Biologic, medical, individual, social, and societal issues change as one ages with HIV infection, but there has been only a small amount of research in this field. Therefore, the Office of AIDS Research of the National Institutes of Health commissioned a working group to develop an outline of the current state of knowledge and areas of critical need for research in HIV and Aging; the working groups' findings and recommendations are summarized in this report. Key overarching themes identified by the group included the following: multimorbidity, polypharmacy, and the need to emphasize maintenance of function; the complexity of assessing HIV versus treatment effects versus aging versus concurrent disease; the inter-related mechanisms of immune senescence, inflammation, and hypercoagulability; the utility of multivariable indices for predicting outcomes; a need to emphasize human studies to account for complexity; and a required focus on issues of community support, caregivers, and systems infrastructure. Critical resources are needed to enact this research agenda and include expanded review panel expertise in aging, functional measures, and multimorbidity, and facilitated use and continued funding to allow long-term follow-up of cohorts aging with HIV.

Aging kidneys undergo structural and functional changes that decrease autoregulatory capacity and increase susceptibility to acute injury. Acute kidney injury associates with duration and location of hospitalization, mortality risk, progression to chronic kidney disease, and functional status in daily living. Definition and diagnosis of acute kidney injury are based on changes in creatinine, which is an inadequate marker and might identify patients when it is too late. The incidence of acute kidney injury is rising and increases with advancing age, yet clinical studies have been slow to address geriatric issues or the heterogeneity in etiologies, outcomes, or patient preferences among the elderly. Here we examine some of the current literature, identify knowledge gaps, and suggest potential research questions regarding acute kidney injury in older adults. Answering these questions will facilitate the integration of geriatric issues into future mechanistic and clinical studies that affect management and care of acute kidney injury.

CD4+ T cells of the Th17 subtype are over-represented in the aged immune system. Dendritic cells (DC) play a critical role in naïve CD4+ T cell differentiation. However, expression of cytokines by aged DC that promote differentiation or survival of Th17 cells has not been extensively investigated. Using bone marrow-derived DC from C57BL/6 mice of different ages we compared cytokine production after DC activation by Toll-like receptor agonists for TLR4 and/or TLR7/8. DC-derived TNF-α and IL-12p70 production and expression of DC co-stimulatory molecules did not vary significantly by age indicating that TLR expression, function and signal transduction were intact in aged DC. There were relatively minor age-related changes in TGF-β and IL-6 which promote Th17 differentiation, but IL-23, a Th17-suvival cytokine, increased more than 40-fold across the lifespan. DC-derived prostaglandin E2 (PGE2) also increased with age and the up-regulation of IL-23 expression by aged DC was blocked by indomethacin that prevents PGE2 production, and by antagonists of PGE2 receptors. Exogenous PGE2 added to DC cultures further enhanced IL-23 production from aged but not young DCs. These data indicate that age-related changes in DC PGE2 production are necessary, but not sufficient to induce DC IL-23 production. Such changes may play a role in the expansion of Th17 cells in the aged immune system., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF), a heterogeneous disease with respect to clinical presentation and rates of progression, disproportionately affects older adults. The diagnosis of IPF is descriptive, based on clinical, radiologic, and histopathologic examination, and definitive diagnosis is hampered by poor interobserver agreement and lack of a consensus definition. There are no effective treatments. Cellular, molecular, genetic, and environmental risk factors have been identified for IPF, but the initiating event and the characteristics of preclinical stages are not known. IPF is predominantly a disease of older adults, and the processes underlying normal aging might significantly influence the development of IPF. Yet, the biology of aging and the principles of medical care for this population have been typically ignored in basic, translational, or clinical IPF research. In August 2009, the Association of Specialty Professors, in collaboration with the American College of Chest Physicians, the American Geriatrics Society, the National Institute on Aging, and the National Heart, Lung, and Blood Institute, held a workshop, summarized herein, to review what is known, to identify research gaps at the interface of aging and IPF, and to suggest priority areas for future research. Efforts to answer the questions identified will require the integration of geriatrics, gerontology, and pulmonary research, but these efforts have great potential to improve care for patients with IPF.

Age-associated changes in immune response increase the risk of infection and promote inflammation and autoimmunity in older adults. The newly discovered cytokine IL-23 contributes to the maintenance and expansion of Th-17 cells, which promote proinflammatory responses. Our preliminary findings suggested that Th-17 responses are increased in aged mice. IL-23 consists of p40 and p19 subunits. Expression of the p19 subunit is regulated at the transcriptional level by NF-kappaB p65 and c-Rel transcription factors. Using bone-marrow-derived dendritic cells (DCs) from C57BL/6 mice, we show that IL-23 protein production and p19 subunit mRNA levels are significantly increased in DCs from aged mice after activation with TLR ligands (LPS + R848) when compared with DCs of young adult mice. We found that the increase in p19 expression in aged cells is associated with chromatin remodeling characterized by di- and tri-methylation of histone H3K4 and binding of mainly c-Rel at the p19 promoter. In young DCs, the promoter is tri-methylated only at H3K4 and bound by both p65 and c-Rel. C-Rel knockdown restores p65 binding in aged cells but does not activate p19 expression, suggesting that c-Rel is critical for p19 expression. In addition, p65 knockdown significantly increases c-Rel binding and p19 expression in young DCs to levels close to those detected in old cells. Furthermore, the decrease in p65 binding at the p19 promoter in old DCs was specific to the p19 gene since p65 binding to the IL-12p40 promoter was not significantly different between old and young DCs. Our results demonstrate that selective changes in H3K4 methylation, and c-Rel and p65 binding at the p19 promoter occur in DCs and contribute to the upregulation of the p19 subunit expression and IL-23 protein production observed in aged mice. This suggests epigenetic and transcriptional mechanisms contribute to dysregulated inflammatory and autoimmune responses associated with aging.

The herpes zoster vaccine has proven to reduce the incidence of herpes zoster and postherpetic neuralgia, a debilitating condition that can remain for years after zoster rash has resolved. However, few eligible adults have received the vaccine. Findings from survey-based studies on patient uptake of influenza and pneumococcal polysaccharide vaccines suggest that physician recommendations and standing orders can increase vaccine uptake. However, certain barriers unique to zoster vaccination (eg, reimbursement concerns) will need to be addressed.

Chronic kidney disease is a large and growing problem among aging populations. Although progression of chronic kidney disease to end-stage renal disease (ESRD) is a costly and important clinical event with substantial morbidity, it appears less frequently in aging people compared with cardiovascular mortality. The measurement of kidney function and management of kidney disease in older individuals remain challenging, partly because the pathophysiologic mechanisms underlying age-related decline in kidney function, the interactions between age and other risk factors in renal progression, and the associations of chronic kidney disease with other comorbidities in older people are understudied and poorly understood. The Association of Specialty Professors, the American Society of Nephrology, the American Geriatrics Society, the National Institute on Aging, and the National Institute of Diabetes and Digestive and Kidney Diseases held a workshop, summarized in this article, to review what is known about chronic kidney disease, identify research gaps and resources available to address them, and identify priority areas for future research. Answers to emerging research questions will support the integration of geriatrics and nephrology and thus improve care for older patients at risk for chronic kidney disease.

Residents of long-term care facilities (LTCFs) are at great risk for infection. Most residents are older and have multiple comorbidities that complicate recognition of infection; for example, typically defined fever is absent in more than one-half of LTCF residents with serious infection. Furthermore, LTCFs often do not have the on-site equipment or personnel to evaluate suspected infection in the fashion typically performed in acute care hospitals. In recognition of the differences between LTCFs and hospitals with regard to hosts and resources present, the Infectious Diseases Society of America first provided guidelines for evaluation of fever and infection in LTCF residents in 2000. The guideline presented here represents the second edition, updated by data generated over the intervening 8 years. It focuses on the typical elderly person institutionalized with multiple chronic comorbidities and functional disabilities (e.g., a nursing home resident). Specific topic reviews and recommendations are provided with regard to what resources are typically available to evaluate suspected infection, what symptoms and signs suggest infection in a resident of an LTCF, who should initially evaluate the resident with suspected infection, what clinical evaluation should be performed, how LTCF staff can effectively communicate about possible infection with clinicians, and what laboratory tests should be ordered. Finally, a general outline of how a suspected outbreak of a specific infectious disease should be investigated in an LTCF is provided.

Serious infections are a major obstacle limiting the usefulness of unrelated donor marrow transplantation. Graft-versus-host disease (GVHD) and its therapy are associated with a high risk of opportunistic infection. In this study, patients were randomized to receive 1 of 2 GVHD prophylaxis strategies, marrow T cell depletion, and cyclosporine (TCD) or methotrexate/cyclosporine (M/C) after transplantation. The patients underwent transplantation between March 1995 and October 2000 as part of a multicenter randomized trial. As a secondary analysis, we analyzed infections in this study cohort. Among the 404 patients who underwent transplantation, a total of 1598 infections were reported. The rates of serious and fatal infections did not differ between the TCD and M/C groups. Bacterial infections accounted for 1/3 of serious infections in each treatment arm. A significantly higher incidence of severe cytomegalovirus (CMV) and life-threatening or fatal aspergillus infections was observed in the patients receiving TCD (CMV, 28% vs 17% [P = .02]; aspergillosis, 16% vs 7% [P < .01]). The only independent risk factor for serious infection was the development of grade III-IV acute GVHD (aGVHD; hazard ratio = 1.41; 95% confidence interval = 1.03-1.91). Strategies to speed immune recovery, even in the absence of GVHD, are needed to overcome the risk of infection after unrelated donor transplantation.

Aging results in a general waning of immunity and enhanced susceptibility to many intracellular pathogens. However, in some instances, aging is accompanied by alternative immune responses that can be equal to, or even more effective, than those of young adults. Brucella spp. are intracellular bacteria and important human and animal pathogens, but there are no data regarding the effect of age on host defense in brucellosis. Young or old adult mice (DBA/2 or BALB/c) were infected with either an attenuated B. abortus strain that over-expressed the Brucella superoxide dismutase (strain RB51-SOD) or a fully virulent strain (strain 2308). Survival, organism burden in the spleen, and immune responses were assessed. All young adult and aged mice survived infection with RB51-SOD (up to 6 x 10(8) cfu) or strain 2308 (up to 8 x 10(8) cfu). Old mice had a lower organism burden in the spleen than young adult mice five or more weeks after infection. Antibody and cytokine responses were Th1-focused in young adult mice, but Th-mixed in older mice, including evidence of the newly defined Th17 subtype immune response. Immunization with the RB51-SOD strain provided protection vs. strain 2308 challenge in young and aged BALB/c, but only young adult DBA/2 mice. Thus, clinical outcomes of Brucella infection in aged mice are equal or superior to those of young adult mice; immune responses in older mice are less-Th1 specific suggesting alternate pathways may contribute to host defense vs. Brucella in aged mice.