Translational research in immune senescence: assessing the relevance of current models.

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.

Chronic wound repair and healing in older adults: current status and future research.

The incidence of chronic wounds is increased among older adults, and the impact of chronic wounds on quality of life is particularly profound in this population. It is well established that wound healing slows with age. However, the basic biology underlying chronic wounds and the influence of age-associated changes on wound healing are poorly understood. Most studies have used in vitro approaches and various animal models, but observed changes translate poorly to human healing conditions. The impact of age and accompanying multi-morbidity on the effectiveness of existing and emerging treatment approaches for chronic wounds is also unknown, and older adults tend to be excluded from randomized clinical trials. Poorly defined outcomes and variables, lack of standardization in data collection, and variations in the definition, measurement, and treatment of wounds also hamper clinical studies. The Association of Specialty Professors, in conjunction with the National Institute on Aging and the Wound Healing Society, held a workshop, summarized in this paper, to explore the current state of knowledge and research challenges, engage investigators across disciplines, and identify key research questions to guide future study of age-associated changes in chronic wound healing.

Aging promotes B-1b cell responses to native, but not protein-conjugated, pneumococcal polysaccharides: implications for vaccine protection in older adults.

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.

Membrane-bound IL-12 and IL-23 serve as potent mucosal adjuvants when co-presented on whole inactivated influenza vaccines.

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.

JC polyoma virus interacts with APOL1 in African Americans with nondiabetic nephropathy.

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.

Age-related degenerative functional, radiographic, and histological changes of the shoulder in nonhuman primates.

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.

Mesenteric panniculitis as a possible cause of fever of unknown origin.

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.

The Academic Learning Health System: A Framework for Integrating the Multiple Missions of Academic Medical Centers.

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.

Association of APOL1 variants with mild kidney disease in the first-degree relatives of African American patients with non-diabetic end-stage renal disease.

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.

A randomized, controlled trial of Panax quinquefolius extract (CVT-E002) to reduce respiratory infection in patients with chronic lymphocytic leukemia.

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.

Acute kidney injury in older adults.

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.

Embedding and Sustaining a Focus on Function in Specialty Research and Care.

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.

Automated Frailty Screening At-Scale for Pre-Operative Risk Stratification Using the Electronic Frailty Index.

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.

Prediction, progression, and outcomes of chronic kidney disease in older adults.

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.

Clinical practice guideline for the evaluation of fever and infection in older adult residents of long-term care facilities: 2008 update by the Infectious Diseases Society of America.

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.

Use of Functional Assessment to Define Therapeutic Goals and Treatment.

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.

A 360-degree assessment of teaching effectiveness using a structured-videorecorded observed teaching exercise for faculty development.

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.

Pathways, Contributors, and Correlates of Functional Limitation Across Specialties: Workshop Summary.

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.