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It has long been known that aging, at both the cellular and organismal levels, contributes to the development and progression of the pathology of many chronic diseases. However, much less research has examined the inverse relationship—the contribution of chronic diseases and their treatments to the progression of aging‐related phenotypes. Here, we discuss the impact of three chronic diseases (cancer, HIV/AIDS, and diabetes) and their treatments on aging, putative mechanisms by which these effects are mediated, and the open questions and future research directions required to understand the relationships between these diseases and aging.

AbstractRationale, aims, and objectivesNovel health care delivery models are needed to reduce health care use while delivering effective and safe care. We developed a model of a neurologist integrated and colocated in primary care leveraging “curbside,” electronic, and traditional consultations. Our objective was to examine the impact on health care resource use of diagnostic testing and referrals for face‐to‐face neurological consultation and adverse outcomes associated with electronic and curbside consultations.MethodsConsecutive patients from December 1, 2014, to March 13, 2015, were included in the analysis about whom contact was made between a primary care clinician and a colocated neurologist.ResultsOver 3.5 months of the pilot, 359 unique patients generated 429 consultations (179 curbsides, 68 electronic consultations, and 182 face‐to‐face visits). The integrated model resulted in avoidance of 78 face‐to‐face tertiary neurology consultations, 39 brain magnetic resonance imaging, 50 electromyograms, and 53 other advanced imaging studies. Earlier curbside consultation may have prevented unnecessary testing or face‐to‐face tertiary neurology consultations in 40 (22%) patients. Earlier face‐to‐face consultation may have avoided expensive testing in 31 (17%) patients. No cases met criteria for an adverse outcome. The number of referrals to tertiary neurology declined by 64%, and the total number of face‐to‐face visits per month declined by 25%.ConclusionColocated neurology in a primary care medical home offers a promising intervention to deliver high‐value care.

AbstractIntroductionWe hypothesized that common Alzheimer's disease (AD)‐associated variants within the triggering receptor expressed on myeloid (TREM) gene cluster influence disease through gene expression.MethodsExpression microarrays on temporal cortex and cerebellum from ∼400 neuropathologically diagnosed subjects and two independent RNAseq replication cohorts were used for expression quantitative trait locus analysis.ResultsA variant within a DNase hypersensitive site 5′ of TREM2, rs9357347‐C, associates with reduced AD risk and increased TREML1 and TREM2 levels (uncorrected P = 6.3 × 10−3 and 4.6 × 10−2, respectively). Meta‐analysis on expression quantitative trait locus results from three independent data sets (n = 1006) confirmed these associations (uncorrected P = 3.4 × 10−2 and 3.5 × 10−3, Bonferroni‐corrected P = 6.7 × 10−2 and 7.1 × 10−3, respectively).DiscussionOur findings point to rs9357347 as a functional regulatory variant that contributes to a protective effect observed at the TREM locus in the International Genomics of Alzheimer's Project genome‐wide association study meta‐analysis and suggest concomitant increase in TREML1 and TREM2 brain levels as a potential mechanism for protection from AD.

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium ( n Stage1 : 111,666; n Stage2 : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea ( PPM1J , EDEM3, ACP1, SPEG, EYA4, CYP1A1 , and ATXN2L ; P Stage1 <3.7×10 −7 ), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 ( P =5.4×10 −8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2 -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

AbstractControl of knee motion in small animal models is necessary to study the effect of mechanical load on the healing process. This can be especially challenging in mice, which are being increasingly used for various orthopedic reconstruction models. We explored the feasibility of botulinum toxin (Botox; Allergan, Dublin, Ireland) paralysis and a newly designed external fixator to restrict motion of the knee in mice undergoing anterior cruciate ligament (ACL) reconstruction. Nineteen C57BL/6 mice were allocated to two groups: (1) Botox group (n = 9) and (2) external fixator group (n = 10). Mice in Botox group received two different doses of Botox: 0.25 unit (n = 3) and 0.5 unit (n = 6). Injection was performed 72 hours prior to ACL reconstruction into the quadriceps, hamstring, and calf muscles of the right hind leg. Mice in external fixator group received an external fixator following ACL reconstruction. Mice were monitored for survival, tolerance, and achievement of complete knee immobilization. All mice were meant for sacrifice on day 14 postoperatively. No perceptible change in gait was observed with 0.25 unit of Botox. All mice that received 0.5 unit of Botox had complete hind limb paralysis documented by footprint analysis 2 days after injection but failed to tolerate anesthesia and were euthanized 24 hours after operation due to their critical condition. In contrast, the external fixator was well tolerated and effectively immobilized the limb. There was a single occurrence of intraoperative technical error in the external fixator group that led to euthanasia. No mechanical failure or complication was observed. Botox paralysis was not a viable option for postoperative restriction of motion and joint loading in mice. However, external fixation was an effective method for complete knee immobilization and can be used in murine models requiring postoperative control of knee loading. This study introduces a robust research tool to allow control of postoperative joint loading in animal models such as ACL reconstruction, permitting study of the effects of mechanical load on the biologic aspects of tendon-to-bone healing.

AbstractBackground.Preclinical and epidemiological data suggest that metformin might have antineoplastic properties against colon cancer (CC). However, the effect of metformin use on patient survival in stage III CC after curative resection is unknown. The survival outcomes were comparable regardless of the duration of metformin use.Patients and Methods.Before randomization to FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin) with or without cetuximab, 1,958 patients with stage III CC enrolled in the N0147 study completed a questionnaire with information on diabetes mellitus (DM) and metformin use. Cox models were used to assess the association between metformin use and disease-free survival (DFS), overall survival (OS), and the time to recurrence (TTR), adjusting for clinical and/or pathological factors.Results.Of the 1,958 patients, 1,691 (86%) reported no history of DM, 115 reported DM with metformin use (6%), and 152 reported DM without metformin use (8%). The adjuvant treatment arms were pooled, because metformin use showed homogeneous effects on outcomes across the two arms. Among the patients with DM (n = 267), DFS (adjusted hazard ratio [aHR], 0.90; 95% confidence interval [CI], 0.59–1.35; p = .60), OS (aHR, 0.99; 95% CI, 0.65–1.49; p = .95), and TTR (aHR, 0.87; 95% CI, 0.56–1.35; p = .53) were not different for the metformin users compared with the nonusers after adjusting for tumor and patient factors. The survival outcomes were comparable regardless of the duration of metformin use (&lt;1, 1–5, 6–10, ≥11 years) before randomization (ptrend = .64 for DFS, ptrend = .84 for OS, and ptrend = .87 for TTR). No interaction effects were observed between metformin use and KRAS, BRAF mutation status, tumor site, T/N stage, gender, or age.Conclusions.Patients with stage III CC undergoing adjuvant chemotherapy who used metformin before the diagnosis of CC experienced DFS, OS, and TTR similar to those for non-DM patients and DM patients without metformin use.

Purpose: To assess whether exposure to modified shock index (MSI) in the first 24 hours of intensive care unit (ICU) admission is associated with increased in-hospital mortality. Methods: Adult critically ill patients were included in a case–control design with 1:2 matching. Cases (death) and controls (alive) were abstracted by a reviewer blinded to exposure status (MSI). Cases were matched to controls on 3 factors—age, end-stage renal disease, and ICU admission diagnosis. Results: Eighty-three cases and 159 controls were included. On univariate analysis, lorazepam administration (odds ratio [OR]: 5.75, confidence interval [CI] = 2.28-14.47; P ≤ .01), shock requiring vasopressors (OR: 3.62, CI = 1.77-7.40; P ≤ .01), maximum MSI (OR: 2.77 per unit, CI = 1.63-4.71; P ≤ .001), and elevated acute physiologic and chronic health evaluation (APACHE) III score at 1 hour (OR: 1.41 per 10 units, CI = 1.19-1.66; P ≤ .001) were associated with mortality. Maximum MSI (OR: 1.93 per unit, CI = 1.07-3.48, P = .03) and APACHE III score at 1 hour (OR: 1.29 per 10 units, CI = 1.09-1.53; P = .003) remained significant with mortality in the multivariate analysis. The optimal cutoff point for high MSI and mortality was 1.8. Conclusion: Critically ill patients who demonstrate an elevated MSI within the first 24 hours of ICU admission have a significant mortality risk. Given that MSI is easily calculated at the bedside, clinicians may institute interventions earlier which could improve survival.

ObjectiveTo assess the safety and efficacy of short‐term meal replacement therapy followed by topiramate for body mass index (BMI) reduction in adolescents with severe obesity.MethodsAdolescents (ages 12–18 years) with severe obesity (BMI ≥1.2 times the 95th percentile or BMI ≥35 kg/m2) were recruited for this double‐blind, randomized, placebo‐controlled trial. Participants completed 4 weeks of meal replacement therapy followed by randomization (1:1) to either 24 weeks of topiramate 75 mg/day or placebo. Mean changes were compared between groups.ResultsThirty adolescents (mean age 15.2 ± 1.7 years, mean BMI 40.3 ± 4.6 kg/m2) completed the meal replacement phase and were randomized; 21 completed the study. The difference in mean percent change in BMI between the topiramate and placebo groups was not significant (−1.9%; 95% CI: −5.2% to +1.5%; P = 0.291). Significant improvements in visceral fat and very‐low‐density lipoprotein cholesterol were observed in the topiramate compared with the placebo group. There were no concerning changes in neurocognitive function or bone health.ConclusionsIn this pilot study, 4 weeks of meal replacement therapy followed by 24 weeks of low‐dose topiramate compared with meal replacement therapy alone did not result in significant BMI reduction for adolescents with severe obesity.