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AbstractIntroductionFamily history (FH) of Alzheimer's disease (AD) affects mitochondrial function and may modulate effects of translocase of the outer mitochondrial membrane 40 kDa (TOMM40) rs10524523 ('523) poly‐T length on memory decline.MethodsFor 912 nonapolipoprotein ε4 middle‐aged adults and 365 aged adults across the AD spectrum, linear mixed models gauged FH and TOMM40 '523 interactions on memory and global cognition between baseline and up to 10 years later. A cerebrospinal fluid mitochondrial function biomarker was also assessed.ResultsFor FH negative participants, gene‐dose preservation of memory and global cognition was seen for “very long” versus “short” carriers. For FH positive, an opposite gene‐dose decline was seen for very long versus short carriers. Maternal FH was a stronger predictor in aged, but not middle‐aged, participants. Similar gene‐dose effects were seen for the mitochondrial biomarker aspartate aminotransferase.DiscussionThese results may clarify conflicting findings on TOMM40 poly‐T length and AD‐related decline.

Rationale: Increasing evidence indicates that alterations of the cerebral microcirculation may play a role in Alzheimer disease, the leading cause of late-life dementia. The amyloid-β peptide (Aβ), a key pathogenic factor in Alzheimer disease, induces profound alterations in neurovascular regulation through the innate immunity receptor CD36 (cluster of differentiation 36), which, in turn, activates a Nox2-containing NADPH oxidase, leading to cerebrovascular oxidative stress. Brain perivascular macrophages (PVM) located in the perivascular space, a major site of brain Aβ collection and clearance, are juxtaposed to the wall of intracerebral resistance vessels and are a powerful source of reactive oxygen species. Objective: We tested the hypothesis that PVM are the main source of reactive oxygen species responsible for the cerebrovascular actions of Aβ and that CD36 and Nox2 in PVM are the molecular substrates of the effect. Methods and Results: Selective depletion of PVM using intracerebroventricular injection of clodronate abrogates the reactive oxygen species production and cerebrovascular dysfunction induced by Aβ applied directly to the cerebral cortex, administered intravascularly, or overproduced in the brain of transgenic mice expressing mutated forms of the amyloid precursor protein (Tg2576 mice). In addition, using bone marrow chimeras, we demonstrate that PVM are the cells expressing CD36 and Nox2 responsible for the dysfunction. Thus, deletion of CD36 or Nox2 from PVM abrogates the deleterious vascular effects of Aβ, whereas wild-type PVM reconstitute the vascular dysfunction in CD36-null mice. Conclusions: The data identify PVM as a previously unrecognized effector of the damaging neurovascular actions of Aβ and unveil a new mechanism by which brain-resident innate immune cells and their receptors may contribute to the pathobiology of Alzheimer disease.

Heart failure (HF) patients demonstrate impaired pulmonary, circulatory, and nervous system responses to exercise. While HF demonstrates prolonged [time constant (τ)] pulmonary O2 uptake (V̇o2) on-kinetics, contributing to exercise intolerance, it is unknown whether abnormal V̇o2 kinetics couple with ventilatory and circulatory dysfunction secondary to impaired group III/IV afferents in HF. Because lower lumbar intrathecal fentanyl inhibits locomotor muscle afferents, resulting in improved exercise ventilation and hemodynamics, we tested these hypotheses: HF will demonstrate 1) rapid V̇o2 on-kinetics and 2) attenuated steady-state V̇o2 amplitude and O2 deficit (O2def) during exercise with fentanyl versus placebo. On separate visits (randomized), breath-by-breath V̇o2 was measured in HF (ejection fraction: 27 ± 6%, New York Heart Association class I–III) and age- and sex-matched controls (both n = 9, ages: 60 ± 6 vs. 63 ± 8 yr, P = 0.37) during cycling transitions at 65% peak workload (78 ± 24 vs. 115 ± 39 W, P < 0.01) with intrathecal fentanyl or placebo. Regardless of group or condition, optimal phase II (primary component) curve fits reflected a phase I period equal to 35 s (limb-to-lung timing) via single-exponential functions. Condition did not affect steady-state V̇o2, the phase II τ of V̇o2, or O2def within controls ( P > 0.05). Without differences in steady-state V̇o2, reduced O2def in fentanyl versus placebo within HF (13 ± 4 vs. 22 ± 15 ml/W, P = 0.04) was accounted for by a rapid phase II τ of V̇o2 in fentanyl versus placebo within HF (45 ± 11 vs. 57 ± 14 s, P = 0.04), respectively. In an integrative manner, these data demonstrate important effects of abnormal locomotor muscle afferents coupled to pulmonary and circulatory dysfunction in determining impaired exercise V̇o2 in HF. Effects of abnormal muscle afferents on impaired exercise V̇o2 and hence exercise intolerance may not be discernable by independently assessing steady-state V̇o2 in HF. NEW & NOTEWORTHY Inhibition of locomotor muscle afferents results in rapid primary-component O2 uptake (V̇o2) on-kinetics accounting for the decreased O2 deficit in heart failure (HF). This study revealed that abnormal musculoskeletal–neural afferents couple with pulmonary and circulatory dysfunction to provoke impaired exercise V̇o2 in HF. Steady-state V̇o2 cannot properly phenotype abnormal muscle afferent contributions to impaired exercise V̇o2 in HF.

While dementia caregivers are regarded as a population with high unmet needs, there is little consensus as to how caregivers’ needs should be conceptualized and measured. This article describes how dementia caregivers’ needs are currently assessed in the scientific literature with the goal of suggesting guidelines for the enhancement of future measurement of caregiver needs. A review of 26 articles identified overarching themes within measurement approaches including variation in methodological rigor, proxy indicators of need, dual needs assessment of caregiver and person with dementia (PWD), and third-party needs assessment. We recommend future research dedicate theoretical attention to the conceptualization and classification of caregivers’ needs to build a stronger foundation for measurement. The measurement development process should capitalize on mixed-methodology and follow instrument development and validation guidelines set forth by measurement theory. Reliable and valid instruments are essential to developing services and policies that address dementia caregivers’ needs.

AbstractAn 8‐year‐old girl born to a family with more than three generations of dominant dystrophic epidermolysis bullosa (DDEB) presented with life‐threatening confluent skin erosions, mitten hand deformity, and failure to thrive. Reassessment of her family history and genetic testing showed compound heterozygous COL7A mutations, one inherited from her DDEB‐affected mother and one from her unaffected, healthy father. This family illustrates the risk of unexpected, severe, autosomal recessive epidermolysis bullosa (EB) in a family with milder, multigenerational autosomal dominant EB. Clinicians should recognize the clinical spectrum of dystrophic EB and recommend genetic consultation when the phenotype conflicts with family history.

187 Background: Patient-reported evaluations of interpersonal quality of care are essential elements of quality of cancer care assessment. At times, patients may be unable to report themselves on their care experience and systems may rely on proxy reports. The validity of this approach is dependent on the degree to which family caregiver assessments are concordant with patient assessments. Methods: A VA cohort of colorectal cancer (CRC) patients and their caregivers both completed a self-administered questionnaire on the quality of VA cancer care in 3 specific domains: surgery, chemotherapy overall and chemotherapy nursing care, all measured on a 5-point Likert scale. Because the kappa statistic penalizes skewed distributions which are commonly seen in patient satisfaction reports, agreement between patients and caregivers on perceptions of quality care were measured using Gwet’s AC2 statistic. Stratified analyses on caregiver burden, race, education, and age as well as patient’s stage of disease were used to assess variation in agreement. Results: 417 caregiver-patient dyads completed the survey (70% response rate), of whom 362 (86.8%) had surgery and 195 (46.8%) had chemotherapy. Overall agreement was high for the 3 quality of care domains: AC2 (95% CI): 0.870 (0.838, 0.903) for surgery, 0.835 (0.786, 0.884) for chemotherapy overall and 0.906 (0.868, 0.944) for chemotherapy nurses. Stratified analyses of agreement showed particular populations of higher or lower agreement; however the findings were inconsistent across the three domains and most were not statistically significant. Patients with lower stage (I-II) had higher agreement than higher stages (III-IV) (AC2: 0.967 and 0.879 respectively, P = 0.006) but only in the chemotherapy nurses domain. For the surgery domain, age was the only significant difference in agreement (0.816, 0.912, and 0.838 for < 50, 51-65, and > 65 respectively, P = 0.03). Conclusions: Family caregiver reports on the quality of CRC care were highly concordant with patient reports. Therefore, family caregivers may be able to provide reasonable proxy report on measures of quality of cancer care when patient reports are unavailable.

PURPOSE: To estimate the efficacy of contralateral prophylactic mastectomy in women with a personal and family history of breast cancer. PATIENTS AND METHODS: We followed the course of 745 women with a first breast cancer and a family history of breast and/or ovarian cancer who underwent contralateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993. Family history information and cancer follow-up information were obtained from the medical record, a study-specific questionnaire, and telephone follow-up. Life-tables for contralateral breast cancers, which consider age at first breast cancer, current age, and type of family history, were used to calculate the number of breast cancers expected in our cohort had they not had a prophylactic mastectomy. RESULTS: Of the 745 women in our cohort, 388 were premenopausal (age < 50 years) and 357 were post- menopausal. Eight women developed a contralateral breast cancer. Six events were observed among the premenopausal women, compared with 106.2 predicted, resulting in a risk reduction of 94.4% (95% confidence interval [CI], 87.7% to 97.9%). For the 357 postmenopausal women, 50.3 contralateral breast cancers were predicted, whereas only two were observed, representing a 96.0% risk reduction (95% CI, 85.6% to 99.5%). CONCLUSION: The incidence of contralateral breast cancer seems to be reduced significantly after contralateral prophylactic mastectomy in women with a personal and family history of breast cancer.

Abstract Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome‐wide association study (GWAS) for late‐onset AD in Stage 1 sample including whites of European Ancestry, African‐Americans, Japanese, and Israeli‐Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome‐wide significant (GWS) associations in single‐nucleotide polymorphism (SNP)–based tests ( P < 5 × 10 −8 ) were identified for SNPs in PFDN1/HBEGF , USP6NL/ECHDC3 , and BZRAP1‐AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence ( P < 2.7 × 10 −6 ) for gene‐based association in the total sample with a novel locus, TPBG ( P = 1.8 × 10 −6 ). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.