South Africa is a middle-income country with high levels of income inequality and a rapidly aging population and increasing dementia prevalence. Little is known about which risk factors for dementia ...are important and how they differ by social determinants of health as well as key demographic characteristics such as sex and wealth. We sought to calculate the population attributable risks (PARs) for established potentially modifiable risk factors for dementia among these different groups.
We obtained risk factor prevalence from population-based surveys for established dementia risk factors (diabetes, midlife hypertension, midlife obesity, physical inactivity, depression, smoking, low educational attainment, social isolation). We used relative risk estimates reported in previous meta-analyses and estimated PARs using Levin's formula and accounting for communality. We tested for one-way and two-way interactions by sex and wealth using Pearson's χ2. In stratified analyses, we performed tests for trend using logistic regression.
The prevalence of established risk factors for dementia ranged from 5% for depression to 64% for low education. After accounting for communality, the risk factors contributing the greatest PAR were low education (weighted PAR 12%, 95% CI 7% to 18%), physical inactivity (9, 5-14%), and midlife hypertension (6, 5-14%). Together, 45% of dementia cases may be attributable to modifiable risk factors (95% CI 25-59%). We found significant interactions (
< 0.005) between sex, wealth, or both (sex
wealth) and each risk factor except social isolation and physical activity. Low education was inversely associated with wealth in both male and female. The PAR for midlife hypertension, obesity, and diabetes was associated with increasing wealth, and was higher in female. In contrast, the PAR for smoking was higher in male (8% vs. 2%) and was associated with increasing wealth among female only. We found that either a strategy of large reductions in selected risk factors with the highest PAR (midlife hypertension, smoking, physical inactivity) or small reductions across all risk factors could potentially reduce dementia cases by as many as 250,000 by 2050.
The potential impact on dementia risk by decreasing exposure to established dementia risk factors is large and differs by sex and social determinants of health like wealth. Risk factor PAR should inform national and local health policy dementia initiatives in South Africa including which risk factors to target in the whole population and which to target in high-risk groups for maximum public health benefit.
Pes anserinus bursitis is a differential diagnosis for knee pain, that may be misdiagnosed. Without proper physical examination and thorough history taking, the diagnosis of pes anserinus may be ...delayed. We present a case report of this condition, involving both primary care and the emergency department. This case illustrates one possible presentation of this condition, and also demonstrates the risks of overreliance on imaging modalities in primary care, without also performing a proper physical examination of musculoskeletal presentations. The teamwork between physiotherapists and clinicians, in this case, highlights the value of a multidisciplinary team in sports medicine. This case report lends evidence that pes anserinus bursitis should be considered as a possible diagnosis for knee pain and emphasises the importance of physical examination.
Veliparib, a PARP inhibitor, demonstrated clinical activity in combination with oral cyclophosphamide in patients with BRCA-mutant solid tumors in a phase I trial. To define the relative contribution ...of PARP inhibition to the observed clinical activity, we conducted a randomized phase II trial to determine the response rate of veliparib in combination with cyclophosphamide compared with cyclophosphamide alone in patients with pretreated BRCA-mutant ovarian cancer or in patients with pretreated primary peritoneal, fallopian tube, or high-grade serous ovarian cancers (HGSOC).
Adult patients were randomized to receive cyclophosphamide alone (50 mg orally once daily) or with veliparib (60 mg orally once daily) in 21-day cycles. Crossover to the combination was allowed at disease progression.
Seventy-five patients were enrolled and 72 were evaluable for response; 38 received cyclophosphamide alone and 37 the combination as their initial treatment regimen. Treatment was well tolerated. One complete response was observed in each arm, with three partial responses (PR) in the combination arm and six PRs in the cyclophosphamide alone arm. Genetic sequence and expression analyses were performed for 211 genes involved in DNA repair; none of the detected genetic alterations were significantly associated with treatment benefit.
This is the first trial that evaluated single-agent, low-dose cyclophosphamide in HGSOC, peritoneal, fallopian tube, and BRCA-mutant ovarian cancers. It was well tolerated and clinical activity was observed; the addition of veliparib at 60 mg daily did not improve either the response rate or the median progression-free survival.
Summary
Over 50% of patients with systemic LCH are not cured with front‐line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with ...clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long‐term efficacy, late toxicities, relative cost and patient‐reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.
Prion protein (PrP) concentration controls the kinetics of prion replication and is a genetically and pharmacologically validated therapeutic target for prion disease. In order to evaluate PrP ...concentration as a pharmacodynamic biomarker and assess its contribution to known prion disease risk factors, we developed and validated a plate-based immunoassay reactive for PrP across 6 species of interest and applicable to brain and cerebrospinal fluid (CSF). PrP concentration varied dramatically across different brain regions in mice, cynomolgus macaques, and humans. PrP expression did not appear to contribute to the known risk factors of age, sex, or common PRNP genetic variants. CSF PrP was lowered in the presence of rare pathogenic PRNP variants, with heterozygous carriers of P102L displaying 55%, and D178N just 31%, of the CSF PrP concentration of mutation-negative controls. In rodents, pharmacologic reduction of brain Prnp RNA was reflected in brain parenchyma PrP and, in turn in CSF PrP, validating CSF as a sampling compartment for the effect of PrP-lowering therapy. Our findings support the use of CSF PrP as a pharmacodynamic biomarker for PrP-lowering drugs and suggest that relative reduction from individual baseline CSF PrP concentration may be an appropriate marker for target engagement.
Objective: The objective of this study was to examine the dependence of item memory and relational memory on medial temporal lobe (MTL) structures. Patients with amnesia, who either had extensive MTL ...damage or damage that was relatively restricted to the hippocampus, were tested, as was a matched comparison group. Disproportionate relational memory impairments were predicted for both patient groups, and those with extensive MTL damage were also expected to have impaired item memory. Method: Participants studied scenes, and were tested with interleaved 2-alternative forced-choice probe trials. Probe trials were either presented immediately after the corresponding study trial (Lag 1), 5 trials later (Lag 5), or 9 trials later (Lag 9) and consisted of the studied scene along with a manipulated version of that scene in which 1 item was replaced with a different exemplar (item memory test) or was moved to a new location (relational memory test). Participants were to identify the exact match of the studied scene. Results: As predicted, patients were disproportionately impaired on the test of relational memory. Item memory performance was marginally poorer among patients with extensive MTL damage, but both groups were impaired relative to matched comparison participants. Impaired performance was evident at all lags, including the shortest possible lag (Lag 1). Conclusions: The results are consistent with the proposed role of the hippocampus in relational memory binding and representation, even at short delays, and suggest that the hippocampus may also contribute to successful item memory when items are embedded in complex scenes.
PURPOSE: Survivors of Ebola virus disease (EVD) are at risk for ocular complications after infection. We sought to identify demographic factors associated with the likelihood to present for eye ...examination among Ebola survivors enrolled in a longitudinal natural history study of EVD. METHODS: The Partnership for Research on Vaccines and Infectious Diseases in Liberia (PREVAIL) III Ebola natural history study is a 5-year study that seeks to identify long-term sequelae of EVD, including ocular sequelae. All survivors enrolled in the PREVAIL parent study from June 2015 to March 2016 were asked to return for comprehensive eye examination through June 2016. Logistic regression was conducted using self-reported survivor status, age, gender, and distance from the hospital as covariates. RESULTS: A total of 1448 subjects enrolled in the parent PREVAIL III longitudinal cohort during the defined window, of which 1375 (95.0%) followed up for baseline eye examination. Ebola survivors (635/661, 96.1%) and adult close contacts (727/767, 94.8%) demonstrated a comparable likelihood for presenting for eye examination (odds ratio OR 0.68, 95% confidence interval CI 0.36–1.28). In an adjusted model, age over 50 (OR 10.2, 95% CI 1.35–77.3) and living outside Montserrado County (OR 0.18, 95% CI 0.10–0.33) were associated with the likelihood of presenting for a baseline comprehensive eye examination. CONCLUSION: Most EVD survivors and their close contacts who enrolled during the study window presented for eye examinations. Older participants and those who lived closer to clinical facilities were most likely to present. Focused strategies accounting for these factors may assist with organizations planning survivor care in the setting of EVD.
The incidence of neural tube defects (NTDs) declined by about 40 % in Canada with the introduction of a national folic acid (FA) fortification program. Despite the fact that few Canadians currently ...exhibit folate deficiency, NTDs are still the second most common congenital abnormality. FA fortification may have aided in reducing the incidence of NTDs by overcoming abnormal one carbon metabolism cycling, the process which provides one carbon units for methylation of DNA. We considered that NTDs persisting in a folate-replete population may also occur in the context of FA-independent compromised one carbon metabolism, and that this might manifest as abnormal DNA methylation (DNAm). Second trimester human placental chorionic villi, kidney, spinal cord, brain, and muscle were collected from 19 control, 22 spina bifida, and 15 anencephalic fetuses in British Columbia, Canada. DNA was extracted, assessed for methylenetetrahydrofolate reductase (MTHFR) genotype and for genome-wide DNAm using repetitive elements, in addition to the Illumina Infinium HumanMethylation450 (450k) array.
No difference in repetitive element DNAm was noted between NTD status groups. Using a false discovery rate <0.05 and average group difference in DNAm ≥0.05, differentially methylated array sites were identified only in (1) the comparison of anencephaly to controls in chorionic villi (n = 4 sites) and (2) the comparison of spina bifida to controls in kidney (n = 3342 sites).
We suggest that the distinctive DNAm of spina bifida kidneys may be consequent to the neural tube defect or reflective of a common etiology for abnormal neural tube and renal development. Though there were some small shifts in DNAm in the other tested tissues, our data do not support the long-standing hypothesis of generalized altered genome-wide DNAm in NTDs. This finding may be related to the fact that most Canadians are not folate deficient, but it importantly opens the field to the investigation of other epigenetic and non-epigenetic mechanisms in the etiology of NTDs.
Assessing the relative importance of environmental and anthropogenic influences on the distribution of wild populations is an important step in designing spatially explicit plans for their management ...and protection. We examined environmental variables correlated with the spatial distribution of eastern Pacific harbor seals (Phoca vitulina richardii), a marine mammal common to coastal waters, in a large, highly urbanized estuary. We assessed the relationship between prey abundance, depth, bottom relief, proximity to terrestrial haul-out sites and 3 potential sources of anthropogenic influence, and the in-water spatial distribution of seals. We identified locations of seals using satellite-linked telemetry, and used partial Mantel tests to assess which environmental variables were most strongly linked to seal foraging distribution, given spatial autocorrelation within variables. Mann–Whitney tests were used to compare environmental characteristics of locations of seals with a random distribution of locations. Because harbor seals are central-place foragers, we incorporated spatial distribution of seals relative to the central place into our analyses. High prey abundance and proximity to the haul-out site were strongly associated with the spatial distribution of seals. Harbor seals also tended to use deeper waters and areas of high bottom relief within the estuary. There was no consistent spatial relationship between the 3 anthropogenic factors and the distribution of seals, although seals tended to be found closer than expected to sites of high human activity. In highly impacted coastal areas where limited alternate suitable habitat exists, foraging seals may need to rely on disturbed (suboptimal) areas, and as a result may habituate to human presence in areas rich in food resources.
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