Dementia before death in ageing societies--the promise of prevention and the reality.

BACKGROUND: Dementia and severe cognitive impairment are very closely linked to ageing. The longer we live the more likely we are to suffer from these conditions. Given population increases in longevity it is important to understand not only risk and protective factors for dementia and severe cognitive impairment at given ages but also whether protection affects cumulative risk. This can be explored by examining the effect on cumulative risk by time of death of factors found consistently to reduce risk at particular ages, such as education and social status. METHODS AND FINDINGS: In this analysis we report the prevalence of dementia and severe cognitive impairment in the year before death in a large population sample. In the Medical Research Council Cognitive Function and Ageing Study (a 10-y population-based cohort study of individuals 65 and over in England and Wales), these prevalences have been estimated by age, sex, social class, and education. Differences have been explored using logistic regression. The overall prevalence of dementia at death was 30%. There was a strong increasing trend for dementia with age from 6% for those aged 65-69 y at time of death to 58% for those aged 95 y and above at time of death. Higher prevalences were seen for severe cognitive impairment, with similar patterns. People with higher education and social class had significantly reduced dementia and severe cognitive impairment before death, but the absolute difference was small (under 10%). CONCLUSIONS: Reducing risk for dementia at a given age will lead to further extension of life, thus cumulative risk (even in populations at lower risk for given ages) remains high. Ageing of populations is likely to result in an increase in the number of people dying with dementia and severe cognitive impairment even in the presence of preventative programmes. Policy development and research for dementia must address the needs of individuals who will continue to experience these conditions before death

APOE and ACE polymorphisms and dementia risk in the older population over prolonged follow-up: 10 years of incidence in the MRC CFA Study.

BACKGROUND: dementia risk conferred by apolipoprotein-E (APOE) and angiotensin-1-converting enzyme (ACE) polymorphisms have been reported for the MRC Cognitive Function and Ageing Study (CFAS) at 6-year follow-up. We concentrate on incident dementia risk over 10 years. METHODS: participants come from MRC CFAS, a multi-centre longitudinal population-based study of ageing in England and Wales. Three follow-up waves of data collection were used: 2, 6 and 10 years. Logistic regressions were undertaken to investigate associations between APOE (n = 955) and ACE (n = 856) alleles/genotypes and incident dementia. Two types of control groups were used: non-demented and highly functioning non-demented. Results were back-weighted. RESULTS: compared to APOE epsilon3, epsilon2 conferred protection of odds ratio (OR) = 0.3 (95% confidence interval, CI = 0.1-0.6) and epsilon4 risk of OR = 2.9 (95% CI = 1.7-4.9) for incident dementia. Compared to epsilon3/epsilon3, the epsilon3/epsilon4 and epsilon4/epsilon4 genotypes conferred risks of OR = 3.6 (95% CI = 1.8-7.3) and OR = 7.9 (95% CI = 1.6-39.2), respectively. The epsilon3/epsilon2 genotype protected against dementia (OR = 0.2, 95% CI = 0.1-0.7), and epsilon2/epsilon2 had a similar protective effect but with wide CIs (OR = 0.3, 95% CI = 0.1-1.7). Restricting the control group accentuated these differentials. The effects of ACE alleles/genotypes on incident dementia risk were small. CONCLUSIONS: APOE but not ACE is associated with late-onset incident dementia in the population. Using longer term follow-up with proper adjustment for attrition and incident cases increases estimates of risk

Using biomarkers to predict TB treatment duration (Predict TB): a prospective, randomized, noninferiority, treatment shortening clinical trial

Background : By the early 1980s, tuberculosis treatment was shortened from 24 to 6 months, maintaining relapse rates of 1-2%. Subsequent trials attempting shorter durations have failed, with 4-month arms consistently having relapse rates of 15-20%. One trial shortened treatment only among those without baseline cavity on chest x-ray and whose month 2 sputum culture converted to negative. The 4-month arm relapse rate decreased to 7% but was still significantly worse than the 6-month arm (1.6%, P<0.01).  We hypothesize that PET/CT characteristics at baseline, PET/CT changes at one month, and markers of residual bacterial load will identify patients with tuberculosis who can be cured with 4 months (16 weeks) of standard treatment.Methods: This is a prospective, multicenter, randomized, phase 2b, noninferiority clinical trial of pulmonary tuberculosis participants. Those eligible start standard of care treatment. PET/CT scans are done at weeks 0, 4, and 16 or 24. Participants who do not meet early treatment completion criteria (baseline radiologic severity, radiologic response at one month, and GeneXpert-detectable bacilli at four months) are placed in Arm A (24 weeks of standard therapy). Those who meet the early treatment completion criteria are randomized at week 16 to continue treatment to week 24 (Arm B) or complete treatment at week 16 (Arm C). The primary endpoint compares the treatment success rate at 18 months between Arms B and C.Discussion: Multiple biomarkers have been assessed to predict TB treatment outcomes. This study uses PET/CT scans and GeneXpert (Xpert) cycle threshold to risk stratify participants. PET/CT scans are not applicable to global public health but could be used in clinical trials to stratify participants and possibly become a surrogate endpoint. If the Predict TB trial is successful, other immunological biomarkers or transcriptional signatures that correlate with treatment outcome may be identified. TRIAL REGISTRATION: NCT02821832

All-oral direct-acting Antiviral Therapy Against Hepatitis C Virus (HCV) in Human Immunodeficiency Virus/HCV– Coinfected Subjects in Real-World Practice: Madrid Coinfection Registry Findings

We evaluated treatment outcomes in a prospective registry of human immunodeficiency virus/hepatitis C virus (HCV)–coinfected patients treated with interferon-free direct-acting antiviral agent–based therapy in hospitals from the region of Madrid between November 2014 and August 2016.We assessed sustained viral response at 12 weeks after completion of treatment and used multivariable logistic regression to identify predictors of treatment failure.We evaluated 2,369 patients, of whom 59.5% did not have cirrhosis, 33.9% had compensated cirrhosis, and 6.6% had decompensated cirrhosis. The predominant HCV genotypes were 1a (40.9%), 4 (22.4%), 1b (15.1%), and 3 (15.0%). Treatment regimens included sofosbuvir (SOF)/ledipasvir (61.9%), SOF plus daclatasvir (14.6%), dasabuvir plus ombitasvir/paritaprevir/ritonavir (13.2%), and other regimens (10.3%). Ribavirin was used in 30.6% of patients. Less than 1% of patients discontinued therapy owing to adverse events. The frequency of sustained viral response by intention-to-treat analysis was 92.0% (95% confidence interval, 90.9%-93.1%) overall, 93.8% (92.4%-95.0%) for no cirrhosis, 91.0% (88.8%-92.9%) for compensated cirrhosis, and 80.8% (73.7%-86.6%) for decompensated cirrhosis. The factors associated with treatment failure were male sex (adjusted odds ratio, 1.75; 95% confidence interval, 1.14-2.69), Centers for Diseases Control and Prevention category C (adjusted odds ratio, 1.65; 95% confidence interval, 1.12-2.41), a baseline cluster of differentiation 4– positive (CD41) T-cell count <200/mm3 (adjusted odds ratio, 2.30; 95% confidence interval, 1.35-3.92), an HCV RNA load 800,000 IU/mL (adjusted odds ratio, 1.63; 95% confidence interval, 1.14-2.36), compensated cirrhosis (adjusted odds ratio, 1.35; 95% confidence interval, 0.96-1.89), decompensated cirrhosis (adjusted odds ratio, 2.92; 95% confidence interval, 1.76-4.87), and the use of SOF plus simeprevir, SOF plus ribavirin, and simeprevir plus daclatasvir. Conclusion: In this large real-world study, direct-acting antiviral agent–based therapy was safe and highly effective in coinfected patients; predictors of failure included gender, human immunodeficiency virus–related immunosuppression, HCV RNA load, severity of liver disease, and the use of suboptimal direct-acting antiviral agent–based regimens

High density lipoproteins-based therapies for cardiovascular disease

Atherosclerosis is the leading cause of death in developed countries. High density lipoproteins (HDL) cholesterol level correlates inversely with the risk of cardiovascular diseases. Thus, HDL has obtained lots of interest for drug development. In this review, we summarized the mechanisms for the antiatherogenic function of HDL, current HDL-based drugs in clinical use and the future direction for HDL-based therapy development

Family-based Genome-wide Association Study of South Indian Pedigrees Supports WNT7B as a Central Corneal Thickness Locus

Purpose To identify genetic risk factors contributing to central corneal thickness (CCT) in individuals from South India, a population with a high prevalence of ocular disorders. Methods: One hundred ninety-five individuals from 15 large South Indian pedigrees were genotyped using the Omni2.5 bead array. Family-based association for CCT was conducted using the score test in MERLIN. Results: Genome-wide association study (GWAS) identified strongest association for single nucleotide polymorphisms (SNPs) in the first intron of WNT7B and CCT (top SNP rs9330813; β = −0.57, 95% confidence interval [CI]: −0.78 to −0.36; P = 1.7 × 10−7). We further investigated rs9330813 in a Latino cohort and four independent European cohorts. A meta-analysis of these data sets demonstrated statistically significant association between rs9330813 and CCT (β = −3.94, 95% CI: −5.23 to −2.66; P = 1.7 × 10−9). WNT7B SNPs located in the same genomic region that includes rs9330813 have previously been associated with CCT in Latinos but with other ocular quantitative traits related to myopia (corneal curvature and axial length) in a Japanese population (rs10453441 and rs200329677). To evaluate the specificity of the observed WNT7B association with CCT in the South Indian families, we completed an ocular phenome-wide association study (PheWAS) for the top WNT7B SNPs using 45 ocular traits measured in these same families including corneal curvature and axial length. The ocular PheWAS results indicate that in the South Indian families WNT7B SNPs are primarily associated with CCT. Conclusions: The results indicate robust evidence for association between WNT7B SNPs and CCT in South Indian pedigrees, and suggest that WNT7B SNPs can have population-specific effects on ocular quantitative traits

Modifiable risk factors remain significant causes of medium term mortality after first time Coronary artery bypass grafting

<p>Abstract</p> <p>Background</p> <p>Whilst there is much current data on early outcomes after Coronary artery bypass grafting(CABG), there is relatively little data on medium term outcomes in the current era. The purpose of this study is to present a single surgeon series comprising of all first time CABG patients operated on with the technique of cross clamp fibrillation from Feb-1996 to through to Jan-2003, and to seek risk factors for medium term mortality in these patients.</p> <p>Methods</p> <p>Data was collected from Hospital Episode Statistics and departmental patient administration and tracking systems and cross checked using database techniques. Patient outcomes were searched using the National Health Service strategic tracing service.</p> <p>Results</p> <p>Mean follow up was 5.3 years(0–9.4 years) and was complete for all patients. 30-day survival was 98.4%, 1-year survival 95% and 8-year survival 79%. Cox-regression analysis revealed that several modifiable pre-operative risk factors remain significant predictors of medium term mortality, including Diabetes(Hazard Ratio(HR) 1.73, 95%CI 1.21–2.45), Chromic obstructive pulmonary disease(HR 2.02, 95%CI 1.09–3.72), Peripheral vascular disease(HR 1.68, 95%CI 1.13–2.5), Body mass index>30(HR 1.54, 95%CI 1.08–2.20) and current smoker at operation(HR 1.67, 95%CI 1.03–2.72). However hypertension(HR 1.31, 95%CI 0.95–1.82) and Hypercholestrolaemia(HR 0.81, 95%CI 0.58–1.13) were not predictive which may reflect adequate post-operative control.</p> <p>Conclusion</p> <p>Coronary artery bypass surgery using cross clamp fibrillation is associated with a very low operative mortality. Medium term survival is also good but risk factors such as smoking at operation, Chronic obstructive pulmonary disease, obesity and diabetes negatively impact this survival and should be aggressively treated in the years post-surgery.</p