The Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT): Study Design and Participants

Background: Lifestyle and life-environment factors have undergone drastic changes in Japan over the last few decades. Further, many molecular epidemiologic studies have reported that genetic, epigenetic, and other biomarker information may be useful in predicting individual disease risk.Methods: The Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT) was launched in 2011 to identify risk factors for lifestyle-related disease, elucidate factors that extend healthy life expectancy, and contribute toward personalized healthcare based on our more than 20 years’ experience with the JPHC Study. From 2011 through 2016, a baseline survey was conducted at 16 municipalities in seven prefectures across the country. A self-administered questionnaire was distributed to all registered residents aged 40–74, which mainly asked about lifestyle factors, such as socio-demographic situation, personal medical history, smoking, alcohol and dietary habits. We obtained informed consent from each participant to participate in this long follow-up study of at least 20 years, including consent to the potential use of their residence registry, medical records, medical fee receipts, care insurance etc., and to the provision of biospecimens (blood and urine), including genomic analysis.Results: As of December 31, 2016, we have established a population-based cohort of 115,385 persons (Response rate 44.1%), among whom 55,278 (47.9% of participants) have provided blood and urine samples. The participation rate was slightly higher among females and in the older age group.Conclusion: We have established a large-scale population-based cohort for next-generation epidemiological study in Japan

Reversal of Cardiac Dysfunction After Long-Term Expression of SERCA2a by Gene Transfer in a Pre-Clinical Model of Heart Failure

ObjectivesThe aim of this study was to examine the effects of sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) gene transfer in a swine heart failure (HF) model.BackgroundReduced expression and activity of SERCA2a have been documented in HF. Prior studies have reported the beneficial effects of short-term SERCA2a overexpression in rodent models. However, the effects of long-term expression of SERCA2a in pre-clinical large animal models are not known.MethodsYorkshire-Landrace pigs were used (n = 16) to create volume overload by percutaneously severing chordae tendinae of the mitral apparatus with a bioptome to induce mitral regurgitation. At 2 months, pigs underwent intracoronary delivery of either recombinant adeno-associated virus type 1 (rAAV1) carrying SERCA2a under a cytomegalovirus promoter (rAAV1.SERCA2a) (n = 10; group 1) or saline (n = 6; group 2).ResultsAt 2 months, study animals were found to be in a compensated state of volume-overload HF (increased left ventricular internal diastolic and systolic diameters [LVIDd and LVIDs]). At 4 months, gene transfer resulted in: 1) positive left ventricular (LV) inotropic effects (adjusted peak left ventricular pressure rate of rise (dP/dt)max/P, 21.2 ± 3.2 s−1 group 1 vs. 15.5 ± 3.0 s−1 group 2; p < 0.01); 2) improvement in LV remodeling (% change in LVIDs −3.0 ± 10% vs. +15 ± 11%, respectively; p < 0.01). At follow-up, brain natriuretic peptide levels remained stable in group 1 after gene transfer, in contrast to rising levels in group 2. Further, cardiac SERCA2a expression was significantly decreased in group 2 whereas in group 1 it was restored to normal levels. There was no histopathological evidence of acute myocardial inflammation or necrosis.ConclusionsUsing a large-animal, volume-overload model of HF, we report that long-term overexpression of SERCA2a by in vivo rAAV1-mediated intracoronary gene transfer preserved systolic function, potentially prevented diastolic dysfunction, and improved ventricular remodeling

Initial Surgical Versus Conservative Strategies in Patients With Asymptomatic Severe Aortic Stenosis

AbstractBackgroundCurrent guidelines generally recommend watchful waiting until symptoms emerge for aortic valve replacement (AVR) in asymptomatic patients with severe aortic stenosis (AS).ObjectivesThe study sought to compare the long-term outcomes of initial AVR versus conservative strategies following the diagnosis of asymptomatic severe AS.MethodsWe used data from a large multicenter registry enrolling 3,815 consecutive patients with severe AS (peak aortic jet velocity >4.0 m/s, or mean aortic pressure gradient >40 mm Hg, or aortic valve area <1.0 cm2) between January 2003 and December 2011. Among 1,808 asymptomatic patients, the initial AVR and conservative strategies were chosen in 291 patients, and 1,517 patients, respectively. Median follow-up was 1,361 days with 90% follow-up rate at 2 years. The propensity score–matched cohort of 582 patients (n = 291 in each group) was developed as the main analysis set for the current report.ResultsBaseline characteristics of the propensity score–matched cohort were largely comparable, except for the slightly younger age and the greater AS severity in the initial AVR group. In the conservative group, AVR was performed in 41% of patients during follow-up. The cumulative 5-year incidences of all-cause death and heart failure hospitalization were significantly lower in the initial AVR group than in the conservative group (15.4% vs. 26.4%, p = 0.009; 3.8% vs. 19.9%, p < 0.001, respectively).ConclusionsThe long-term outcome of asymptomatic patients with severe AS was dismal when managed conservatively in this real-world analysis and might be substantially improved by an initial AVR strategy. (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis Registry; UMIN000012140

Genetic Predisposition to Ischemic Stroke

Background and Purpose—The prediction of genetic predispositions to ischemic stroke (IS) may allow the identification of individuals at elevated risk and thereby prevent IS in clinical practice. Previously developed weighted multilocus genetic risk scores showed limited predictive ability for IS. Here, we investigated the predictive ability of a newer method, polygenic risk score (polyGRS), based on the idea that a few strong signals, as well as several weaker signals, can be collectively informative to determine IS risk.Methods—We genotyped 13 214 Japanese individuals with IS and 26 470 controls (derivation samples) and generated both multilocus genetic risk scores and polyGRS, using the same derivation data set. The predictive abilities of each scoring system were then assessed using 2 independent sets of Japanese samples (KyushuU and JPJM data sets).Results—In both validation data sets, polyGRS was shown to be significantly associated with IS, but weighted multilocus genetic risk scores was not. Comparing the highest with the lowest polyGRS quintile, the odds ratios for IS were 1.75 (95% confidence interval, 1.33–2.31) and 1.99 (95% confidence interval, 1.19–3.33) in the KyushuU and JPJM samples, respectively. Using the KyushuU samples, the addition of polyGRS to a nongenetic risk model resulted in a significant improvement of the predictive ability (net reclassification improvement=0.151; P<0.001).Conclusions—The polyGRS was shown to be superior to weighted multilocus genetic risk scores as an IS prediction model. Thus, together with the nongenetic risk factors, polyGRS will provide valuable information for individual risk assessment and management of modifiable risk factors

Digital reconstructed radiography with multiple color image overlay for image-guided radiotherapy.

Registration of patient anatomical structures to the reference position is a basic part of the patient set-up procedure. Registration of anatomical structures between the site of beam entrance on the patient surface and the distal target position is particularly important. Here, to improve patient positional accuracy during set-up for particle beam treatment, we propose a new visualization methodology using digitally reconstructed radiographs (DRRs), overlaid DRRs, and evaluation of overlaid DRR images in clinical cases. The overlaid method overlays two DRR images in different colors by dividing the CT image into two CT sections at the distal edge of the target along the treatment beam direction. Since our hospital uses fixed beam ports, the treatment beam angles for this study were set at 0 and 90 degrees. The DRR calculation direction was from the X-ray tube to the imaging device, and set to 180/270 degrees and 135/225 degrees, based on the installation of our X-ray imaging system. Original and overlaid DRRs were calculated using CT data for two patients, one with a parotid gland tumor and the other with prostate cancer. The original and overlaid DRR images were compared. Since the overlaid DRR image was completely separated into two regions when the DRR calculation angle was the same as the treatment beam angle, the overlaid DRR visualization technique was able to provide rich information for aiding recognition of the relationship between anatomical structures and the target position. This method will also be useful in patient set-up procedures for fixed irradiation ports