The gut microbiota and coronary artery calcification in Japanese men.

BACKGROUND: The gut microbiota differs between patients with coronary artery disease (CAD) and healthy controls; however, it currently remains unclear whether these differences exist prior to the onset of CAD. We herein investigated the gut microbiota associated with subclinical coronary artery calcification (CAC) in a Japanese population. METHODS: A total of 663 Japanese men were enrolled in this cross-sectional study. Computed tomography and gut microbiology tests were performed, and CAC scores were calculated using the Agatston method. Participants were categorized into 4 groups based on their CAC scores: CAC = 0, 0

Factors affecting the sodium-glucose cotransporter 2 inhibitors-related initial decline in glomerular filtration rate and its possible effect on kidney outcome in chronic kidney disease with type 2 diabetes: The Japan Chronic Kidney Disease Database.

AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors often cause a transient decrease in glomerular filtration rate (GFR) shortly after the initiation, referred to as the 'initial drop'. However, the clinical significance of this initial drop in real-world practice remains unclear. MATERIALS AND METHODS: Using the nationwide Japan Chronic Kidney Disease Database, we examined factors that affected the initial drop, in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). We also evaluated the effects of the initial drop on a composite kidney outcome (a decline in GFR of ≥50% or progression to end-stage kidney disease). RESULTS: Data from 2053 patients with CKD and T2DM newly prescribed an SGLT2 inhibitor were analysed. The follow-up period after SGLT2 inhibitor administration was 1015 days (interquartile range: 532, 1678). Multivariate linear regression models revealed that the concomitant use of the renin-angiotensin system inhibitors and diuretics, urinary protein levels ≥2+, and changes in GFR before the initiation of the SGLT2 inhibitor were associated with a larger initial GFR decline (ß = -0.609, p = .039; ß = -2.298, p < .001; ß = -0.936, p = .048; ß = -0.079, p < .001, respectively). Patients in the quartile with the largest initial GFR decline experienced a higher incidence of the subsequent composite kidney outcome than those in the other quartiles (p < .001). CONCLUSIONS: The concomitant use of renin-angiotensin system inhibitors and diuretics, higher urine protein levels and pre-treatment GFR changes were associated with a larger initial GFR decline. Of these factors, the use of a diuretic had the largest effect. Furthermore, patients with CKD and T2DM experiencing an excessive initial GFR drop might be at a higher risk of adverse kidney outcomes.

Awareness of Being Prescribed Antihypertensive Medications and Cardiovascular Outcomes.

BACKGROUND: Hypertension is a major cause of cardiovascular disease (CVD). In patients with hypertension, unawareness of the disease often results in poor blood pressure control and increases the risk of CVD. However, data in nationwide surveys regarding the proportion of unaware individuals and the implications of such on their clinical outcomes are lacking. We aimed to clarify the association between unawareness of being prescribed antihypertensive medications among individuals taking antihypertensive medications and the subsequent risk of developing CVD.Methods and Results: This retrospective cohort study analyzed data from the JMDC Claims Database, including 313,715 individuals with hypertension treated with antihypertensive medications (median age 56 years). The primary endpoint was a composite of myocardial infarction, angina pectoris, stroke, heart failure, and atrial fibrillation. Overall, 19,607 (6.2%) individuals were unaware of being prescribed antihypertensive medications. During the follow-up period, 33,976 composite CVD endpoints were documented. Despite their youth, minimal comorbidities, and the achievement of better BP control with a reduced number of antihypertensive prescriptions, unawareness of being prescribed antihypertensive medications was associated with a greater risk of developing composite CVD. Hazard ratios of unawareness of being prescribed antihypertensive medications were 1.16 for myocardial infarction, 1.25 for angina pectoris, 1.15 for stroke, 1.36 for heart failure, and 1.28 for atrial fibrillation. The results were similar in several sensitivity analyses, including the analysis after excluding individuals with dementia. CONCLUSIONS: Among individuals taking antihypertensive medications, assessing the awareness of being prescribed antihypertensive medications may help identify those at high risk for CVD-related events.

Association of serum magnesium levels with renal prognosis in patients with chronic kidney disease.

BACKGROUND: Magnesium deficiency is associated with various health conditions, but its impact on the progression of chronic kidney disease (CKD) remains unclear. This study aimed to investigate the association between serum magnesium levels and prognosis of renal function in CKD patients. METHODS: This is an analysis of the Japan Chronic Kidney Disease Database Ex　(J-CKD-DB-Ex), which is a multicenter prospective cohort including CKD patients enrolled from January 1, 2014 to December 31, 2020. We included adult outpatients with CKD stage G3 and G4 at the time of initial magnesium measurement. Patients were classified by magnesium levels as low (<1.7 mg/dl), normal (1.7-2.6 mg/dl), or high (>2.6 mg/dl). The primary outcomes were the composite of an eGFR < 15 ml/min/1.73 m2 or a ≥30% reduction in eGFR from the initial measurement, which was defined as CKD progression. We applied the Kaplan-Meier analysis and Cox regression hazard model to examine the association between magnesium levels and CKD progression. RESULTS: The analysis included 9868 outpatients during the follow-up period. The low magnesium group was significantly more likely to reach CKD progression. Cox regression, adjusting for covariates and using the normal magnesium group as the reference, showed that the hazard ratio for the low magnesium group was 1.20 (1.08-1.34). High magnesium was not significantly associated with poor renal outcomes compared with normal magnesium. CONCLUSION: Based on large real-world data, this study demonstrated that low magnesium levels are associated with poorer renal outcomes.

Kidney outcomes associated with haematuria and proteinuria trajectories among patients with IgA nephropathy in real-world clinical practice: The Japan Chronic Kidney Disease Database.

AIM: Among patients with Immunoglobulin A (IgA) nephropathy, we aimed to identify trajectory patterns stratified by the magnitude of haematuria and proteinuria using repeated urine dipstick tests, and assess whether the trajectories were associated with kidney events. METHODS: Using a nationwide multicentre chronic kidney disease (CKD) registry, we analysed data from 889 patients with IgA nephropathy (mean age 49.3 years). The primary outcome was a sustained reduction in eGFR of 50% or more from the index date and thereafter. During follow-up (median 49.0 months), we identified four trajectories (low-stable, moderate-decreasing, moderate-stable, and high-stable) in both urine dipstick haematuria and proteinuria measurements, respectively. RESULTS: In haematuria trajectory analyses, compared to the low-stable group, the adjusted hazard ratios (HRs) (95% confidence interval [CI]) for kidney events were 2.59 (95% CI, 1.48-4.51) for the high-stable, 2.31 (95% CI, 1.19-4.50) for the moderate-stable, and 1.43 (95% CI, (0.72-2.82) for the moderate-decreasing groups, respectively. When each proteinuria trajectory group was subcategorized according to haematuria trajectories, the proteinuria group with high-stable and with modest-stable haematuria trajectories had approximately 2-times higher risk for eGFR reduction ≥50% compared to that with low-stable haematuria trajectory. CONCLUSION: Assessments of both haematuria and proteinuria trajectories using urine dipstick could identify high-risk IgA nephropathy patients.

Racial difference in the association between non-alcoholic fatty liver disease and incident type 2 diabetes: findings from the CARDIA study.

AIMS/HYPOTHESIS: Type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) are prevalent diseases of metabolic origin. We examined the association between NAFLD and the development of type 2 diabetes among non-Asian adults, and whether the association differs by race. METHODS: We analysed data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based prospective cohort study. Participants underwent non-contrast abdominal computed tomography (CT) at baseline (2010-2011) and assessment of glucose measures at the follow-up exam (2015-2016). NAFLD was defined as liver attenuation ≤51 Hounsfield units on CT images after exclusion for other liver fat causes. Race was self-reported. We used targeted maximum likelihood estimation (TMLE) with machine-learning algorithms to estimate difference in type 2 diabetes risk between the NAFLD and non-NAFLD groups. RESULTS: Of the 1995 participants without type 2 diabetes at baseline (mean age±SD, 50.0±3.6 years; 59% women; 55.0% White and 45.0% Black), 21.7% of White and 16.8% of Black participants had NAFLD at baseline, and 3.7% of White and 8.0% of Black participants developed type 2 diabetes at follow up. After multivariable adjustment, risk difference for type 2 diabetes associated with NAFLD vs no NAFLD was 4.1% (95% CI 0.3%, 7.9%) among White participants and -1.9% (95% CI -5.7%, 2.0%) in Black participants. CONCLUSIONS/INTERPRETATION: NAFLD was associated with a higher risk of type 2 diabetes among White participants but not among Black participants. This finding suggests that the effect of liver fat on impaired glucose metabolism may be smaller in Black than in White individuals.

Association between proprotein convertase subtilisin/kexin type 9 and subclinical cerebrovascular disease in the community.

BACKGROUND AND PURPOSE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a new target for reducing low-density lipoprotein cholesterol and incident cardiovascular disease, including stroke. However, the clinical relevance of circulating PCSK9 levels has been poorly elucidated in the general population, particularly in association with subclinical cerebrovascular disease including cerebral small vessel disease (CSVD) and intracranial artery stenosis (ICAS). METHODS: In community-dwelling Japanese men (n = 526) aged 46-82 years without a history of cardiovascular disease, the associations of serum PCSK9 levels with the prevalence of CSVD and ICAS were assessed using magnetic resonance imaging. CSVD included lacunar infarction, deep and subcortical white matter hyperintensity, periventricular hyperintensity and cerebral microbleeds. RESULTS: The median (interquartile range) age at baseline and serum PCSK9 levels were 69 (63-74) years and 240 (205-291) ng/ml, respectively. After adjusting for traditional cardiovascular risk factors including low-density lipoprotein cholesterol, multivariable Poisson regression with robust error variance revealed a significant association between PCSK9 levels (per 1 SD) and ICAS (relative risks 1.18, 95% confidence interval 1.02-1.37). Multivariable ordinal logistic regression for ICAS, with stenosis graded as mild (<50%) or moderate-severe (≥50%), revealed a similar association (common odds ratio 1.31, 95% confidence interval 1.04-1.64). However, no significant association was observed between serum PCSK9 levels and CSVD. CONCLUSIONS: Higher circulating PCSK9 levels were independently associated with an ICAS prevalence but not with CSVD prevalence. The quantification of circulating PCSK9 levels may help to identify individuals at high risk for cerebrovascular disease in the general population.

Epidemiology of Acute Aortic Dissection in a General Population of 1.4 Million People in Japan　- Shiga Stroke and Heart Attack Registry.

BACKGROUND: Acute aortic dissection (AAD) is a life-threatening cardiovascular disease, with a reported incidence rate ranging from 2.5 to 7.2 per 100,000 person-years in several population-based registries in Western countries, but epidemiological data are lacking in Japan.Methods and Results: The Shiga Stroke and Heart Attack Registry is an ongoing multicenter population-based registry of cerebro-cardiovascular diseases. We enrolled patients who developed AAD, defined by any imaging examination method from 2014 to 2015 in Shiga Prefecture. Death certificates were used to identify cases that were not registered at acute care hospitals. The incidence rates of AAD were calculated by age categories and adjusted using standard populations for comparison. We evaluated differences in patient characteristics between Stanford type A-AAD and type B-AAD subtypes. A total of 402 incident cases with AAD were analyzed. The age-adjusted incidence rates using the 2015 Japanese population and the 2013 European Standard Population were 15.8 and 12.2 per 100,000 person-years, respectively. Compared with cases of type B-AAD, those with type A-AAD were older (75.0 vs. 69.9 years, P=0.001) and more likely to be women (62.3% vs. 28.6%, P<0.001). CONCLUSIONS: Population-based incidence rates of AAD in Japan appear to be higher than in previous reports from Western countries. Incident cases with type A-AAD were older and female predominance.

Association of Blood Pressure Classification Using the 2017 American College of Cardiology/American Heart Association Blood Pressure Guideline With Risk of Heart Failure and Atrial Fibrillation.

BACKGROUND: Heart failure (HF) and atrial fibrillation (AF) are growing in prevalence worldwide. Few studies have assessed to what extent stage 1 hypertension in the 2017 American College of Cardiology/American Heart Association blood pressure (BP) guidelines is associated with incident HF and AF. METHODS: Analyses were conducted with a nationwide health claims database collected in the JMDC Claims Database between 2005 and 2018 (n=2 196 437; mean age, 44.0±10.9 years; 58.4% men). No participants were taking antihypertensive medication or had a known history of cardiovascular disease. Each participant was categorized as having normal BP (systolic BP <120 mm Hg and diastolic BP <80 mm Hg; n=1 155 885), elevated BP (systolic BP 120-129 mm Hg and diastolic BP <80 mm Hg; n=337 390), stage 1 hypertension (systolic BP 130-139 mm Hg or diastolic BP 80-89 mm Hg; n=459 820), or stage 2 hypertension (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg; n=243 342). Using Cox proportional hazards models, we identified associations between BP groups and HF/AF events. We also calculated the population attributable fractions to estimate the proportion of HF and AF events that would be preventable if participants with stage 1 and stage 2 hypertension were to have normal BP. RESULTS: Over a mean follow-up of 1112±854 days, 28 056 incident HF and 7774 incident AF events occurred. After multivariable adjustment, hazard ratios for HF and AF events were 1.10 (95% CI, 1.05-1.15) and 1.07 (95% CI, 0.99-1.17), respectively, for elevated BP; 1.30 (95% CI, 1.26-1.35) and 1.21 (95% CI, 1.13-1.29), respectively, for stage 1 hypertension; and 2.05 (95% CI, 1.97-2.13) and 1.52 (95% CI, 1.41-1.64), respectively, for stage 2 hypertension versus normal BP. Population attributable fractions for HF associated with stage 1 and stage 2 hypertension were 23.2% (95% CI, 20.3%-26.0%) and 51.2% (95% CI, 49.2%-53.1%), respectively. The population attributable fractions for AF associated with stage 1 and stage 2 hypertension were 17.4% (95% CI, 11.5%-22.9%) and 34.3% (95% CI, 29.1%-39.2%), respectively. CONCLUSIONS: Both stage 1 hypertension and stage 2 hypertension were associated with a greater incidence of HF and AF in the general population. The American College of Cardiology/American Heart Association BP classification system may help identify adults at higher risk for HF and AF events.

Glycemic status and the association of change in blood pressure with incident cardiovascular disease.

BACKGROUND: The clinical benefit of blood pressure (BP) reduction in individuals with diabetes has not been fully elucidated. We sought to identify the clinical impact of BP reduction on incident cardiovascular disease in people having diabetes and hypertension. METHODS: We conducted a retrospective cohort study including 754,677 individuals (median age 47 years, 75.8 % men) with stage 1/stage 2 hypertension. Participants were categorized using fasting plasma glucose (FPG) at baseline as normal FPG (FPG < 100 mg/dL) (n = 517,372), prediabetes (FPG:100-125 mg/dL) (n = 197,836), or diabetes mellitus (FPG ≥126 mg/dL) (n = 39,469). The primary outcome was heart failure (HF), and the secondary outcomes included ischemic heart disease (IHD) including myocardial infarction and angina pectoris, and stroke. RESULTS: Over a mean follow-up of 1111 ± 909 days, 18,429 HFs, 17,058 IHDs, and 8,795 strokes were recorded. Reduction in BP of< 120/80 mmHg at 1year was associated with a lower risk of developing HF (HR:0.77, 95% CI:0.72-0.82), IHD (HR:0.84, 95% CI:0.79-0.89), and stroke (HR:0.75, 95% CI:0.69-0.82) in individuals with normal FPG, whereas it was not associated with a risk of developing HF (HR:0.98, 95% CI:0.81-1.17) and stroke (HR:0.82, 95% CI:0.62-1.09) in those with DM. Interaction analyses showed that the influence of BP reduction on incident HF was attenuated with people with prediabetes or DM. A multitude of sensitivity analyses confirmed our results. CONCLUSIONS: The association of BP reduction with the risk of developing HF was attenuated with deteriorating glucose tolerance. The optimal management strategy for hypertensive people with prediabetes or DM for the prevention of developing cardiovascular disease (particularly HF) is needed to be established.

Blood Pressure Variability Early After Liver Transplantation Predicts Long-Term Mortality.

Cardiovascular disease is a leading cause of mortality after liver transplantation (LT). Elevated blood pressure (BP) in LT recipients (LTRs) is associated with increased cardiovascular events (CVEs) and decreased survival. Increased visit-to-visit BP variability in the general population is associated with adverse outcomes. Whether BP variability is associated with adverse outcomes in LTRs is unknown. We analyzed data from adult LTRs within a single large transplant center in the United States between 2010 and 2016. Day-to-day BP variability within the first 60 days after LT was measured using variability independent of the mean (VIM). To assess the association between early post-LT BP variability and future CVEs or mortality, we used Cox proportional hazard regression. Among 512 LTRs (34.4% women; 10.7% Black; mean age, 56.5 years), increased systolic BP (SBP) variability was associated with a decreased risk of mortality (adjusted hazard ratio [aHR], 0.97/1 unit VIM; 95% confidence interval [CI], 0.94-0.99). This was particularly true for men (aHR, 0.94; 95% CI, 0.91-0.98), patients with pre-LT atherosclerotic cardiovascular disease (aHR, 0.95; 95% CI, 0.92-0.98), and patients without pre-LT diabetes mellitus (aHR, 0.96; 95% CI, 0.93-1.00). There was no significant effect of BP variability on CVEs. Results were consistent when competing risk analysis was used with death as the competing risk. Increased diastolic BP variability was not associated with a significant effect on CVEs (hazard ratio [HR], 0.96; 95% CI, 0.90-1.02) nor mortality (HR, 1.00; 95% CI, 0.95-1.06). Increased SBP variability, independent of mean BP, is associated with decreased mortality in LTRs. We postulate that increased BP variability reflects a better vascular recovery in patients undergoing LT, but further research is needed as to the mechanism underlying our observation.

Threshold of BMI for the Development of Hypertension among Japanese Adults.

BACKGROUND: The optimal value of BMI for the development of hypertension and the influence of BMI on the development of stage 1 or stage 2 hypertension remain unclear. OBJECTIVES: We sought to identify the BMI threshold for the prevention of hypertension and how changes in BMI would influence the risk of developing hypertension. METHODS: We analyzed 1,262,356 participants (median age: 43 y; 50.9% men) with normal blood pressure [BP; systolic BP (SBP) <120 mmHg and diastolic BP (DBP) <80 mmHg] or elevated BP (SBP: 120-129 mmHg and DBP <80 mmHg). The primary outcome was stage 1 (SBP 130-139 mmHg or DBP 80-89 mmHg) or stage 2 hypertension (SBP ≥140 mmHg or DBP ≥90 mmHg). We analyzed the relation between baseline BMI, change in BMI, and the risk of developing hypertension using generalized additive models with a smoothing spline. RESULTS: During the median follow-up of 851 d, 341,212 cases of stage 1 hypertension and 70,968 cases of stage 2 hypertension were detected. The risk of developing stage 1 or stage 2 hypertension increased steeply after BMI (kg/m2) exceeded 20. The annual change in BMI was positively correlated with the risk of developing stage 1 or 2 hypertension. Contour mapping using generalized additive models demonstrated an additive increase in the risk of developing hypertension with higher baseline BMI and increases in BMI over 1 y. Body-weight gain increases the risk of developing hypertension even in underweight or normal-weight individuals based on the WHO classification. CONCLUSIONS: In Japanese adults with normal or elevated BP, the risk of developing hypertension increased with BMI when baseline BMI was >20. Body-weight gain additively interacted with baseline BMI during hypertension development. Our results underscore the importance of maintaining body weight in preventing the development of hypertension.

Semiquantitative assessed proteinuria and risk of heart failure: analysis of a nationwide epidemiological database.

BACKGROUND: Heart failure (HF) is increasing in prevalence worldwide. We explored whether adults with trace and positive proteinuria were at a high risk for incident HF compared with those with negative proteinuria using a nationwide epidemiological database. METHODS: This is an observational cohort study using the JMDC Claims Database collected between 2005 and 2020. This is a population-based sample [n = 1 021 943; median age 44 years (interquartile range 37-52); 54.8% men]. No participants had a known history of cardiovascular disease (CVD). Each participant was categorized into three groups according to the urine dipstick test results: negative proteinuria (n = 902 273), trace proteinuria (n = 89 599) and positive proteinuria (≥1+; n = 30 071). The primary outcome was HF. The secondary outcomes were myocardial infarction (MI), stroke and atrial fibrillation (AF). We performed multivariable Cox regression analyses to identify the association between the proteinuria category and incident HF and other CVD events. RESULTS: Over a mean follow-up of 1150 ± 920 days, 17 182 incident HF events occurred. After multivariable adjustment, hazard ratios for HF events were 1.09 [95% confidence interval (CI) 1.03-1.15] and 1.59 (95% CI 1.49-1.70) for trace proteinuria and positive proteinuria versus negative proteinuria, respectively. This association was present irrespective of clinical characteristics. A stepwise increase in the risk of MI, stroke and AF with proteinuria category was also observed. Our primary results were confirmed in participants after multiple imputations for missing values and in those having no medications for hypertension, diabetes mellitus and dyslipidemia. The discriminative predictive value for HF events improved by adding the results of urine dipstick tests to traditional risk factors [net reclassification improvement 0.0497 (95% CI 0.0346-0.0648); P < 0.001]. CONCLUSIONS: Not only positive proteinuria, but also trace proteinuria was associated with a greater incidence of HF in the general population. Semiquantitative assessment of proteinuria would be informative for the risk stratification of HF.

Cardiovascular Risk of Isolated Systolic or Diastolic Hypertension in Young Adults.

BACKGROUND: Little is known regarding health outcomes associated with isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), or systolic and diastolic hypertension (SDH) among young adults with stage 1 hypertension, defined using the 2017 American College of Cardiology/American Heart Association blood pressure (BP) guideline. METHODS: From a nationwide health screening database, we included 6 424 090 participants, aged 20 to 39 years, who were not taking antihypertensive medication at the baseline examination in 2003 to 2007. Participants were categorized as having normal BP (untreated systolic BP [SBP] <120/diastolic BP [DBP] <80 mm Hg; n=2 665 310); elevated BP (SBP 120-129/DBP <80 mm Hg; n=705 344); stage 1 IDH (SBP <130/DBP 80-89 mm Hg; n=1 271 505); stage 1 ISH (SBP 130-139/DBP <80 mm Hg; n=255 588); stage 1 SDH (SBP 130-139/DBP 80-89 mm Hg; n=711 503); and stage 2 hypertension (SBP ≥140, DBP ≥90 mm Hg; n=814 840). The primary outcome was composite cardiovascular disease (CVD) events, including myocardial infarction, stroke, heart failure, and CVD-related death. RESULTS: The median age of the participants was 30 years and 60.9% were male. Over a median follow-up of 13.2 years, 44 070 new CVD events occurred. With normal BP as the reference, multivariable-adjusted hazard ratios (95% CIs) for CVD events were 1.14 (1.09-1.18) for elevated BP, 1.32 (1.28-1.36) for stage 1 IDH, 1.36 (1.29-1.43) for stage 1 ISH, 1.67 (1.61-1.72) for stage 1 SDH, and 2.40 (2.33-2.47) for stage 2 hypertension. CONCLUSIONS: Among young adults, stage 1 ISH, IDH, and SDH were all associated with higher CVD risks than normal BP. The CVD risks of stage 1 ISH and IDH were similar to each other but lower than the risk of stage 1 SDH. Categorizing young adults with stage 1 hypertension further into stage 1 ISH, IDH, and SDH may improve risk stratification for identifying high-risk individuals.

Nighttime Blood Pressure Phenotype and Cardiovascular Prognosis: Practitioner-Based Nationwide JAMP Study.

BACKGROUND: Ambulatory and home blood pressure (BP) monitoring parameters are better predictors of cardiovascular events than are office BP monitoring parameters, but there is a lack of robust data and little information on heart failure (HF) risk. The JAMP study (Japan Ambulatory Blood Pressure Monitoring Prospective) used the same ambulatory BP monitoring device, measurement schedule, and diary-based approach to data processing across all study centers and determined the association between both nocturnal hypertension and nighttime BP dipping patterns and the occurrence of cardiovascular events, including HF, in patients with hypertension. METHODS: This practitioner-based, nationwide, multicenter, prospective, observational study included patients with at least 1 cardiovascular risk factor, mostly hypertension, and free of symptomatic cardiovascular disease at baseline. All patients underwent 24-hour ambulatory BP monitoring at baseline. Patients were followed annually to determine the occurrence of primary end point cardiovascular events (atherosclerotic cardiovascular disease and HF). RESULTS: A total of 6,359 patients (68.6±11.7 years of age, 48% men) were included in the final analysis. During a mean±SD follow-up of 4.5±2.4 years, there were 306 cardiovascular events (119 stroke, 99 coronary artery disease, 88 HF). Nighttime systolic BP was significantly associated with the risk of atherosclerotic cardiovascular disease and HF (hazard ratio adjusted for demographic and clinical risk factors per 20-mm Hg increase: 1.18 [95% CI, 1.02-1.37], P=0.029; and 1.25 [95% CI, 1.00-1.55], P=0.048, respectively). Disrupted circadian BP rhythm (riser pattern, nighttime BP higher than daytime BP) was significantly associated with higher overall cardiovascular disease risk (1.48 [95% CI, 1.05-2.08]; P=0.024), and especially HF (2.45 [95% CI, 1.34-4.48]; P=0.004) compared with normal circadian rhythm. CONCLUSIONS: Nighttime BP levels and a riser pattern were independently associated with the total cardiovascular event rate, in particular for HF. These findings suggest the importance of antihypertensive strategies targeting nighttime systolic BP. Registration: URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000020377.

Reflection-type vapor cell for micro atomic clocks using local anodic bonding of 45° mirrors.

This Letter reports the design, fabrication, and evaluation of reflection-type planar vapor cells for chip-scale atomic clocks. The cell with 2-8 mm cavity length contains two 45° Bragg reflector mirrors assembled using a local anodic bonding. Coherent population trapping resonance of Rb atoms is observed, realizing an atomic clock operation. Allan deviations at an averaging time of 1 s are ${2.2} \times {{1}}{{{0}}^{- 10}}$ and ${9.5} \times {{1}}{{{0}}^{- 11}}$ for 2 mm long and 6 mm long vapor cells, respectively. These results show that planar vapor cells compatible with a system-in-package are feasible without degradation of clock stabilities compared to conventional vertically stacked cells.

Gut Microbiome over a Lifetime and the Association with Hypertension.

PURPOSE OF REVIEW: Microorganisms living within an ecosystem create microbial communities and play key roles in ecosystem functioning. During their lifespan, humans share their bodies with a variety of microorganisms. More than 10-100 trillion symbiotic microorganisms live on and within human beings, and the majority of these microorganisms populate the distal ileum and colon (referred to as the gut microbiota). Interactions between the gut microbiota and the host involve signaling via chemical neurotransmitters and metabolites, neuronal pathways, and the immune system. Hypertension is a complex and heterogeneous pathophenotype. A reductionist approach that assumes that all patients who have the same signs of a disease share a common disease mechanism and thus should be treated similarly is insufficient for optimal blood pressure management. Herein, we have highlighted the contribution of the gut microbiome to blood pressure regulation in humans. RECENT FINDINGS: Gut dysbiosis-an imbalance in the composition and function of the gut microbiota-has been shown to be associated with hypertension. Gut dysbiosis occurs via environmental pressures, including caesarean section, antibiotic use, dietary changes, and lifestyle changes over a lifetime. This review highlights how gut dysbiosis may affect a host's blood pressure over a lifetime. The review also clarifies future challenges in studies of associations between the gut microbiome and hypertension.

Contribution of chemotherapy to improved prognosis in stage 4 gastric cancer: trend analysis of a regional population-based cancer registry in Japan.

OBJECTIVES: Little is known about time trends in the prognosis of gastric cancer (GC), since the introduction of new chemotherapeutic agents. This study aimed to analyze how the increased number of available chemotherapeutic options affected the prognosis of GC and which patient types benefited within in a large population. METHODS: From a population-based cancer registry in Japan, 35,751 cases of GC were identified. Of these, 8214 cases were stage 4. The time trend for 3-year survival in stage 4 GC according to patient characteristics (age and tumor location) was estimated in relation to the introduction of new anticancer drugs. Multiple imputation was performed for sensitivity analysis to strengthen the missing data. In addition, we estimated the 5-year survival rate for distal-GC (DGC) and proximal-GC (PGC), and the hazard ratio (HR) was estimated by Cox proportional hazard model. RESULTS: Improvement of overall survival was accelerated in stage 4 cases over time. The prognosis was improved from 11.4% to 13.2%, subsequent to the approval of several oncologic drugs since 2009. Younger patients were more likely to have improved survival rates in response to the increase in chemotherapy options (< 60-year-old, 5.4%: 60-70, 2.2%; 70-80, 0.3%) from 2007 to 2015. The HR for DGC vs. PGC was 1.11 (95% CI 1.08-1.15), and PGC showed a higher rate of improved outcomes (2.4% vs. 0.6%). CONCLUSIONS: This analysis showed that improvement in the GC survival rate was accelerated by the introduction of new chemotherapeutic strategies and it was most evident among younger patients and in patients with PGC.

Does This Adult Patient Have Hypertension?: The Rational Clinical Examination Systematic Review.

Importance: Office blood pressure (BP) measurements are not the most accurate method to diagnose hypertension. Home BP monitoring (HBPM) and 24-hour ambulatory BP monitoring (ABPM) are out-of-office alternatives, and ABPM is considered the reference standard for BP assessment. Objective: To systematically review the accuracy of oscillometric office and home BP measurement methods for correctly classifying adults as having hypertension, defined using ABPM. Data Sources: PubMed, Cochrane Library, Embase, ClinicalTrials.gov, and DARE databases and the American Heart Association website (from inception to April 2021) were searched, along with reference lists from retrieved articles. Data Extraction and Synthesis: Two authors independently abstracted raw data and assessed methodological quality. A third author resolved disputes as needed. Main Outcomes and Measures: Random effects summary sensitivity, specificity, and likelihood ratios (LRs) were calculated for BP measurement methods for the diagnosis of hypertension. ABPM (24-hour mean BP ≥130/80 mm Hg or mean BP while awake ≥135/85 mm Hg) was considered the reference standard. Results: A total of 12 cross-sectional studies (n = 6877) that compared conventional oscillometric office BP measurements to mean BP during 24-hour ABPM and 6 studies (n = 2049) that compared mean BP on HBPM to mean BP during 24-hour ABPM were included (range, 117-2209 participants per analysis); 2 of these studies (n = 3040) used consecutive samples. The overall prevalence of hypertension identified by 24-hour ABPM was 49% (95% CI, 39%-60%) in the pooled studies that evaluated office measures and 54% (95% CI, 39%-69%) in studies that evaluated HBPM. All included studies assessed sensitivity and specificity at the office BP threshold of 140/90 mm Hg and the home BP threshold of 135/85 mm Hg. Conventional office oscillometric measurement (1-5 measurements in a single visit with BP ≥140/90 mm Hg) had a sensitivity of 51% (95% CI, 36%-67%), specificity of 88% (95% CI, 80%-96%), positive LR of 4.2 (95% CI, 2.5-6.0), and negative LR of 0.56 (95% CI, 0.42-0.69). Mean BP with HBPM (with BP ≥135/85 mm Hg) had a sensitivity of 75% (95% CI, 65%-86%), specificity of 76% (95% CI, 65%-86%), positive LR of 3.1 (95% CI, 2.2-4.0), and negative LR of 0.33 (95% CI, 0.20-0.47). Two studies (1 with a consecutive sample) that compared unattended automated mean office BP (with BP ≥135/85 mm Hg) with 24-hour ABPM had sensitivity ranging from 48% to 51% and specificity ranging from 80% to 91%. One study that compared attended automated mean office BP (with BP ≥140/90 mm Hg) with 24-hour ABPM had a sensitivity of 87.6% (95% CI, 83%-92%) and specificity of 24.1% (95% CI, 16%-32%). Conclusions and Relevance: Office measurements of BP may not be accurate enough to rule in or rule out hypertension; HBPM may be helpful to confirm a diagnosis. When there is uncertainty around threshold values or when office and HBPM are not in agreement, 24-hour ABPM should be considered to establish the diagnosis.

Association Between Sleep Apnea and Blood Pressure Control Among Blacks.

BACKGROUND: Blacks have a high prevalence of hypertension and uncontrolled blood pressure (BP), each of which may be partially explained by untreated sleep apnea. We investigated the association of sleep apnea with uncontrolled BP and resistant hypertension in blacks. METHODS: Between 2012 and 2016, Jackson Heart Sleep Study participants (N=913) underwent an in-home Type 3 sleep apnea study, clinic BP measurements, and anthropometry. Moderate or severe obstructive sleep apnea (OSA) was defined as a respiratory event index ≥15, and nocturnal hypoxemia was quantified as percent sleep time with <90% oxyhemoglobin saturation. Prevalent hypertension was defined as either a systolic BP ≥130 mm Hg or diastolic BP >80mm Hg, use of antihypertensive medication, or self-report of a diagnosis of hypertension. Controlled BP was defined as systolic BP <130 mm Hg and diastolic BP <80 mm Hg; uncontrolled BP as systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg with use of 1 to 2 classes of antihypertensive medication; and resistant BP as systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg with the use of ≥3 classes of antihypertensive medication (including a diuretic) or use of ≥4 classes of antihypertensive medication regardless of BP level. Multinomial logistic regression models were fit to determine the association between OSA severity and uncontrolled BP or resistant hypertension (versus controlled BP) after multivariable adjustment. RESULTS: The analytic sample with hypertension (N=664) had a mean age of 64.0 (SD,10.6) years, and were predominately female (69.1%), obese (58.6%), and college educated (51.3%). Among the sample, 25.7% had OSA, which was untreated in 94% of participants. Overall, 48% of participants had uncontrolled hypertension and 14% had resistant hypertension. After adjustment for confounders, participants with moderate or severe OSA had a 2.0 times higher odds of resistant hypertension (95% confidence interval [CI], 1.14-3.67). Each standard deviation higher than <90% oxyhemoglobin saturation was associated with an adjusted odds ratio for resistant hypertension of 1.25 (95% CI 1.01-1.55). OSA and <90% oxyhemoglobin saturation were not associated with uncontrolled BP. CONCLUSION: Untreated moderate or severe OSA is associated with increased odds of resistant hypertension. These results suggest that untreated OSA may contribute to inadequate BP control in blacks.