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This is a post hoc multivariate analysis of the modified World Federation of Neurosurgical Societies (WFNS) grading project, multicenter prospective observational study including 38 neurosurgical institutions across Japan. Japan Neurosurgical Society WFNS grading committee conducted a modified WFNS grading project as a nationwide prospective registry study. We investigate the clinical outcome of both surgical and endovascular interventions after aneurysmal subarachnoid hemorrhage (SAH) in Japan. A total of 792 patients received surgical intervention and 417 patients received endovascular treatment. Eight hundred patients were female, and 409 patients were male. The mean age was 61.5 ± 13.7 years. At 3 month follow-up, there was no statistically significant difference in good clinical outcome between surgical (68.2%) and endovascular (60.9%) group (odds ratio, 0.89; 95% confidence interval, 0.68-1.16; p = 0.381). Unfavorable outcome rate was 31.8% (238 patients) in the surgical group and 39.1% (154 patients) in the endovascular group. Male, elderly people, modified Rankin scale condition before onset, high-grade modified WFNS clinical grading scale, intracerebral hematoma, posttreatment normal pressure hydrocephalus, and neurological deficit due to symptomatic vasospasm were risk factors for the clinical outcome. Treatment modality was not a statistical factor for clinical outcomes. Surgical clipping has still a major role in the management of SAH in Japan. The present study was not a randomized controlled study, but clinical outcome is not influenced by treatment modalities.

This cross-sectional study investigates the association between life expectancy before COVID-19 and excess mortality during the pandemic in aging countries.

Background: A 2017 meta-analysis of data from 25 randomised controlled trials (RCTs) of vitamin D supplementation for the prevention of acute respiratory infections (ARIs) revealed a protective effect of this intervention. We aimed to examine the link between vitamin D supplementation and prevention of ARIs in an updated meta-analysis. Methods: For this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov registry for studies listed from database inception to May 1, 2020. Double-blind RCTs of vitamin D3, vitamin D2, or 25-hydroxyvitamin D (25[OH]D) supplementation for any duration, with a placebo or low-dose vitamin D control, were eligible if they had been approved by a research ethics committee, and if ARI incidence was collected prospectively and prespecified as an efficacy outcome. Studies reporting results of long-term follow-up of primary RCTs were excluded. Aggregated study-level data, stratified by baseline 25(OH)D concentration and age, were obtained from study authors. Using the proportion of participants in each trial who had one or more ARIs, we did a random-effects meta-analysis to obtain pooled odds ratios (ORs) and 95% CIs to estimate the effect of vitamin D supplementation on the risk of having one or more ARIs (primary outcome) compared with placebo. Subgroup analyses were done to estimate whether the effects of vitamin D supplementation on the risk of ARI varied according to baseline 25(OH)D concentration (vs 25·0–49·9 nmol/L vs 50·0–74·9 nmol/L vs >75·0 nmol/L), vitamin D dose (daily equivalent of vs 400–1000 IU vs 1001–2000 IU vs >2000 IU), dosing frequency (daily vs weekly vs once per month to once every 3 months), trial duration (≤12 months vs >12 months), age at enrolment (vs 1·00–15·99 years vs 16·00–64·99 years vs ≥65·00 years), and presence versus absence of airway disease (ie, asthma only, COPD only, or unrestricted). Risk of bias was assessed with the Cochrane Collaboration Risk of Bias Tool. The study was registered with PROSPERO, CRD42020190633. Findings: We identified 1528 articles, of which 46 RCTs (75 541 participants) were eligible. Data for the primary outcome were obtained for 48 488 (98·1%) of 49 419 participants (aged 0–95 years) in 43 studies. A significantly lower proportion of participants in the vitamin D supplementation group had one or more ARIs (14 332 [61·3%] of 23 364 participants) than in the placebo group (14 217 [62·3%] of 22 802 participants), with an OR of 0·92 (95% CI 0·86–0·99; 37 studies; I2=35·6%, pheterogeneity=0·018). No significant effect of vitamin D supplementation on the risk of having one or more ARIs was observed for any of the subgroups defined by baseline 25(OH)D concentration. However, protective effects of supplementation were observed in trials in which vitamin D was given in a daily dosing regimen (OR 0·78 [95% CI 0·65–0·94]; 19 studies; I2=53·5%, pheterogeneity=0·003), at daily dose equivalents of 400–1000 IU (0·70 [0·55–0·89]; ten studies; I2=31·2%, pheterogeneity=0·16), for a duration of 12 months or less (0·82 [0·72–0·93]; 29 studies; I2=38·1%, pheterogeneity=0·021), and to participants aged 1·00–15·99 years at enrolment (0·71 [0·57–0·90]; 15 studies; I2=46·0%, pheterogeneity=0·027). No significant interaction between allocation to the vitamin D supplementation group versus the placebo group and dose, dose frequency, study duration, or age was observed. In addition, no significant difference in the proportion of participants who had at least one serious adverse event in the vitamin supplementation group compared with the placebo group was observed (0·97 [0·86–1·07]; 36 studies; I2=0·0%, pheterogeneity=0·99). Risk of bias within individual studies was assessed as being low for all but three trials. Interpretation: Despite evidence of significant heterogeneity across trials, vitamin D supplementation was safe and overall reduced the risk of ARI compared with placebo, although the risk reduction was small. Protection was associated with administration of daily doses of 400–1000 IU for up to 12 months, and age at enrolment of 1·00–15·99 years. The relevance of these findings to COVID-19 is not known and requires further investigation. Funding: None.

Background Coil embolization of aneurysms of the ophthalmic segment of the internal carotid artery (ICA-OphA ANs) has potential risks of visual complications. We analyzed this risk and focused on the relationship of the ophthalmic artery (OphA) origin with the aneurysm neck. Methods From January 2003 to April 2018, 179 unruptured ICA-OphA ANs were treated with endovascular surgery in our institution. Two ruptured and four aneurysms with missing data were excluded. Finally, 173 unruptured aneurysms were included in this study. The aneurysms were classified into three groups according to the location of the OphA origin: Separate, Shared, and Dome type. We retrospectively assessed visual complications based on the relationship between types of aneurysm and postoperative angiographic findings for the OphA. Results Visual deficits remained permanent in eleven cases (6.4%). In the Dome type, visual complications were significantly more frequent compared to the Separate type. Change in the OphA flow was significantly associated with a higher complication rate of 2.9%, but patients with changed OphA flow had a significant rate of 7.5% ( p = 0.020). We found no significant difference in the incidence of visual complications concerning the use of perioperative antithrombotic therapy. Conclusions The location of OphA origin regarding the aneurysmal neck and postoperative OphA flow were significantly correlated with the visual outcome after coil embolization for ICA-OphA ANs. Post-procedural flow in the OphA was an important factor affecting the rate of ischemic retinal complications. Retinal embolic events occurred with preserved flow in the OphA, albeit at a lower rate.

Some controversy remains on thresholds for deficiency or sufficiency of serum 25-hydroxyvitamin D (25(OH)D) levels. Moreover, 25(OH)D levels sufficient for bone health might differ from those required for cancer survival. This study aimed to explore these 25(OH)D threshold levels by applying the machine learning method of multivariable adaptive regression splines (MARS) in post hoc analyses using data from the AMATERASU trial, which randomly assigned Japanese patients with digestive tract cancer to receive vitamin D or placebo supplementation. Using MARS, threshold 25(OH)D levels were estimated as 17 ng/mL for calcium and 29 ng/mL for parathyroid hormone (PTH). Vitamin D supplementation increased calcium levels in patients with baseline 25(OH)D levels ≤17 ng/mL, suggesting deficiency for bone health, but not in those >17 ng/mL. Vitamin D supplementation improved 5-year relapse-free survival (RFS) compared with placebo in patients with intermediate 25(OH)D levels (18–28 ng/mL): vitamin D, 84% vs. placebo, 71%; hazard ratio, 0.49; 95% confidence interval, 0.25–0.96; p = 0.04. In contrast, vitamin D supplementation did not improve 5-year RFS among patients with low (≤17 ng/mL) or with high (≥29 ng/mL) 25(OH)D levels. MARS might be a reliable method with the potential to eliminate guesswork in the estimation of threshold values of biomarkers.

BACKGROUND Acute respiratory events (ARE) occasionally occur during induction chemotherapy as a complication in patients with advanced neuroblastoma. AIMS The present study aimed to identify the predictive factors of ARE, defined as severe hypoxia, during initial induction chemotherapy in patients with newly diagnosed advanced neuroblastoma. METHODS AND RESULTS The medical records of 75 consecutive patients in whom stage III or IV neuroblastoma was newly diagnosed between January 2003 and December 2018 at two medical institutions were retrospectively reviewed. The outcome was ARE, which were assessed by measuring oxygen saturation between days 1 and 14 of initial induction chemotherapy. Severe hypoxia was defined as grade 3 or higher according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE v4.0) or decreased oxygen saturation at rest (e.g., pulse oximeter

Ecological studies have suggested fewer COVID-19 morbidities and mortalities in Bacillus Calmette&ndash, Gu&eacute, rin (BCG)-vaccinated countries than BCG-non-vaccinated countries. However, these studies obtained data during the early phase of the pandemic and did not adjust for potential confounders, including PCR-test numbers per population (PCR-tests). Currently&mdash, more than four months after declaration of the pandemic&mdash, the BCG-hypothesis needs reexamining. An ecological study was conducted by obtaining data of 61 factors in 173 countries, including BCG vaccine coverage (%), using morbidity and mortality as outcomes, obtained from open resources. &lsquo, Urban population (%)&rsquo, and &lsquo, insufficient physical activity (%)&rsquo, in each country was positively associated with morbidity, but not mortality, after adjustment for PCR-tests. On the other hand, recent BCG vaccine coverage (%) was negatively associated with mortality, but not morbidity, even with adjustment for percentage of the population &ge, 60 years of age, morbidity, PCR-tests and other factors. The results of this study generated a hypothesis that a national BCG vaccination program seems to be associated with reduced mortality of COVID-19, although this needs to be further examined and proved by randomized clinical trials.

In high-risk neuroblastoma, the presence of an MYCN gain/amplification (MYCN-GA) is not always a risk factor of cancer-specific death. We herein examined the effect modification of high-dose chemotherapy with autologous hematopoietic stem cell rescue (HDC-autoSCR) in terms of the interaction between MYCN status and remission status (complete remission or very good partial remission [CR/VGPR] vs. partial remission or less [≤PR]). The present study recruited patient data from 1992 to 2017 in the Japan Society of Hematopoietic Cell Transplantation’s national registry. The MYCN status was known in 586 of 950 patients with a single course of HDC-autoSCR. Cumulative hazard curves for neuroblastoma-specific death showed that a subgroup with MYCN-GA and ≤PR had a significantly poorer prognosis than three other subgroups, namely, the MYCN-NGA/ ≤ PR, MYCN-NGA/CR/VGPR, and MYCN-GA/CR/VGPR subgroups even after adjusting for non-infants and stage IV disease (hazard ratio: 2.79; 95% confidence interval: 1.91–4.09; P

Background Placement of feeding jejunostomy (PFJ) during esophagectomy is an effective method to maintain adequate nutrition, but is associated with serious complications such as bowel obstruction and jejunal torsion. The purpose of the current study was to analyze the incidence, clinical features, and risk factors of bowel obstruction associated with feeding jejunostomy (BOFJ) after PFJ. Methods This was a retrospective cohort study of 70 patients who underwent esophagectomy with three-field lymph node dissection for esophageal cancer and treated with PFJ between March 2013 and December 2019 in our hospital. Abdominal dissection was performed under hand-assisted laparoscopic surgery (HALS) from March 2013 to March 2015, and was changed to complete laparoscopic surgery in April 2015. We compared patients with and without BOFJ, and the incidence of BOFJ was evaluated. The primary endpoint was incidence of BOFJ after PFJ. Results Six patients (8.5%) were diagnosed with BOFJ, all of whom were symptomatic and in the HALS group. In addition, 3 cases displayed histories of recurrent BOFJ (3, 3, and 5 times). Laparotomy was performed in all cases. Subgroup analysis of the HALS group showed a significant difference only in straight-line distance between the jejunostomy and navel as a significant pre- and perioperative factor (117 mm [101–130 mm] vs. 89 mm [51–150 mm], p p = 0.010), not HD (48 mm [40–59 mm] vs. 46 mm [22–60 mm], p = 0.199). Conclusions VD between the jejunostomy and navel was associated with BOFJ after PFJ with HALS esophagectomy. PFJ

Clinical evidence suggesting the beneficial effects of vitamin D on survival of patients with cancer has been accumulating. Recent articles were thoroughly reviewed to determine if there is enough evidence to conclude that vitamin D supplementation improves survival of patients with cancer. Meta-analyses of observational studies showed that higher blood 25-hydroxyvitamin D levels in patients with cancer at a variety of sites were associated with lower cancer-specific and overall mortalities. Moreover, meta-analyses of randomized clinical trials (RCTs) also suggested that vitamin D supplementation improved the survival of patients with cancer. However, each RCT used in these meta-analyses, as well as very recent RCTs, e.g., the SUNSHINE and the AMATERASU trial, did not show statistical significance in the primary results. For now, compelling evidence that vitamin D supplementation effectively improves survival of patients with cancer is lacking. Thus, confirmatory RCTs are still obligatory for the future.

Dysfunctional variants of ATP-binding cassette transporter subfamily G member 2 (ABCG2), a urate transporter in the kidney and intestine, are the major causes of hyperuricemia and gout. A recent study found that ABCG2 is a major transporter of uremic toxins; however, few studies have investigated the relationship between ABCG2 gene polymorphisms and mortality. This prospective cohort study of 1214 hemodialysis patients investigated the association between serum uric acid levels and ABCG2 genotype and mortality. Genotyping of dysfunctional ABCG2 variants, Q126X (rs72552713) and Q141K (rs2231142), was performed using the patients’ DNA. During the study period, 220 patients died. Lower serum uric acid levels were associated with higher mortality (hazard ratio [HR] 1.89, 95% confidence interval [CI] 1.14–3.10, P ≤ 0.001). ABCG2 dysfunction, estimated by genetic variants, had a significant positive association with serum uric acid levels (full function: 7.4 ± 1.2 mg/dl, 3/4 function: 7.9 ± 1.3 mg/dl, 1/2 function: 8.2 ± 1.4 mg/dl, ≤ 1/4 function: 8.7 ± 1.3 mg/dl, P ≤ 0.001). This association remained significant on multiple regression analysis. The Cox proportional hazard analysis indicated that the ABCG2 ≤ 1/4 function type was significantly associated with higher mortality (HR 6.66, 95% CI 2.49 to 17.8, P ≤ 0.001) than the other function types. These results showed that ABCG2 plays a physiologically important role in uric acid excretion, and that ABCG2 dysfunction is a risk factor for mortality in hemodialysis patients. Electronic supplementary material The online version of this article (10.1007/s13577-020-00342-w) contains supplementary material, which is available to authorized users.

In the coronavirus disease 2019 (COVID-19) pandemic, more than half of the cases of transmission may occur via asymptomatic individuals, which makes it difficult to contain. However, whether viral load in the throat during admission is different between asymptomatic and symptomatic patients is not well known. By conducting a prospective cohort study of patients with asymptomatic or mild COVID-19, cycle threshold (Ct) values of the polymerase chain reaction test for COVID-19 were examined every other day during admission. The Ct values during admission increased more steadily in symptomatic patients and febrile patients than in asymptomatic patients, with significance (p = 0.01 and p = 0.004, respectively), although the Ct values as a whole were not significantly different between the two groups. Moreover, the Ct values as a whole were higher in patients with dysosmia/dysgeusia than in those without it (p = 0.02), whereas they were lower in patients with a headache than those without (p = 0.01). Patients who were IgG-positive at discharge maintained higher Ct values, e.g., more than 35, during admission than those with IgG-negative (p = 0.03). Assuming that viral load and Ct values are negatively associated, the viral loads as a whole and their changes by time may be different by symptoms and immune reaction, i.e., IgG-positive at discharge.

Because vitamin D responsive elements have been found to be located in the PD-L1 gene, vitamin D supplementation was hypothesized to regulate serum PD-L1 levels and thus alter survival time of cancer patients. A post hoc analysis of the AMATERASU randomized, double-blind, placebo-controlled trial of postoperative vitamin D3 supplementation (2000 IU/day) in 417 patients with stage I to stage III digestive tract cancer from the esophagus to the rectum was conducted. Postoperative serum PD-L1 levels were measured by ELISA and divided into quintiles (Q1–Q5). Serum samples were available for 396 (95.0%) of the original trial. Vitamin D supplementation significantly (p = 0.0008) up-regulated serum PD-L1 levels in the lowest quintile (Q1), whereas it significantly (p = 0.0001) down-regulated them in the highest quintile (Q5), and it did not either up- or down-regulate them in the middle quintiles (Q2–Q4). Significant effects of vitamin D supplementation, compared with placebo on death (HR, 0.34, 95% CI, 0.12–0.92) and relapse/death (HR, 0.37, 95% CI, 0.15–0.89) were observed in the highest quintile (Q5) of serum PD-L1, whereas significant effects were not observed in other quintiles (Pinteraction = 0.02 for death, Pinteraction = 0.04 for relapse/death). Vitamin D supplementation significantly reduced the risk of relapse/death to approximately one-third in the highest quintile of serum PD-L1.

To evaluate anxiety felt by glaucoma patients.In total, 472 glaucoma patients responded to a questionnaire on anxiety, subjective symptoms, and vision-related quality of life (VR-QOL) associated with glaucoma. Anxiety was evaluated using the State-Trait Anxiety Inventory (STAI), state anxiety (STAI-State) subscale along with our novel questionnaire, assessing visual function and subjective symptoms, specialized for glaucoma. VR-QOL was evaluated using 5 subitems from the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25). Adherence to ophthalmic antiglaucoma agents was confirmed. As indexes of visual function, corrected visual acuity (measured by eye chart), mean deviation (MD) score (measured with static perimetry), and 4 thresholds at the center of vision were determined. Stages were classified according to the Aulhorn Classification. From the STAI-State scores, the prevalence of anxiety in glaucoma patients was evaluated. We analyzed the correlation between the STAI-State and VFQ-25, anxiety, subjective symptoms, adherence, and visual function indexes.In total, 78% of glaucoma patients experienced at least an intermediate level of anxiety. The STAI-State correlated significantly with anxiety and subjective symptoms as measured by our novel questionnaire, particularly for questions "current anxiety about loss of vision" and "current anxiety in life" (r=0.468 and 0.500; both P0.0001). However, STAI-State correlated weakly with VFQ-25, and not at all with visual function indexes and adherence.Many glaucoma patients feel anxiety. The STAI-State is correlated with the VR-QOL and anxiety in glaucoma patients, making it useful for understanding the anxiety present in glaucoma patients.

Background: Few studies have addressed how human papilloma virus (HPV) infection in oropharyngeal squamous cell carcinoma (OPSCC) affects the outcome of surgical therapy; furthermore, the relationship between the presence of HPV DNA and neck lymph node (LN) metastasis has not been well established. Methods: A total of 65 patients who underwent surgery as a first-line therapy for OPSCC were enrolled in this study. In HPV-positive patients, the presence of HPV DNA in metastatic neck LN lesions was evaluated. Results: The HPV-positive patients had significantly better overall survival than the HPV-negative patients (log-rank test, p = 0.04), whereas HPV infection status did not significantly affect disease-free survival (log-rank test, p = 0.65). In all of the HPV-positive OPSCC patients who developed cervical LN metastasis, the same HPV DNA type was found in both the primary tumour and the metastases. Conclusions: The present results suggest that HPV infection is a determining factor for good prognosis in patients undergoing first-line surgical therapy for OPSCC.

BackgroundEpigenetic silencing of the O6-methylguanine-DNA methyltransferase (MGMT) DNA repair enzyme via promoter hypermethylation (hmMGMT) may increase mutations in the TP53 oncosuppressor gene and contribute to carcinogenesis. The effects of smoking, which is a risk factor for head and neck squamous cell carcinoma (HNSCC), were investigated to determine whether they up- or down-regulate hmMGMT. Additionally, the impact of hmMGMT and disruptive TP53-mutations on relapse was investigated in patients with HNSCC.MethodsThis study included 164 patients with HNSCC who were negative for both p16 protein expression and human papilloma virus infection. The association of smoking and hmMGMT was investigated using multiple logistic regression analysis. Competing risk regression was used to evaluate the effects of hmMGMT and TP53-mutations in exon 2 to 11 on relapse of HNSCC.ResultshmMGMT was observed in 84% of the 164 patients. TP53-mutations, specifically, G:C>A:T transition, were more frequent in patients with hmMGMT (32%) than in those without hmMGMT (8%). The frequency of disruptive TP53-mutations was not significantly different between groups. Compared with nonsmoking, heavy smoking of 20 pack-years or more was significantly associated with decreased hmMGMT (adjusted odds ratio, 0.08; 95% CI, 0.01 to 0.56; P = 0.01). Patients who had both hmMGMT and disruptive TP53-mutations showed a significantly higher relapse rate than all other patients (subdistribution hazard ratio, 1.77; 95% CI, 1.07 to 2.92; P = 0.026).ConclusionsIt was found that hmMGMT was suppressed by heavy smoking, and hmMGMT combined with disruptive TP53-mutations may indicate a poor prognosis in patients with HNSCC.

The AMATERASU randomized trial of vitamin D3 supplementation (2,000 IU/day; UMIN000001977) showed the potential benefit of vitamin D in a subgroup of patients with digestive tract cancer. By conductingThe primary outcome was relapse-free survival (RFS). On IHC using pathologic specimens, the degree of p53 protein expression parallel withThe p53 status of 372 patients' pathologic specimens was evaluated. In a subgroup of patients with p53-positive cancer (These results generate a hypothesis that vitamin D supplementation may improve RFS in patients with p53-positive digestive tract cancer.The results are still preliminary, but potentially important, because

IMPORTANCE: Randomized clinical trials of vitamin D supplementation for secondary prevention in patients with cancer are needed, given positive results of observational studies. OBJECTIVE: To determine whether postoperative vitamin D(3) supplementation can improve survival of patients with digestive tract cancers overall and in subgroups stratified by 25-hydroxyvitamin D (25[OH]D) levels. DESIGN, SETTING, AND PARTICIPANTS: The AMATERASU trial, a randomized, double-blind, placebo-controlled trial conducted at a single university hospital in Japan. Enrollment began in January 2010 and follow-up was completed in February 2018. Patients aged 30 to 90 years with cancers of the digestive tract from the esophagus to the rectum, stages I to III, were recruited. Of 439 eligible patients, 15 declined and 7 were excluded after operation. INTERVENTIONS: Patients were randomized to receive oral supplemental capsules of vitamin D (2000 IU/d; n = 251) or placebo (n = 166) from the first postoperative outpatient visit to until the end of the trial. MAIN OUTCOMES AND MEASURES: The primary outcome was relapse-free survival time to relapse or death. The secondary outcome was overall survival time to death due to any cause. Subgroups analyzed had baseline serum 25(OH)D levels of 0 to less than 20 ng/mL, 20 to 40 ng/mL, and greater than 40 ng/mL; because of small sample size for the highest-baseline-level group, interactions were tested only between the low- and middle-baseline-level groups. RESULTS: All 417 randomized patients (mean age, 66 years; male, 66%; esophageal cancer, 10%; gastric cancer, 42%; colorectal cancer, 48%) were included in the analyses. There was 99.8% follow-up over a median 3.5 (interquartile range, 2.3-5.3) years, with maximal follow-up of 7.6 years. Relapse or death occurred in 50 patients (20%) randomized to vitamin D and 43 patients (26%) randomized to placebo. Death occurred in 37 (15%) in the vitamin D group and 25 (15%) in the placebo group. The 5-year relapse-free survival was 77% with vitamin D vs 69% with placebo (hazard ratio [HR] for relapse or death, 0.76; 95% CI, 0.50-1.14; P = .18). The 5-year overall survival in the vitamin D vs placebo groups was 82% vs 81% (HR for death, 0.95; 95% CI, 0.57-1.57; P = .83). In the subgroup of patients with baseline serum 25(OH)D levels between 20 and 40 ng/mL, the 5-year relapse-free survival was 85% with vitamin D vs 71% with placebo (HR for relapse or death, 0.46; 95% CI, 0.24-0.86; P = .02; P = .04 for interaction). Fractures occurred in 3 patients (1.3%) in the vitamin D group and 5 (3.4%) in the placebo group. Urinary stones occurred in 2 patients (0.9%) in the vitamin D group and 0 in the placebo group. CONCLUSIONS AND RELEVANCE: Among patients with digestive tract cancer, vitamin D supplementation, compared with placebo, did not result in significant improvement in relapse-free survival at 5 years. TRIAL REGISTRATION: UMIN Identifier: UMIN000001977

Background: Programmed death-ligand 1 (PD-L1) is expressed not only on some cancer cells, but also on the outer surface of placental syncytiotrophoblasts, which is assumed to induce maternal immune tolerance to fetal tissue via programmed death-1 (PD-1) receptors on T cells. Recently, levels of soluble forms of PD-L1 (sPD-L1) were reported to be higher in the serum of pregnant women (PW) than in non-pregnant women (non-PW). However, there have been no reports of the functional significance of PW's serum containing high sPD-L1 levels. Therefore, the aim of the present study was to clarify the role of sPD-L1 in the sera of PW as an immunosuppressive molecule by in vitro assays.Methods: As a post-hoc analysis of our previous cohort study, 330 pairs of serum from PW during the third trimester and cord blood (CB) from paired offspring without major complications were examined. Serum levels of sPD-L1 and sPD-1 were measured by ELISA. On mixed lymphocyte culture (MLC), 3H-thymidine uptakes in the presence of PW's, offspring's, or non-PW's serum were compared. Peripheral blood mononuclear cells (PBMCs) were cultured in the presence of PW's serum stimulated with PHA, and then cytokine levels were measured in supernatants by multiple cytokine analysis with or without anti-PD-L1blocking antibody.Results: The median sPD-L1 level was 8.3- and 6.9-fold higher in PW than in offspring and non-PW, respectively, whereas sPD-1 levels were lower in PW and offspring than in non-PW. On MLC, 3H-thymidine uptake in the presence of autoantigen was strongly reduced by co-culture with serum of both PW and offspring, compared with serum of non-PW. In contrast, uptake in the presence of alloantigen was moderately inhibited by PW's serum, whereas it was less suppressed by offspring's serum, compared with non-PW's serum. In the culture of PBMCs, tumor necrosis factor-α, interferon gamma, interleukin (IL)-2, and IL-4 levels were significantly higher in the presence of anti-PD-L1 blocking antibody than in culture not treated with antibody (all P < 0.05) or culture treated with isotype control antibody (all P < 0.05).Conclusion: The levels of sPD-L1 are elevated in PW's serum, which may, at least in part, suppress maternal immunity.

Background In our prior randomized trial on preventing influenza, asthma attacks as a secondary outcome occurred less often in the vitamin D group than in the placebo group. We aimed to clarify whether low-dose, short-term vitamin D supplementation, in addition to standard treatments, improves control of childhood asthma. Methods We conducted a randomized, double-blind, placebo-controlled trial comparing vitamin D3 supplements (800 IU/day) with placebo for 2 months in schoolchildren with asthma. The primary outcomes were frequency and severity of asthma judging from changes in asthma control levels defined by the Global Initiative for Asthma (GINA) by collaborating doctors at 2 and 6 months. Results Japanese schoolchildren with asthma (n = 89) were randomly assigned to receive vitamin D (n = 54) or placebo (n = 35). At 2 months, GINA asthma control was significantly more improved in the vitamin D group compared with the placebo group (P = 0.015). Childhood asthma control test (CACT) scores, a secondary outcome, were also significantly (P = 0.004) improved in the vitamin D group compared with the placebo group at 2 months, and differences remained significant (P = 0.012) at 6 months. The proportion of patients with a peak expiratory flow rate

Because vitamin D may have beneficial effects on glucose metabolism in pregnant women with gestational diabetes mellitus, we explored whether maternal 25-hydroxyvitamin D (25OHD) levels in normal pregnancy have association with diabetes-related hormone levels and glycated albumin (GA). A prospective cohort study was performed to collect serum samples from 612 pairs of pregnant women and cord blood of their offspring. Levels of 25OHD and GA in maternal and cord blood were measured by radioimmunoassay and enzyme assay, respectively. Using cord serum, 12 diabetes-related hormones were assayed. Spearman’s rank correlation coefficient was used to quantify the strength of association between biomarkers. A prominent association between maternal and cord 25OHD levels (r = 0.76, 95% confidence intervals (CIs): 0.73–0.79, P < 0.0001) and weak association between maternal and cord GA (r = 0.22, 95% CIs: 0.14–0.30, P < 0.0001) were shown. Among the 12 diabetes-related hormones, both maternal and cord 25OHD levels showed prominent negative associations with glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These results suggest that decreased maternal 25OHD may be associated with decreased cord 25OHD and increased cord GLP-1 and GIP levels, which may be involved with the transfer of maternal glucose to the fetus.

Background&mdash, This study aimed to explore whether living alone or with a spouse only affects the short-term prognosis of acute ischemic stroke patients. Methods&mdash, We conducted a retrospective cohort study of patients with a diagnosis of acute ischemic stroke from April 2014 to February 2019 in Japan. The primary outcome was defined as worsening by at least one grade on the modified Rankin Scale (mRS). The secondary outcome was set as the degree of worsening on the mRS. The outcomes were compared between three groups of patients: (1) those living alone (ALONE), (2) those living with their spouse only (SPOUSE), and (3) OTHERs. Results&mdash, In total, 365 patients were included in this study: 111 (30%) ALONE, 133 (36%) SPOUSE, and 121 (33%) OTHERs. Cardiogenic embolisms were observed more frequently in ALONE than in OTHERs. The primary outcome occurred in 88 (79.3%) patients in ALONE and in 96 (72.2%) patients in SPOUSE, both of which were higher than the 72 (59.5%) in OTHERs. After adjusting with 19 variables, the risk of worsening was higher in ALONE (odds ratio (OR): 2.90, 95% confidence interval (CI): 1.50&ndash, 5.58) and SPOUSE (OR: 1.83, 95% CI: 1.00&ndash, 3.33) compared with OTHERs. Conclusions&mdash, In patients with acute ischemic stroke, not only living alone but also living with a spouse only may be associated with a worse short-term prognosis, independent of other cardiovascular risks.

Fibroblast growth factor 23 (FGF23) is associated with cardiovascular disease and all-cause mortality in patients with diabetes mellitus. Insulin resistance has recently been reported to increase FGF23 levels, and resistin is a peptide that mainly regulates insulin resistance. However, few studies have investigated the association between FGF23 and resistin. A total of 422 patients with diabetes mellitus were recruited for this cross-sectional study to examine the association between resistin and intact FGF23. The mean ( ± standard deviation) age was 63.1 ± 11.9 years, and the median HbA1c was 6.7% (range, 6.1–7.1%). The mean estimated glomerular filtration rate (eGFR) was 66.2 ± 23.1 mL/min/m2. Multiple regression analysis for resistin showed that logFGF23 (coefficient (Coef): 1.551; standard error (SE): 0.739; P = 0.036), C-peptide (Coef: 0.798; SE: 0.229; P = 0.001), ghrelin (Coef: 1.061; SE: 0.332; P = 0.001), intact parathyroid hormone (Coef: 0.022; SE: 0.099; P = 0.030), and eGFR (Coef: −0.091; SE: 0.017; P

Importance Cow’s milk formula (CMF) is used to supplement breastfeeding (BF) at birth without clear clinical evidence to support the practice. Objective To determine whether avoiding supplementation with CMF at birth can decrease risks of sensitization to cow’s milk protein and/or clinical food allergy, including cow’s milk allergy (CMA), overall and in subgroups stratified by 25-hydroxyvitamin D (25[OH]D) levels. Design, Setting, and Participants The Atopy Induced by Breastfeeding or Cow’s Milk Formula (ABC) trial, a randomized, nonblinded clinical trial, began enrollment October 1, 2013, and completed follow-up May 31, 2018, at a single university hospital in Japan. Participants included 330 newborns at risk for atopy; of these, 312 were included in the analysis. Data were analyzed from September 1 through October 31, 2018. Interventions Immediately after birth, newborns were randomized (1:1 ratio) to BF with or without amino acid–based elemental formula (EF) for at least the first 3 days of life (BF/EF group) or BF supplemented with CMF (≥5 mL/d) from the first day of life to 5 months of age (BF plus CMF group). Main Outcomes and Measures The primary outcome was sensitization to cow’s milk (IgE level, ≥0.35 allergen units [UA]/mL) at the infant’s second birthday. Secondary outcomes were immediate and anaphylactic types of food allergy, including CMA, diagnosed by oral food challenge test or triggered by food ingestion, with food-specific IgE levels of at least 0.35 UA/mL. Subgroup analysis was prespecified by tertiles of serum 25(OH)D levels at 5 months of age. Results Of the 312 infants included in the analysis (160 female [51.3%] and 152 male [48.7%]), 151 of 156 (96.8%) in the BF/EF and BF plus CMF groups were followed up until their second birthday. The primary outcome occurred in 24 infants (16.8%) in the BF/EF group, which was significantly fewer than the 46 infants (32.2%) in the BF plus CMF group (relative risk [RR], 0.52; 95% CI, 0.34-0.81). The middle tertile of the 25(OH)D subgroup, but not the low and high tertiles, had a significant interaction with the intervention (RR, 0.19; 95% CI, 0.07-0.50;P = .02). The prevalence of food allergy at the second birthday was significantly lower in the BF/EF than in the BF plus CMF groups for immediate (4 [2.6%] vs 20 [13.2%]; RR, 0.20; 95% CI, 0.07-0.57) and anaphylactic (1 [0.7%] vs 13 [8.6%]; RR, 0.08; 95% CI, 0.01-0.58) types. Conclusions and Relevance The evidence suggests that sensitization to cow’s milk and food allergy, including CMA and anaphylaxis, are primarily preventable by avoiding CMF supplementation for at least the first 3 days of life. Trial Registration http://umin.ac.jpIdentifier:UMIN000011577

Background We evaluated whether oral vitamin D supplementation during the winter and early spring reduces the incidence of influenza and upper respiratory infections in patients with inflammatory bowel disease (IBD). Methods A randomized, double-blind, controlled trial was conducted to compare the effects of vitamin D supplementation (500 IU/day) and a placebo. The primary outcome was the incidence of influenza; the secondary outcome was the incidence of upper respiratory infection. Prespecified subgroup analyses were performed according to 25-hydroxyvitamin D (25-OHD) levels (low

Anastomotic leakage (AL) and surgical site infection (SSI) are prevalent complications of colorectal surgery. To lower this risk, we standardized our surgical procedures in 2012, with a preferential use of laparoscopic approach (LS) for both colon and rectal surgery, combined with triangulating anastomosis (TA) for colon surgery and defunctioning ileostomy (DI) for low anterior resection. Our aim was to evaluate the outcomes of our standardized procedures. The incidence rate of AL (primary outcome) and of reoperation and SSI (secondary outcome) was compared before (early period, n = 648) and after (late period, n = 541) standardization, through a retrospective analysis. The incidence rate of AL (6.6 versus 1.8%; P = 0.001), reoperation (3.5 versus 0.7%; P = 0.0012), and SSI (7.7 versus 4.6%; P = 0.029) was lower in late than in the early period. For colon cancer, TA and LS reduced the risk of AL (2.1 versus 0.3%, P = 0.020, for TA, and 3.2 versus 0.4%, P = 0.0027, for LS) and reoperation (2.9 versus 0.3%, P = 0.003, for TA, and 2.5 versus 0.2%, P = 0.0040, for LS). For rectal cancer, the incidence of all adverse outcomes (AL, reoperation, and SSI) was lower in cases treated by LS. However, the incidence of AL was lower in the late than in early period (P = 0.002) and with LS (P = 0.002). On multivariate analysis, late period and LS were independent factors of a lower risk of adverse outcomes. Our surgical standardization seems to be effective in lowering the risks of AL, reoperation, and SSI after colorectal cancer surgery.

Purpose: Higher serum 25-hydroxyvitamin D (25(OH)D) levels are reportedly associated with better survival in early-stage non–small cell lung cancer (NSCLC). Therefore, whether vitamin D supplementation can improve the prognosis of patients with NSCLC was examined (UMIN000001869). Patients and Methods: A randomized, double-blind trial comparing vitamin D supplements (1,200 IU/day) with placebo for 1 year after operation was conducted. The primary and secondary outcomes were relapse-free survival (RFS) and overall survival (OS), respectively. Prespecified subgroup analyses were performed with stratification by stage (early vs. advanced), pathology (adenocarcinoma vs. others), and 25(OH)D levels (low, Results: Patients with NSCLC (n = 155) were randomly assigned to receive vitamin D (n = 77) or placebo (n = 78) and followed for a median of 3.3 years. Relapse and death occurred in 40 (28%) and 24 (17%) patients, respectively. In the total study population, no significant difference in either RFS or OS was seen with vitamin D compared with the placebo group. However, by restricting the analysis to the subgroup with early-stage adenocarcinoma with low 25(OH)D, the vitamin D group showed significantly better 5-year RFS (86% vs. 50%, P = 0.04) and OS (91% vs. 48%, P = 0.02) than the placebo group. Among the examined polymorphisms, DBP1 (rs7041) TT and CDX2 (rs11568820) AA/AG genotypes were markers of better prognosis, even with multivariate adjustment. Conclusions: In patients with NSCLC, vitamin D supplementation may improve survival of patients with early-stage lung adenocarcinoma with lower 25(OH)D levels. Clin Cancer Res; 24(17); 4089–97. ©2018 AACR.

Magnetic resonance image (MRI) is now widely used for imaging follow-up for post coiling brain aneurysms. However, the accuracy on the estimation of residual aneurysm, which is crucial for the retreatment planning, remains to be controversial. The purpose of this study is to evaluate a new post-processing technique that provides improved estimation of the residual aneurysm after coil embolization. One hundred aneurysms on 93 patients who underwent coil embolization for brain aneurysm were evaluated using the 1.5 Tesla time-resolved magnetic resonance angiography (TR-MRA) one year after the treatment. To minimize the inter-observer variability caused by the window level adjustment, an automatic post processing protocol using the full-width at half-maximum (FWHM) value was utilized. The result was then compared with that from the conventional cerebral angiography. Of the 97 aneurysms that underwent both TR-MRA and DSA, 23 (23.7%) showed residual neck / dome during follow-up. After window level adjustment, the size of the parent artery in the TR-MRA was consistent with that in the DSA. The reconstructed Volume Rendering images provided clear contours of the residual aneurysms and contributed to the understanding the configuration of residual aneurysm. The largest and the smallest diameter of the residual aneurysms was larger in the TR-MRA than in the DSA (8.05 vs. 7.72 mm, p = 0.0004; 4.99 vs. 4.19 mm, p = 0.007 respectively). The sensitivity, specificity, and positive and negative predictive values of TR-MRA compared to DSA were 100%, 97%, 73%, and 100%, respectively. Using the FWHM value to optimize the window level adjustment, the size of the residual component observed in the TR-MRA was larger compared to that in the DSA whereas the size of neck and the parent artery showed consistency between the two modalities. This image processing technique can be used as an effective screening tool for evaluating residual component in post-coiling brain aneurysms.

Background Chronic rhinosinusitis (CRS) can be classified into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). CRSwNP displays more intense eosinophilic infiltration and the presence of Th2 cytokines. Mucosal eosinophilia is associated with more severe symptoms and often requires multiple surgeries because of recurrence; however, even in eosinophilic CRS (ECRS), clinical course is variable. In this study, we wanted to set objective clinical criteria for the diagnosis of refractory CRS. Methods This was a retrospective study conducted by 15 institutions participating in the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC). We evaluated patients with CRS treated with endoscopic sinus surgery (ESS), and risk of recurrence was estimated using Cox proportional hazard models. Multiple logistic regression models and receiver operating characteristics curves were constructed to create the diagnostic criterion for ECRS. Results We analyzed 1716 patients treated with ESS. To diagnose ECRS, the JESREC scoring system assessed unilateral or bilateral disease, the presence of nasal polyps, blood eosinophilia, and dominant shadow of ethmoid sinuses in computed tomography (CT) scans. The cutoff value of the score was 11 points (sensitivity: 83%, specificity: 66%). Blood eosinophilia (>5%), ethmoid sinus disease detected by CT scan, bronchial asthma, aspirin, and nonsteroidal anti-inflammatory drugs intolerance were associated significantly with recurrence. Conclusion We subdivided CRSwNP in non-ECRS, mild, moderate, and severe ECRS according to our algorithm. This classification was significantly correlated with prognosis. It is notable that this algorithm may give useful information to clinicians in the refractoriness of CRS before ESS or biopsy.

Ovarian clear cell carcinoma (OCCC) is a chemotherapy‑resistant epithelial ovarian cancer with poor prognosis. To identify genomic alterations involved in the development of OCCC, we analyzed somatic copy number alterations in OCCC using comparative genomic hybridization (CGH). Here we showed that the chromosomal regions 8p11.21, 8p11.22, 12p13.31 and 20q13.2 were amplified in OCCC. We also demonstrated that small segments in the chromosomal regions 3q26.1, 4q13.2 and 22q11.23 were deleted. Kaplan‑Meier survival analyses revealed that patients with amplification within 8p11.21 or a deletion within 3q26.1 had a shorter progression‑free survival (PFS) time than those without such alterations. In addition, patients with amplification in three of the four chromosomal regions 8p11.21, 8p11.22, 12p13.31 and 20q13.2 had shorter overall survival (OS). We also demonstrated that amplification of 12p13.3 or three of the four chromosomal regions 8p11.21, 8p11.22, 12p13.31 and 20q13.2, or a deletion in the chromosomal region 3q26.1 was associated with chemotherapy resistance. Our findings suggest that copy number alterations in 8p11.21‑22, 12p13.31, 20q13.2, 3q26.1, 4q13.2 and 22q11.23 are critical for the development and survival of OCCC.

Summary Background A previous aggregate data meta-analysis of randomised controlled trials showed that vitamin D supplementation reduces the rate of asthma exacerbations requiring treatment with systemic corticosteroids. Whether this effect is restricted to patients with low baseline vitamin D status is unknown. Methods For this systematic review and one-step and two-step meta-analysis of individual participant data, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science for double-blind, placebo-controlled, randomised controlled trials of vitamin D 3 or vitamin D 2 supplementation in people with asthma that reported incidence of asthma exacerbation, published between database inception and Oct 26, 2016. We analysed individual participant data requested from the principal investigator for each eligible trial, adjusting for age and sex, and clustering by study. The primary outcome was the incidence of asthma exacerbation requiring treatment with systemic corticosteroids. Mixed-effects regression models were used to obtain the pooled intervention effect with a 95% CI. Subgroup analyses were done to determine whether effects of vitamin D on risk of asthma exacerbation varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration, age, ethnic or racial origin, body-mass index, vitamin D dosing regimen, use of inhaled corticosteroids, or end-study 25(OH)D levels; post-hoc subgroup analyses were done according to sex and study duration. This study was registered with PROSPERO, number CRD42014013953. Findings Our search identified 483 unique studies, eight of which were eligible randomised controlled trials (total 1078 participants). We sought individual participant data for each and obtained it for seven studies (955 participants). Vitamin D supplementation reduced the rate of asthma exacerbation requiring treatment with systemic corticosteroids among all participants (adjusted incidence rate ratio [aIRR] 0·74, 95% CI 0·56–0·97; p=0·03; 955 participants in seven studies; high-quality evidence). There were no significant differences between vitamin D and placebo in the proportion of participants with at least one exacerbation or time to first exacerbation. Subgroup analyses of the rate of asthma exacerbations treated with systemic corticosteroids revealed that protective effects were seen in participants with baseline 25(OH)D of less than 25 nmol/L (aIRR 0·33, 0·11–0·98; p=0·046; 92 participants in three studies; moderate-quality evidence) but not in participants with higher baseline 25(OH)D levels (aIRR 0·77, 0·58–1·03; p=0·08; 764 participants in six studies; moderate-quality evidence; p interaction =0·25). p values for interaction for all other subgroup analyses were also higher than 0·05; therefore, we did not show that the effects of this intervention are stronger in any one subgroup than in another. Six studies were assessed as being at low risk of bias, and one was assessed as being at unclear risk of bias. The two-step meta-analysis did not reveal evidence of heterogeneity of effect ( I 2 =0·0, p=0·56). Interpretation Vitamin D supplementation reduced the rate of asthma exacerbations requiring treatment with systemic corticosteroids overall. We did not find definitive evidence that effects of this intervention differed across subgroups of patients. Funding Health Technology Assessment Program, National Institute for Health Research (reference number 13/03/25).

Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect.Design Systematic review and meta-analysis of individual participant data (IPD) from randomised controlled trials.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015.Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome.Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity

Low vitamin D levels are associated with poorer outcomes after stroke. However, it is not clear whether post-stroke vitamin D supplementation can improve these outcomes. In this study, we investigated the effects of vitamin D supplementation on outcomes in hospitalized patients undergoing rehabilitation after acute stroke. A multicenter, randomized, controlled, double-blind, parallel-group trial was conducted from January 2012 through July 2017. One hundred patients admitted to a convalescent rehabilitation ward after having an acute stroke were randomized, and each one received either vitamin D3 (2000 IU/day) or a placebo. The primary outcome was a gain in the Barthel Index scores at week 8. Secondary outcomes were seen in Barthel Index efficiency, hand grip strength, and calf circumference at week 8. Ninety-seven patients completed the study. There were no significant differences in the demographic characteristics between the groups. The mean (&plusmn, standard deviation) gain in the Barthel Index score was 19.0 &plusmn, 14.8 in the supplementation group and 19.5 &plusmn, 13.1 in the placebo group (p = 0.88). The Barthel Index efficiency was 0.32 &plusmn, 0.31 in the supplementation group and 0.28 &plusmn, 0.21 in the placebo group (p = 0.38). There were no between-group differences in the other secondary outcomes. Our findings suggest that oral vitamin D3 supplementation does not improve rehabilitation outcomes after acute stroke.

Background\ud \ud Several clinical trials of vitamin D to prevent asthma exacerbation and improve asthma control have been conducted in children and adults, but a meta-analysis restricted to double-blind, randomised, placebo-controlled trials of this intervention is lacking.\ud Objectives\ud \ud To evaluate the efficacy of administration of vitamin D and its hydroxylated metabolites in reducing the risk of severe asthma exacerbations (defined as those requiring treatment with systemic corticosteroids) and improving asthma symptom control.\ud Search methods\ud \ud We searched the Cochrane Airways Group Trial Register and reference lists of articles. We contacted the authors of studies in order to identify additional trials. Date of last search: January 2016.\ud Selection criteria\ud \ud Double-blind, randomised, placebo-controlled trials of vitamin D in children and adults with asthma evaluating exacerbation risk or asthma symptom control or both.\ud Data collection and analysis\ud \ud Two review authors independently applied study inclusion criteria, extracted the data, and assessed risk of bias. We obtained missing data from the authors where possible. We reported results with 95% confidence intervals (CIs).\ud Main results\ud \ud We included seven trials involving a total of 435 children and two trials involving a total of 658 adults in the primary analysis. Of these, one trial involving 22 children and two trials involving 658 adults contributed to the analysis of the rate of exacerbations requiring systemic corticosteroids. Duration of trials ranged from four to 12 months, and the majority of participants had mild to moderate asthma. Administration of vitamin D reduced the rate of exacerbations requiring systemic corticosteroids (rate ratio 0.63, 95% CI 0.45 to 0.88; 680 participants; 3 studies; high-quality evidence), and decreased the risk of having at least one exacerbation requiring an emergency department visit or hospitalisation or both (odds ratio (OR) 0.39, 95% CI 0.19 to 0.78; number needed to treat for an additional beneficial outcome, 27; 963 participants; 7 studies; high-quality evidence). There was no effect of vitamin D on % predicted forced expiratory volume in one second (mean difference (MD) 0.48, 95% CI -0.93 to 1.89; 387 participants; 4 studies; high-quality evidence) or Asthma Control Test scores (MD -0.08, 95% CI -0.70 to 0.54; 713 participants; 3 studies; high-quality evidence). Administration of vitamin D did not influence the risk of serious adverse events (OR 1.01, 95% CI 0.54 to 1.89; 879 participants; 5 studies; moderate-quality evidence). One trial comparing low-dose versus high-dose vitamin D reported two episodes of hypercalciuria, one in each study arm. No other study reported any adverse event potentially attributable to administration of vitamin D. No participant in any included trial suffered a fatal asthma exacerbation. We did not perform a subgroup analysis to determine whether the effect of vitamin D on risk of severe exacerbation was modified by baseline vitamin D status, due to unavailability of suitably disaggregated data. We assessed two trials as being at high risk of bias in at least one domain; neither trial contributed data to the analysis of the outcomes reported above.\ud Authors' conclusions\ud \ud Meta-analysis of a modest number of trials in people with predominantly mild to moderate asthma suggests that vitamin D is likely to reduce both the risk of severe asthma exacerbation and healthcare use. It is as yet unclear whether these effects are confined to people with lower baseline vitamin D status; further research, including individual patient data meta-analysis of existing datasets, is needed to clarify this issue. Children and people with frequent severe asthma exacerbations were under-represented; additional primary trials are needed to establish whether vitamin D can reduce the risk of severe asthma exacerbation in these groups.

Background The UDP-glucuronosyltransferase 2 family, polypeptide B17 (UGT2B17) gene encodes an enzyme that modifies carcinogens, C19 steroids, xenobiotics, and anticancer chemotherapeutic agents by glucuronidation. Pediatric cancers are much more sensitive to anticancer agents than adult cancers. Therefore, we examined the effects of a deletion polymorphism in the UGT2B17 gene on prognosis in pediatric cancer. Methods A total of 145 DNA samples were collected from children with malignant diseases. Copy number variants (CNVs) of the UGT2B17 gene were determined using polymerase chain reaction (PCR). Survival analyses were computed to analyze effects of UGT2B17 gene deletion on relapse-free rates in lymphoblastic and nonlymphoblastic malignancies. Results The UGT2B17 gene was deleted in 64% of children with lymphoblastic malignancies but in 83% of children with nonlymphoblastic malignancies. Moreover, in nonlymphoblastic malignancies, children without deletion polymorphism in the UGT2B17 gene had significantly higher relapse rates than those with the deletion polymorphism (hazard ratio, 16.1; 95% confidence interval [CI], 1.67–154; P = 0.016), which remained significant (P = 0.032) after adjustment for age, sex, underlying diseases, advanced stage, and adverse events (HR, 22.4; 95% CI, 1.10–454; P = 0.043). There was a significant interaction between UGT2B17 gene deletion and nonlymphoblastic malignancies. In the early subgroup, i.e., stage 1–3 or standard/intermediate risk, children without a deletion polymorphism in the UGT2B17 gene showed higher relapse rates than children with more advanced disease (log-rank test: P = 0.0004). Conclusions Deletion polymorphism in the UGT2B17 gene may improve the relapse-free rate in children with nonlymphoblastic malignancies. This article is protected by copyright. All rights reserved.

Recent studies have suggested that low levels of 25-hydroxyvitamin D (25OHD) are associated with cardiovascular risks in medical patients. However, these associations have not been well documented in high risk surgical patients. We hypothesized that serum 25OHD, 1,25-dihydroxyvitamin D (1,25OHD) would be associated with the cardiac operative risk stratification score. The study was conducted with a cross-sectional design at a single academic medical center in Japan. Two hundred five adult patients scheduled for major cardiovascular surgery were included consecutively. Cardiac operative risk was evaluated with the European System for Cardiac Operative Risk Evaluation (EuroSCORE) scoring system. Correlations between 25OHD and 1,25OHD, and EuroSCORE were assessed using simple and multiple linear regression models. Mean 25OHD and 1,25OHD were 20.1 ± 7.1 ng/mL and 51.2 ± 19.2 pg/mL, respectively. Half and 88% of the study population showed deficient (

Enhanced S-cone syndrome (ESCS) is an autosomal recessive retinal disorder characterized by an increased number of S-cones over L/M cones and rods. Mutations in the NR2E3 gene, encoding a photoreceptor-specific nuclear receptor, are identified in patients with ESCS. The purpose of this study is to report the ophthalmic features of a 25-year-old Portuguese male with a typical ESCS phenotype and a novel homozygous NR2E3 mutation.The patient underwent a detailed ophthalmic examination including fundus photography, fluorescein angiography (FAF), fundus autofluorescence imaging (FAI), and spectral domain optical coherence tomography (SD-OCT). Full-field electroretinography (ERG), S-cone ERG, and multifocal ERG were performed. Mutation screening of the NR2E3 gene was performed with polymerase chain reaction amplification and direct sequencing.The patient had poor visual acuity but good color vision. Funduscopy showed degenerative changes from the vascular arcades to the midperipheral retina. The SD-OCT revealed macular schisis and cystoid changes that had no fluorescein leakage. The posterior pole showed diffusely increased autofluorescence compared with eccentric areas in both eyes. International-standard full-field ERG showed the typical pathognomonic changes associated with ESCS and the short-wavelength flash ERG was simplified, delayed, and similar to the standard photopic flash ERG. Multifocal ERG showed widespread delay and reduction. Genetic analysis revealed a novel homozygous mutation (p.C83Y), which resides in the second zinc finger of the DNA-binding domain.This homozygous mutation is likely to affect binding to target DNA sites, resulting in a non-functional behavior of NR2E3 protein. It is associated with a typical form of ESCS with a nondetectable rod response and reduced/delayed mfERG responses at all eccentricities.

Background and Methods: We conducted a large-scale case-control study that explored the association of 358 single nucleotide polymorphisms (SNPs) in 185 patients with end-stage renal disease. A variety of SNPs were recognized as significant in simple association studies. In addition, haplotype analysis identified the gene for the alpha 1C subunit of the voltage-dependent L-type calcium channel (CACNA1C) as having a significant association with secondary hyperparathyroidism (intact parathyroid hormone level >200 pg/ml) among 61 haplotypes. Since CACNA1C is a relatively large molecule, we examined 84 SNP markers from the CACNA1C region located on chromosome 12 by haplotype case-control association analysis. Results: Sixteen SNPs of 14 genes were significant according to allelic and/or genotypic studies (p < 0.05 by Fisher’s exact test). Three different SNPs were from the CACNA1C gene. Next, we performed haplotype-based association testing with a focus on the CACNA1C region, revealing an odds ratio (OR) of 1.63 and 95% confidence interval (CI) of 1.05–2.52. The second major haplotype with a frequency of 27% was also significant and acted as a protective haplotype (p = 0.022 by Fisher’s exact test, with an OR of 0.55 and 95% CI of 0.33–0.90). Conclusion: These results suggest that CACNA1C may be associated with secondary hyperparathyroidism. In addition, the haplotype-based approach may be useful to screen for key molecules associated with complex traits.

Objective To compare the efficacy and safety of nifekalant, a pure class III anti-arrhythmic drug, and lidocaine in patients with shock-resistant in-hospital ventricular fibrillation (VF) or ventricular tachycardia (VT). Patients and methods Between August 2005 and March 2008, we conducted a prospective, two-arm, cluster observational study, in which participating hospitals were pre-registered either to the nifekalant arm or the lidocaine arm. Patients were enrolled if they had in-hospital VF or VT resistant to at least two defibrillation shocks. Congenital or drug-induced long QT syndrome was excluded. The primary end-point was termination of VF or VT with/without additional shock. The secondary end-points were return of spontaneous circulation (ROSC), 1-month survival and survival to hospital discharge. We also assessed the frequency of adverse events, including asystole, pulseless electrical activity and torsade de pointes. Results In total, 55 patients were enrolled. After nifekalant, 22 of 27 patients showed termination of VF or VT, as compared with 15 of 28 patients treated with lidocaine with/without additional shock (odds ratio (OR): 3.8; 95% confidence interval (CI): 1.1–13.0; P = 0.03). Twenty-three of 27 patients given nifekalant showed ROSC, as compared with 15 of 28 patients given lidocaine (OR: 5.0; 95% CI: 1.4–18.2; P = 0.01). There was no difference in 1-month survival or survival to hospital discharge between the nifekalant and lidocaine arms. There was a higher incidence of asystole with lidocaine (7 of 28 patients) than with nifekalant (0 of 27 patients) ( P = 0.005). Torsade de pointes was not observed. Conclusion Nifekalant was more effective than lidocaine for termination of arrhythmia and for ROSC in patients with shock-resistant in-hospital VF or VT (umin-CTR No. UMIN 000001781).

BACKGROUND AND AIM Magnifying endoscopy combined with narrow-band imaging (ME-NBI) has been used for differential diagnosis of various focal lesions. The aim of our study was to evaluate ME-NBI criteria for cancer diagnosis in superficial depressed gastric lesions in comparison to conventional white light endoscopy (WLE). PATIENTS AND METHODS ME-NBI and WLE images of 100 superficial gastric depressions (55 depressed cancers, 45 benign depressions) were independently evaluated by 11 endoscopists blinded to the diagnosis in each case. The presence or absence of predefined ME-NBI findings relating to microvasculature and fine mucosal structure (FMS) was recorded. A general diagnosis of benign or malignant also had to be given on the basis of a general assessment of features of color and shape as shown in the ME-NBI and WLE images, respectively, without regard to any prespecified criteria. RESULTS Multivariate and ROC analysis demonstrated that the triad of FMS disappearance, microvascular dilation, and heterogeneity appeared to be the best combination for diagnosis of gastric cancer. ME-NBI diagnosis with the triad attained a good specificity (85 %, theoretically calculated if all of the triad were positive), which was significantly ( P < 0.001) superior to WLE general diagnosis (65 %), and comparable with ME-NBI general diagnosis (80 %). The sensitivities of the three diagnoses (ME-NBI with the triad 69 %, WLE general diagnosis 71 %, ME-NBI general diagnosis 72 %) were comparably moderate. The kappa values (interobserver concordance) for ME-NBI diagnosis with the triad (0.47) and ME-NBI general diagnosis (0.48) were superior to the kappa value for WLE diagnosis (0.34). CONCLUSION The triad of FMS disappearance, microvascular dilation, and heterogeneity has good specificity for the diagnosis of superficial depressed gastric carcinoma, but the sensitivity needs to be improved.

Purpose We investigated whether hilar radioaerosol deposition affects the clearance rate of technetium-99m-labeled diethylenetriaminepentaacetic acid (99mTc-DTPA) from peripheral alveolar regions. Materials and methods A total of 38 patients underwent 99mTc-DTPA inhalation lung scintigraphy. Six region of interest (ROI) patterns were adopted: ROI 1 was outlined around the entire hemithorax, and ROIs 2–6 were outlined around the hemithorax but excluded square ROIs of different size in the hilar region. Half-times (T½) were calculated with time-activity curves using onecompartment and two-compartment analyses. The T½ of ROIs 1–5 were plotted against the T½ of ROI 6, and regression lines were obtained with the least-squares method. The absolute values of the differences between surveyed values and regression line were calculated. The Wilcoxon test for trend and a single linear regression model were used to determine statistical significance. Results There were significant reductions in the absolute values of the differences between surveyed values and regression line from ROIs 1–5 by one-component analysis and the fast component of two-compartment analysis (P < 0.001). Conclusion Our results suggest that the deposition of radioaerosol in the hilar region affects the clearance rate of 99mTc-DTPA from the alveoli in damaged lungs. The hilar region should be excluded from ROIs when alveolar epithelial permeability is evaluated.

Backgrounds and Purpose— The authors evaluated the incidence of rupture of unruptured intracranial saccular aneurysm during observation. Methods— Between January 2003 and December 2006, a total of 419 patients with 529 unruptured intracranial saccular aneurysms were observed without treatment. The mean follow-up duration was 905.3 days. Aneurysm size was measured by 3-dimensional CT angiography. Clinical and 3-dimensional CT angiography follow-up were obtained every 6 months. Results— Nineteen aneurysms ruptured during observation resulting in a 1.4% rupture rate per year. A history of subarachnoid hemorrhage (hazard ratio, 7.3; 95% CI, 2.5 to 21.2), posterior circulation aneurysm (hazard ratio, 2.9; 95% CI, 1.1 to 8), and large size were significant independent predictors for aneurysm rupture. Conclusions— Size, history of subarachnoid hemorrhage, and posterior circulation aneurysms were significant risk factors for prediction of rupture of unruptured intracranial saccular aneurysms.

Aim: Menopause is a risk factor for cardiovascular disease (CVD) in women because of the reduction in endogenous estrogen. Recently, single nucleotide polymorphisms (SNPs) of the estrogen receptor α (ESR-1) gene (c.454-397T>C) associated with the prognosis of myocardial infarction in postmenopausal women were identified; however, the mechanism by which genetic variation of ESR-1 contributes to the pathogenesis of CVD is unknown. Circulating levels of adipokines and inflammatory cytokines predict CVD risk; hence, this study aimed to investigate whether ESR-1 genotypes (c.454-397T>C) might influence circulating levels of adipokines and inflammatory cytokines in postmenopausal women with type 2 diabetes.Methods: Sixty-three postmenopausal women with type 2 diabetes were recruited. Serum levels of adiponectin, resistin, interleukin-6 (IL-6), and high-sensitive C-reactive protein (hs-CRP) were determined.Results: The genotype of ESR-1 was closely associated with serum adiponectin, which was decreased in subjects with the T allele and was lowest in those with the T/T genotype. Multiple logistic regression analysis revealed independent contribution of the homozygote for the T allele to low serum levels of adiponectin.Conclusion: The T allele of the c.454-397T>C SNP of ESR-1 is associated with low serum levels of adiponectin, which may lead to a high risk of CVD in postmenopausal women.

The aim of the present paper was to clarify the factors influencing subjective daytime sleepiness in patients with obstructive sleep apnea syndrome (OSAS). Subjects included 230 adult male OSAS patients aged 20–73 years. Single and multiple linear regression analyses were performed to estimate the association between the Epworth Sleepiness Scale (ESS) and the following variables: Minnesota Multiphasic Personality Inventory (MMPI), Self-Rating Depression Scale (SDS), age, body mass index (BMI), sleep duration during the preceding month and apnea–hypopnea index (AHI). Single linear regression analysis showed that age had a negative association with ESS score, while BMI, AHI, SDS, hypochondriasis (Hs), hysteria, psychopathic deviant, psychasthenia, schizophrenia and hypomania on the MMPI had a positive association with ESS score. However, the other remaining parameters such as nocturnal sleep duration during the preceding month, depression, masculinity–femininity, paranoia, social introversion on the MMPI had no statistical association with ESS score. Multiple linear regression analysis with stepwise elimination method was applied to choose the significant factors associated with ESS. It was found that three variables including age, AHI and Hs scores were independent factors influencing ESS score. The R2 for the model was 0.14, suggesting that these factors account for 14% of possible variance of subjective daytime sleepiness of OSAS patients. These results suggest that subjective daytime sleepiness in patients with OSAS may be influenced not only by the severity of respiratory disorder indices but also by certain personality characteristics affecting Hs score and by age.

Object Metabolic syndrome (MetS) develop by accumulation of excess central obesity occurring insulin resistance. In 2005, the Japanese Society of Internal Medicine, in collaboration with seven other Japanese societies defined the diagnostic criterion for Japan-specific MetS. Smoking also causes insulin resistance to develop. To clarify whether smoking is correlated with MetS and how long MetS remains after smoking cessation we undertook a retrospective study. Methods The subjects comprised of 22,892 Japanese who visited the Health-Care Center at Jikei University Hospital in Tokyo for medical check-ups. The participants completed a simple, self-administered questionnaire on their lifestyle including smoking information. MetS was diagnosed with the above criterion. The odds ratio (OR) with a 95% confidential interval (95%CI) of MetS was calculated using multiple logistic regression analysis adjusted by age and gender. Results Compared with never smokers (n=9,434: 41%), the odds ratio (95% CI) of MetS onset for current smokers (n=7,634: 33%) and past smokers (n=5,824: 25%) were 1.20 (1.07-1.35) and 1.21 (1.08-1.37). In the current smokers, the odds ratio of MetS increased with the smoking number, and it significantly occurred by smoking ≥20 cigarettes per day. After quitting, the longer cessation period is related to the lesser chance of developing of MetS. But, MetS remained for at least 10 years and over in the subjects who smoked 20 or more cigarettes per day, and for over 20 years in the subjects who smoked 40 cigarettes and more. Conclusion Not only current smoking habits but also past smoking may contribute to the occurrence of MetS.

Background Barrett's esophagus with specialized intestinal metaplasia (SIM) from columnar-lined esophagus is difficult to distinguish with routine endoscopy. Objective To examine the values of fine mucosal patterns and the capillary patterns observed by magnifying endoscopy with narrow band imaging (MENBI) for the detection of SIM in columnar-lined esophagus and superficial Barrett's adenocarcinoma. We also undertook a histologic investigation regarding whether the capillary pattern observed by MENBI corresponds to the 3-dimensional (3D) structure of the capillary as depicted by using a confocal laser-scanning microscope (CLSM). Design To compare the findings of MENBI, at 217 sites of columnar-lined esophagus, with histologic findings. Capillaries of the superficial mucosal layer were observed and were analyzed by 3D with a CLSM in 45 biopsied specimens. Patients Fifty-eight patients, including 4 with superficial Barrett's adenocarcinoma. Setting Jikei University Hospital, Tokyo, Japan. Results Upon observation, all 6 adenocarcinoma sites were classified as irregular patterns in both the fine mucosal patterns and capillary patterns. The most characteristic endoscopic patterns of SIM were revealed to be the cerebriform fine mucosal pattern (sensitivity, 56%; specificity, 79%; odds ratio, 4.78) and ivy- or deoxyribonucleic acid (DNA)-like capillary pattern (sensitivity, 77%; specificity, 94%; odds ratio, 51.6). The addition of capillary patterns to fine mucosal patterns improved the accuracy of diagnosing SIM (P Conclusions MENBI was able to precisely visualize the structure of capillaries in the superficial mucosal layer. The addition of capillary patterns to fine mucosal patterns appeared to improve the diagnostic value for detecting SIM and superficial Barrett's adenocarcinoma upon observation by MENBI.

PURPOSE We assessed vision-related quality of life (VR-QOL) in glaucoma patients and examined the relationship between VR-QOL and indices of visual function and subjective symptoms. PATIENTS AND METHODS Four hundred seventy-two glaucoma patients completed a questionnaire concerning VR-QOL and subjective symptoms of glaucoma. VR-QOL was based on 5 subscales selected from the National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25), whereas subjective symptoms were examined using original questions that we prepared. The following were selected as visual function indices: corrected visual acuity measured with a distance visual acuity chart, mean deviation scores measured with a static perimeter, and 4 threshold levels in the innermost center of a visual field (4 pericentral test points). Disease staging was conducted according to the Aulhorn classification system. Correlations of visual function with VR-QOL were evaluated using the Spearman test. RESULTS Correlations were observed in almost all subscales of the NEI VFQ-25, including correlations with corrected vision, disease stage, mean deviation score, and minimum threshold values of the 4-point pericentral test on the temporal side (P

Background Smoking induces oncogenic TP53-mutations in head and neck squamous cell carcinomas (HNSCCs). Disruptive mutations of TP53-gene and expression of p16 protein [p16 (+)] in tumor tissue associate with worse and better prognosis, respectively. UDP-glucuronosyltransferase 2 family, polypeptide B17 (UGT2B17) detoxifies smoking-related metabolites. Differences among ethnic groups in UGT2B17 are extremely high. Homozygous deletions of UGT2B17 gene (UGT2B17-deletion) are a common copy number variant (CNV) among Japanese, but not a common CNV among Africans and Europeans. Thus, we examined Japanese patients with HNSCC to explore if UGT2B17-deletion and/or p16 (+) modify effects of smoking on TP53-mutations and affect relapse. Methods We conducted a posthoc analysis of a prospective cohort. Polymerase chain reaction, immunohistochemistry, and direct sequencing were used to determine UGT2B17-deletion, p16 (+), and detailed TP53-mutations, respectively. Results UGT2B17-deletion was observed in 80% of this study population. For this 80%, TP53-mutations were significantly more common among smokers than non-smokers (P = 0.0016), but this difference between smokers and nonsmokers was not significant for the 20% with UGT2B17. In patients with UGT2B17-deletion and p16 (+), simultaneously, TP53-mutations were much more common among smokers than among non-smokers (81% versus 17%; P = 0.0050). Patients with both UGT2B17-deletion and disruptive TP53-mutations had higher relapse rates than other patients (hazard ratio, 2.22; 95% confidence interval, 1.30 to 3.80, P = 0.004) in a stepwise method. Conclusions These results suggest that UGT2B17-deletion interacting with p16 (+) may modify effects of smoking on TP53-mutations and may further interact with the disruptive TP53-mutations to raise relapse rates among Japanese patients with HNSCC.