We report the first genome-wide association study in 1000 bipolar I patients and 1000 controls, with a replication of the top hits in another 409 cases and 1000 controls in the Han Chinese ...population. Four regions with most strongly associated single-nucleotide polymorphisms (SNPs) were detected, of which three were not found in previous GWA studies in the Caucasian populations. Among them, SNPs close to specificity protein 8 (SP8) and ST8 α-N-acetyl- neuraminide α-2,8-sialyltransferase (ST8SIA2) are associated with Bipolar I, with P-values of 4.87 × 10(-7) (rs2709736) and 6.05 × 10(-6) (rs8040009), respectively. We have also identified SNPs in potassium channel tetramerization domain containing 12 gene (KCTD12) (rs2073831, P=9.74 × 10(-6)) and in CACNB2 (Calcium channel, voltage-dependent, β-2 subunit) gene (rs11013860, P=5.15 × 10(-5)), One SNP nearby the rs1938526 SNP of ANK3 gene and another SNP nearby the SNP rs11720452 in chromosome 3 reported in previous GWA studies also showed suggestive association in this study (P=6.55 × 10(-5) and P=1.48 × 10(-5), respectively). This may suggest that there are common and population-specific susceptibility genes for bipolar I disorder.
We report a detection of the baryon acoustic oscillation (BAO) feature in the three-dimensional correlation function of the transmitted flux fraction in the Lyα forest of high-redshift quasars. The ...study uses 48 640 quasars in the redshift range 2.1 ≤ z ≤ 3.5 from the Baryon Oscillation Spectroscopic Survey (BOSS) of the third generation of the Sloan Digital Sky Survey (SDSS-III). At a mean redshift z = 2.3, we measure the monopole and quadrupole components of the correlation function for separations in the range 20 h-1 Mpc < r < 200 h-1 Mpc. A peak in the correlation function is seen at a separation equal to (1.01 ± 0.03) times the distance expected for the BAO peak within a concordance ΛCDM cosmology. This first detection of the BAO peak at high redshift, when the universe was strongly matter dominated, results in constraints on the angular diameter distance DA and the expansion rate H at z = 2.3 that, combined with priors on H0 and the baryon density, require the existence of dark energy. Combined with constraints derived from cosmic microwave background observations, this result implies H(z = 2.3) = (224 ± 8) km s-1 Mpc-1, indicating that the time derivative of the cosmological scale parameter ȧ = H(z = 2.3)/(1 + z) is significantly greater than that measured with BAO at z ~ 0.5. This demonstrates that the expansion was decelerating in the range 0.7 < z < 2.3, as expected from the matter domination during this epoch. Combined with measurements of H0, one sees the pattern of deceleration followed by acceleration characteristic of a dark-energy dominated universe.
Summary
Background
The sensitivity of current upper limit of normal (ULN) of serum alanine aminotransferase (ALT) levels for detecting chronic liver disease has been challenged recently.
Aim
To ...identify modulating factors for serum ALT levels and to refine its ULN threshold.
Methods
We enrolled 34 346 consecutive subjects who completed the health check‐up at Taipei Veterans General Hospital from 2002 to 2009. ULN was set for healthy ALT level to the 95th percentile of the reference healthy population.
Results
A group of 21 282 subjects were used as a training set to define an ULN with the highest sensitivity; afterwards, this ULN was validated in another set of 13 064 subjects. A reference healthy population was selected from the training set after excluding subjects with any abnormalities in independent risk factors associated with elevated serum ALT level (>40 IU/L) by multivariate analysis like body mass index, waist circumference, glucose, cholesterol, high‐density lipoprotein‐cholesterol, triglyceride, hepatitis B virus surface antigen, anti‐hepatitis C virus antibody and fatty liver. The new ULN of serum ALT level defined as the 95% percentile in the healthy population were 21 IU/L and 17 IU/L for men and women respectively. These cut‐off values had the highest Youden's index and areas under the corresponding receiver operating curves among four widely applied thresholds in both the training and validation sets.
Conclusions
The suggested threshold of upper limit of normal provides better discrimination between healthy and unhealthy status. Viral hepatitis, metabolic syndrome and fatty liver are the major risk factors of elevated serum alanine aminotransferase levels.
Abstract
Background
Clinical research on nutritional and metabolic interventions in critically ill patients is heterogenous regarding time points, outcomes and measurement instruments used, impeding ...intervention development and data syntheses, and ultimately worsening clinical outcomes. We aimed to identify and develop a set of core outcome domains and associated measurement instruments to include in all research in critically ill patients.
Methods
An updated systematic review informed a two-stage modified Delphi consensus process (domains followed by instruments). Measurement instruments for domains considered ‘essential’ were taken through the second stage of the Delphi and a subsequent consensus meeting.
Results
In total, 213 participants (41 patients/caregivers, 50 clinical researchers and 122 healthcare professionals) from 24 countries contributed. Consensus was reached on time points (30 and 90 days post-randomisation). Three domains were considered ‘essential’ at 30 days (survival, physical function and Infection) and five at 90 days (survival, physical function, activities of daily living, nutritional status and muscle/nerve function). Core ‘essential’ measurement instruments reached consensus for survival and activities of daily living, and ‘recommended’ measurement instruments for physical function, nutritional status and muscle/nerve function. No consensus was reached for a measurement instrument for Infection. Four further domains met criteria for ‘recommended,’ but not ‘essential,’ to measure at 30 days post-randomisation (organ dysfunction, muscle/nerve function, nutritional status and wound healing) and three at 90 days (frailty, body composition and organ dysfunction).
Conclusion
The CONCISE core outcome set is an internationally agreed minimum set of outcomes for use at 30 and 90 days post-randomisation, in nutritional and metabolic clinical research in critically ill adults.
The relationship between the resulting grain size and the applied working strain rate and temperature for the friction stir processing in AZ31 Mg is systemically examined. The Zener–Holloman ...parameter is utilized in rationalizing the relationship. The grain orientation distribution is also studied using the X-ray diffraction.
This international, randomized, double-blind phase III study (ONO-4538-52/TASUKI-52) evaluated nivolumab with bevacizumab and cytotoxic chemotherapy as first-line treatment for nonsquamous ...non-small-cell lung cancer (NSCLC).
Between June 2017 and July 2019, this study enrolled treatment-naïve patients with stage IIIB/IV or recurrent nonsquamous NSCLC without sensitizing EGFR, ALK, or ROS1 alterations. They were randomly assigned in a 1 : 1 ratio to receive nivolumab or placebo in combination with carboplatin, paclitaxel, and bevacizumab every 3 weeks for up to six cycles, followed by nivolumab/placebo with bevacizumab until progressive disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by an independent radiology review committee (IRRC).
Overall, 550 patients from Japan, Korea, and Taiwan were randomized; of these patients, 273 and 275 received the nivolumab and placebo combinations, respectively. In the present preplanned interim analysis with a median follow up of 13.7 months, the IRRC-assessed median PFS was significantly longer in the nivolumab arm than in the placebo arm (12.1 versus 8.1 months; hazard ratio 0.56; 96.4% confidence interval 0.43-0.71; P < 0.0001). The PFS benefit was observed across all patients with any programmed death-ligand 1 (PD-L1) expression levels including PD-L1-negative patients. The IRRC-assessed objective response rates were 61.5% and 50.5% in the nivolumab and placebo arms, respectively. The incidence of treatment-related adverse events of grade 3 or 4 was comparable between the two arms; treatment-related adverse events leading to death were observed in five and four patients in the nivolumab and placebo arms, respectively.
The TASUKI-52 regimen should be considered a viable new treatment strategy for treatment-naïve patients with advanced nonsquamous NSCLC.
•Nivolumab with carboplatin, paclitaxel, and bevacizumab was evaluated as first-line therapy for nonsquamous NSCLC.•The nivolumab combination therapy provided superior PFS across all patients with any PD-L1 expression levels.•The median PFS of 12.1 months is the longest among all phase III studies for nonsquamous NSCLC without driver mutations.•No new safety signals were observed.
Very few studies have focused on the outcome and management of patients with a single sputum isolate of nontuberculous mycobacterium (NTM) on initial examination. Patients with a single isolate of ...Mycobacterium avium complex (MAC), M. chelonae-abscessus, M. kansasii, or M. fortuitum from at least three sputum samples collected within 1 month were retrospectively identified. Those with follow-up sputum samples within 1 year were included in the analysis. Among the 202 patients included, M. fortuitum (n = 71, 35.1%) and MAC (n = 70, 34.7%) were the most common NTM species isolated, followed by M. chelonae-abscessus (n = 40, 19.8%) and M. kansasii (n = 21, 10.4%). The mean clinical follow-up period was 26.2 months. Forty-four patients (21.8%) had subsequent positive cultures of the same NTM species, while eight (4.0%) had bronchiectasis and developed NTM lung disease (NTM-LD). Neither patients without bronchiectasis nor those with M. fortuitum subsequently developed NTM lung disease. Among bronchiectatic patients with NTM other than M. fortuitum, age ≤65 years (p 0.006, OR 32.13), malignancy (p 0.048, OR 14.35), and initial radiographic score >2 (p 0.027, OR 20.06) were associated with subsequent NTM-LD. In all of the NTM patients, bronchiectasis (p <0.001, OR 5.46) and age ≤65 years (p 0.002, OR 3.29) were significantly associated with subsequent positive NTM culture. In patients with a single isolation of NTM from respiratory specimens, the presence of bronchiectasis and younger age indicates higher risk of subsequent culture-positivity and NTM-LD. Single isolation of M. fortuitum is of little clinical significance. Other patients with NTM, younger age, and more severe radiographic pulmonary lesion also warrant further attention.
Abstract
Background
In patients with rectal cancer, enlarged lateral lymph nodes (LLNs) result in increased lateral local recurrence (LLR) and lower cancer-specific survival (CSS) rates, which can be ...improved with (chemo)radiotherapy ((C)RT) and LLN dissection (LLND). This study investigated whether different LLN locations affect oncological outcomes.
Methods
Patients with low cT3–4 rectal cancer without synchronous distant metastases were included in this multicentre retrospective cohort study. All MRI was re-evaluated, with special attention to LLN involvement and response.
Results
More advanced cT and cN category were associated with the occurrence of enlarged obturator nodes. Multivariable analyses showed that a node in the internal iliac compartment with a short-axis (SA) size of at least 7 mm on baseline MRI and over 4 mm after (C)RT was predictive of LLR, compared with a post-(C)RT SA of 4 mm or less (hazard ratio (HR) 5.74, 95 per cent c.i. 2.98 to 11.05 vs HR 1.40, 0.19 to 10.20; P < 0.001). Obturator LLNs with a SA larger than 6 mm after (C)RT were associated with a higher 5-year distant metastasis rate and lowered CSS in patients who did not undergo LLND. The survival difference was not present after LLND. Multivariable analyses found that only cT category (HR 2.22, 1.07 to 4.64; P = 0.033) and margin involvement (HR 2.95, 1.18 to 7.37; P = 0.021) independently predicted the development of metastatic disease.
Conclusion
Internal iliac LLN enlargement is associated with an increased LLR rate, whereas obturator nodes are associated with more advanced disease with increased distant metastasis and reduced CSS rates. LLND improves local control in persistent internal iliac nodes, and might have a role in controlling systemic spread in persistent obturator nodes.
Members of the Lateral Node Study Consortium are co-authors of this study and are listed under the heading Collaborators.
This multicentre retrospective cohort study, including 1216 patients with low cT3–4 rectal cancer, demonstrated that internal iliac lateral lymph node enlargement is associated with an increased rate of lateral local recurrence, whereas obturator nodes are associated with more advanced disease resulting in increased distant metastasis and reduced cancer-specific survival rates. Lateral lymph node dissection improves local control in persistent internal iliac nodes, and might have a role in controlling systemic spread in persistent obturator nodes.
In order to achieve highly mineralized tooth enamel, enamel proteinases serve the important function of removing the remaining organic matrix in the mineralization and maturation of the enamel ...matrix. Mutations in the kallikrein 4 (KLK4), enamelysin (MMP20), and WDR72 genes have been identified as causing hypomaturation enamel defects in an autosomal-recessive hereditary pattern. In this report, 2 consanguineous families with a hypomaturation-type enamel defect were recruited, and mutational analysis was performed to determine the molecular genetic etiology of the disease. Whole exome sequencing and autozygosity mapping identified novel homozygous mutations in the KLK4 (c.620_621delCT, p.Ser207Trpfs*38) and MMP20 (c.1054G>A, p.Glu352Lys) genes. Further analysis on the effect of the mutations on the translation, secretion, and function of KLK4 and MMP20 revealed that mutant KLK4 was degraded intracellularly and became inactive while mutant MMP20 was expressed at a normal level but secreted only minimally with proteolytic function.
Background We sought to find the therapeutic effect of 5Hz high‐frequency repetitive transcranial magnetic stimulation (rTMS) over the unaffected pharyngeal motor cortex in post‐stroke dysphagic ...patients.
Methods Eighteen patients with unilateral hemispheric stroke oropharyngeal dysphagia that lasted more than 1 month were randomly divided into two groups. They all performed videofluoroscopic swallowing study (VFSS) before rTMS intervention. The experimental group (EG) received 5Hz rTMS over contra‐lesional pharyngeal motor cortex for 10 min per day for 2 weeks. The control group (CG) received sham stimulation under the same condition. Videofluoroscopic swallowing study were performed again just after treatment cessation and 2 weeks afterward. The evaluation was performed using videofluoroscopic dysphagia scale (VDS) and penetration‐aspiration scale (PAS).
Key Results Mean baseline VDS and PAS of EG was 33.6 ± 12.1 and 3.41 ± 2.32 respectively and the scores were reduced to 25.3 ± 9.8 and 1.93 ± 1.52 just after 2 weeks intervention (P < 0.05). This effect lasted for up to 2 weeks after treatment. However, there was no change in the CG. Baseline prevalence of aspiration, pharyngeal residue, delayed triggering of pharyngeal swallowing and abnormal pharyngeal transit time (PTT) in EG was 66.7%, 66.7%, 33.3%, and 44.4%, respectively. After rTMS, the prevalence of aspiration and pharyngeal residue was reduced to 33.3% and 33.3%, respectively. However, the prevalence of delayed triggering and abnormal PTT was not changed.
Conclusions & Inferences A 5Hz high‐frequency rTMS on contra‐lesional pharyngeal motor cortex might be beneficial for post‐stroke dysphagic patients. This intervention can be used as a new treatment method in post‐stroke patients with dysphagia.
PDF
