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Abstract Although self-reported health outcomes are of importance, attempts to validate a clinical applicable instrument (e.g., nomogram) combining sociodemographic and self-reported information on periodontitis have yet to be performed to identify periodontitis cases. Clinical and self-reported periodontitis, along with sociodemographic data, were collected from 197 adults. Akaike information criterion models were developed to identify periodontitis, and nomograms developed based on its regression coefficients. The discriminatory capability was evaluated by receiver-operating characteristic curves. Decision curve analysis was performed. Smoking [OR 3.69 (95%CI 1.89, 7.21)], poor/fair self-rated oral health [OR 6.62 (95%CI 3.23, 13.56)], previous periodontal treatment [OR 9.47 (95%CI 4.02, 22.25)], and tooth loss [OR 4.96 (95%CI 2.47, 9.97)], determined higher probability of having "Moderate/Severe Periodontitis". Age [OR 1.08 (95%CI 1.05, 1.12)], low educational level [OR 1.65 (95%CI 1.34, 2.23)], poor/fair self-rated oral health [OR 3.57 (95%CI 1.82, 6.99)], and previous periodontal treatment [OR 6.66 (95%CI 2.83, 15.68)] determined higher probability for "Any Periodontitis". Both nomograms showed excellent discriminatory capability (AUC of 0.83 (95%CI 0.75, 0.91) and 0.81 (95% CI 0.74, 0.88), good calibration, and slight overestimation of high risk and underestimation of low risk. Hence, our nomograms could help identify periodontitis among adults in Denmark.

Abstract Background We investigated the value of three-dimensional amide proton transfer-weighted imaging (3D-APTWI) in the diagnosis of early-stage breast cancer (BC) and its correlation with the immunohistochemical characteristics of malignant lesions. Methods Seventy-eight women underwent APTWI and dynamic contrast-enhanced (DCE)-MRI. Pathological results were categorized as either benign (n = 43) or malignant (n = 37) lesions. The parameters of APTWI and DCE-MRI were compared between the benign and malignant groups. The diagnostic value of 3D-APTWI was evaluated using the area under the receiver operating characteristic curve (ROC-AUC) to establish a diagnostic threshold. Pearson’s correlation was used to analyze the correlation between the magnetization transfer asymmetry (MTRasym) and immunohistochemical characteristics. Results The MTRasym and time-to-peak of malignancies were significantly lower than those of benign lesions (all p < 0.010). The volume transfer constant, rate constant, and wash-in and wash-out rates of malignancies were all significantly greater than those of benign lesions (all p < 0.010). ROC-AUCs of 3D-APTWI, DCE-MRI, and 3D-APTWI+DCE to differential diagnosis between early-stage BC and benign lesions were 0.816, 0.745, and 0.858, respectively. Only the difference between AUCAPT+DCE and AUCDCE was significant (p < 0.010). When a threshold of MTRasym for malignancy for 2.42%, the sensitivity and specificity of 3D-APTWI for BC diagnosis were 86.5% and 67.6%, respectively; MTRasym was modestly positively correlated with pathological grade (r = 0.476, p = 0.003) and Ki-67 (r = 0.419, p = 0.020). Conclusions 3D-APTWI may be used as a supplementary method for patients with contraindications of DCE-MRI. MTRasym can imply the proliferation activities of early-stage BC. Relevance statement 3D-APTWI can be an alternative diagnostic method for patients with early-stage BC who are not suitable for contrast injection. Key points • 3D-APTWI reflects the changes in the microenvironment of early-stage breast cancer. • Combined 3D-APTWI is superior to DCE-MRI alone for early-stage breast cancer diagnosis. • 3D-APTWI improves the diagnostic accuracy of early-stage breast cancer. Graphical Abstract

Abstract Although zinc deficiency (secondary to malnutrition) has long been considered an important contributor to morbidity and mortality of infectious disease (e.g. diarrhea disorders), epidemiologic data (including randomized controlled trials with supplemental zinc) for such a role in lower respiratory tract infection are somewhat ambiguous. In the current study, we provide the first preclinical evidence demonstrating that although diet‐induced acute zinc deficiency (Zn‐D: ~50% decrease) did not worsen infection induced by either influenza A (H1N1) or methicillin‐resistant staph aureus (MRSA), Zn‐D mice were sensitive to the injurious effects of superinfection of H1N1 with MRSA. Although the mechanism underlying the sensitivity of ZnD mice to combined H1N1/MRSA infection is unclear, it was noteworthy that this combination exacerbated lung injury as shown by lung epithelial injury markers (increased BAL protein) and decreased genes related to epithelial integrity in Zn‐D mice (surfactant protein C and secretoglobins family 1A member 1). As bacterial pneumonia accounts for 25%–50% of morbidity and mortality from influenza A infection, zinc deficiency may be an important pathology component of respiratory tract infections.

Abstract Artificial intelligence methods including deep neural networks (DNN) can provide rapid molecular classification of tumors from routine histology with accuracy that matches or exceeds human pathologists. Discerning how neural networks make their predictions remains a significant challenge, but explainability tools help provide insights into what models have learned when corresponding histologic features are poorly defined. Here, we present a method for improving explainability of DNN models using synthetic histology generated by a conditional generative adversarial network (cGAN). We show that cGANs generate high-quality synthetic histology images that can be leveraged for explaining DNN models trained to classify molecularly-subtyped tumors, exposing histologic features associated with molecular state. Fine-tuning synthetic histology through class and layer blending illustrates nuanced morphologic differences between tumor subtypes. Finally, we demonstrate the use of synthetic histology for augmenting pathologist-in-training education, showing that these intuitive visualizations can reinforce and improve understanding of histologic manifestations of tumor biology.

Abstract We aim to determine whether combined thermal and ultrasound (CTUS) imaging can identify rheumatoid arthritis (RA) patients with at least moderate disease activity (DAS28 > 3.2). Temperature differences of maximum (Tmax), average (Tavg) and minimum (Tmin) temperatures from a control temperature at 22 joints (bilateral hands) were summed up to derive the respective MAX, AVG and MIN per patient. MAX (PD), AVG (PD) and MIN (PD) are CTUS results derived by multiplying MAX, AVG and MIN by a factor of 2 when a patient’s total ultrasound power Doppler (PD) joint inflammation score > median score, which otherwise remained unchanged. Receiver operating characteristic (ROC) analysis was used to determine whether CTUS imaging can identify patients with DAS28 > 3.2. In this cross-sectional study, 814 joints were imaged among 37 RA patients (mean disease duration, 31 months). CTUS (but not single modality) imaging parameters were all significantly greater comparing patients with DAS28 > 3.2 versus those with DAS28 ≤ 3.2 (all P 3.2 were 0.73 , 0.76 and 0.76 for MAX (PD), AVG (PD) and MIN (PD), respectively (with sensitivity ranging from 58 to 61% and specificity all 100%). The use of CTUS in detecting a greater severity of joint inflammation among patients with at least moderate disease activity (DAS28 > 3.2) appears promising and will require further validation in independent RA cohorts.

Abstract This letter presents two transient enhancement techniques for multi‐path switched‐capacitor‐inductor (MP‐SCI) hybrid DC–DC converters to eliminate the line‐transient‐induced voltage coupling to the converter output. Since the existing input‐feedforward method is hard to apply to the MP‐SCI converter, the proposed techniques tackle the intrinsic hard‐charging property with the MP‐SCI topology, preventing the line‐coupling current through topology operation reconfiguration and power‐switch modulation. The proposed controller also achieves adaptive line‐transition detection and automatic flying‐capacitor voltage balancing, ensuring a fast line regulation feature. Implemented with an MP‐SCI topology for a 9 to 14 V‐input to 5 V‐output conversion, the proposed control techniques provide an output (VOUT) overshoot and undershoot as low as 0.5% of the output DC level under a 3‐V input voltage step. From the simulation, the corresponding output variation reduction can be more than 94% when compared with the existing MP‐SCI operations. Besides, the proposed controller is compatible with a voltage‐mode (VM) V2 pulse‐width modulation (PWM) function, achieving a fast load‐transient recovery in six switching cycles and a VOUT variation of 75 mV at a 5 V DC level under a 0‐to‐3 A load step. The peak conversion efficiency can be as high as 95.5%, and the targeted load current delivery is up to 3 A.

Abstract This letter presents an automatic power‐stage implementation and optimization methodology for fully‐integrated reconfigurable switched‐capacitor (SC) DC‐DC converters with fine‐grained voltage conversion ratios (VCRs). The proposed technique resolves the design challenge of a simultaneous realization of full capacitance utilization, optimal sub‐cell sizing ratio, and implementation complexity reduction. It is based on the proposed partitioning algorithms and attains a significant sub‐cell number reduction, particularly for finer‐grained VCR designs, saving the power‐stage area overhead. With a given set of VCRs and hardware constraints, the proposed methodology can generate a specific power‐stage partitioning solution, including the total number and sizing ratio for the power stage sub‐cells, ensuring an optimal power‐stage conduction loss property under a given on‐chip capacitance area. The proposed methodology is applicable to both linear and binary types of SC converters. Compared with the advanced works, the proposed method realizes the number of sub‐capacitors reduction over 50% under the same VCRs. Meanwhile, over 90% of the sub‐cells can be eliminated for linear‐type SC converters with a VCR range of 10:1–2:1, theoretically.

Abstract Dysregulation of expression of functional genes and pathways plays critical roles in the etiology and progression of hepatocellular carcinoma (HCC). Next generation‐based RNA sequencing (RNA‐seq) offers unparalleled power to comprehensively characterize HCC at the whole transcriptome level. In this study, 17 fresh‐frozen HCC samples with paired non‐neoplastic liver tissue from Caucasian patients undergoing liver resection or transplantation were used for RNA‐seq analysis. Pairwise differential expression analysis of the RNA‐seq data was performed to identify genes, pathways, and functional terms differentially regulated in HCC versus normal tissues. At a false discovery rate (FDR) of 0.10, 13% (n = 4335) of transcripts were up‐regulated and 19% (n = 6454) of transcripts were down‐regulated in HCC versus non‐neoplastic tissue. Eighty‐five Kyoto Encyclopedia of Genes and Genomes pathways were differentially regulated (FDR,

Abstract Background The effect of extracellular microenvironment (hypoxia and pH) has been regarded as a key hallmark in cancer progression. The study aims to investigate the effects of carbonic anhydrase IX (CAIX), a key hypoxia-inducible marker, in triple-negative breast cancer (TNBC) in correlation with clinicopathological parameters and predicting survival outcomes. Methods A total of 323 TNBC cases diagnosed at the Department of Anatomical Pathology, Singapore General Hospital from 2003 to 2013 were used. Immunohistochemical staining (IHC) was performed using CAIX antibody and digital mRNA quantification was performed using NanoString assays. CAIX membranous expression was correlated with clinicopathological parameters using Chi-squared test or Fisher’s exact tests. Disease-free survival (DFS) and overall-survival (OS) were estimated using Kaplan–Meier analysis and compared between groups with the log-rank test. Results Forty percent of TNBCs were observed to express CAIX protein and demonstrated significant association with larger tumour size (P = 0.002), higher histological grade (P

Pulmonary lymphomas are rare. With the current less invasive approaches used to obtain material for diagnosis, the diagnosis of pulmonary lymphoma is now frequently established in a small biopsy rather than in a resection. Therefore, the diagnosis has become more challenging and requires correlation with the clinico-radiologic presentation and with ancillary studies (immunohistochemistry, flow cytometry, cytogenetics, and/or molecular analysis). Due to the rarity of pulmonary lymphomas, clinical suspicion of a lymphomatous process is low at initial presentation, and material may be only submitted for histopathology. For this reason, herein, we provide recommendations to arrive at the correct diagnosis of the most common lung B-cell lymphomas (marginal zone lymphoma of mucosa-associated lymphoid tissue, diffuse large B-cell lymphoma, intravascular large B-cell lymphoma, lymphomatoid granulomatosis) in the setting of small biopsies, utilizing only immunohistochemistry. The differential diagnosis varies according to the lymphoma subtype and includes reactive conditions, solid tumors, and other hematolymphoid malignancies. Although morphology and immunohistochemistry may be sufficient to establish a diagnosis, in some cases, the best recommendation is to obtain additional tissue via a VATS biopsy/wedge resection with material submitted for flow cytometry, cytogenetics, and/or molecular studies to be able to properly classify a pulmonary lymphoid process.

Background Diabetes is a risk factor for postoperative complications. Previous meta-analyses have shown that elevated glycated hemoglobin (HbA1c) levels are associated with postoperative complications in various surgical populations. However, this is the first meta-analysis to investigate the association between preoperative HbA1c levels and postoperative complications in patients undergoing elective major abdominal surgery. Methods PRISMA guidelines were adhered to for this study. Six databases were searched up to April 1, 2020. Primary studies investigating the effect of HbA1c levels on postoperative complications after elective major abdominal surgery were included. Risk of bias and quality of evidence assessments were performed. Data were pooled using a random effects model. Meta-regression was performed to evaluate different HbA1c cut-off values. Results Twelve observational studies (25,036 patients) were included. Most studies received a ‘good’ and ‘moderate quality’ score using the NOS and GRADE, respectively. Patients with a high HbA1c had a greater risk of anastomotic leaks (odds ratio [OR]: 2.80, 95% CI [1.63, 4.83], P < 0.001), wound infections (OR: 1.21, 95% CI [1.08, 1.36], P = 0.001), major complications defined as Clavien-Dindo [CD] 3–5 (OR: 2.16, 95% CI [1.54, 3.01], P < 0.001), and overall complications defined as CD 1–5 (OR: 2.12, 95% CI [1.48, 3.04], P < 0.001). Conclusions An HbA1c between 6% and 7% is associated with higher risks of anastomotic leaks, wound infections, major complications, and overall postoperative complications. Therefore, guidelines with an HbA1c threshold > 7% may be putting pre-optimized patients at risk. Future randomized controlled trials are needed to explore causation before policy changes are made.

Increased dental overjet in adolescence is a clinically relevant outcome associated with the complexity and high cost of treatment, indicating the need for prevention strategies. We investigated the long-term impact of breastfeeding and pacifier use on increased overjet (IOVJ) in permanent dentition. A prospective cohort nested in a randomized controlled trial was conducted from birth to 12 years of age (n = 214). Breastfeeding and pacifier use were recorded monthly until 12 months. Overjet was assessed at age 12 years. We employed a causal mediation analysis using parametric regression models assuming no interaction between breastfeeding and pacifier usage. We found a total protective effect of breastfeeding on IOVJ (OR 0.49; 95% CI 0.28–0.96), where 63.1% were mediated by pacifier use (OR 0.61; 95% CI 0.44–0.87). Breastfeeding directly decreased the odds of IOVJ by 20%; however, the confidence interval included the null estimate (OR 0.81; 95% CI 0.41–1.60). In conclusion, breastfeeding protects by half of the IOVJ in adolescence through reducing pacifier use. Oral and general health professionals should collaborate to support WHO breastfeeding guidelines during individual patient counseling. Guidelines for practice, policy or public information require messages that include a common risk approach to oral and general health.

Background CI in SSD strives to restore binaural hearing. With normal acoustic hearing on one ear, the benefits of rehabilitating the deaf ear with an implant are not well established. Objectives We investigate audiologic and quality-of-life measures, and long-term usage patterns of cochlear implantation (CI) in patients with single-sided deafness (SSD) Methods Eight patients with idiopathic sudden sensorineural hearing loss of less than 5-year duration were recruited. Pure tone average (PTA), speech discrimination score (SDS), hearing-in-noise test (HINT), tinnitus handicap inventory (THI), quality-of-life speech spatial qualities (SSQ) scale tests were performed before, and one-year after CI. Long-term usage of CI four-years post-operatively was determined. Results The median PTA of the deaf ear was 96 dBHL (IQR = 90–120) before, and 30 dBHL (IQR = 27–33) after CI ( p = 0.0156). SDS improved from median of 0% (IQR = 0–3) to 33% (IQR = 24–58) ( p = 0.0360). Median signal-to-noise ratio (SNR), particularly of the S 0 N better setting of HINT showed improvement from 6.4 dB (IQR = 5.7–7) to 0.9 dB (IQR = −2.25–6.2) ( p = 0.1094). Despite median THI improving from 24 (IQR = 6–47) to 4 (IQR = 2–7) ( p = 0.1563), two patients experienced worsening of tinnitus. SSQ scores in all subscales showed modest improvement not approaching significance. 5 of 8 (62%) patients stopped using their implant four years after surgery. Conclusion Despite improved audiologic and tinnitus outcome measures, our patients’ SDS remained in non-serviceable range, while quality-of-life measures showed only modest improvement. Majority of our patients stopped using their implant four years post-surgery. Our study suggests that objective measurable benefits of CI in SSD may not translate to actual patient perceived benefits.

A water-soluble cationic kraft lignin (named JLQKL50), synthesized by combining quaternization and crosslinking reactions, was used as an additive to enhance the enzymatic hydrolysis of dilute-alkali-pretreated corn stalk. The chemical constitution of JLQKL50 was investigated by Fourier transform infrared spectroscopy, 1H nuclear magnetic resonance (NMR) and 13C NMR spectroscopy, and elemental analysis. The enzymatic hydrolysis efficiency of corn stalk at solid content of 10% (w/v) was significantly improved from 70.67% to 78.88% after 24 h when JLQKL50 was added at a concentration of 2 g/L. Meanwhile, the enzymatic hydrolysis efficiency after 72 h reached 91.11% with 10 FPU/g of cellulase and 97.92% with 15 FPU/g of cellulase. In addition, JLQKL50 was found capable of extending the pH and temperature ranges of enzymatic hydrolysis to maintain high efficiency (higher than 70%). The decrease in cellulase activity under vigorous stirring with the addition of JLQKL50 was 17.4%, which was much lower than that (29.7%) without JLQKL50. The addition of JLQKL50 reduced the nonproductive adsorption of cellulase on the lignin substrate and improved the longevity, dispersity, and stability of the cellulase by enabling electrostatic repulsion. Therefore, the enzymatic hydrolysis of the corn stalk was enhanced. This study paves the way for the design of sustainable lignin-based additives to boost the enzymatic hydrolysis of lignocellulosic biomass.

Objective To investigate the long-term clinical outcomes of patients with adenomyosis treated by high-intensity focused ultrasound (HIFU). Materials and methods From June 2012 to January 2020, 2311 patients with adenomyosis were treated with HIFU at our center, 1982 patients who have complete clinical data were retrospectively reviewed. Among the patients who completed the follow-up, 485 were treated with HIFU alone, 289 were treated with HIFU followed by GnRH-a, 255 were treated with HIFU combined with Mirena and 594 were treated with HIFU combined with GnRH-a and Mirena. The dysmenorrhea severity pain score and average menorrhagia severity score before and at 3 months, 6 months, 1 year, 2 years, 3 years and 5 years after HIFU were compared. The adverse effects were recorded. In addition, the efficacy between patients treated with GnRH-a and/or Mirena were compared. Results After HIFU ablation, the dysmenorrhea severity pain score and the menorrhagia severity score were significantly decreased at each follow-up time point. However, it was observed that as the follow-up time increased, the effective rate of HIFU treatment in improving dysmenorrhea and menorrhagia decreased. The 6 months and 3 years follow-up results showed that the efficacy of HIFU combined with Mirena and HIFU combined with GnRH-a and Mirena were significantly higher than HIFU alone and HIFU combined with GnRH-a (p

Abstract Introduction The effects of tafamidis on mortality in Val30Met and non-Val30Met patients with transthyretin amyloidosis with polyneuropathy (ATTR-PN) were evaluated. Methods The analyses were based on cumulative data from the Val30Met patients in the 18-month double-blind registration study and its 12-month open-label extension study, the non-Val30Met patients of the 12-month open-label study, and both patient groups in the ongoing 10-year extension study. Kaplan–Meier analyses of time to death from first treatment dose were performed. For the Val30Met group, two treatment groups were analyzed: those who received tafamidis in both the parent and extension studies (T–T) and those who received placebo in the parent study and switched to tafamidis in the extension studies (P–T). Results Kaplan–Meier estimates (95% confidence interval [CI]) were available up to 9 years for the Val30Met group, at which time 85.9% (53.1–96.4) and 91.1% (77.9–96.6) of the patients in the T–T and P–T groups, respectively, were alive. For the non-Val30Met group, estimates were available up to 8 years from the first dose, and the percentage of patients alive was 75.9% (47.7–90.2). Conclusion Long-term tafamidis treatment may confer survival benefit in patients with ATTR-PN. Trial registration ClinicalTrials.gov identifier: NCT00409175, NCT00791492, NCT00630864, and NCT00925002.

Acute liver injury (ALI) is recognized as a serious complication of sepsis in patients in intensive care units (ICUs). S100A8/A9 is known to promote inflammation and immune responses. However, the role of S100A8/A9 in the regulation of sepsis-induced ALI remains known. Our results indicated that S100A8/A9 expression was significantly upregulated in the livers of septic mice 24 h after cecal ligation and a puncture (CLP) operation. Moreover, S100A9-KO in mice markedly attenuated CLP-induced liver dysfunction and injury, promoting the AMPK/ACC/GLUT4-mediated increases in fatty acid and glucose uptake as well as the improvement in mitochondrial function and ATP production. In contrast, treatment with the AMPK inhibitor Compound C reversed the inhibitory effects of S100A9 KO on CLP-induced liver dysfunction and injury in vivo. Finally, the administration of the S100A9 inhibitor Paquinimod (Paq) to WT mice protected against CLP-induced mortality, liver injury and mitochondrial dysfunction. In summary, our findings demonstrate for the first time that S100A9 plays an important pro-inflammatory role in sepsis-mediated ALI by regulating AKT-AMPK-dependent mitochondrial energy metabolism and highlights that targeting S100A9 may be a promising new approach for the prevention and treatment of sepsis-related liver injury.

Excessive daytime sleepiness (EDS) is a significant public health concern, with obstructive sleep apnea (OSA) being a common cause, and a particular relationship exists with the severity of depression. A literature search on OSA, depression, and EDS was performed in PubMed. The chosen evidence was limited to human studies. Available evidence was systematically reviewed to ascertain the association of EDS with depression and OSA according to the general population and some specific population subgroups. In addition, effectiveness of continuous positive airway pressure (CPAP) was analyzed as a standard therapy for improving EDS and depression in patients with OSA. In the general population, patients with OSA, and some other subpopulations, the review contributed to: (1) delineating the prevalence of EDS; (2) substantiating the relationship of EDS and depression; (3) presenting the relationship between EDS and OSA; and (4) revealing that the duration of CPAP is crucial for its therapeutic effects in improving EDS and depressive symptoms in patients with OSA.

Peroxisome proliferator-activated receptor (PPAR) α is widely expressed in the vasculature and has pleiotropic and lipid-lowering independent effects, but its role in the growth and function of vascular smooth muscle cells (VSMCs) during vascular pathophysiology is still unclear. Herein, VSMC-specific PPARα-deficient mice (PparaΔSMC) were generated by Cre-LoxP site-specific recombinase technology and VSMCs were isolated from mice aorta. PPARα deficiency attenuated VSMC apoptosis induced by angiotensin (Ang) II and hydrogen peroxide, and increased the migration of Ang II-challenged cells.

Abstract Background Acute kidney injury (AKI) is a major global health problem. We aim to evaluate the epidemiology, risk factors and outcomes of AKI episodes in our single centre. Methodology We prospectively identified 422 AKI and acute on chronic kidney disease episodes in 404 patients meeting KDIGO definitions using electronic medical records and clinical data from 15th July to 22nd October 2016, excluding patients with baseline estimated GFR (eGFR) of

Abstract The role of programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) in triple negative breast cancer (TNBC) remains to be fully understood. In this study, we investigated the role of PD-1 as a prognostic marker for TNBC in an Asian cohort (n = 269). Samples from patients with TNBC were labeled with antibodies against PD-L1 and PD-1, and subjected to NanoString assays to measure the expression of immune-related genes. Associations between disease-free survival (DFS), overall survival (OS) and biomarker expression were investigated. Multivariate analysis showed that tumors with high PD-1+ immune infiltrates harbored significantly increased DFS, and this increase was significant even after controlling for clinicopathological parameters (HR 0.95; P = 0.030). In addition, the density of cells expressing both CD8 and PD-1, but not the density of CD8−PD-1+ immune infiltrates, was associated with improved DFS. Notably, this prognostic significance was independent of clinicopathological parameters and the densities of total CD8+ cell (HR 0.43, P = 0.011). At the transcriptional level, high expression of PDCD1 within the tumor was significantly associated with improved DFS (HR 0.38; P = 0.027). In line with these findings, high expression of IFNG (HR 0.38; P = 0.001) and IFN signaling genes (HR 0.46; p = 0.027) was also associated with favorable DFS. Inclusion of PD-1 immune infiltrates and PDCD1 gene expression added significant prognostic value for DFS (ΔLRχ2 = 6.35; P = 0.041) and OS (ΔLRχ2 = 9.53; P = 0.008), beyond that provided by classical clinicopathological variables. Thus, PD-1 mRNA and protein expression status represent a promising, independent indicator of prognosis in TNBC.

Hyperuricemia is an important risk factor for vascular inflammation, yet the potential mechanisms of uric acid (UA) in endothelial cells are not well understood. UA has been found to stimulate renin-angiotensin system (RAS) activation in human umbilical vein endothelial cells (HUVECs). (Pro)renin receptor ((P)RR) is widely expressed in endothelial cells and able to induce RAS activation. Whether UA-induced endothelial cell inflammation is via up-regulating (P)RR remained unknown. Primary HUVECs were cultured and treated with UA, under the condition of (P)RR or AT1 silencing. The degree of inflammation in HUVECs was determined by Real-time PCR and monocyte adhesion assay. The protein levels of (P)RR were determined by western blotting or immunofluorescence. Probenecid was used to block UA re-absorption in this study. Adhesion of monocytes to HUVECs was elucidated by microfluidic chip. We found (P)RR is up-regulated in HUVECs following UA stimulation. UA promoted vascular inflammation, which was characterized by up-regulating of cytokines and enhanced monocyte adhesion. Silencing of (P)RR alleviated UA-induced vascular inflammation. Probenecid treatment abolished UA-induced vascular inflammation in HUVECs via suppressing (P)RR up-regulation. This finding was further verified by using microfluidic chip. Our findings indicate that (P)RR plays a critical role in endothelial inflammation in response to UA stimulation.

Abstract Background Emerging evidence suggests that several factors can impact disease progression in transthyretin amyloid polyneuropathy (ATTR-PN). The present analysis used longitudinal data from Val30Met patients participating in the tafamidis (selective TTR stabilizer) clinical development program to evaluate the impact of baseline neurologic severity on disease progression in ATTR-PN. Methods A linear mixed-effects model for repeated measures (MMRM) was constructed using tafamidis and placebo data from the intent-to-treat Val30Met population of the original registration study as well as tafamidis data from the two consecutive open-label extension studies. The second extension study is ongoing, but a prospectively-planned interim analysis involving a cleaned and locked database was conducted (cut-off: December 31, 2014). Val30Met patients are presented by treatment groups as those who received tafamidis during the registration and open-label studies (T-T group), or who received placebo during the registration study and were switched to tafamidis in the open-label studies (P-T group). Neurologic functioning was assessed at baseline and subsequent visits using the Neuropathy Impairment Score–Lower Limbs (NIS-LL). The analysis focused on the disease trajectory over the first 18 months of treatment. Results The T-T (n = 64) and P-T (n = 61) cohorts were predominantly Caucasian and presented with early-stage neurologic disease (mean [standard deviation] baseline NIS-LL values were 8.4 [11.4] and 11.4 [13.5], respectively). The MMRM analysis demonstrated that baseline severity is an independent significant predictor of disease progression in addition to the treatment effect: patients with a lower baseline NIS-LL showed less progression than those with a higher baseline NIS-LL (p

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is a specific autoimmune response to group-A streptococcal (GAS) infections in children and adolescents with a sudden onset of neuropsychiatric disorders including obsessive-compulsive disorder (OCD) or tic-like symptoms. We present a case report of a 27-year-old male patient who had lasting improvement with plasmapheresis, rituximab, and ceftriaxone. Our patient first developed sudden psychosis and confusion after GAS infections at age 17. He had elevated anti-streptolysin O (ASO) titers, negative urine drug screen, no ETOH in blood, normal CBC, normal TSH, normal salicylate, normal acetaminophen, and a normal head CT. The tentative diagnosis of PANDAS was made, and the patient was thereafter treated with antipsychotics, antibiotics, tonsillectomy, and IVIG which resulted in remissions and relapses of his neuropsychiatric symptoms. Once he reached age 27, he received a trial of therapeutic plasma exchange (TPE), rituximab, and ceftriaxone. This eventually resulted in sustained benefit and minimal fluctuations of his clinical symptoms. Our report is noteworthy in three ways.One, he is a 27-year-old adult with PANDAS.Two, he improved after TPE, rituximab, and ceftriaxone. Our literature search yielded minimal data on the use of plasmapheresis for nonteenage adults with PANDAS. Three, he had unusual symptoms of PANDAS, as the typical OCD and/or tic-like symptoms were not observed.

Objective: To investigate the utility of quantitative susceptibility mapping (QSM) and diffusion kurtosis imaging (DKI) as complementary tools in characterizing pathological changes in the deep grey nuclei in early Parkinson’s disease (PD) and their clinical correlates to aid in diagnosis of PD. Method: Patients with a diagnosis of PD made within a year and age-matched healthy controls were recruited. All participants underwent clinical evaluation using the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS III) and Hoehn & Yahr stage (H&Y), and brain 3 T MRI including QSM and DKI. Regions-of-interest (ROIs) in the caudate nucleus, putamen, globus pallidus, and medial and lateral substantia nigra (SN) were manually drawn to compare the mean susceptibility (representing iron deposition) and DKI indices (representing restricted water diffusion) between PD patients and healthy controls and in correlation with MDS-UPDRS III and H&Y, focusing on susceptibility value, mean diffusivity (MD) and mean kurtosis (MK). Results: There were forty-seven PD patients (aged 68.7 years, 51% male, disease duration 0.78 years) and 16 healthy controls (aged 67.4 years, 63% male). Susceptibility value was increased in PD in all ROIs except the caudate, and was significantly different after multiple comparison correction in the putamen (PD: 64.75 ppb, HC: 44.61 ppb, p = 0.004). MD was significantly higher in PD in the lateral SN, putamen and caudate, the regions with the lowest susceptibility value. In PD patients, we found significant association between the MDS-UPDRS III score and susceptibility value in the putamen after correcting for age and sex (β = 0.21, p = 0.003). A composite DKI-QSM diagnostic marker based on these findings successfully differentiated the groups (p

Smart surfaces with dynamically tunable wettability place an important role in microfluidics, biomedical engineering and flexible electronics. Mechanical strain is a promising stimulus to tune the surface wettability, however, it is still a great challenge to achieve both wide-range reversible wettability and high sensitivity. In this study, highly ordered and quasi-periodic ridge patterns with cracks at their peaks were tailored based on a film-substrate system by sputter deposition of zinc (Zn) nanofilm on prestretched polydimethylsiloxane (PDMS). The contact angle (CA) on the ridged Zn/PDMS surface is well tunable between 115° and 143° by adjusting the applied strains. It is remarkable that such a structure possesses wide-range CA variation (~28°) under just 28.6% applied strain, indicating a high responsive sensitivity (η = 98°). This result is attributed to the cracked ridges with both wide-range aspect ratios from 0.07 to 0.54 and high rate of change (~1.70). Moreover, the responsive reversibility of the ridged Zn/PDMS surface remains up to 1000 cycles and 60 days without special protection. The outstanding performances make the ridged surface could be a promising component for various technological applications, especially in small strain required situations.

Background Elevated long‐term systolic blood pressure and resting heart rate (RHR) variability are suggested to amplify the risk of all‐cause mortality (ACM). However, the link between increased RHR and pulse pressure for ACM remained unclear. Methods and Results This study analyzed 46 751 individuals from Kailuan Cohort Study for the end outcome of ACM. A Cox regression model was used to estimate hazard ratios for death events. Kaplan‐Meier analysis was performed to study the differences in survival as stratified by the SD, coefficient of variation, and average real variability of RHR and pulse pressure quartiles. A total of 1667 deaths (65 years of age had a higher risk for ACM across quartiles of RHR‐SD. The hazard ratio (95% CI) for the subjects in quartiles 2, 3, and 4 were 1.81 (1.10–2.97), 2.31 (1.37–1.3.90), and 2.64 (1.63–4.29), respectively. Conclusions An elevated long‐term RHR variability combined with an increased pulse pressure variability or vice versa amplifies the risk of ACM.

Microglial NADPH oxidase (Nox2) plays a key role in chronic neuroinflammation and related dopaminergic neurodegeneration in Parkinson's disease (PD). However, the mechanisms behind Nox2 activation remain unclear. Here, we revealed the critical role of complement receptor 3 (CR3), a microglia-specific pattern recognition receptor, in Nox2 activation and subsequent dopaminergic neurodegeneration by using paraquat and maneb-induced PD model. Suppression or genetic deletion of CR3 impeded paraquat and maneb-induced activation of microglial Nox2, which was associated with attenuation of dopaminergic neurodegeneration. Mechanistic inquiry revealed that blocking CR3 reduced paraquat and maneb-induced membrane translocation of Nox2 cytosolic subunit p47phox, an essential step for Nox2 activation. Src and Erk (extracellular regulated protein kinases) were subsequently recognized as the downstream signals of CR3. Moreover, inhibition of Src or Erk impaired Nox2 activation in response to paraquat and maneb co-exposure. Finally, we found that CR3-deficient mice were more resistant to paraquat and maneb-induced Nox2 activation and nigral dopaminergic neurodegeneration as well as motor dysfunction than the wild type controls. Taken together, our results showed that CR3 regulated Nox2 activation and dopaminergic neurodegeneration through a Src-Erk-dependent pathway in a two pesticide-induced PD model, providing novel insights into the immune pathogenesis of PD. Keywords: CR3, Scavenger receptors, NADPH oxidase, Neuroinflammation, Parkinson's disease

Abstract Elevated resting heart rate (RHR) predicts all-cause death. However, the relationship between RHR variation over years and mortality are still unknown. We aimed to analyze the association between RHR variation and all-cause mortality in the general population without cardiovascular diseases. A total of 46,873 subjects were included from the Kailuan Study (2006–2011). RHR readings were taken during three separate examinations and the RHR variation was defined using the standard deviation (RHR-SD) and the coefficient of variation. Participants were divided into four groups according to the quartiles of RHR-SD. All subjects were followed for a median of 49.4 months from the date of the 3rd examination to December 31, 2014. Up until the follow-up examinations, 973 (2.08%) participants had died. In a multivariate analysis, adjusting for variables potentially associated with death, the highest quartile of RHR-SD remained an independent predictor of all-cause mortality (Hazards ratio = 1.43, 95% confidence interval 1.18–1.74, P

Astrogliosis has long been recognized in Parkinson's disease (PD), the most common neurodegenerative movement disorder. However, the mechanisms of how astroglia become activated remain unclear. Reciprocal interactions between microglia and astroglia play a pivotal role in regulating the activities of astroglia. The purpose of this study is to investigate the mechanism by which microglia regulate astrogliosis by using lipopolysaccharide (LPS) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse PD models. We found that the activation of microglia preceded astroglia in the substantia nigra of mice treated with either LPS or MPTP. Furthermore, suppression of microglial activation by pharmacological inhibition or genetic deletion of NADPH oxidase (NOX2) in mice attenuated astrogliosis. The important role of NOX2 in microglial regulation of astrogliosis was further mirrored in a mixed-glia culture system. Mechanistically, H2O2, a product of microglial NOX2 activation, serves as a direct signal to regulate astrogliosis. Astrogliosis was induced by H2O2 through a process in which extracellularly generated H2O2 diffused into the cytoplasm and subsequently stimulated activation of transcription factors, STAT1 and STAT3. STAT1/3 activation regulated the immunological functions of H2O2-induced astrogliosis since AG490, an inhibitor of STAT1/3, attenuated the gene expressions of both proinflammatory and neurotrophic factors in H2O2-treated astrocyte. Our findings indicate that microglial NOX2-generated H2O2 is able to regulate the immunological functions of astroglia via a STAT1/3-dependent manner, providing additional evidence for the immune pathogenesis and therapeutic studies of PD. Keywords: Parkinson's disease, NADPH oxidase, Microglia, Astrocyte, STATs, H2O2

Background: CD38 is involved in the adenosine pathway, which represents one of the immunosuppressive mechanisms in cancer. CD38 is broadly expressed across immune cell subsets, including human macrophages differentiated in vitro from monocytes, but expression by tissue-resident macrophages remains to be demonstrated.Methods: Tissue samples were obtained from 66 patients with hepatocellular carcinoma (HCC) from Singapore and analyzed using immunohistochemistry. Tumor-infiltrating leukocytes (TILs) were further examined using DEPArray™, and the phenotype of freshly isolated TILs was determined using flow cytometry.Results: CD38 was frequently co-expressed with the macrophage-specific marker CD68. CD38+CD68+ macrophage density was associated with improved prognosis after surgery, while total CD68+ macrophage density was associated with poor prognosis. DEPArray™ analysis revealed the presence of large (>10 μm), irregularly shaped CD45+CD14+ cells that resembled macrophages, with concurrent CD38+ expression. Flow cytometry also revealed that majority of CD14+HLA-DR+ cells expressed CD38.Conclusion: CD38 expression was clearly demonstrated on human macrophages in an in vivo setting. The positive association identified between CD38+ macrophage density and prognosis may have implications for routine diagnostic work.

Sulfur-based cathode chemistries are essential for the development of high energy density alkali-ion batteries. Here, we elucidate the redox kinetics of sulfur confined on carbon nanotubes, comparing its performance in ether-based and carbonate-based electrolytes at room temperature. The solvent is found to play a key role for the electrochemical reactivity of the sulfur cathode in sodium−sulfur (Na−S) batteries. Ether-based electrolytes contribute to a more complete reduction of sulfur and enable a higher electrochemical reversibility. On the other hand, an irreversible solution-phase reaction is observed in carbonate solvents. This study clearly reveals the solvent-dependent Na−S reaction pathways in room temperature Na−S batteries and provides an insight into realizing their high energy potential, via electrolyte formulation design.

Background. Tofacitinib is an oral Janus kinase inhibitor. This open-label, long-term extension (LTE) study (NCT00658359) evaluated long-term tofacitinib treatment in stable kidney transplant recipients (n = 178) posttransplant. Methods. Patients who completed 12 months of cyclosporine (CsA) or tofacitinib treatment in the phase IIb parent study (NCT00483756) were enrolled into this LTE study, evaluating long-term tofacitinib treatment over months 12 to 72 posttransplant. Patients were analyzed by tofacitinib less-intensive (LI) or more-intensive (MI) regimens received in the parent study. For both groups, tofacitinib dose was reduced from 10 to 5 mg twice daily by 6 months into the LTE. Patients were followed up through month 72 posttransplant, with a focus on month 36 results. Results. Tofacitinib demonstrated similar 36-month patient and graft survival rates to CsA. Biopsy-proven acute rejection rates at month 36 were 11.2% for CsA, versus 10.0% and 7.4% (both P > 0.05) for tofacitinib LI and MI, respectively. Least squares mean estimated glomerular filtration rates were 9 to 15 mL/min per 1.73 m2 higher for tofacitinib versus CsA at month 36. The proportions of patients with grade 2/3 interstitial fibrosis and tubular atrophy in month 36 protocol biopsies were 20.0% for LI and 18.2% for MI (both P > 0.05) versus 33.3% for CsA. Kaplan-Meier cumulative serious infection rates at month 36 were numerically higher for tofacitinib LI (43.9%; P = 0.45) and significantly higher for MI (55.9%; P < 0.05) versus CsA (37.1%). Conclusions. Long-term tofacitinib continued to be effective in preventing renal allograft acute rejection and preserving renal function. However, long-term tofacitinib and mycophenolic acid product combination was associated with persistent serious infection risk.

Background Anoectochilus roxburghii is a widespread herbaceous plant with high medicinal value. Wild A. roxburghii resources face extinction due to their slow growth rate and over exploitation. The growing market demand has led to advances in the field of artificial planting of A. roxburghii. Methods to increase the economic benefits of cultivation and the production of medicinal ingredients are very useful. Methods A. roxburghii was exposed to red light, blue light (BL), yellow light (YL), green light, or white light as supplemental lighting at night (18:00–02:00) in a greenhouse or were left in darkness (control, CK) to investigate the effects of various light qualities on growth indices, photosynthetic pigments, chlorophyll fluorescence, root vitality, stomatal density, soluble proteins, sugars, and the accumulation of secondary metabolites. Results Supplementation of BL had a positive effect on A. roxburghii growth and secondary metabolite accumulation. Leaf number, stem diameter, fresh weight, dry weight, chlorophyll a content, and secondary metabolite (total flavonoids, total polyphenols) content increased significantly. YL treatment showed significantly higher soluble sugar and polysaccharide contents than the control. Discussion BL treatment was conducive to promoting the growth and accumulation of secondary metabolites (total flavonoids, total polyphenols); YL treatment significantly increased the content of soluble sugar and polysaccharides more than the control. Polysaccharides and total flavonoids are important medicinal ingredients of Anoectochilus, so future research will focus on the combination of blue and YL.

Breast cancer is the most common malignancy affecting women, but the heterogeneity of the condition is a significant obstacle to effective treatment. Triple negative breast cancers (TNBCs) do not express HER2 or the receptors for estrogen or progesterone, and so often have a poor prognosis. Tumor-infiltrating T cells have been well-characterized in TNBC, and increased numbers are associated with better outcomes; however, the potential roles of B cells and plasma cells have been large. Here, we conducted a retrospective correlative study on the expression of B cell/plasma cell-related genes, and the abundance and localization of B cells and plasma cells within TNBCs, and clinical outcome. We analyzed 269 TNBC samples and used immunohistochemistry to quantify tumor-infiltrating B cells and plasma cells, coupled with NanoString measurement of expression of immunoglobulin metagenes. Multivariate analysis revealed that patients bearing TNBCs with above-median densities of CD38+ plasma cells had significantly better disease-free survival (DFS) (HR = 0.44; 95% CI 0.26–0.77; p = 0.004) but not overall survival (OS), after adjusting for the effects of known prognostic factors. In contrast, TNBCs with higher immunoglobulin gene expression exhibited improved prognosis (OS p = 0.029 and DFS p = 0.005). The presence of B cells and plasma cells was positively correlated (p

BackgroundHypertension has been associated with cognitive dysfunction in the general population and patients with Alzheimer’s disease (AD). However, there are contradictory data regarding the potential association between hypertension and diagnosis of Parkinson’s disease (PD), the second most common neurodegenerative disorder after AD. The purpose of this meta-analysis is to synthesize data from cohort studies to explore the potential association between preexisting hypertension and subsequent PD diagnosis.MethodsThe PubMed and Embase databases were searched to identify all relevant studies. Two independent investigators performed the data extraction. Eligible cohort studies providing risk and precision estimates related to hypertension and PD were selected. Pooled risk ratios (RRs) with 95% confidence interval (CI) were calculated by using a random-effects model or a fixed-effects model. Sensitivity analyses after excluding one study at a time were performed to assess the stability of the results. Publication bias was assessed with Begg’s test and Egger’s test.ResultsSeven cohort studies were identified, including 3,170 persons who were confirmed to have developed PD and 339,517 participants who did not have PD during follow-up. The onset of hypertension before PD diagnosis was significantly associated with an increased risk of motor stage PD (RR = 1.799, 95% CI [1.066–3.037]). This relationship was further confirmed by secondary analyses based on estimates adjusted for potential vascular confounders (RR = 1.319, 95% CI [1.073–1.622]). After excluding one study at a time, the sensitivity analyses still showed that hypertension history was significantly associated with an increased risk of motor stage PD (RR with 95% CI ranging from 1.11 [1.075–1.35] to 1.42 [1.65–1.83]). No publication bias was observed in this meta-analysis.ConclusionThe findings of this meta-analysis suggest that hypertension may be a risk factor for motor stage PD, which may provide novel insights into the etiology and pathogenesis of this neurodegenerative disorder. However, large-scale well-designed studies that consider various confounders are still needed to further verify and clarify the association between hypertension and PD diagnosis.

Background and objectives: It is estimated that 60 million magnetic resonance imaging (MRI) scans are performed annually around the world. Of these, 25% of patients experienced moderate to severe claustrophobia during the procedure. The aim of this study was to determine the prevalence and interethnic variations of patients requiring sedation due to claustrophobia. Another aim was to determine if a wider bore MR scanner was helpful in reducing the incidence of claustrophobia. Methodology: This was an institutional review board-approved study. We retrieved records for 11,813 adult outpatients from the hospital radiological system from 1 January 2012 to 31 December 2012. The data collected included patients’ gender, age, ethnicity, body region scanned, body orientation with respect to the scanner, the types of scanners used, and the need for sedation. Statistical analysis was performed using R 3.0.1. Results: The prevalence of claustrophobic patients requiring sedation was 0.45%, i.e. 53. Of these, 55% were females and 45% males. Among these, 64% were Chinese, 15% Malays, 15% Indians, and 6% were other races. 74% experienced claustrophobia at the 60 cm-wide bore scanners and 26% at 70 cm-wider bore scanners. Referring to Chinese, multivariable regression showed Malays and the Indians were six times and other ethnic groups were 12 times more likely to develop claustrophobia. The incidence of claustrophobia could be reduced by a factor of 2.95 with wider bore scanners. Conclusions: The MR environment is still disturbing to some patients. Feet-in positioning does not significantly minimize claustrophobia. Gender and age had no bearing on claustrophobia. Wider bore MR scanners with a bore size of 70 cm are an obvious choice toward more patient-friendly MR scanners.

PR interval variations have recently been associated with an increased risk of long-term atrial fibrillation (AF), heart block and all-cause mortality. Genome-wide association studies have linked the PR interval with several common variants in the TBX5 gene. Several variants in the TBX5 gene, including rs7312625 and rs883079, have been associated with AF. The purpose of this study was to determine the association of single-nucleotide polymorphisms (SNPs) in the TBX5 gene, rs7312625 and rs883079, with AF in Chinese Han patients.In this case-control association study, large cohorts of AF patients (n = 1132) and controls (n = 1206) were recruited from different hospitals. The genotyping was performed using a Rotor-Gene TM 6000 high-resolution melt system. Rs7312625, rs3825214 and rs883079 were analyzed. We found that SNP 3825214 was significantly associated with AF (P-obs = 0.002, odds ratio [OR] = 0.82), and lone AF (P-obs = 6.77x10-5, odds ratio [OR] = 0.71). SNP rs7312625 was significantly associated with lone AF (P-obs = 0.015, odds ratio [OR] = 1.27), although its association with AF was not significant. No significant association of SNP rs883079 with AF or lone AF was observed. Thus, we analyzed the interaction among these three loci. We demonstrated significant interaction among rs3825214, rs7312625 and rs883079. Four-locus risk alleles showed the highest odds ratio in combined rs3825214 and rs7312625 (P-obs

Background. Conventional flexible bronchoscopy has limited sensitivity in the diagnosis of peripheral lung lesions and is dependent on lesion size. However, advancement of CT imaging offers multiplanar reconstruction facilitating enhanced preprocedure planning. This study aims to report efficacy and safety while considering the impact of patient selection and multiplanar CT planning. Method. Prospective case series of patients with peripheral lung lesions suspected of having lung cancer who underwent flexible bronchoscopy (forceps biopsy and lavage). Endobronchial lesions were excluded. Patients with negative results underwent CT-guided transthoracic needle aspiration, surgical biopsy, or clinical-radiological surveillance to establish the final diagnosis. Results. 226 patients were analysed. The diagnostic yield of bronchoscopy was 80.1% (181/226) with a sensitivity of 84.2% and specificity of 100%. In patients with a positive CT-Bronchus sign, the diagnostic yield was 82.4% compared to 72.8% with negative CT-Bronchus sign (p=0.116). Diagnostic yield was 84.9% in lesions > 20 mm and 63.0% in lesions ≤ 20 mm (p=0.001). Six (2.7%) patients had transient hypoxia and 2 (0.9%) had pneumothorax. There were no serious adverse events. Conclusion. Flexible bronchoscopy with appropriate patient selection and preprocedure planning is more efficacious in obtaining a diagnosis in peripheral lung lesions compared to historical data. This trial is registered with ClinicalTrials.gov Identifier: NCT01374542.

BACKGROUND:Mortality for candidemia ranges from 15% to 35%. Current guidelines recommend inoculating blood into three aerobic and three anaerobic blood culture bottles when candidemia is suspected, without mention of a fungal blood culture bottle. OBJECTIVE:To determine the value of the BACTEC Myco/F Lytic blood culture media in the diagnosis of fungemia. METHODS:A two-year retrospective cross-sectional study was performed for patients who had fungemia with submitted BACTEC Plus Aerobic/F (Aer), BACTEC Plus Anaerobic/F (Anaer) or Myco/F Lytic (Myco) blood culture bottles. RESULTS:The detection rate of fungemia was 77.4% in 93 patients with contemporaneously submitted blood culture bottles when limited to only Aer/Anaer culture results. The detection rate improved significantly with the addition of the Myco culture bottle results (p

Objective. COQ2 mutations have been reported in Japanese multiple system atrophy (MSA) patients. We examined the role of COQ2 in patients with dementia and essential tremor (ET), two common neurodegenerative conditions. Materials & Methods. A total of 2064 subjects, including 560 patients with dementia, 466 patients with ET, and 1038 healthy controls, were included. Genotyping for the COQ2 V393A (T>C) was carried out. Odds ratio (OR) adjusted by age and gender, together with 95% confidence interval (CI), was reported by means of logistic regression. Results. The frequency of the polymorphic variant V393A heterozygous (T/C) was 2.7% in dementia, 1.1% in ET, and 2.5% in controls (OR = 0.70, 95% confidence interval is 0.29–1.72 for dementia, and OR = 0.47, 95% confidence interval is 0.17–1.31, p=0.1217 for ET). There was no significant association between V393A variant with dementia and ET. Conclusion. There was no significant association between V393A variant with dementia and ET. COQ2 gene is unlikely to play a significant role in patients with dementia or ET in our population.

Sunitinib is a tyrosine kinase inhibitor used as first-line treatment for metastatic renal cell carcinoma (mRCC). Asian ethnicity has been previously associated with lower clearance and greater toxicities for sunitinib treatment, relative to Caucasian ethnicity. Research focusing on identifying corresponding biomarkers of efficacy and toxicity has been hitherto conducted in Caucasian populations, and few of the reported associations have been externally validated. Our work thus aims to investigate candidate biomarkers in Asian patients receiving sunitinib, comparing the observed genotype effects with those reported in Caucasian populations. Using data from 97 Asian mRCC patients treated with sunitinib, we correlated 7 polymorphisms in FLT3, ABCB1, VEGFR2, ABCG2 and BIM with patient toxicities, response, and survival. We observed a stronger association of FLT3 738T genotype with leucopenia in our Asian dataset than that previously reported in Caucasian mRCC patients (odds ratio [OR]=8.0; P=0.03). We observed significant associations of FLT3 738T (OR=2.7), ABCB1 1236T (OR=0.3), ABCB1 3435T (OR=0.1), ABCB1 2677T (OR=0.4), ABCG2 421A (OR=0.3) alleles and ABCB1 3435, 1236, 2677 TTT haplotype (OR=0.1) on neutropenia. Primary resistance (OR=0.1, P=0.004) and inferior survival (progression-free: hazard ratio [HR]=5.5, P=0.001; overall: HR=5.0, P=0.005) were associated with the ABCB1 3435, 1236, 2677 TTT haplotype. In conclusion, ABCB1 and FLT3 polymorphisms may be helpful in predicting sunitinib toxicities, response and survival benefit in Asian mRCC patients. We have also validated the association between FLT3 738T and sunitinib-induced leucopenia previously reported in Caucasian populations, but have not validated other reported genetic associations.

Surgery is the primary curative option in patients with hepatocellular carcinoma (HCC). Current prognostic models for HCC are developed on datasets of primarily patients with advanced cancer, and may be less relevant to resectable HCC. We developed a postoperative nomogram, the Singapore Liver Cancer Recurrence (SLICER) Score, to predict outcomes of HCC patients who have undergone surgical resection.Records for 544 consecutive patients undergoing first-line curative surgery for HCC in one institution from 1992-2007 were reviewed, with 405 local patients selected for analysis. Freedom from relapse (FFR) was the primary outcome measure. An outcome-blinded modeling strategy including clustering, data reduction and transformation was used. We compared the performance of SLICER in estimating FFR with other HCC prognostic models using concordance-indices and likelihood analysis.A nomogram predicting FFR was developed, incorporating non-neoplastic liver cirrhosis, multifocality, preoperative alpha-fetoprotein level, Child-Pugh score, vascular invasion, tumor size, surgical margin and symptoms at presentation. Our nomogram outperformed other HCC prognostic models in predicting FFR by means of log-likelihood ratio statistics with good calibration demonstrated at 3 and 5 years post-resection and a concordance index of 0.69. Using decision curve analysis, SLICER also demonstrated superior net benefit at higher threshold probabilities.The SLICER score enables well-calibrated individualized predictions of relapse following curative HCC resection, and may represent a novel tool for biomarker research and individual counseling.

BACKGROUND: The effect of metformin, pioglitazone and sitagliptin on β-cell function in the treatment of type 2 diabetes is controversial. Therefore, we performed a systematic review and meta-analysis to obtain a better understanding in the β-cell effects of metformin, pioglitazone and sitagliptin. METHODS: We searched Pubmed and the Cochrane Center Register of Controlled Trials to identify relevant studies. Trials investigating effects of sitagliptin, metformin or pioglitazone on β-cell function were identified. The primary outcomes were homeostasis model assessment of β-cells (HOMA-β) and proinsulin/insulin ratio (PI/IR). Secondary outcome was hemoglobin A1c level. We used version 2 of the Comprehensive Meta Analysis software for all statistical analyses. RESULTS: Metformin monotherapy was more effective than sitagliptin in improving HOMA-β (18.01% (95% CI 11.09% to 24.94%) vs. 11.29% (95% CI 9.21% to 13.37%), P = 0.040) and more effective (-0.137 (95% CI -0.082 to -0.192)) than both sitagliptin (-0.064 (95% CI -0.036 to -0.092), P = 0.019) and pioglitazone (-0.068 (95% CI -0.044 to -0.093), P = 0.015) in decreasing PI/IR. Metformin and sitagliptin combined (40.23% (95%CI 32.30% to 48.16%)) were more effective than sitagliptin and pioglitazone (11.82% (95% CI 6.61% to 17.04%), P = 0.000) and pioglitazone and metformin(9.81% (95% CI 1.67% to 17.95%), P = 0.022) in improving HOMA-β and decreasing PI/IR (-0.177 (95% CI -0.118 to -0.237); -0.080 (95% CI -0.045 to -0.114), P = 0.007; -0.038 (95% CI, -0.005 to 0.071), P = 0.023). LIMITATIONS: The included RCTs were of short duration (12-54 weeks). We could not determine long term effects on β-cells. CONCLUSIONS: Metformin improves β-cell function more effectively than pioglitazone or sitagliptin in type 2 diabetes patients. Metformin and sitagliptin improved HOMA-β and PI/IR more than other combinations.

Early diagnosis of hepatocellullar carcinoma (HCC) remains a challenge. The current practice of serum alpha-fetoprotein (AFP) measurement is inadequate. Here we utilized a proteomic approach to identify novel serum biomarkers for distinguishing HCC patients from non-cancer controls. We profiled the serum proteins in a group of 58 resectable HCC patients and 11 non-HCC chronic hepatitis B (HBV) carrier samples from the Singapore General Hospital (SGH) using the RayBio® L-Series 507 Antibody Array and found 113 serum markers that were significantly modulated between HCC and control groups. Selected potential biomarkers from this list were quantified using a multiplex sandwich enzyme-linked immunosorbent assay (ELISA) array in an expanded SGH cohort (126 resectable HCC patients and 115 non-HCC chronic HBV carriers (NC group)), confirming that serum prolactin and monocyte chemoattractant protein-1 (MCP-1) were significantly upregulated in HCC patients. This finding of serum MCP-1 elevation in HCC patients was validated in a separate cohort of serum samples from the Mochtar Riady Institute for Nanotechnology, Indonesia (98 resectable HCC, 101 chronic hepatitis B patients and 100 asymptomatic HBV/HCV carriers) by sandwich ELISA. MCP-1 and prolactin levels were found to correlate with AFP, while MCP-1 also correlated with disease stage. Subsequent receiver operating characteristic (ROC) analysis of AFP, prolactin and MCP-1 in the SGH cohort and comparing their area under the ROC curve (AUC) indicated that neither prolactin nor MCP-1 on their own performed better than AFP. However, the combination of AFP+MCP-1 (AUC, 0.974) had significantly superior discriminative ability than AFP alone (AUC, 0.942; p

Genome Wide Association Studies (GWASs) have identified trait-associated polymorphisms via a hypothesis-free approach. However, it is challenging when attempting to reproduce GWAS findings in different populations as it fundamentally relies on the similar patterns of linkage disequilibrium (LD) between the unknown causal variants and the genotyped single nucleotide polymorphisms (SNPs). To address this potential limitation, we examined the regional LD pattern of leucine-rich repeat kinase 2 (LRRK2) gene, which is responsible for both autosomal dominant and sporadic Parkinson's disease (PD), in Caucasians (CEU), Japanese (JPT) and Chinese (CHB) from HapMap and Chinese (CHS), Malays (MAS) and Indians (INS) from the Singapore Genome Variation Project (SGVP) utilizing the traditional heatmaps and targeted analysis of LRRK2 gene via Monte Carlo simulation through varLD scores of these ethnic groups. Both heatmaps and targeted analysis showed that LD pattern of JPT was different from that of INS (P=0.0001); while LD pattern of CEU was different from that in Asian except for INS (all P=0.0001). Our study suggests that there is a higher chance to detect associations between PD and those trait-associated SNPs of LRRK2 gene found in Caucasian studies in INS, while those found in Japanese studies are likely to be better replicated among CHB.