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Plants' complex immune systems include nucleotide-binding domain and leucine-rich repeat-containing (NLR) proteins, which help recognize invading pathogens. In solanaceous plants, the NRC (NLR required for cell death) family includes helper NLRs that form a complex genetic network with multiple sensor NLRs to provide resistance against pathogens. However, the evolution and function of NRC networks outside solanaceous plants are currently unclear. Here, we conducted phylogenomic and macroevolutionary analyses comparing NLRs identified from different asterid lineages and found that NRC networks expanded significantly in most lamiids but not in Ericales and campanulids. Using transient expression assays in Nicotiana benthamiana, we showed that NRC networks are simple in Ericales and campanulids, but have high complexity in lamiids. Phylogenetic analyses grouped the NRC helper NLRs into three NRC0 subclades that are conserved, and several family-specific NRC subclades of lamiids that show signatures of diversifying selection. Functional analyses revealed that members of the NRC0 subclades are partially interchangeable, whereas family-specific NRC members in lamiids lack interchangeability. Our findings highlight the distinctive evolutionary patterns of the NRC networks in asterids and provide potential insights into transferring disease resistance across plant lineages., Competing Interests: Conflict of interest statement. The authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The predatory gall midge, Aphidoletes aphidimyza (Rondani), and tobacco aphid cocoon wasp, Aphidius gifuensis Ashmead, are important natural enemies of Myzus persicae (Sulzer) (Hemiptera: Aphididae). Predation by A. aphidimyza and A. gifuensis can regulate M. persicae; however, how interspecific interference competition affects their foraging efficiency is unknown. Here, we investigated the consumption and parasitization abilities of A. aphidimyza 3rd instar larva and A. gifuensis adults under various conditions. Consumption of parasitized aphids by A. aphidimyza 3rd instar larvae was significantly lower than that of nonparasitized controls, with a substantial increase in handling time. The presence of A. gifuensis adults did not significantly affect the predation capacity of A. aphidimyza larvae. Relative to controls, A. aphidimyza larvae predation trace (PT) and imago activity significantly decreased A. gifuensis parasitism rates at different aphid densities. Further, A. aphidimyza larvae PT increased the A. gifuensis handling time of M. persicae, whereas the presence of A. aphidimyza adults had the opposite effect. Coexistence with heterospecific natural enemies reduced the parasitic capacity of A. gifuensis, whereas A. aphidimyza larvae predation capability was influenced to a lesser extent. Our results demonstrate that intraguild interactions strongly influence the predatory and parasitic efficacy of A. aphidimyza and A. gifuensis, although the effect on A. gifuensis was more pronounced. For effective biological control of M. persicae using A. aphidimyza and A. gifuensis, we recommend releasing A. aphidimyza first to mitigate intraguild predation and enhance the overall success of the pest control program., (© The Author(s) 2024. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: The Fugl-Meyer assessment for upper extremity (FMA-UE) is a measure for assessing upper extremity motor function in patients with stroke. However, the considerable administration time of the assessment decreases its feasibility. This study aimed to develop an accumulative assessment system of upper extremity motor function (AAS-UE) based on the FMA-UE to improve administrative efficiency while retaining sufficient psychometric properties., Methods: The study used secondary data from 3 previous studies having FMA-UE datasets, including 2 follow-up studies for subacute stroke individuals and 1 test-retest study for individuals with chronic stroke. The AAS-UE adopted deep learning algorithms to use patients' prior information (ie, the FMA-UE scores in previous assessments, time interval of adjacent assessments, and chronicity of stroke) to select a short and personalized item set for the following assessment items and reproduce their FMA-UE scores., Results: Our data included a total of 682 patients after stroke. The AAS-UE administered 10 different items for each patient. The AAS-UE demonstrated good concurrent validity (r = 0.97-0.99 with the FMA-UE), high test-retest reliability (intra-class correlation coefficient = 0.96), low random measurement error (percentage of minimal detectable change = 15.6%), good group-level responsiveness (standardized response mean = 0.65-1.07), and good individual-level responsiveness (30.5%-53.2% of patients showed significant improvement). These psychometric properties were comparable to those of the FMA-UE., Conclusion: The AAS-UE uses an innovative assessment method, which makes good use of patients' prior information to achieve administrative efficiency with good psychometric properties., Impact: This study demonstrates a new assessment method to improve administrative efficiency while retaining psychometric properties, especially individual-level responsiveness and random measurement error, by making good use of patients' basic information and medical records., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hidradenitis suppurativa (HS) is a painful chronic skin condition of apocrine gland regions. This retrospective cohort study aimed to assess the impact of hormonal contraception type on HS disease control in adult women. In total, 160 patients were included, with the majority identifying as Black or African American (73.1%). Multivariate logistic regression showed that oestrogen-progesterone users were 3.14 times more likely to experience stable or improved HS than progesterone-only users (adjusted odds ratio 3.14, 95% CI 1.18-8.35; P = 0.02). Further investigation is needed to elucidate the antiandrogenic mechanisms affecting HS symptom response to hormonal contraceptives., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Contrast-induced nephropathy has become increasingly prevalent as the age and prevalence of comorbidities in the general population have increased. Most cases of contrast-induced nephropathy are reversible; however, some may progress to acute kidney disease, and subsequently, to chronic kidney disease. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are known for their renoprotective effects. However, whether the use of these inhibitors affects the risk of contrast-induced kidney injury remains unclear., Methods: Data were collected from the Taipei Medical University Clinical Research Database. We included patients with diabetes who had contrast exposure between 2016 and 2020 because of computed tomography or coronary angiography. The primary outcome was the risk of a major adverse kidney event (MAKE), which encompassed acute kidney disease, chronic kidney disease progression, and the need for renal replacement therapy. Overlap weighting was performed to reduce the effects of potential confounders., Results: This study included 12 421 patients, who were divided into two groups: SGLT2i users (n = 920) and nonusers (n = 11 501). The follow-up period after contrast exposure was 6 months. The risk of a MAKE was lower in SGLT2i users than in nonusers (incidence, 36.9 vs. 49.9 per 1000 person-months, respectively; P = .0011). Furthermore, the incidence of acute kidney disease or chronic kidney disease progression was significantly lower in the SGLT2i users than in nonusers. However, no significant between-group difference was noted in the incidence of other MAKEs., Conclusions: SGLT2i may be safely used in diabetic patients needing contrast exposure. The risk of a MAKE may be lower in SGLT2i users than in nonusers., (© The Author(s) 2023. Published by Oxford University Press on behalf of Fellowship of Postgraduate Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The Movement Assessment Battery for Children-2 (MABC-2) is a popular assessment of children's motor skills in both Western and Eastern countries. Since children's motor skills are strongly influenced by the sociocultural context, it is essential to specifically examine the applicability of the MABC-2 in different cultures. The performance on the MABC-2 age band 1 of children in Taiwan was compared with the standardized sample from the United Kingdom. The sex differences in the performance on the MABC-2 were also investigated., Methods: Children aged 3 to 6 years were recruited and categorized into 4 age groups. The researchers assessed the children with the MABC-2 age band 1, containing 8 tasks categorized into 3 components: manual dexterity, aiming and catching, and balance. Z tests and effect sizes were used to examine the cultural differences in the 3 components and in the total scale of the MABC-2. Independent t tests were used to check for sex differences in the MABC-2., Results: Data on 615 children with a mean age of 4.95 years (SD = 0.97) were collected. Clinically significant differences (effect size > 0.5) were found in 2 components and the total scale of the MABC-2 across most age groups. Children in Taiwan performed better on manual dexterity, balance, and the total scale. Marginally clinically significant differences (absolute effect size > 0.4) were found in the aiming and catching component for the children aged 3 and 6 years old; children in Taiwan scored lower on aiming and catching than did children in the United Kingdom. Girls had significantly higher scores on manual dexterity, balance, and the total scale, while boys had significantly higher scores on aiming and catching., Conclusions: Cultural and sex differences exist in the MABC-2. Constructing a norm for children in Taiwan of different sex and modification of the items are suggested for application of the MABC-2 in Taiwan., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: The frequency of an acute increase in serum creatinine (sCr) of >30%, following treatment of sodium-glucose cotransporter-2 inhibitors (SGLT2is) and its clinical implications in patients with type 2 diabetes remains unclear., Methods and Results: We used medical data from a multicentre health care provider in Taiwan and recruited 11 657 and 8117 diabetic patients with baseline/follow-up sCr data available within 12 weeks of SGLT2i and dipeptidyl peptidase-4 inhibitor (DPP4i) treatment from 1 June 2016 to 31 December 2018. Participants receiving SGLT2i or DPP4i were categorized by initial sCr change into three groups: >30% sCr increase, 0-30% increase, or no-sCr increase. Participants receiving SGLT2i were associated with a higher proportion of sCr increase of 0-30% (52.7 vs. 42.6%) but a lower proportion of sCr increase of >30% (5.9 vs. 9.6%) when compared with DPP4i. In contrast to DPP4i, the mean estimated glomerular filtration rate over time became stable after 24 weeks in three categories of sCr increase following SGLT2i initiation. Compared with no sCr increase, an initial sCr increase of >30% was associated with a higher risk of major adverse cardiovascular events {adjusted hazard ratio (aHR): 2.91, [95% confidence interval (95% CI):1.37-6.17]}, heart failure hospitalization (HHF) [aHR:1.91, (95% CI:1.08-3.40)], and composite renal outcome [aHR:1.53, (95% CI:1.05-2.25)] in the SGLT2i group; an initial sCr increase of >30% associated with a higher risk of HHF and composite renal outcome in the DPP4i group after multivariate adjustment. Overall, participants receiving SGLT2i were associated with a lower risk of HHF [aHR:0.64, (95% CI:0.48-0.85)] and composite renal outcomes [aHR:0.40, (95% CI:0.34-0.48)] compared with DPP4i after multivariate adjustment, and the treatment benefit was persistent across three categories of sCr increase (P interaction > 0.05)., Conclusion: A modest increase in serum creatinine (<30%) was common following SGLT2i initiation, and was not associated with worse clinical outcomes, therefore should not stop therapy prematurely, but a larger increase in creatinine following drug therapy was not typical and should raise concern and review of the patient., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (LncRNA MALAT1) has been proven to promote osteogenesis in different health conditions. However, the role of plasma MALAT1 in postmenopausal osteoporosis (PMOP) has not been investigated., Objective: To investigate whether plasma MALAT1 expressions are associated with severity of PMOP., Methods: A total of 126 patients with PMOP and 126 healthy female control individuals were drafted into study participation. Plasma MALAT1 was detected using RT-PCR. Bone formation marker bone-specific alkaline phosphatase plasma concentration was determined using chemiluminescence immunoassay. Levels of bone absorption marker cross-linked N-telopeptidases of type I collagen were measured in duplicate using enzyme immunoassay. Bone mineral density (BMD) was examined in the total hips, femoral neck, and lumbar (L1-L4) spine using dual-energy x-ray absorptiometry. We used Genant semiquantitative (GSQ) criteria to assess the degree of vertebral deformity and fracture. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the potential diagnostic value of MALAT1 with regard to the GSQ grading. We used the Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) to evaluate the symptomatic severity in and functional ability of the study participants., Results: Plasma MALAT1 expressions were significantly lower in patients with PMOP, compared with healthy controls. Plasma MALAT1 expressions in patients with PMOP were positively associated with total hip, femoral neck, and lumbar (L1-L4) spine BMD. In total, 95 patients experienced vertebral deformity or fracture (VF), and 31 had no fractures. Plasma MALAT1 expressions were markedly decreased in patients with VF, compared with patients without fractures. Plasma MALAT1 expressions were negatively related to GSQ grading in patients with VF. ROC curve analysis demonstrated that decreased plasma MALAT1 expression exhibits decent diagnostic value with regard to GSQ grading. Finally, we discovered that plasma MALAT1 expression was also negatively associated with VAS and ODI., Conclusion: Plasma MALAT1 expressions are negatively associated with severity of PMOP., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Nephropathy is a severe complication of type 1 diabetes (T1DM). However, the interaction between the PDHA1-regulated mechanism and CD4+ T cells in the early stage of kidney tubular injury remains unknown., Objective: To evaluate the role of PDHA1 in the regulation of tubular cells and CD4+ T cells and further to study its interaction in tubular cell injury in T1DM., Methods: Plasma and total RNA were collected from T cells of T1DM patients (n = 35) and healthy donors (n = 33) and evaluated for neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1, PDHA1, and biomarkers of CD4+ T cells including T helper 1 cells (Th1) and regulatory T cells (Treg) markers. HK-2 cells cocultured with CD4+ T cells from T1DM patients or healthy donors (HDs) to evaluate the interaction with CD4+ T cells., Results: Increased PDHA1 gene expression levels in CD4+ T cells were positively associated with the plasma level of NGAL in T1DM patients and HDs. Our data demonstrated that the Th1/Treg subsets skewed Th1 in T1DM. Knockdown of PDHA1 in kidney tubular cells decreased ATP/ROS production, NAD/NADH ratio, mitochondrial respiration, and cell apoptosis. Furthermore, PDHA1 depletion induced impaired autophagic flux. Coculture of tubular cells and T1DM T cells showed impaired CPT1A, upregulated FASN, and induced kidney injury., Conclusion: Our findings indicate that Th1 cells induced tubular cell injury through dysregulated metabolic reprogramming and autophagy, thereby indicating a new therapeutic approach for kidney tubular injury in T1DM., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Single-index models have gained increased popularity in time-to-event analysis owing to their model flexibility and advantage in dimension reduction. We propose a semiparametric framework for the rate function of a recurrent event counting process by modelling its size and shape components with single-index models. With additional monotone constraints on the two link functions for the size and shape components, the proposed model possesses the desired directional interpretability of covariate effects and encompasses many commonly used models as special cases. To tackle the analytical challenges arising from leaving the two link functions unspecified, we develop a two-step rank-based estimation procedure to estimate the regression parameters with or without informative censoring. The proposed estimators are asymptotically normal, with a root- n convergence rate. To guide model selection, we develop hypothesis testing procedures for checking shape and size independence. Simulation studies and a data example on a hematopoietic stem cell transplantation study are presented to illustrate the proposed methodology.

Background: In 2016 in Taiwan, inoculation with the Bacillus Calmette-Guérin (BCG) Tokyo-172 vaccine was postponed from 24 hours after birth to 5-8 months of age. We reviewed BCG-induced adverse reactions reported to the Vaccine Injury Compensation Program (VICP) to identify differences between early and delayed BCG inoculation., Methods: Clinical presentations of BCG-related adverse reactions reported to VICP for the 2012-2017 birth cohort were reviewed until the end of 2019. The correlations between inoculation age and complications were evaluated., Results: We analyzed 233 BCG adverse reactions, including regional lymphadenitis (33.9%), injection site reactions (35.2%), osteitis/osteomyelitis (27.9%), and distant soft tissue infections (3.0%). The incidence of osteitis/osteomyelitis was lower when vaccination was done after 5 months of age (relative risk [RR], 0.32; 95% confidence interval [CI], .16-.64). Injection site reactions (RR, 8.82; 95% CI, 5.04-15.44) and lymphadenitis (RR, 2.24; 95% CI, 1.44-3.45) were significantly more common in vaccinees older than 5 months. Shorter onset durations of mild adverse reactions (lymphadenitis and injection site reactions) were reported in vaccinees older than 5 months, while no statistical significance was found regarding osteitis/osteomyelitis., Conclusions: Osteomyelitis and distant soft tissue infection may occur less frequently when BCG inoculation occurs after 5 months of age, although mild adverse reactions can be more frequent, symptom onset times can be shortened. As few severe reactions might occur more than 2 years after BCG inoculation and the policy of delayed BCG inoculation was implemented in 2016, a longer observational period is needed to clarify the exact severe complications decrement., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective: The Fugl-Meyer motor scale (FM) is a well-validated measure for assessing upper extremity and lower extremity motor functions in people with stroke. The FM contains numerous items (50), which reduces its clinical usability. The purpose of this study was to develop a short form of the FM for people with stroke using a machine-learning methodology (FM-ML) and compare the efficiency (ie, number of items) and psychometric properties of the FM-ML with those of other FM versions, including the original FM, the 37-item FM, and the 12-item FM., Methods: This observational study with follow-up used secondary data analysis. For developing the FM-ML, the random lasso method of ML was used to select the 10 most informative items (in terms of index of importance). Next, the scores of the FM-ML were calculated using an artificial neural network. Finally, the concurrent validity, predictive validity, responsiveness, and test-retest reliability of all FM versions were examined., Results: The FM-ML used fewer items (80% fewer than the FM, 73% fewer than the 37-item FM, and 17% fewer than the 12-item FM) to achieve psychometric properties comparable with those of the other FM versions (concurrent validity: Pearson r = 0.95-0.99 vs 0.91-0.97; responsiveness: Pearson r = 0.78-0.91 vs 0.33-0.72; and test-retest reliability: intraclass correlation coefficient = 0.88-0.92 vs 0.93-0.98)., Conclusion: The findings preliminarily support the efficiency and psychometric properties of the 10-item FM-ML., Impact: The FM-ML has potential to substantially improve the efficiency of motor function assessments in patients with stroke., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Progression of chronic disease is often manifested by repeated occurrences of disease-related events over time. Delineating the heterogeneity in the risk of such recurrent events can provide valuable scientific insight for guiding customized disease management. In this paper, we propose a new sensible measure of individual risk of recurrent events and present a dynamic modeling framework thereof, which accounts for both observed covariates and unobservable frailty. The proposed modeling requires no distributional specification of the unobservable frailty, while permitting the exploration of dynamic effects of the observed covariates. We develop estimation and inference procedures for the proposed model through a novel adaptation of the principle of conditional score. The asymptotic properties of the proposed estimator, including the uniform consistency and weak convergence, are established. Extensive simulation studies demonstrate satisfactory finite-sample performance of the proposed method. We illustrate the practical utility of the new method via an application to a diabetes clinical trial that explores the risk patterns of hypoglycemia in Type 2 diabetes patients.

Background: With the advent of precision oncology, liquid biopsies are quickly gaining acceptance in the clinical setting. However, in some cases, the amount of DNA isolated is insufficient for Next-Generation Sequencing (NGS) analysis. The nCounter platform could be an alternative, but it has never been explored for detection of clinically relevant alterations in fluids., Methods: Circulating-free DNA (cfDNA) was purified from blood, cerebrospinal fluid, and ascites of patients with cancer and analyzed with the nCounter 3 D Single Nucleotide Variant (SNV) Solid Tumor Panel, which allows for detection of 97 driver mutations in 24 genes., Results: Validation experiments revealed that the nCounter SNV panel could detect mutations at allelic fractions of 0.02-2% in samples with ≥5 pg mutant DNA/µL. In a retrospective analysis of 70 cfDNAs from patients with cancer, the panel successfully detected EGFR, KRAS, BRAF, PIK3CA, and NRAS mutations when compared with previous genotyping in the same liquid biopsies and paired tumor tissues [Cohen kappa of 0.96 (CI = 0.92-1.00) and 0.90 (CI = 0.74-1.00), respectively]. In a prospective study including 91 liquid biopsies from patients with different malignancies, 90 yielded valid results with the SNV panel and mutations in EGFR, KRAS, BRAF, PIK3CA, TP53, NFE2L2, CTNNB1, ALK, FBXW7, and PTEN were found. Finally, serial liquid biopsies from a patient with NSCLC revealed that the semiquantitative results of the mutation analysis by the SNV panel correlated with the evolution of the disease., Conclusions: The nCounter platform requires less DNA than NGS and can be employed for routine mutation testing in liquid biopsies of patients with cancer., (© American Association for Clinical Chemistry 2021.)

Objectives: Although commercial iliac branch devices offer a new and valid endovascular approach to treating iliac aneurysm and effectively preserve antegrade flow of the internal iliac artery, their use may not be suited for all types of challenging anatomy, especially isolated common iliac artery aneurysm. Our custom-made iliac bifurcation device has a unique design and excludes both combined and isolated iliac branch aneurysm. This study validated the efficacy and safety of the custom device by comparing clinical outcomes between groups receiving commercial and custom devices., Methods: Data of consecutive patients receiving iliac bifurcation device implantation for iliac aneurysm with or without concomitant endovascular repair for abdominal aortic aneurysm from January 2010 to May 2019 were reviewed., Results: Iliac bifurcation device implantation with or without concomitant abdominal aortic aneurysm stent grafting was completed in 46 patients (commercial, n = 35; custom, n = 11). No significant differences were observed regarding postoperative complications, occlusion or endoleak. Comparisons of primary (80.8% vs 85.7%, P = 0.88) and secondary (86.5% vs 85.7%, P = 0.85) patency and freedom from reintervention (88.2% vs 100%, P = 0.33), all-cause mortality (78.6% vs 100%, P = 0.25) and aneurysm-related mortality (100% vs 100%, P = 1.00) also indicated no differences at a 5-year surveillance point. Furthermore, the iliac aneurysms of the groups displayed similar shrinkage 1 year after procedures., Conclusions: For iliac aneurysm, the novel custom-made iliac bifurcation device is an adaptable design not inferior to commercial devices with regard to postoperative complications, bridge occlusion, endoleak and short-term aneurysm remodelling. It provides an alternative for treatment, particularly when certain anatomic challenges are present., Clinical Trial Registration: 2018-07-050BC, 2017-01-023ACF., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Parkinson's disease is a neurodegenerative disorder with a multifactorial aetiology. Nevertheless, the genetic predisposition in many families with multi-incidence disease remains unknown. This study aimed to identify novel genes that cause familial Parkinson's disease. Whole exome sequencing was performed in three affected members of the index family with a late-onset autosomal-dominant parkinsonism and polyneuropathy. We identified a novel heterozygous substitution c.941A>C (p.Tyr314Ser) in the mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene, which co-segregates with disease within the family. Additional analysis of 699 unrelated Parkinson's disease probands with autosomal-dominant Parkinson's disease and 1934 patients with sporadic Parkinson's disease revealed another two variants in UQCRC1 in the probands with familial Parkinson's disease, c.931A>C (p.Ile311Leu) and an allele with concomitant splicing mutation (c.70-1G>A) and a frameshift insertion (c.73&#95;74insG, p.Ala25Glyfs*27). All substitutions were absent in 1077 controls and the Taiwan Biobank exome database from healthy participants (n = 1517 exomes). We then assayed the pathogenicity of the identified rare variants using CRISPR/Cas9-based knock-in human dopaminergic SH-SY5Y cell lines, Drosophila and mouse models. Mutant UQCRC1 expression leads to neurite degeneration and mitochondrial respiratory chain dysfunction in SH-SY5Y cells. UQCRC1 p.Tyr314Ser knock-in Drosophila and mouse models exhibit age-dependent locomotor defects, dopaminergic neuronal loss, peripheral neuropathy, impaired respiratory chain complex III activity and aberrant mitochondrial ultrastructures in nigral neurons. Furthermore, intraperitoneal injection of levodopa could significantly improve the motor dysfunction in UQCRC1 p.Tyr314Ser mutant knock-in mice. Taken together, our in vitro and in vivo studies support the functional pathogenicity of rare UQCRC1 variants in familial parkinsonism. Our findings expand an additional link of mitochondrial complex III dysfunction in Parkinson's disease., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Infertility may negatively impact sexual function. Women with fertility problems usually prioritize treatment for infertility, but their sexual function in each trimester of pregnancy is poorly researched., Aim: To compare the sexual function and sexual healthcare needs of women who underwent successful in vitro fertilization (IVF group) and women who conceived naturally (CN group) during each trimester., Methods: Longitudinal prospective cohort study was conducted from August 2016 to July 2018. The IVF group (n = 100) was recruited from a leading reproductive treatment center; the CN group (n = 100), at the prenatal clinic of a medical center in central Taiwan. Questionnaires were mailed to women in the 10th-11th gestational week; 70 women in the IVF group and 75 in the CN group completed all 3 questionnaires, during the 10th-11th, 20th-21st, and 30th-31st gestational weeks., Main Outcome Measures: Female Sexual Function Index and Nursing Intervention on Sexual Healthcare needs were compared between groups in each trimester., Results: Most participants reported sexual dysfunction concerns during pregnancy. In the first trimester, the Female Sexual Function Index score was significantly lower in the IVF group than in the CN group (18.13 ± 6.27 vs 20.34 ± 5.87, respectively; P < .05). Sexual healthcare needs at the permission level were significantly lower in the IVF group than in the CN group (10.78 ± 2.41 vs 11.79 ± 2.67, respectively; P < .05)., Conclusion: The IVF group had lower sexual function in the first trimester than the CN group. Sexual function improved in the second trimester in the IVF group but decreased throughout pregnancy in the CN group. The CN group had a greater need for sexual healthcare nursing intervention at the permission level than the IVF group. Huang C-Y, Liou C-F, Lu Y-C, et al. Differences in the Sexual Function and Sexual Healthcare Needs of Pregnant Women Who Underwent In Vitro Fertilization and Women Who Conceived Naturally at Each Trimester: A Prospective Cohort Study. Sex Med 2020;8:709-717., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Patients' sexual concerns are private, sensitive issues, and providing sexual health care (SHC) is a legitimate area of concern for the nursing practice., Aims: This study tests a structural equation model for factors that affect SHC among Taiwanese nurses., Methods: A cross-sectional study was performed between August 2014 and July 2015. A total of 471 registered nurses from a medical center in Taiwan were enrolled in this study. All nurses participated anonymously and completed 3 questionnaires: Nursing Attitude in Sexual Health Care scale, Nursing Intervention in Sexual Health scale, and Gender Role Orientation scale. The Permission-Limited Information-Specific Suggestions-Intensive Therapy model based on scale was application, and theory of planned behavior was used to examine the relationship of these 3 scales in nurses., Main Outcome Measures: SHC surveys were developed for nurses. These valid and reliable instruments included Nursing Attitude in Sexual Health Care, Nursing Intervention in Sexual Health, and Gender Role Orientation., Results: The fitted structural equation model was valid. The construct reliability of latent variables ranged from 0.730 to 0.942, which met the requirement of 0.70. The attitude about SHC (β = 0.182, P < .001), subjective norms on SHC (β = 0.146, P < .001), and confidence about SHC (β = 0.583, P < .001) had significant effects on the behavioral intention to provide SHC. Subsequently, the behavioral intention to provide SHC had a significant, direct effect on the behavioral frequency of providing SHC (β = 0.356, P < .001). However, gender role orientation was not significantly associated with behavioral intention and behavioral frequency to provide SHC., Conclusions: The good fit for the structural equation model suggests that the predictors of behavioral intention and behaviors of providing SHC include attitude, subjective norms, and perceived control. The stronger behavioral intention of providing SHC resulted in a higher frequency of providing SHC. However, the relationship between gender role orientation and SHC had no significant effect. Huang C-Y, Liou C-F, Lee S-H, et al. The Relationship Between Gender Role Orientation and Sexual Health Care in Taiwanese Nurses: A Structural Equation Model. Sex Med 2020;8:565-573., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Gelsemium elegans (G. elegans) has been used in traditional Chinese medicine. This plant is highly toxic to humans, but can promote the growth of pigs and goats in the veterinary clinic. It is a very complex mixture containing tens or hundreds of different components. Therefore, multiple-component pharmacokinetic studies of G. elegans are a major challenge due to the lack of authentic standards of the components. The purpose of this study was to investigate the plasma pharmacokinetics of multiple components after a single oral dose of G. elegans in goat using a sensitive ultra-performance liquid chromatography coupled to tandem mass spectrometry method for the simultaneous semiquantification of multiple alkaloids without standards. The method was validated in terms of the specificity, LOD, LOQ, linearity, accuracy, precision and matrix effects. To validate the global pharmacokinetic characteristics, the results obtained from the semiquantitative analysis of three authentic compounds (gelsemine, koumine and humantenmine) were compared with the absolute quantification from our recently published method. The results showed that the two methods had similar analytical results, and the obtained values of Tmax, T1/2 and MRT0-t of the three alkaloids were similar between the two methods. In addition, the values of Cmax and AUC0-t of the three alkaloids after normalization were close to the real values, which indicated that this semiquantitative method could be used in the pharmacokinetic study of multiplecomponents. Then the pharmacokinetic parameters of 23 other G. elegans alkaloids in goats were obtained. The results suggested that the gelsedine-type alkaloids were the major active ingredients that predict and explain the efficacy and toxicity of G. elegans., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Cinnamomi ramulus (called Guizhi in Chinese) is a traditional medicine used to treat gastrointestinal dysfunction, cancer, arthritis, osteoporosis, spleen deficiency, Alzheimer's disease and obesity. This review aimed to provide a systematic summary on the geographical distribution, botany, traditional application, phytochemistry, pharmacology, pharmacokinetics, toxicology and other aspects of Cinnamomi ramulus., Key Finding: So far, more than 121 chemical compounds have been isolated from Cinnamomi ramulus, including volatile oil, organic acids, triterpenoid saponins, coumarins, tannins, flavonoids and flavonoid glycosides, steroids and polysaccharides. This paper reviews the pharmacological effects of Cinnamomi ramulus on antibacterial, anti-inflammatory, antiviral, antitumour, antipyretic and analgesic, antidiabetic and antiplatelet aggregation effects. Furthermore, the present review also indicates that Cinnamomi ramulus has the potential to develop into drugs for treating various diseases with high efficacy and low toxicity., Summary: The convictive evidence from modern pharmacology research supports the traditional application of Cinnamomi ramulus. However, further studies on the structure-activity relationship of some of the isolated compounds may improve their biological potency. More toxicological studies will also contribute to the progress of clinical trial studies., (© 2019 Royal Pharmaceutical Society.)

Background: Glioma-associated microglia/macrophages (GAMs) comprise macrophages of peripheral origin and brain-intrinsic microglia, which support tumor progression. Chemokine C-C ligand 5 (CCL5) is an inflammatory mediator produced by immune cells and is involved in tumor growth and migration in several cancers, including glioma. However, the mechanisms detailing how CCL5 facilitates glioma invasion remain largely unresolved., Methods: Glioma migration and invasion were determined by wound healing, transwell assay, and 3D µ-slide chemotaxis assay. The expression levels of CCL5, CD68, matrix metalloproteinase 2 (MMP2), phosphorylated Ca2+/calmodulin-dependent protein kinase II (p-CaMKII), p-Akt, and phosphorylated proline-rich tyrosine kinase 2 were determined by cytokine array, quantitative PCR, western blot, or immunohistochemistry. Zymography and intracellular calcium assays were used to analyze MMP2 activity and intracellular calcium levels, respectively., Results: CCL5 modulated the migratory and invasive activities of human glioma cells in association with MMP2 expression. In response to CCL5, glioma cells underwent a synchronized increase in intracellular calcium levels and p-CaMKII and p-Akt expression levels. CCL5-directed glioma invasion and increases in MMP2 were suppressed after inhibition of p-CaMKII. Glioma cells tended to migrate toward GAM-conditioned media activated by granulocyte-macrophage colony-stimulating factor (GM-CSF) in which CCL5 was abundant. This homing effect was associated with MMP2 upregulation, and could be ameliorated either by controlling intracellular and extracellular calcium levels or by CCL5 antagonism. Clinical results also revealed the associations between CCL5 and GAM activation., Conclusion: Our results suggest that modulation of glioma CaMKII may restrict the effect of CCL5 on glioma invasion and could be a potential therapeutic target for alleviating glioma growth., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cantharidin (CTD), a sesquiterpenoid bioactive substance, has been reported to exhibit anticancer activity against various types of cancer cells. The aim of the present study was to investigate the apoptosis effects and the underlying mechanisms of CTD on osteosarcoma U-2 OS cells. Results showed that CTD induced cell morphologic changes, reduced total viable cells, induced DNA damage, and G 2 /M phase arrest. CTD increased the production of reactive oxygen species and Ca 2+ , and elevated the activities of caspase-3 and -9, but decreased the level of mitochondrial membrane potential. Furthermore, CTD increased the ROS- and ER stress-associated protein expressions and increased the levels of pro-apoptosis-associated proteins, but decreased that of anti-apoptosis-associated proteins. Based on these observations, we suggested that CTD decreased cell number through G 2 /M phase arrest and the induction of cell apoptosis in U-2 OS cells and CTD could be a potential candidate for osteosarcoma treatments.

Background: Prosthetic joint infections (PJIs) often require long-course antibiotic therapy. However, recent studies argue against the current practice and raise concerns such as the development of antibiotic resistance, side effects of medications and medical costs., Objectives: To review and compare the outcomes of short-course and long-course antibiotics in PJIs., Methods: We conducted a systemic review and meta-analysis using a predefined search term in PubMed and EMBASE databases. Studies that met the inclusion criteria from inception to June 2018 were included. The quality of the included studies was assessed., Results: A total of 10 articles and 856 patients were analysed, comprising 9 observational studies and 1 randomized controlled trial. Our meta-analysis showed no significant difference between short-course and long-course antibiotics (relative risk = 0.87, 95% CI = 0.62-1.22). Additionally, the older the studied group was, the more short-course antibiotics were favoured., Conclusions: When treating PJI patients following debridement, antibiotics and implant retention, an 8 week course of antibiotic therapy for total hip arthroplasty and a 75 day course for total knee arthroplasty may be a safe approach. For two-stage exchange, a shorter duration of antibiotic treatment during implant-free periods is also generally safe with the usage of antibiotic-loaded cement spacers., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Lupeol, one of the common components from the fruits and natural foods, has been reported to exert antitumor activities in many human cancer cell lines; however, its effects on osteosarcoma cell metastasis were not elucidated. In the present study, lupeol at 10-25 μM induced cell morphological changes and decreased total viable cell number in U-2 OS cells. Lupeol (5-15 μM) suppressed cell mobility, migration, and invasion by wound healing and transwell chamber assays, respectively. Lupeol inhibited the activities of MMP-2 and -9 in U-2 OS cells by gelatin zymography assay. Lupeol significantly decreased PI3K, pAKT, β-catenin, and increased GSK3β. Furthermore, lupeol decreased the expressions of Ras, p-Raf-1, p-p38, and β-catenin. Lupeol also decreased uPA, MMP-2, MMP-9, and N-cadherin but increased VE-cadherin in U-2 OS cells. Based on these observations, we suggest that lupeol can be used in anti-metastasis of human osteosarcoma cells in the future.

Objective: In this study, we aim to describe the post-sepsis syndrome from the perspective of the sepsis survivors., Design and Setting: The study is a prospective, observational online international survey., Participants: Sepsis survivors enrolled via social media from 13 September 2014 to 13 September 2016., Interventions: None., Main Outcome Measures: Physiologic, physical and psychological function post-sepsis; and patient satisfaction with sepsis-centered care., Results: 1731 completed surveys from 41 countries were analyzed, with 79.9% female respondents, age 47.6 ± 14.4 years. The majority of respondents (47.8%) had sepsis within the last year. Survivors reported an increase in sensory, integumentary, digestive, breathing, chest pain, kidney and musculoskeletal problems after sepsis (all P-value <0.0001). Physical functions such as daily chores, running errands, spelling, reading and reduced libido posed increased difficulty (all P-value <0.0001). Within 7 days prior to completing the survey, the survivors reported varying degrees of anxiety, depression, fatigue and sleep disturbance. Sepsis survivors reported dissatisfaction with a number of hospital support services, with up to 29.3% of respondents stating no social services support was provided for their condition., Conclusions: Sepsis survivors suffer from a myriad of physiologic, physical and psychological challenges. Survivors overall reveal dissatisfaction with sepsis-related care, suggesting areas for improvement both in-hospital and post-discharge., (© The Author(s) 2018. Published by Oxford University Press in association with the International Society for Quality in Health Care. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The mechanisms underlying how arsenic methylation capacity affects bladder cancer (BC) are still unclear. The objective of this study was to explore the effects of polymorphisms of arsenic (+3 oxidation state) methyltransferase (AS3MT) on BC risk. We conducted a hospital-based study and enrolled 216 BC and 648 healthy controls from 2007 to 2011. Urinary arsenic profiles were measured using high-performance liquid chromatography-hydride generation-atomic absorption spectrometry. The gene polymorphisms of AS3MT were identified using the Sequenom MassARRAY platform with iPLEX Gold chemistry. Inefficient arsenic methylation capacity (high monomethylarsonic acid percentage [MMA%] and low dimethylarsinic acid percentage [DMA%]) was associated with increased risk of BC in a dose-response relationship. AS3MT rs11191438 (C > G) G/G genotype, AS3MT rs10748835 (A > G) G/G genotype, and AS3MT rs1046778 (C > T) T/T genotype were found to be related to BC risk, where the odds ratio (OR) (95% CI) was 0.50 (0.31-0.82), 0.49 (0.30-0.79), and 0.54 (0.36-0.80), respectively. The combination of AS3MT haplotype 2 (AS3MT rs11191453, rs11191454, rs10748835, and rs1046778)'s high-risk haplotype (C-G-A-C, T-A-A-C, and T-G-G-T) was significantly associated with increased risk of BC. Among controls, only 3 of the 9 candidate genotypes evaluated, rs1119438 C/C, rs10748835 A/A and rs1046778 C/C, were associated with significantly higher MMA% compared with the other genotypes. No other genotypes or haplotypes were related to arsenic methylation capacity. High MMA%, low DMA% and AS3MT rs1046778 C/C + C/T genotype predicted a significantly higher risk of BC according to stepwise multiple logistic regression analyses. AS3MT gene polymorphisms and arsenic methylation capacity appeared to affect BC risk independently.

MicroRNAs (miRNAs) are small non-coding RNAs of ∼ 22 nucleotides that are involved in negative regulation of mRNA at the post-transcriptional level. Previously, we developed miRTarBase which provides information about experimentally validated miRNA-target interactions (MTIs). Here, we describe an updated database containing 422 517 curated MTIs from 4076 miRNAs and 23 054 target genes collected from over 8500 articles. The number of MTIs curated by strong evidence has increased ∼1.4-fold since the last update in 2016. In this updated version, target sites validated by reporter assay that are available in the literature can be downloaded. The target site sequence can extract new features for analysis via a machine learning approach which can help to evaluate the performance of miRNA-target prediction tools. Furthermore, different ways of browsing enhance user browsing specific MTIs. With these improvements, miRTarBase serves as more comprehensively annotated, experimentally validated miRNA-target interactions databases in the field of miRNA related research. miRTarBase is available at http://miRTarBase.mbc.nctu.edu.tw/., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Objectives: To report our preliminary results of an aggressive technique, the Provisional Extension To Induce Complete Attachment (PETTICOAT), in repair of acute DeBakey type I aortic dissection., Methods: From April 2014 to November 2014, 18 patients with acute DeBakey type I aortic dissection were reviewed retrospectively. Nine patients underwent open repair combined with proximal stent grafting and distal bare stenting (PETTICOAT group). For comparison, another 9 patients underwent open repair combined with proximal stent grafting (NON-PETTICOAT group) were included. Open repair entailed ascending aorta plus total arch replacement under circulatory arrest, with variable aortic root work. Mortality and morbidity were recorded, and computed tomography was performed to evaluate the aortic remodelling at 6 months postoperatively., Results: Preoperative parameters were similar. In the PETTICOAT group, one early mortality was noted. One complication of cardiac tamponade and sternal wound infection led to reopen surgeries. In the NON-PETTICOAT group, one case of transient ischaemic attack took place. Compared with the NON-PETTICOAT group, a significant increase in diameter of true lumen (median, 0.6 vs 0.1 mm, P < 0.01) and a decrease in diameter of false lumen (FL; median, -0.9 vs 0.0 mm, P < 0.01) at the level of lowest renal artery were noted in the PETTICOAT group. Moreover, significant FL volume regression (median, -102.0 vs -42.2 mm(3), P = 0.03) was observed in the PETTICOAT group. More cases of total thrombosis or regression of FL down to the level of renal artery were also noted in the PETTICOAT group (5/8 vs 0/9, P < 0.01). Two patients of the NON-PETTICOAT group received endovascular distal aortic reintervention at 6 months., Conclusions: The PETTICOAT technique in the management of acute DeBakey type I dissection is a feasible and promising method to promote distal aortic remodelling. However, outcomes are preliminary and further follow-up is required., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Introduction: Although palliative chemotherapy during end-of-life care is used for relief of symptoms in patients with metastatic cancer, chemotherapy may lead to more aggressive end-of-life care and less use of hospice service. This is a population-based study of the association between palliative chemotherapy and aggressiveness of end-of-life care., Patients and Methods: Using the National Health Insurance Research Database of Taiwan, we identified 49,920 patients with metastatic cancer who underwent palliative chemotherapy from January 1, 2009, to December 31, 2011. Patients who received chemotherapy 2-6 months before death were included. Aggressiveness of end-of-life care was examined by previously reported indicators. Cardiopulmonary resuscitation and endotracheal tube intubation were included as indicators of aggressive end-of-life care. The association between palliative chemotherapy and hospice care was studied., Results: Palliative chemotherapy was associated with more aggressive treatment. After adjustment for patient age, sex, Charlson Comorbidity Index score, cancer group, primary physician's specialty, postdiagnosis survival, hospital characteristics, hospital caseload, urbanization, and geographic regions, more than one emergency room visit (p < .001), more than one intensive care unit admission (p < .001), and endotracheal intubation (p = .02) during end-of-life care were significantly more common in patients receiving palliative chemotherapy. Patients who did not receive palliative chemotherapy received more hospice care in the last 6 months of life (p < .001)., Conclusion: Although the decision to initiate palliative chemotherapy was made several months before death, this study showed that palliative chemotherapy was associated with more aggressive end-of-life care, including more emergency room visits and intensive care unit admissions, and endotracheal intubation. The patients who received palliative chemotherapy received less hospice service toward the end of life., Implications for Practice: Palliative chemotherapy is used for patients with incurable cancer toward the end of life (EOL). Aggressiveness of EOL care and hospice care are related to the quality of life of these patients. This study of data from the Taiwanese National Health Insurance Research Database found that palliative chemotherapy led to more aggressive EOL care and less hospice care. There is a need to provide patients with terminal cancer access to care information that best meets their needs, especially those patients who receive palliative chemotherapy., (©AlphaMed Press.)

The oriental fruit fly, Bactrocera dorsalis (Hendel), reduces the quantity and quality of many host fruits through the process of oviposition and larval feeding, and this insect has been considered a major insect pest in several Asian countries for decades. Using an earlier-developed, female-specific system that combines the toxicity of the ricin A chain (RTA) and the alternative RNA splicing property of doublesex ( Bddsx ), we show that transgenic male flies harboring the RTA-Bddsx transgene unevenly repress the pest population through inheritable effects. In age-stage, two-sex life-table analyses, high larval mortality and a delay in pupation were observed after introducing the transgene. The high male to female ratio in DsRed + flies demonstrates the lethal effect of ricin on females. The fitness of both the DsRed + - and DsRed - -transformed females was reduced as shown in the decrease of the net reproductive rate ( R0 ), intrinsic rate ( r ), and finite rate (λ) values compared with the wild-type populations. The integrity of the RTA-Bddsx transgene remained in more than 80% of DsRed + males after ten generations, supporting the stable inheritance of the transgene. All of the data from this study support the proposed RTA-Bddsx SIT approach, which provides a species-specific and environmentally friendly method of suppressing, rather than eradiating, B. dorsalis., (© The Authors 2016. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Recent evidence suggests that childhood obesity is increasing in children with typical development (TD) and in children with autism spectrum disorders (ASD). The associations between physical activity (PA) levels and physical fitness components have not yet been objectively examined in this population but may have clinical implications for the development of secondary health complications., Objective: The aims of this study were: (1) to compare PA and physical fitness between secondary school-aged male students with ASD and their peers with TD and (2) to assess possible interrelationships between PA and physical fitness levels in each group., Design: This was a cross-sectional study., Methods: Physical activity was recorded every 10 seconds by using accelerometry in 70 male students with (n=35) and without (n=35) ASD for up to 5 weekdays and 2 weekend days. The Brockport Physical Fitness Test was used to assess physical fitness., Results: The primary findings were: (1) participants with ASD were less physically active overall and engaged in moderate-to-vigorous PA for a lower percentage of time compared with participants with TD during weekdays; (2) participants with ASD had significantly lower scores on all physical fitness measures, except body composition; and (3) group-dependent relationships existed between physical fitness profiles and PA levels., Limitations: The study design limits causal inference from the results., Conclusion: Specific interventions for maximizing PA and physical fitness levels in secondary school-aged male students with ASD are urgently needed., (© 2016 American Physical Therapy Association.)

Background: Nontuberculous mycobacteria (NTM) infection has attracted increasing attention in recent years; however, NTM otomastoiditis is extremely rare. Surgery combined with antibiotic therapy is the current mainstay of treatment; however, the reported duration of medication still varies. In this study, we aimed to analyze patients with NTM otomastoiditis and establish a more efficient treatment strategy., Methods: Medical records and temporal bone images of patients with NTM otomastoiditis were retrospectively analyzed. In addition, a comprehensive review of cases with NTM otomastoiditis in the literature was also performed., Results: Twenty-two patients were identified in our institution, and all patients had refractory otorrhea. The rates of granulation tissue, otalgia, and facial palsy were 90.9%, 31.8%, and 9.1%, respectively. Soft tissue attenuation via imaging studies was demonstrated in all of the middle ear cavities. All patients received medical treatment, 20 (90.9%) underwent surgery, and 4 (18.2%) underwent revision surgery. The median time to cure was similar between the "prolonged-course" and "standard-course" antibiotic groups (3.0 vs 3.3 months; P = .807). However, the former had a longer median duration of antibiotic therapy (6.0 vs 3.0 months; P = .01). In the literature review, 54 (96.4%) patients received medical treatment, 51 (91.1%) underwent surgery, and 27 (48.2%) underwent revision surgery., Conclusions: NTM otomastoiditis should be suspected if a patient has chronic refractory otorrhea and ear granulation tissue. Surgery, which is the mainstay of treatment, should be complemented with antibiotics. In those without temporal bone osteomyelitis, antibiotic treatment can be stopped after a dry ear is achieved., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

MicroRNAs (miRNAs) are small non-coding RNAs of approximately 22 nucleotides, which negatively regulate the gene expression at the post-transcriptional level. This study describes an update of the miRTarBase (http://miRTarBase.mbc.nctu.edu.tw/) that provides information about experimentally validated miRNA-target interactions (MTIs). The latest update of the miRTarBase expanded it to identify systematically Argonaute-miRNA-RNA interactions from 138 crosslinking and immunoprecipitation sequencing (CLIP-seq) data sets that were generated by 21 independent studies. The database contains 4966 articles, 7439 strongly validated MTIs (using reporter assays or western blots) and 348 007 MTIs from CLIP-seq. The number of MTIs in the miRTarBase has increased around 7-fold since the 2014 miRTarBase update. The miRNA and gene expression profiles from The Cancer Genome Atlas (TCGA) are integrated to provide an effective overview of this exponential growth in the miRNA experimental data. These improvements make the miRTarBase one of the more comprehensively annotated, experimentally validated miRNA-target interactions databases and motivate additional miRNA research efforts., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

This paper outlines a numerical scheme for accurate, detailed, and high-throughput image analysis of plant roots. In contrast to existing root image analysis tools that focus on root system-average traits, a novel, fully automated and robust approach for the detailed characterization of root traits, based on a graph optimization process is presented. The scheme, firstly, distinguishes primary roots from lateral roots and, secondly, quantifies a broad spectrum of root traits for each identified primary and lateral root. Thirdly, it associates lateral roots and their properties with the specific primary root from which the laterals emerge. The performance of this approach was evaluated through comparisons with other automated and semi-automated software solutions as well as against results based on manual measurements. The comparisons and subsequent application of the algorithm to an array of experimental data demonstrate that this method outperforms existing methods in terms of accuracy, robustness, and the ability to process root images under high-throughput conditions., (© The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

This paper proposes a new estimation procedure for the survival time distribution with left-truncated and right-censored data, where the distribution of the truncation time is known up to a finite-dimensional parameter vector. The paper expands on the Vardis multiplicative censoring model (Vardi, 1989. Multiplicative censoring, renewal processes, deconvolution and decreasing density: non-parametric estimation. Biometrika 76: , 751-761), establishes the connection between the likelihood under a generalized multiplicative censoring model and that for left-truncated and right-censored survival time data, and derives an Expectation-Maximization algorithm for model estimation. A formal test for checking the truncation time distribution is constructed based on the semiparametric likelihood ratio test statistic. In particular, testing the stationarity assumption that the underlying truncation time is uniformly distributed is performed by embedding the null uniform truncation time distribution in a smooth alternative (Neyman, 1937. Smooth test for goodness of fit. Skandinavisk Aktuarietidskrift 20: , 150-199). Asymptotic properties of the proposed estimator are established. Simulations are performed to evaluate the finite-sample performance of the proposed methods. The methods and theories are illustrated by analyzing the Canadian Study of Health and Aging and the Channing House data, where the stationarity assumption with respect to disease incidence holds for the former but not the latter., (© The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Dengue viruses (DENVs) infect >300 million people annually, causing 96 million cases of dengue disease and 22 000 deaths [1]. A safe vaccine that protects against DENV disease is a global health priority [2]., Methods: We enrolled 72 flavivirus-naive healthy adults in a phase 1 double-blinded, randomized, placebo-controlled dose-escalation trial (low and high dose) of a live attenuated recombinant tetravalent dengue vaccine candidate (TDV) given in 2 doses 90 days apart. Volunteers were followed for safety, vaccine component viremia, and development of neutralizing antibodies to the 4 DENV serotypes., Results: The majority of adverse events were mild, with no vaccine-related serious adverse events. Vaccinees reported injection site pain (52% vs 17%) and erythema (73% vs 25%) more frequently than placebo recipients. Low levels of TDV-serotype 2 (TDV-2), TDV-3, and TDV-4 viremia were observed after the first but not second administration of vaccine. Overall seroconversion rates and geometric mean neutralization titers after 2 doses were 84.2% and 54.1, respectively, for DENV serotype 1 (DENV-1); 92.1% and 292.8, respectively, for DENV-2; 86.8% and 32.3, respectively, for DENV-3; and 71.1% and 15.0, respectively, for DENV-4. More than 90.0% of high-dose recipients had trivalent or broader responses., Conclusions: TDV was generally well tolerated, induced trivalent or broader neutralizing antibodies to DENV in most flavivirus-naive vaccinees, and is undergoing further development., Clinical Trials Registration: NCT01110551., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Endothelial progenitor cells (EPCs) promote angiogenesis and are therefore key contributors to a wide variety of angiogenesis-related autoimmune diseases such as rheumatoid arthritis (RA). However, the signaling mechanisms through which these progenitor cells influence RA pathogenesis remain unknown. The aim of this study was to examine whether resistin plays a role in the pathogenesis of and angiogenesis associated with RA by circulating EPCs. We found that levels of resistin in synovial fluid and tissue from patients with RA and from mice with collagen-induced arthritis were overexpressed and promoted the homing of EPCs into the synovium, thereby inducing angiogenesis. EPCs isolated from healthy donors were used to investigate the signal transduction pathway underlying EPC migration and tube formation after treatment with resistin. We found that resistin directly induced a significant increase in expression of vascular endothelial growth factor (VEGF) in EPCs. We also found that the expression of microRNA-206 (miR-206) was negatively correlated with the expression of resistin during EPC-mediated angiogenesis. Notably, the increased expression of VEGF was associated with decreased binding of miR-206 to the VEGF-A 3' untranslated region through protein kinase C delta-dependent AMP-activated protein kinase signaling pathway. Moreover, blockade of resistin reduced EPC homing into synovial fluid and angiogenesis in vivo. Taken together, our study is the first to demonstrate that resistin promotes EPCs homing into the synovium during RA angiogenesis via a signal transduction pathway that involves VEGF expression in primary EPCs. These findings provide support for resistin as a therapeutic target for the patients with RA. Stem Cells 2015;33:2243-2255., (© 2015 AlphaMed Press.)

This paper proposes a unified framework to characterize the rate function of a recurrent event process through shape and size parameters. In contrast to the intensity function, which is the event occurrence rate conditional on the event history, the rate function is the occurrence rate unconditional on the event history, and thus it can be interpreted as a population-averaged count of events in unit time. In this paper, shape and size parameters are introduced and used to characterize the association between the rate function λ (·) and a random variable X . Measures of association between X and λ (·) are defined via shape- and size-based coefficients. Rate-independence of X and λ (·) is studied through tests of shape-independence and size-independence, where the shape-and size-based test statistics can be used separately or in combination. These tests can be applied when X is a covariable possibly correlated with the recurrent event process through λ (·) or, in the one-sample setting, when X is the censoring time at which the observation of N (·) is terminated. The proposed tests are shape- and size-based, so when a null hypothesis is rejected, the test results can serve to distinguish the source of violation.

Background: Plasmodium falciparum reticulocyte-binding protein homologue 5 (PfRH5) is a blood-stage parasite protein essential for host erythrocyte invasion. PfRH5-specific antibodies raised in animals inhibit parasite growth in vitro, but the relevance of naturally acquired PfRH5-specific antibodies in humans is unclear., Methods: We assessed pre-malaria season PfRH5-specific immunoglobulin G (IgG) levels in 357 Malian children and adults who were uninfected with Plasmodium. Subsequent P. falciparum infections were detected by polymerase chain reaction every 2 weeks and malaria episodes by weekly physical examination and self-referral for 7 months. The primary outcome was time between the first P. falciparum infection and the first febrile malaria episode. PfRH5-specific IgG was assayed for parasite growth-inhibitory activity., Results: The presence of PfRH5-specific IgG at enrollment was associated with a longer time between the first blood-stage infection and the first malaria episode (PfRH5-seropositive median: 71 days, PfRH5-seronegative median: 18 days; P = .001). This association remained significant after adjustment for age and other factors associated with malaria risk/exposure (hazard ratio, .62; P = .02). Concentrated PfRH5-specific IgG purified from Malians inhibited P. falciparum growth in vitro., Conclusions: Naturally acquired PfRH5-specific IgG inhibits parasite growth in vitro and predicts protection from malaria. These findings strongly support efforts to develop PfRH5 as an urgently needed blood-stage malaria vaccine., Clinical Trials Registration: NCT01322581.

Background: ATPase-family, AAA domain containing 3A (ATAD3A) is located on human chromosome 1p36.33, and high endogenous expression may associate with radio- and chemosensitivity. This study was conducted to investigate the significance of ATAD3A in glioblastoma multiforme (GBM)., Methods: Clinical significance of ATAD3A expression was assessed by immunohistochemistry in 67 GBM specimens, and prognostic value was assessed in 32 GBM patients statistically. To investigate in vitro phenotypic effects of ATAD3A, cell viability was measured using a clonogenic survival assay under either knockdown or ectopic expression of ATAD3A in GBM cell lines. The effects of ATAD3A knockdown on targeted DNA repair-associated proteins in T98G cells were evaluated using immunofluorescence and Western blotting., Results: Clinically, high expression of ATAD3A was independent of O(6)-DNA methylguanine-methyltransferase methylation status and correlated with worse prognosis. In vitro, high ATAD3A-expressing T98G cells were more resistant to radiation-induced cell death compared with control and low endogenous ATAD3A U87MG cells. After silencing ATAD3A, T98G cells became more sensitive to radiation. On the other hand, enforced ATAD3A expression in U87MG cells exhibited increased radioresistance. ATAD3A may coordinate with aldo-keto reductase genes and participate in bioactivation or detoxication of temozolomide. Surprisingly, deficient DNA repair after irradiation was observed in T98G/ATAD3A knockdown as a result of decreased nuclear ataxia telangiectasia mutated kinase and histones H2AX and H3, which was also evidenced by the sustained elevation of poly (ADP-ribose) polymerase prior to and after radiation treatment., Conclusion: Our data suggest that high expression of ATAD3A is an independent biomarker for radioresistance in GBM. ATAD3A could be a potential target for therapy.

Background: We have reported that minocycline (Mino) induced autophagic death in glioma cells. In the present study, we characterize the upstream regulators that control autophagy and switch cell death from autophagic to apoptotic., Methods: Western blotting and immunofluorescence were used to detect the expressions of eukaryotic translation initiation factor 2α (eIF2α), transcription factor GADD153 (CHOP), and glucose-regulated protein 78 (GRP78). Short hairpin (sh)RNA was used to knock down eIF2α or CHOP expression. Autophagy was assessed by the conversion of light chain (LC)3-I to LC3-II and green fluorescent protein puncta formation. An intracranial mouse model and bioluminescent imaging were used to assess the effect of Mino on tumor growth and survival time of mice., Results: The expression of GRP78 in glioma was high, whereas in normal glia it was low. Mino treatment increased GRP78 expression and reduced binding of GRP78 with protein kinase-like endoplasmic reticulum kinase. Subsequently, Mino increased eIF2α phosphorylation and CHOP expression. Knockdown of eIF2α or CHOP reduced Mino-induced LC3-II conversion and glioma cell death. When autophagy was inhibited, Mino induced cell death in a caspase-dependent manner. Rapamycin in combination with Mino produced synergistic effects on LC3 conversion, reduction of the Akt/mTOR/p70S6K pathway, and glioma cell death. Bioluminescent imaging showed that Mino inhibited the growth of glioma and prolonged survival time and that these effects were blocked by shCHOP., Conclusions: Mino induced autophagy by eliciting endoplasmic reticulum stress response and switched cell death from autophagy to apoptosis when autophagy was blocked. These results coupled with clinical availability and a safe track record make Mino a promising agent for the treatment of malignant gliomas.

Background: In experimental models of human and mouse malaria, sterilizing liver stage immunity that blocks progression of Plasmodium infection to the symptomatic blood stage can be readily demonstrated. However, it remains unclear whether individuals in malaria-endemic areas acquire such immunity., Methods: In Mali, 251 healthy children and adults aged 4-25 years who were free of blood-stage Plasmodium infection by polymerase chain reaction (PCR) were enrolled in a longitudinal study just prior to an intense 6-month malaria season. Subsequent clinical malaria episodes were detected by weekly active surveillance and self-referral. Asymptomatic P. falciparum infections were detected by blood-smear microscopy and PCR analysis of dried blood spots that had been collected every 2 weeks for 7 months., Results: As expected, the risk of clinical malaria decreased with increasing age (log-rank test, P = .0038). However, analysis of PCR data showed no age-related differences in P. falciparum infection risk (log-rank test, P = .37)., Conclusions: Despite years of exposure to intense P. falciparum transmission, there is no evidence of acquired, sterile immunity to P. falciparum infection in this population, even as clinical immunity to blood-stage malaria is clearly acquired. Understanding why repeated P. falciparum infections do not induce sterile protection may lead to insights for developing vaccines that target the liver stage in malaria-endemic populations.

Phosphorus (P) is essential for plant growth. MicroRNAs (miRNAs) play a key role in phosphate homeostasis. However, little is known about P effect on miRNA expression in barley (Hordeum vulgare L.). In this study, we used Illumina's next-generation sequencing technology to sequence small RNAs (sRNAs) in barley grown under P-deficient and P-sufficient conditions. We identified 221 conserved miRNAs and 12 novel miRNAs, of which 55 were only present in P-deficient treatment while 32 only existed in P-sufficient treatment. Total 47 miRNAs were significantly differentially expressed between the two P treatments (|log2| > 1). We also identified many other classes of sRNAs, including sense and antisense sRNAs, repeat-associated sRNAs, transfer RNA (tRNA)-derived sRNAs and chloroplast-derived sRNAs, and some of which were also significantly differentially expressed between the two P treatments. Of all the sRNAs identified, antisense sRNAs were the most abundant sRNA class in both P treatments. Surprisingly, about one-fourth of sRNAs were derived from the chloroplast genome, and a chloroplast-encoded tRNA-derived sRNA was the most abundant sRNA of all the sRNAs sequenced. Our data provide valuable clues for understanding the properties of sRNAs and new insights into the potential roles of miRNAs and other classes of sRNAs in the control of phosphate homeostasis.

Angiotensin II (Ang II) is a risk factor for cardiovascular disease. We used a traditional Chinese medicine, alpinate oxyphyllae fructus (AOF), to evaluate its effect on Ang II-induced cardiac apoptosis and mitochondrial dysfunction. Ang II-treated H9c2 cells were administered AOF of 20-100 µg/mL concentrations. Ang II significantly increased TUNEL-positive nuclei in the H9c2 cells, effect was inhibited by AOF administration in both pre-treated and post-treated H9c2 cells. Caspases 9 and 3 activities were increased by Ang II and downregulated by AOF administration, especially in pre-treatment. AOF treatment reversed Ang II-induced mitochondria membrane potential instability in H9c2 cells as observed by JC-1 stain assay. Furthermore, pro-apoptotic proteins Bad and cytochrome c increased and decreased respectively under AOF administration. The levels of p-Bad anti-apoptotic protein were significantly increased after AOF treatment. This study indicates that mitochondrial dependent apoptosis induced by Ang II.

This study shows that the ECM degradation-associated pathway, including uPA and tPA and the downstream MMP-2/-9 protein, was significantly suppressed in HA22T cells treated with a Zanthoxylum avicennae extract (YBBE). The endogenous inhibitors, including TIMP-1/-2 and PAI-1, were enhanced in HA22T cells by the YBBE treatment. The expression of MMP-2/-9 and TIMP-1/-2 was respectively assessed by using RT-PCR and a zymography assay. The mRNA levels and enzymatic activity of MMP-2/-9 were down-regulated by the YBBE treatment in a dose-dependent manner, while the TIMP-1/-2 levels were conversely markedly increased. The PP2A siRNA or PP2A inhibitor totally reversed the YBBE effects, confirming the essential role of PP2A in YBBE inhibiting the HA22T cell migration and invasion effects. Xenografted animal experiments on nude mice demonstrated similiar results to the in vitro system. Both the in vitro and in vivo models clearly demonstrate that YBBE inhibited the highly metastatic HA22T liver cancer cell migration and invasion effects through PP2A activation.

The IGF-IR/PI3K/Akt signaling pathway inhibited GSK3-β activity by phosphorylation and this promoted β-catenin nuclear localization. Our previous study indicated that β-catenin mRNA level was significantly higher in tumor areas than in non-tumor ones, especially in late pathologic stage tumors. However, β-catenin inhibition resulted in significantly suppressed migration and invasion ability of HA22T cells. Thus, Wnt/β-catenin pathway over-activation might be involved in metastatic enhancement of apicidin-resistant HA22T cell metastasis. Apicidin-resistant (AR) HA22T cells showed higher β-catenin nuclear accumulation and significantly decreased GSK-3-β protein level, in relation to parental cells. Results also indicated that AR cells increased abundantly in Tbx3, a downstream target of Wnt/β-catenin that it is implicated in liver cancer. AR cells also inhibited the MEK/ERK/PEA3 pathway which promoted MMP-2 activation. But, apicidin-resistant effect was totally reversed by LY294002 and AG1024. In conclusion, Apicidin-R HA22T cells activated the Wnt/β-catenin pathway and induced, MMP-2 expression via IGF-IR/PI3K/Akt signaling further enhancing cell the metastatic effects.

Survival data from prevalent cases collected under a cross-sectional sampling scheme are subject to left-truncation. When fitting an additive hazards model to left-truncated data, the conditional estimating equation method (Lin & Ying, 1994), obtained by modifying the risk sets to account for left-truncation, can be very inefficient, as the marginal likelihood of the truncation times is not used in the estimation procedure. In this paper, we use a pairwise pseudolikelihood to eliminate nuisance parameters from the marginal likelihood and, by combining the marginal pairwise pseudo-score function and the conditional estimating function, propose an efficient estimator for the additive hazards model. The proposed estimator is shown to be consistent and asymptotically normally distributed with a sandwich-type covariance matrix that can be consistently estimated. Simulation studies show that the proposed estimator is more efficient than its competitors. A data analysis illustrates application of the method.