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Substance use during adolescence might cause substantial health burden. Little is known regarding profiles of multiple illicit substance users compared to single illicit substance users in adolescent population in Taiwan.We enrolled 106 adolescent illicit drug users who received addiction treatment referred by juvenile courts in Taiwan between September, 2016 and September, 2021. We divided them into two groups: single versus multiple illicit drug users, and further compared their socio-demographic characteristics, psychiatric and substance comorbidities. The independent t test or Mann-Whitney U test was used for continuous variables and Pearson's chi-square test for nominal variables. Multivariate logistic regression was used to examine the suicide and violence risk among adolescents.71.7% of participants were multiple illicit drug users while 28.3% of them were single drug users. Multiple illicit substance users were more likely to use methamphetamine (p = 0.005), ketamine (p 0.001), new psychoactive substance (NPS) (p 0.001), MDMA (p = 0.003), and nitrous oxide (p 0.001) compared to single illicit substance users. In addition, multiple illicit drug users were more likely to have ADHD (p = 0.030), major depressive disorder (p = 0.050), and lifetime suicidal attempts (p = 0.048) compared to single illicit drug users. In further analysis (NPS vs. traditional drugs), we found NPS users tended to use larger numbers of illicit drugs (p 0.001) and were more likely to have substance-induced psychotic disorder (p = 0.008), ADHD (p = 0.011), suicidal attempts (p = 0.020).Our findings highlight the distinct profiles of multiple illicit drug users compared to single illicit drug users among adolescent population. High suicidality and high psychiatric comorbidities in multiple illicit drug users call for special need for suicide screening and a more integrated care incorporating psychiatric and substance treatment.

Coronavirus disease 2019 (COVID-19) is a rapidly spreading disease that has caused an extensive burden to the world. Consequently, a large number of clinical trials have examined the efficacy of traditional Chinese medicine (TCM) for treating and preventing COVID-19, with coinciding proliferation of reviews summarizing these studies.This study aimed to evaluate the methodological quality and evidence quality of systematic reviews and meta-analyses on the efficacy of TCM.Seven electronic databases, including PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Chongqing VIP, Wanfang Data and SinoMed, were searched for systematic reviews and meta-analyses in October 2021. Search terms such as "Chinese medicine," "Lianhua Qingwen" and "COVID-19" were used.Systematic reviews and meta-analyses of randomized controlled trials that evaluated the efficacy of TCM treatment of COVID-19 were included.A Measurement Tool to Assess Systematic Reviews Version 2.0 (AMSTAR 2) was used to evaluate the methodological quality. The quality of evidence was graded using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Data extraction and analysis were performed by two reviewers independently.There were 17 meta-analyses included in our overview. The intervention group was defined as TCM combined with Western medicine, while the control group was Western medicine alone. The methodological quality of all the included studies was moderate to poor. A total of 89 outcome indicators were evaluated, of which, 8 were rated as moderate quality, 39 as low quality, and 41 as very low quality. Only one outcome measure was graded as being of high quality. The moderate quality of evidence indicated that, for the treatment of COVID-19, the clinical efficacy of TCM in combination with Western medicine was better, in terms of lung recovery, rate of conversion to severe/critical cases, symptom scores, duration of symptoms, mortality, and length of hospital stay.Evidence from the included studies shows that, compared with conventional Western medical therapy alone, the addition of TCM to COVID-19 treatment may improve clinical outcomes. Overall, the quality of evidence of TCM for COVID-19 was moderate to poor. Meta-analyses of the use of TCM in the treatment of COVID-19 can be used for clinical decision making by accounting for the experiences of clinical experts, medical policies, and other factors.

GDC‐0334 is a novel small molecule inhibitor of transient receptor potential cation channel member A1 (TRPA1), a promising therapeutic target for many nervous system and respiratory diseases. The pharmacokinetic (PK) profile and pharmacodynamic (PD) effects of GDC‐0334 were evaluated in this first‐in‐human (FIH) study. A starting single dose of 25 mg was selected based on integrated preclinical PK, PD, and toxicology data following oral administration of GDC‐0334 in guinea pigs, rats, dogs, and monkeys. Human PK and PK‐PD of GDC‐0334 were characterized after single and multiple oral dosing using a population modeling approach. The ability of GDC‐0334 to inhibit dermal blood flow (DBF) induced by topical administration of allyl isothiocyanate (AITC) was evaluated as a target‐engagement biomarker. Quantitative models were developed iteratively to refine the parameter estimates of the dose‐concentration‐effect relationships through stepwise estimation and extrapolation. Human PK analyses revealed that bioavailability, absorption rate constant, and lag time increase when GDC‐0334 was administered with food. The inhibitory effect of GDC‐0334 on the AITC‐induced DBF biomarker exhibited a clear sigmoid‐Emax relationship with GDC‐0334 plasma concentrations in humans. This study leveraged emerging preclinical and clinical data to enable iterative refinement of GDC‐0334 mathematical models throughout the FIH study for dose selection in subsequent cohorts throughout the study. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? GDC‐0334 is a novel, small molecule TRPA1 inhibitor and a pharmacokinetic‐pharmacodynamic (PK‐PD) modeling strategy could be implemented in a systematic and step‐wise manner to build and learn from emerging data for early clinical development. WHAT QUESTION DID THIS STUDY ADDRESS? Can noncompartmental and population‐based analyses be used to describe the PK and PD characteristics of GDC‐0334 in preclinical and clinical studies? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? GDC‐0334 exposure generally increased with dose in rats, dogs, and monkeys. The starting dose (25 mg) in the clinical study was determined based on the preclinical data. GDC‐0334 exhibited linear PK in humans and the bioavailability was increased with food. The inhibitory effect of GDC‐0334 on dermal blood flow induced by the TRPA1 agonist allyl isothiocyanate in humans indicates a clear PK‐PD relationship. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? The models developed based on TRPA1 agonist‐induced dermal blood flow inhibition data can be used to predict PK‐PD relationships in future preclinical and clinical studies evaluating new drug entities that target TRPA1.

Orthopedic insoles (OIs) with medial arch support and heel cushion are widely used to manage lower extremity injuries, but their effects on postural balance in patients with chronic stroke have not been adequately explored.Design: Double-blinded, sham-controlled, randomized crossover trial.A total of 32 ambulatory patients (20 men and 12 women, aged between 30 and 76 years) with more than 6 months since stroke onset.All participants received one assessment session wearing OIs and one session wearing sham insole (SI) in a random order with a 1-day interval.Our primary outcome was the Berg Balance Scale score. Secondary outcomes included the Functional Reach Test, Timed Up and Go test, and computerized posturography. All were performed in both sessions. Subgroup analyses regarding demographic and functional variables were conducted to identify potential responders.Significant between-insole differences favoring OIs were seen in all clinical tests (P0.05), but were seen only in the static medial-lateral sway in computerized posturography assessment (P = 0.04). An approximate 2-point difference in the BBS score favoring OIs was observed in all subgroups, not reaching the minimal clinically important difference.The use of OIs generated small but significant positive effects on improving postural balance among patients with chronic stroke. Additional biomechanical and clinical studies are required to evaluate their potential for routine clinical use.NCT03194282.

Introduction Etrolizumab is a novel, dual-action anti-β7 integrin antibody studied in phase 3 trials in patients with inflammatory bowel disease. An autoinjector (AI) is being developed in parallel to complement the prefilled syringe with needle safety device (PFS-NSD) for subcutaneous (SC) administration in these trials. Here we demonstrate the comparable pharmacokinetics, tolerability, and safety of both devices. Methods This randomized, open-label, two-part study in healthy participants evaluated the comparability of etrolizumab exposure between the AI and the PFS-NSD. Part 1 (pilot) involved a small number of participants, and initial results were used to finalize the design of the larger part 2 (pivotal) study. In both parts, participants were randomly assigned to receive a single SC dose of etrolizumab 105 mg by AI or PFS-NSD. Randomization was stratified by body weight. Primary pharmacokinetic outcomes were Cmax, AUClast, and AUC0–inf. Results One hundred and eighty healthy participants (part 1, n = 30; part 2, n = 150) received a single SC dose of etrolizumab by AI or PFS-NSD. Primary pharmacokinetic results from part 1 supported modification of the part 2 study design. Results from part 2 demonstrated that etrolizumab exposure was equivalent between devices, with geometric mean ratios (GMRs) between AI and PFS-NSD of 102% (90% confidence interval [CI] 94.2–111) for Cmax, 98.0% (90% CI 89.3–107) for AUClast, and 97.6% (90% CI 88.6–107) for AUC0–inf. Median tmax and mean terminal t1/2 were also similar between devices. GMRs and 90% CIs of all primary pharmacokinetic parameters were fully contained within the predefined equivalence limits (80–125%). Conclusion This pharmacokinetic study demonstrated that single SC injections of etrolizumab 105 mg using an AI or a PFS-NSD resulted in equivalent etrolizumab exposure and similar safety and tolerability in healthy participants. Taken together, these results support the use of an AI for etrolizumab administration. Trial Registration NCT02996019.

Molecular hydrogen (H(2)) is a physiologically inert gas. However, during the last 10 years, increasing evidence has revealed its biological functions under pathological conditions. More specifically, H(2) has protective effects against a variety of diseases, particularly nervous system disorders, which include ischemia/reperfusion injury, traumatic injury, subarachnoid hemorrhage, neuropathic pain, neurodegenerative diseases, cognitive dysfunction induced by surgery and anesthesia, anxiety, and depression. In addition, H(2) plays protective roles mainly through anti-oxidation, anti-inflammation, anti-apoptosis, the regulation of autophagy, and preservation of mitochondrial function and the blood-brain barrier. Further, H(2) is easy to use and has neuroprotective effects with no major side-effects, indicating that H(2) administration is a potential therapeutic strategy in clinical settings. Here we summarize the H(2) donors and their pharmacokinetics. Meanwhile, we review the effectiveness and safety of H(2) in the treatment of various nervous system diseases based on preclinical and clinical studies, leading to the conclusion that H(2) can be a simple and effective clinical therapy for CNS diseases such as ischemia-reperfusion brain injury, Parkinson’s disease, and diseases characterized by cognitive dysfunction. The potential mechanisms involved in the neuroprotective effect of H(2) are also analyzed.

To carry out a systematic review to help resolve the controversy of ischemic stroke (IS)/transient ischemic attack (TIA) in patients with primary immune thrombocytopenia (ITP). A database search of PubMed and Ovid Embase was conducted for epidemiologic studies published up to December 17, 2019. The effective size was estimated by pooled prevalence, annualized incidence/risk, relative risk (RR), and their corresponding 95% confidence intervals (CIs). The systematic review included 14 eligible studies from 11 publications. The pooled annualized cumulative incidence was 0.15% (95% CI, 0.03–0.26%) per person-years. And the pooled annualized cumulative risk of IS/TIA of ITP was 0.86% (95% CI, 0.33–1.39%) per year based on 3 population-based cohort studies. There was a higher risk of incident IS/TIA in ITP patients than ITP-free subjects (pooled unadjusted or adjusted RR with 95% CI, 1.46 [1.22–1.74] or 1.50 [1.29–1.73]). IS/TIA was not uncommon in patients with primary ITP. ITP patients have a higher risk of IS/TIA compared with the reference cohorts. Healthcare professionals should take into account the risk of IS/TIA when treating ITP patients with or without a history of IS/TIA.

Background: In the setting of the COVID-19 pandemic, the conduct of elective cancer surgery has become an issue because of the need to balance the requirement to treat patients with the possibility of transmission of the virus by asymptomatic carriers. A particular concern is the potential for viral transmission by way of aerosol which may be generated during perioperative care. There are currently no guidelines for the conduct of elective lung resection surgery in this context. Methods: A working group composed of 1 thoracic surgeon, 2 anesthesiologists and 1 critical care specialist assessed the risk for aerosol during lung resection surgery and proposed steps for mitigation. After external review, a final draft was approved by the Committee for the Governance of Perioperative and Surgical Activities of the Hôpital Maisonneuve-Rosemont, in Montreal, Canada. Results: The working group divided the risk for aerosol into 6 time-points: (1) intubation and extubation; (2) Lung isolation and patient positioning; (3) access to the chest; (4) conduct of the surgical procedure; (5) procedure termination and lung re-expansion; (6) chest drainage. Mitigating strategies were proposed for each time-point. Conclusions: The situation with COVID-19 is an opportunity to re-evaluate operating room protocols both for the purposes of this pandemic and similar situations in the future. In the context of lung resection surgery, specific time points during the procedure seem to pose specific risks for the genesis of aerosol and thus should be the focus of attention.

Background The aim of this study was to demonstrate a novel method of assessing data quality for an orthopaedic registry and its effects on data quality metrics. Methods A quality controlled clinical patient registry was implemented, comprising six observational cohorts of shoulder and knee pathologies. Data collection procedures were co-developed with clinicians and administrative staff in accordance with the relevant dataset and organised into the registry database software. Quality metrics included completeness, consistency and validity. Data were extracted at scheduled intervals (3 months) and quality metrics reported to stakeholders of the registry. Results The first patient was enrolled in July 2017 and the data extracted for analysis over 4 quarters, with the last audit in August 2018 (N = 189). Auditing revealed registry completeness was 100% after registry deficiencies were addressed. However, cohort completeness was less accurate, ranging from 12 to 13% for height & weight to 90–100% for operative variables such as operating surgeon, consulting surgeon and hospital. Consistency and internal validation improved to 100% after issues in registry processes were rectified. Conclusions A novel method to assess data quality in a clinical orthopaedic registry identified process shortfalls and improved data quality over time. Real-time communication, a comprehensive data framework and an integrated feedback loop were necessary to ensure adequate quality assurance. This model can be replicated in other registries and serve as a useful quality control tool to improve registry quality and ensure applicability of the data to aid clinical decisions, especially in newly implemented registries. Trial registration ACTRN12617001161314; registration date 8/08/2017. Retrospectively registered.

Background: Haglund’s deformity, which is characterized by a bony prominence of the posterosuperior aspect of the calcaneus, causes posterior heel pain. To date, there is no standard radiographic parameter to diagnose symptomatic Haglund’s deformity. Herein, we proposed novel radiographic measurements to distinguish between patients with and without symptomatic Haglund’s deformity. Methods: We retrospectively evaluated ankle radiographs of 43 patients who underwent surgery for symptomatic Haglund’s deformity (Haglund group) and 41 healthy individuals (control group) free of heel complaints. Fowler–Phillip angle (FPA), Heneghan–Pavlov parallel pitch lines (PPL), Haglund’s deformity height, bump height, and bump-calcaneus ratio were measured and compared between the groups. Furthermore, the reliability and cut-off value of each parameter were validated via ICC and ROC curve analysis, respectively. Results: The bump height (p < 0.001) and the bump-calcaneus ratio (p < 0.001) showed significant differences between the control and Haglund groups, unlike FPA, PPL, and Haglund’s deformity height. ROC curve analysis revealed that the AUC of bump-calcaneus ratio was larger than that of bump height. The optimal threshold was 4 mm or higher for bump height and 7.5% or higher for bump-calcaneus ratio. The intra- and inter- observer ICCs were, respectively, 0.965 and 0.898 for bump height and 0.930 and 0.889 for bump-calcaneus ratio. Conclusions: This study proposes two novel radiographic parameters to identify operatively treated Haglund’s deformity, namely bump height and bump-calcaneus ratio. They are easy to measure and intuitive. Both of them are effective diagnostic parameters for Haglund’s deformity. Furthermore, bump-calcaneus ratio is more reliable diagnostic parameter than bump height.

Objectives Postoperative pulmonary complications increase mortality, length, and cost of hospitalization. A better diaphragmatic strength may help face an increased work of breathing postoperatively. We, therefore, sought to determine if a low preoperative diaphragm thickening fraction (TFdi) determined by ultrasonography helped predict the occurrence of postoperative pulmonary complications after cardiac surgery independently of indicators of frailty, sarcopenia, and pulmonary function. Design Prospective observational cohort study. Setting Montreal Heart Institute, an academic cardiac surgery center in Canada. Patients Adults undergoing nonemergency cardiac surgery. Interventions We measured the preoperative thickness of the right and left hemidiaphragms at their zone of apposition at end-expiration (Tdi,ee) and peak-inspiration (Tdi,ei) with ultrasonography. Maximal thickening fraction of the diaphragm during inspiration (TFdi,max) was calculated using the following formula: TFdi,max = (Tdi,ei-Tdi,ee)/Tdi,ee. We also evaluated other potential risk factors including demographic parameters, comorbidities, Clinical Frailty Scale, grip strength, 5-meter walk test, and pulmonary function tests. We repeated TFdi,max measurements within 24 hours of extubation. The primary composite outcome of this study was the occurrence of postoperative pulmonary complications, defined as pneumonia, clinically significant atelectasis, or prolonged mechanical ventilation (> 24 hr). Measurement and main results Of the 115 patients included, 34 (29.6%) developed postoperative pulmonary complications, including two with pneumonia, four with prolonged mechanical ventilation, and 32 with clinically significant atelectasis. Those with postoperative pulmonary complications had prolonged ICU and hospital length of stays. They had a lower TFdi,max (37% [interquartile range, 31-45%] vs 44% [interquartile range, 33-58%]; p = 0.03). In multiple logistic regression, a TFdi,max less than 38.1% was associated with postoperative pulmonary complications (odds ratio, 4.9; 95% CI, 1.81-13.50; p = 0.002). All patients who developed pneumonia or prolonged mechanical ventilation had a TFdi,max less than 38.1%. Respiratory rate and diabetes were also independently associated with postoperative pulmonary complications, while pulmonary function tests and the assessed indicators of frailty and sarcopenia were not. Conclusions A low preoperative TFdi,max can help to identify patients at increased risk of postoperative pulmonary complications after cardiac surgery.

Restrictive fluid management strategies have been proposed to reduce complications in liver transplant recipients. We conducted a systematic review to evaluate the effects of restrictive perioperative fluid management strategies, compared with liberal ones, on postoperative outcomes in adult liver transplant recipients. Our primary outcome was acute kidney injury (AKI). Our secondary outcomes were bleeding, mortality, and other postoperative complications. We searched major databases (CINAHL, EMB Reviews, EMBASE, MEDLINE, and the grey literature) from their inception to 10 July 2018 for randomized-controlled trials (RCTs) and observational studies comparing two fluid management strategies (or observational studies reporting two outcomes with available data on fluid volume received) in adult liver transplant recipients. Study selection, data abstraction, and risk of bias assessment were performed by at least two investigators. Data from RCTs were pooled using risk ratios (RR) and mean differences (MD) with random-effect models. We found seven RCTs and 29 observational studies. Based on RCTs, fluid management strategies did not have any effect on AKI, mortality, or any other postoperative complications. Intraoperative RCTs suggested that a restrictive fluid management strategy reduced pulmonary complications (RR, 0.69; 95% confidence interval [CI], 0.47 to 0.99; n = 283; I2 = 27%), duration of mechanical ventilation (MD, -13.04 hr; 95% CI, -22.2 to -3.88; n = 130; I2 = 0%) and blood loss (MD, -1.14 L; 95% CI, -1.72 to -0.57; n = 151; I2 = 0%). Based on low or very low levels of evidence, we did not find any association between restrictive fluid management strategies and AKI, but we observed possible protective effects of intraoperative restrictive fluid management strategies on other outcomes. PROSPERO (CRD42017054970); registered 18 May, 2017.

Recent imaging studies of amyloid and tau in cognitively normal elderly subjects imply that Alzheimer’s pathology can be tolerated by the brain to some extent due to compensatory mechanisms operating at the cellular and synaptic levels. The present study investigated the effects of an allosteric inhibitor of phosphodiesterase-4D (PDE4D), known as BPN14770 (2-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)acetic Acid), on impairment of memory, dendritic structure, and synaptic proteins induced by bilateral microinjection of oligomeric amyloid beta (Aβ1–42 into the hippocampus of humanized PDE4D (hPDE4D) mice. The hPDE4D mice provide a unique and powerful genetic tool for assessing PDE4D target engagement. Behavioral studies showed that treatment with BPN14770 significantly improved memory acquisition and retrieval in the Morris water maze test and the percentage of alternations in the Y-maze test in the model of Aβ impairment. Microinjection of oligomeric Aβ1–42 caused decreases in the number of dendrites, dendritic length, and spine density of pyramid neurons in the hippocampus. These changes were prevented by BPN14770 in a dose-dependent manner. Furthermore, molecular studies showed that BPN14770 prevented Aβ-induced decreases in synaptophysin, postsynaptic density protein 95, phosphorylated cAMP-response element binding protein (CREB)/CREB, brain-derived neurotrophic factor, and nerve growth factor inducible protein levels in the hippocampus. The protective effects of BPN14770 against Aβ-induced memory deficits, synaptic damage, and the alteration in the cAMP-meditated cell signaling cascade were blocked by H-89 (N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride), an inhibitor of protein kinase A. These results suggest that BPN14770 may activate compensatory mechanisms that support synaptic health even with the onset of amyloid pathology in Alzheimer’s disease. SIGNIFICANCE STATEMENT This study demonstrates that a phosphodiesterase-4D allosteric inhibitor, BPN14770, protects against memory loss and neuronal atrophy induced by oligomeric Aβ1–42. The study provides useful insight into the potential role of compensatory mechanisms in Alzheimer’s disease in a model of oligomeric Aβ1–42 neurotoxicity.

Background Under stress stimulation, p25 is generated by cleavage of p35 and acts as an activator of cyclin-dependent kinase 5 (Cdk5) like p35. Unlike Cdk5/p35, which is important for brain development, aberrant activity of Cdk5/p25 plays a pathological role in neurodegenerative diseases, such as Alzheimer's disease, by inducing hyperphosphorylation of downstream substrates related to pathological progression. A truncated fragment of the c-terminus of p35, the Cdk5 inhibitory peptide (CIP), selectively inhibits Cdk5/ p25 activity in cultured neurons and in CIP/p25 tetra-transgenic mice. Objective First, we aimed to establish a p25 overexpression adult mouse model, then to evaluate whether CIP delivered by adeno-associated virus serotype 9 (AAV9) can ameliorate neuronal toxicity induced by p25. Methods The p25 overexpression mouse model was established by intracerebroventricular (i.c.v.) injection of AAV8-GFP-p25 in 8-week-old mice. One month later, these mice were i.c.v. injected with AAV9-CIP-T2A-mCherry or AAV9 vector as control. Pathological and behavioral changes were assessed 3-months post-injection in all mice. Results The p25 overexpression mice displayed hyperphosphorylation of tau at multiple sites, activation of astrocytes, and elevated inflammatory factors, including IL-1 and TNF-α, which were significantly decreased by the administration of CIP. However, Aβ deposition and microgliosis were not obvious in p25 overexpression mice. In addition, a significant learning decline and anxiety-like behavior were induced by p25 toxicity, and CIP treatment improved learning ability in p25 mice. Conclusion AAV-mediated p25 overexpression mouse model is easy to construct to study p25-induced neuronal toxicity. Application of CIP after p25 insult reverses the pathological changes and behavioral abnormalities.

Research on frailty has expanded in the last decade, but direct evidence supporting its implementation in clinical practice may be limited. This mapping review synthesizes the contexts-of-use and overall clinical applicability of recent pre-COVID frailty research. We sampled 476 articles from articles published on frailty in PubMed and EMBASE in 2017-2018, of which 150 articles were fully appraised for the contexts-of-use, definitions, and interventions. A clinical applicability framework was used to classify articles as practice-changing, practice-informing, or not practice-informing. Of the 476 sampled articles, 31% (n = 150) used frailty in functions that could inform a clinical indication: predictor or mediator (26%, n = 125), selection criterion (3%, n = 15), and effect modifier (2%, n = 10). Articles spanned all health disciplines, and cohort studies comprised 91% (n = 137) of studies and trials 9% (n = 13). Thirty-eight frailty definitions using varied cut-offs and a wide range of interventions were identified. Among all articles, 13% (n = 63) of articles were practice-informing, 2% (n = 11) potentially practice-changing, and 0.2% (n = 1) clearly practice-changing. Lack of well-defined intervention and identifiable effect (96%) or originality (83%) were predominant reasons reducing applicability. Only a minority of recent frailty research provides direct evidence of applicability to practice. Future research on frailty should focus on translating frailty, as a risk factor, into a clinical indication and address definition ambiguity.

Cyclic nucleotide phosphodiesterases (PDEs) control the intracellular concentrations of cAMP and cGMP in virtually all mammalian cells. Accordingly, the PDE family regulates a myriad of physiological functions, including cell proliferation, differentiation and apoptosis, gene expression, central nervous system function, and muscle contraction. Along this line, dysfunction of PDEs has been implicated in neurodegenerative disorders, coronary artery diseases, chronic obstructive pulmonary disease, and cancer development. To date, 11 PDE families have been identified; however, their distinct roles in the various pathologies are largely unexplored and subject to contemporary research efforts. Indeed, there is growing interest for the development of isoform-selective PDE inhibitors as potential therapeutic agents. Similarly, the evolving knowledge on the various PDE isoforms has channeled the identification of new PET probes, allowing isoform-selective imaging. This review highlights recent advances in PDE-targeted PET tracer development, thereby focusing on efforts to assess disease-related PDE pathophysiology and to support isoform-selective drug discovery.

Estrogen deficiency leads to mitochondrial defects that precede Alzheimer's disease (AD)-associated pathological changes in a postmenopausal mouse model. Biochanin A (BCA) is a phytoestrogen isolated from Trifolium pratense L. used to relieve postmenopausal problems in women. In previous work, we observed that oral BCA treatment led to neuroprotection in an ovariectomized rat model. The objective of this study was to investigate whether and how BCA protects against hippocampal mitochondrial damage in a postmenopausal model of AD.APP/PS1 mice underwent bilateral ovariectomy and then, seven days later, received oral BCA at 20 or 40 mg/kg, or oral estradiol at 0.5 mg/kg, daily for 90 days. Sham animals were not ovariectomized and received no additional treatments. Cognitive function was examined using the passive avoidance task, novel object recognition test, and Morris water maze test. The level of circulating estrogen in vivo was assessed indirectly by measuring the wet weight of the uterus. We detected Aβ deposition and PGC-1α in brain by immunohistochemistry; p62, by immunofluorescence; and ERα, ERβ, PGC-1α, NRF1, mtTFA, Drp1, OPA1, Mfn2, Beclin1, LC3B, Pink1, and Parkin by immunoblotting.BCA treatment rescued cognitive decline and reduced Aβ deposition and BACE1 expression in the hippocampus of ovariectomized APP/PS1 mice. BCA reversed the imbalance of mitochondrial dynamics caused by ovariectomy by increasing the expression of phospho-Drp1 (ser637), OPA1, and Mfn2. BCA reversed abnormal mitophagy induced by ovariectomy by increasing the expression of Beclin1, LC3B, Pink1, and Parkin, as well as by reducing the expression of p62.BCA treatment enhances learning and memory abilities and alleviates AD symptoms in a postmenopausal model of AD. A possible mechanism is that BCA rescues the reduction of mitochondrial biogenesis, imbalance of mitochondrial dynamics, and abnormal mitophagy caused by ovariectomy. This study supports further research on BCA to develop treatments for postmenopausal women with AD.

Background Microcirculatory disturbance is closely associated with multiple diseases such as ischemic and septic stroke. Luteolin (3,4,5,7-tetrahydroxyflavone) is a vascular protective flavonoid present in several dietary foods. However, how luteolin plays a role in microcirculatory disturbance is still unknown. The purpose of this study was to find out the influence of luteolin on the lipopolysaccharide (LPS)-induced microcirculatory disturbance, focusing on its effect on leukocyte adhesion and the underlying mechanism of this effect. Methods After injecting LPS into rats, we used an inverted intravital microscope to observe the velocity of red blood cells in venules, numbers of leukocytes adherent to and emigrated across the venular wall, hydrogen peroxide production in venular walls and mast cell degranulation. Intestinal microcirculation blood flow was measured by High-resolution Laser Doppler Perfusion Imaging. Histological changes of small intestine and mesenteric arteries were evaluated. Additionally, cell adhesion stimulated by LPS was tested on EA.hy926 and THP-1 cells. The production of pro-inflammatory cytokines, adhesion molecules and the activation of TLR4/Myd88/NF-κB signaling pathway were determined. Results The results showed luteolin significantly inhibited LPS-induced leukocyte adhesion, hydrogen peroxide production and mast cell degranulation, and increased intestinal microcirculation blood flow and ameliorated pathological changes in the mesenteric artery and the small intestine. Furthermore, luteolin inhibited the release of pro-inflammatory cytokines, the expression of TLR4, Myd88, ICAM-1, and VCAM-1, the phosphorylation of IκB-α and NF-κB/p65 in LPS stimulated EA.hy926. Conclusions Our findings revealed that it is likely that luteolin can ameliorate microcirculatory disturbance. The inhibitory effects of luteolin on the leukocyte adhesion stimulated by LPS, which participates in the development of microcirculatory disturbance, are mediated through the regulation of the TLR4/Myd88/NF-κB signaling pathway.

Preserving both esthetic and functional outcome remains challenging in facial burn injuries. The major issue is the initial treatment of injury. In this study, we focused on patients with partial-thickness facial burns admitted to the burn unit of Tri-Service General Hospital, Taipei, from November 2016 to November 2018. In 21 included patients, customized mask-style, transparent hydrogel-based dressing was applied to the burns. The mean age of included patients was 37.4 years. The mean area of burn injury was 11.9% of total body surface area, and the mean area of second-degree facial burns was 162.3 cm2. Full reepithelialization took, on average, 10.86 days. Scarring was acceptable in terms of texture and color, and no hypertrophic or keloidal scarring was noted. The mean Vancouver Scar Scale score was 2.07. Use of the hydrogel-based dressing masks seems to be a promising means of reducing pain, providing uninterrupted wound healing, facilitating observation, and positively affecting scarring in patients with second-degree facial burns.

SARS-CoV-2 infection causing the novel coronavirus disease 2019 (COVID–19) has been responsible for more than 2.8 million deaths and nearly 125 million infections worldwide as of March 2021. In March 2020, the World Health Organization determined that the COVID–19 outbreak is a global pandemic. The urgency and magnitude of this pandemic demanded immediate action and coordination between local, regional, national, and international actors. In that mission, researchers require access to high-quality biological materials and data from SARS-CoV-2 infected and uninfected patients, covering the spectrum of disease manifestations. The “Biobanque québécoise de la COVID-19” (BQC19) is a pan–provincial initiative undertaken in Québec, Canada to enable the collection, storage and sharing of samples and data related to the COVID-19 crisis. As a disease-oriented biobank based on high-quality biosamples and clinical data of hospitalized and non-hospitalized SARS-CoV-2 PCR positive and negative individuals. The BQC19 follows a legal and ethical management framework approved by local health authorities. The biosamples include plasma, serum, peripheral blood mononuclear cells and DNA and RNA isolated from whole blood. In addition to the clinical variables, BQC19 will provide in-depth analytical data derived from the biosamples including whole genome and transcriptome sequencing, proteome and metabolome analyses, multiplex measurements of key circulating markers as well as anti-SARS-CoV-2 antibody responses. BQC19 will provide the scientific and medical communities access to data and samples to better understand, manage and ultimately limit, the impact of COVID-19. In this paper we present BQC19, describe the process according to which it is governed and organized, and address opportunities for future research collaborations. BQC19 aims to be a part of a global communal effort addressing the challenges of COVID–19.

Background Sexualized drug use or “chemsex” in Taiwan commonly incorporates the use of methamphetamine. Our study aimed to assess the extent of severity of dependence of methamphetamine among MSM in Taiwan as well as motivations for engagement in chemsex. Methods Direct messages were sent to users of a large MSM social networking application in Taiwan between November 2018 and January 2019. MSM who had at least one experience of using drugs during sex in the preceding 12 months were invited to complete an online survey that assessed their sexual behavior, substance use and motivations for engaging in chemsex. The Severity of Dependence Scale was used to assess methamphetamine dependency. Multivariable logistic regression was used to determine the factors associated with methamphetamine dependency. Results From a total of 1906 responses, 517 had used methamphetamine in their lifetime and were included in the analysis. The majority (87.2%) used more than one substance when engaging in chemsex in the past six months, while a quarter reported injection of methamphetamine within the last six months. The most commonly reported motivations for participants to engage in chemsex were to have fun, for relaxation, and to increase the intensity of the sexual experience. Nearly half (46.0%) exhibited signs of methamphetamine dependency. Lower monthly income, injection of methamphetamine, ever feeling lonely in the past 3 months and concerns about their substance use expressed by others were significantly associated with methamphetamine dependency. Conclusion A high proportion of MSM population who engaged in chemsex were at risk of developing methamphetamine dependency. While motivations for engaging in chemsex were diverse and suggest potential for enhanced sexual experience for some, community health organization for gay men's health and healthcare providers should be vigilant at identifying the risk of methamphetamine dependency and provide in-time, brief intervention or referrals when needed.

The French society of clinical biology "Biochemical markers of COVID-19" has set up a working group with the primary aim of reviewing, analyzing and monitoring the evolution of biological prescriptions according to the patient's care path and to look for markers of progression and severity of the disease. This study covers all public and private sectors of medical biology located in metropolitan and overseas France and also extends to the French-speaking world. This article presents the testimonies and data obtained for the "Overseas and French-speaking countries" sub-working group made up of 45 volunteer correspondents, located in 20 regions of the world. In view of the delayed spread of the SARS-CoV-2 virus, the overseas regions and the French-speaking regions have benefited from feedback from the first territories confronted with COVID-19. Thus, the entry of the virus or its spread in epidemic form could be avoided, thanks to the rapid closure of borders. The overseas territories depend very strongly on air and/or sea links with the metropolis or with the neighboring continent. The isolation of these countries is responsible for reagent supply difficulties and has necessitated emergency orders and the establishment of stocks lasting several months, in order to avoid shortages and maintain adequate patient care. In addition, in countries located in tropical or intertropical zones, the diagnosis of COVID-19 is complicated by the presence of various zoonoses (dengue, Zika, malaria, leptospirosis, etc.).

BACKGROUND AND OBJECTIVES Previous studies have revealed that the electroacupuncture or auricular-point pressure as a single treatment approach is beneficial for relieving insomniac symptoms among patients under methadone maintenance treatment (MMT). This study is designed to evaluate the clinical efficacy of combining two treatments. METHODS This study was a randomized, controlled, crossover trial. A total of 50 participants were recruited from the Linsen Chinese Medicine and Kunming Branches of Taipei City Hospital and randomly assigned to Groups A (25 participants) and B (25 participants). In Group A (electroacupuncture at the Hegu point (LI4) and Zusanli point (ST36) and auricular-point pressure on the Shenmen point) and Group B (only auricular-point), the interventions were implemented biweekly for 4 weeks. After a 1-week washout period, a crossover of the groups was performed. Sleep quality, according to the Pittsburgh Sleep Quality Index (PSQI), and daily attendance rate of MMT were evaluated. RESULTS Combined therapy significantly improved sleep quality, especially in the PSQI subscales of subjective sleep quality (60.91% vs 20.93%, P

Rationale: Patients who receive invasive mechanical ventilation (IMV) are usually exposed to opioids as part of their sedation regimen. The rates of posthospital prescribing of opioids are unknown. Objectives: To determine the frequency of persistent posthospital opioid use among patients who received IMV. Methods: We assessed opioid-naive adults who were admitted to an ICU, received IMV, and survived at least 7 days after hospital discharge in Ontario, Canada over a 26-month period (February, 2013 through March, 2015). The primary outcome was new, persistent opioid use during the year after discharge. We assessed factors associated with persistent use by multivariable logistic regression. Patients receiving IMV were also compared with matched hospitalized patients who did not receive intensive care (non-ICU). Measurements and Main Results: Among 25,085 opioid-naive patients on IMV, 5,007 (20.0%; 95% confidence interval [CI], 19.5–20.5) filled a prescription for opioids in the 7 days after hospital discharge. During the next year, 648 (2.6%; 95% CI, 2.4–2.8) of the IMV cohort met criteria for new, persistent opioid use. The patient characteristic most strongly associated with persistent use in the IMV cohort was being a surgical (vs. medical) patient (adjusted odds ratio, 3.29; 95% CI, 2.72–3.97). The rate of persistent use was slightly higher than for matched non-ICU patients (2.6% vs. 1.5%; adjusted odds ratio, 1.37 [95% CI, 1.19–1.58]). Conclusions: A total of 20% of IMV patients received a prescription for opioids after hospital discharge, and 2.6% met criteria for persistent use, an average of 300 new persistent users per year in a population of 14 million. Receipt of surgery was the factor most strongly associated with persistent use.

Despite the establishment of successful surgical techniques and rehabilitation protocols for anterior cruciate ligament (ACL) reconstruction, published return to sport rates are less than satisfactory. This has led orthopaedic surgeons and researchers to develop more robust patient selection methods, and investigate prognostic patient characteristics. No previous studies have integrated baseline characteristics and responses to patient-reported outcome measures (PROMs) of patients with ACL rupture presenting for surgical review. Patients electing to undergo ACL reconstruction under the care of a single orthopaedic surgeon at a metropolitan public hospital were enrolled in a clinical quality registry. Patients completed Veterans RAND 12-item Health Survey (VR-12) Physical Component Summary and Mental Component Summary scores, Tegner activity scale, and International Knee Documentation Committee (IKDC) questionnaires at presentation. Total scores were extracted from the electronic registry, and a machine learning approach (k-means) was used to identify subgroups based on similarity of questionnaire responses. The average scores in each cluster were compared using analysis of variance (ANOVA; Kruskal–Wallis) and nominal logistic regression was performed to determine relationships between cluster membership and patient age, gender, body mass index (BMI), and injury-to-examination delay. A sample of 107 patients with primary ACL rupture were extracted, with 97 (91%) available for analysis with complete datasets. Four clusters were identified with distinct patterns of PROMs responses. These ranged from lowest (Cluster 1) to highest scores for VR-12 and IKDC (Cluster 4). In particular, Cluster 4 returned median scores within 6 points of the patient acceptable symptom state for the IKDC score for ACL reconstruction (70.1, interquartile range: 59–78). Significant (p

Surgical management of cancer may induce stress and increase the likelihood of cancer metastasis and recurrence. Appropriate surgical and anesthetic techniques may affect the patient's outcome. Although numerous studies have been performed, conflicting results have been obtained regarding the effect of anesthetic techniques on the outcome of patients with cancer. We conducted this study to evaluate the association of anesthetic techniques with overall and recurrence-free survival in patients who had undergone gastric cancer surgery. This retrospective study reviewed the electronic medical records of patients, who had visited our hospital and had been diagnosed with gastric cancer between July 1st, 2006 to June 30th, 2016. Univariate analysis of the potential prognostic factors was performed using the log-rank test for categorical factors, and parameters with a P-value

Deemed as incurable, Alzheimer's disease (AD) research is becoming less convoluted as our understanding of its pathology increases. With current treatments focusing on merely mitigating the symptoms of AD, there have been many attempts to find a molecular culprit to serve as the single underlying cause and therapeutic target for clinical applications to approach the disease from its roots. Indeed, over the course of decades, the endless search for a singular target culprit in AD has uncovered a cascade of pathological defects, adding on to each other throughout the progression of the disease. The developmental patterns of amyloid-β (Aβ) oligomers have been studied as a means to discover the complex molecular interplay between various immune responses, genetic mutations, pathway disturbances, and regulating factors that disturb synapse homeostasis before disease manifestation. This new understanding has shifted the underlying goal of the research community from merely removing Aβ oligomers to finding methods that can predict high risk individuals and resorting to cocktail-drug treatments in an attempt to regulate multiple pathways that cumulatively result in the debilitating symptoms of the disease. By utilizing various assays from immuno-targeting to molecular biomarkers, we then interfere in the molecular cascades in an endeavor to avoid synapse dysfunction before disease maturity. Here, we review the current literature supporting the importance of synapses in AD, our current understanding of the molecular interactions leading up to clinical diagnoses, and the techniques used in targeted therapies.

Stress can cause a variety of central nervous system disorders, which are critically mediated by the γ-aminobutyric acid (GABA) system in various brain structures. GABAergic neurons have different subsets, some of which coexpress certain neuropeptides that can be found in the digestive system. Accumulating evidence demonstrates that the gut-brain axis, which is primarily regulated by the vagus nerve, is involved in stress, suggesting a communication between the “gut-vagus-brain” pathway and the GABAergic neuronal system. Here, we first summarize the evidence that the GABAergic system plays an essential role in stress responses. In addition, we review the effects of stress on different brain regions and GABAergic neuron subpopulations, including somatostatin, parvalbumin, ionotropic serotonin receptor 5-HT3a, cholecystokinin, neuropeptide Y, and vasoactive intestinal peptide, with regard to signaling events, behavioral changes, and pathobiology of neuropsychiatric diseases. Finally, we discuss the gut-brain bidirectional communications and the connection of the GABAergic system and the gut-vagus-brain pathway.

The switch from methadone to buprenorphine-naloxone for individuals with heroin dependence is associated with several obstacles and challenges. Such patients may experience discomfort from discontinuing methadone, precipitated withdrawal symptoms induced by buprenorphine-naloxone, and poor psychosocial adjustments such as anticipatory anxiety regarding severe opioid withdrawal. We herein describe a 46-year-old man with a history of heroin dependence who underwent Traditional Chinese Medicine (TCM)-facilitated switching from methadone to buprenorphine-naloxone. No precipitated withdrawal was induced by buprenorphine-naloxone. The drug-switching process was successful and smooth. He maintained abstinence from heroin for the following year. In this case, we applied TCM for enhancement of methadone metabolism and detoxification, analgesic effects, and anxiolytic and hypnotic effects during the drug switch. We observed that TCM effectively facilitated the switch from methadone to buprenorphine-naloxone in our case. Further studies regarding TCM-facilitated treatment for heroin dependence should be conducted.

Multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), and other neurodegenerative diseases of central nervous system (CNS) disorders are serious human health problems. Rho-kinase (ROCK) is emerging as a potentially important therapeutic target relevant to inflammatory neurodegeneration diseases. This is supported by studies showing the beneficial effects of fasudil, a ROCK inhibitor, in inflammatory neurodegeneration diseases. MS is an autoimmune disease resulting from inflammation and demyelination in the white matter of the CNS. It has been postulated that activation of Rho/ROCK causes neuropathological changes accompanied with related clinical symptoms, which are improved by treatment with ROCK inhibitors. Therefore, inhibition of abnormal activation of the Rho/ROCK signaling pathway appears to be a new mechanism for treating CNS diseases. In this review, we extensively discussed the role of ROCK inhibitors, summarized the efficacy of fasudil in the MS conventional animal model of experimental autoimmune encephalomyelitis (EAE), both in vivo and in vitro, and highlighted the mechanism involved. Overall, the findings collected in this review support the role of the ROCK signaling pathway in neurodegenerative diseases. Hence, ROCK inhibitors such as fasudil can be novel, and efficacious treatment for inflammatory neurodegenerative diseases.

ADHD comorbidity has been associated with delayed diagnosis of ASD, but no study has investigated this association in an Asian country. Children with ASD were included and divided into three groups: ADHD before ASD, ADHD same/after ASD, and ASD only. Timing of ASD and ADHD diagnoses were assessed. The logistic regression model was performed to investigate the likelihood of being diagnosed with ASD after 6 years of age between three groups. ADHD before ASD (OR 10.93) group was more likely to being diagnosed with ASD after 6 years of age compared with ADHD same/after ASD (OR: 1.37) and ASD only groups. ADHD comorbidity would delay the diagnosis of ASD in the general clinical settings in Taiwan.

Inhibitors of phosphodiesterases (PDEs) have been widely studied as therapeutics for treatment of human diseases, but improvement on inhibitor selectivity is still desirable for enhancement of inhibitor potency. Here, we report identification of a water-containing subpocket as a PDE4-specific pocket for inhibitor binding. We designed against the pocket and synthesized two enantiomers of PDE4 inhibitor Zl-n-91. The (S)-Zl-n-91 enantiomer showed the IC50 values of 12 and 20 nM respectively for the catalytic domains of PDE4D2 and PDE4B2B, thousand folds of selectivity over other PDE families, and potent neuroprotection activities. Crystal structures of the PDE4D2 catalytic domain in complex with each Zl-n-91 enantiomer revealed that (S)-, but not (R)-Zl-n-91, formed a hydrogen bond with the bound water in the pocket, thus explaining its higher affinity. The structural superposition between the PDE families revealed that this water-containing subpocket is unique to PDE4 and thus valuable for design of PDE4 selective inhibitors.

BackgroundAttention-deficit hyperactivity disorder (ADHD) increases the risk of suicidal behaviours through psychiatric comorbidities; however, a significant direct association has not been observed between ADHD and suicide attempts.AimsTo evaluate the risk of suicide attempt in adolescents and young adults with ADHD.MethodUsing a nationwide, population-based insurance claims database, this longitudinal cohort study enrolled 20 574 adolescents and young adults with ADHD and 61 722 age- and gender-matched controls between 2001 and 2009. Any suicide attempt was identified from enrolment to 31 December 2011. The association between ADHD medications and the likelihood of suicide attempt was assessed.ResultsADHD was an independent risk factor for any suicide attempt (hazard ratio = 3.84, 95% CI = 3.19–4.62) and repeated suicide attempts (hazard ratio = 6.52, 95% CI = 4.46–9.53). Subgroup analyses of men, women, adolescents and young adults demonstrated the same trend. Methylphenidate or atomoxetine treatment did not increase the risk of suicide attempt or repeated suicide attempts. Long-term methylphenidate treatment was associated with a significantly decreased risk of repeated suicide attempts in men (hazard ratio = 0.46, 95% CI = 0.22–0.97).ConclusionADHD was a risk factor for suicide attempt and a stronger predictor of repeated suicide attempts, independent of comorbidities. Further investigation is warranted to explore the mechanism underlying the association between ADHD and suicidal behaviours.Declaration of interestNone.

Phosphodiesterase 7 (PDE7), one of the 11 phosphodiesterase (PDE) families, specifically hydrolyzes cyclic 3', 5'-adenosine monophosphate (cAMP). PDE7 is involved in many important functional processes in physiology and pathology by regulating intracellular cAMP signaling. Studies have demonstrated that PDE7 is widely expressed in the central nervous system (CNS) and potentially related to pathogenesis of many CNS diseases. Here, we summarized the classification and distribution of PDE7 in the brain and its functional roles in the mediation of CNS diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and schizophrenia. It is expected that the findings collected here will not only lead to a better understanding of the mechanisms by which PDE7 mediates CNS function and diseases, but also aid in the development of novel drugs targeting PDE7 for treatment of CNS diseases.

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease. Although anti-fibrotic treatments, such as pirfenidone, are available that reduce the rate of disease progression, these medications have limitations in tolerability, and IPF patients still have poor prognoses. GDC-3280, an orally available small molecule that was designed to improve upon pirfenidone's activity, has anti-fibrotic activity in animal models. This first-in-human, phase 1 trial evaluated GDC-3280 to determine its safety, tolerability, and pharmacokinetics (PK). METHODS Single and multiple ascending-doses of GDC-3280 were administered to healthy volunteers in two parts. Part A consisted of 6 treatment groups, each receiving a single, oral dose of GDC-3280 (25-1600 mg) or placebo in the fasted state. Part A also assessed the effect of food and coadministration of a proton pump inhibitor (rabeprazole) on the tolerability and PK of single doses of 400- and 800-mg GDC-3280. Part B consisted of 3 treatment groups who received either 200- or 275-mg GDC-3280 twice daily or 525-mg once daily after a low-fat meal for 7 days. The trial monitored treatment-emergent adverse events (TEAEs) and assessed the pharmacokinetics of GDC-3280 in blood and urine samples. RESULTS Fifty-six subjects (42 GDC-3280, 14 placebo) in Part A and 24 subjects (18 GDC-3280, 6 placebo) in Part B received treatment. No deaths, serious adverse events, or dose-limiting adverse events occurred, and no subjects withdrew due to a TEAE. In both Parts A and B, most TEAEs were mild. The most frequent TEAEs in Part A were headache and nausea. TEAEs occurred more often when GDC-3280 was administered with food. Pretreatment and coadministration with rabeprazole had no effect on GDC-3280 tolerability. In Part B, the most frequent TEAEs were nausea, dizziness, nasal congestion, and cough. Transient, treatment-related increases in serum creatinine occurred at doses greater than 400 mg in Part A (12%-18% from baseline) and after multiple doses in each group in Part B (20%-34% from baseline). GDC-3280 was generally readily absorbed with a median tmax < 4.0 h following single- or repeat-dose oral administration. In Part A, less-than-dose-proportional increases in systemic exposure occurred, and in Part B, dose-proportional increases occurred within the dose range tested. At doses of 200 mg or lower, more than 50%-70% of orally administered doses were recovered in urine as unchanged GDC-3280 when subjects received a single dose of GDC-3280, suggesting renal excretion is one of the major routes of elimination. Administration of single doses of 400- and 800-mg GDC-3280 after a meal caused statistically significant increases in exposure due to increased rates of absorption compared to the fasted state. Pretreatment and coadministration of rabeprazole dosing led to decreases in exposure compared to GDC-3280 alone, indicating a weak drug-drug interaction. Following repeat dose administration, steady-state plasma concentrations of GDC-3280 were achieved within 2 days with an apparent terminal half-life (t1/2) between 5 and 6 h. CONCLUSIONS Single and multiple doses of GDC-3280 were generally well tolerated, with acceptable safety and pharmacokinetic profiles that support twice-daily, oral administration with food in future clinical trials.

OBJECTIVE Several cross-sectional studies have reported a relationship between posttraumatic stress disorder (PTSD) and epilepsy. However, the temporal association between PTSD and epilepsy has rarely been investigated. We hypothesized that the risk of developing epilepsy later in life would be higher in patients with PTSD than in those without PTSD. METHODS Using the Taiwan National Health Insurance Research Database, 6425 individuals with PTSD and 24,980 age-/sex-matched controls were enrolled between 2002 and 2009 in our study and followed up to the end of 2011. Those who developed epilepsy during the follow-up period were identified. RESULTS Individuals with PTSD had a higher incidence of developing epilepsy (2.65 versus 0.33 per 1000 person-years, p < .001), with an earlier onset of epilepsy (37.53 years [15.80 years] versus 48.11 years [23.97 years], p = .002) than did the controls. Individuals with PTSD had an elevated risk of developing epilepsy (hazard ratio [HR] = 3.72, 95% confidence interval [CI] = 2.27-6.11) during the follow-up after adjustment for demographic data and medical and psychiatric comorbidities. Sensitivity analyses after excluding the observation in the first year (HR = 2.53, 95% CI = 1.44-4.47) and the first 3 years (HR = 2.14, 95% CI = 1.15-4.01) revealed consistent results. CONCLUSIONS These results supported a temporal association between PTSD and the development of epilepsy. Further studies are warranted to investigate the underlying pathophysiological pathways that explain the longitudinal association of PTSD with subsequent epilepsy.

Collection and analysis of health data are crucial to achieving high-quality clinical care, research, and quality improvement. This review explores existing hospital, regional, provincial and national data platforms in Canada to identify gaps and barriers, and recommend improvements for data science. The Canadian Critical Care Trials Group and the Canadian Critical Care Translational Biology Group undertook an environmental survey using list-identified names and keywords in PubMed and the grey literature, from the Canadian context. Findings were grouped into sections, corresponding to geography, purpose, and patient sub-group initiatives, using a narrative qualitative approach. Emerging themes, impressions, and recommendations towards improving data initiatives were generated. In Canada, the Canadian Institute for Health Information Discharge Abstract Database contains high-level clinical data on every adult and child discharged from acute care facilities; however, it does not contain data from Quebec, critical care-specific severity of illness risk-adjustment scores, physiologic data, or data pertaining to medication use. Provincially mandated critical care platforms in four provinces contain more granular data, and can be used to risk adjust and link to within-province data sets; however, no inter-provincial collaborative mechanism exists. There is very limited infrastructure to collect and link biological samples from critically ill patients nationally. Comprehensive international clinical data sets may inform future Canadian initiatives. Clinical and biological data collection among critically ill patients in Canada is not sufficiently coordinated, and lags behind other jurisdictions. An integrated and inclusive critical care data platform is a key clinical and scientific priority in Canada.

To assess temporal trends in pre-existing opioid exposure prior to hospitalization among elderly intensive care unit (ICU) patients and its association with adverse outcomes.We performed a population-based retrospective cohort study using health administrative data from the province of Ontario, Canada. We included all older adult (65 years) admissions to an ICU between April 2002 and March 2015. The exposure was opioid use before admission categorized as chronic use, intermittent use, and non-use.The cohort included 711,312 elderly patient admissions to an ICU. Of these, 6.8% (n = 48,363) were chronic opioid users, 28.1% (n = 200,149) intermittent users, and 65.0% (n = 462,800) non-users. Compared with non-users, chronic opioid users and intermittent users had higher in-hospital mortality (adjusted odds ratio: 1.12, 95% CI, 1.09-1.15, p 0.0001 for chronic users; adjusted odds ratio: 1.09, 95% CI, 1.07-1.11, p 0.0001 for intermittent users), and a lower subdistribution hazard of time to hospital discharge, translating to a longer hospital length of stay (adjusted hazard ratio: 0.87, 95% CI, 0.85-0.88, p 0.0001 for chronic users; adjusted hazard ratio: 0.93, 95% CI, 0.92-0.94, p 0.0001 for intermittent users).Among elderly ICU patients, opioid exposure prior to admission is prevalent and use is associated with higher in-hospital mortality.

Novel pyridine- and pyrimidine-based allosteric inhibitors are reported that achieve PDE4D subtype selectivity through recognition of a single amino acid difference on a key regulatory domain, known as UCR2, that opens and closes over the catalytic site for cAMP hydrolysis. The design and optimization of lead compounds was based on iterative analysis of X-ray crystal structures combined with metabolite identification. Selectivity for the activated, dimeric form of PDE4D provided potent memory enhancing effects in a mouse model of novel object recognition with improved tolerability and reduced vascular toxicity over earlier PDE4 inhibitors that lack subtype selectivity. The lead compound, 28 (BPN14770), has entered mid-stage, human Phase 2 clinical trials for the treatment of Fragile X Syndrome.

BACKGROUND Evidence has shown a significant association between bipolar disorder and prevalence of risky sexual behaviors. However, the relationship between bipolar disorder and risk for sexually transmitted infections (STIs) requires further investigation, as do the effects of bipolar disorder medications on STI risk. METHODS In the present study, data from 26,028 adolescents and young adults with bipolar disorder (ICD-9-CM code 296 except 296.2x, 296.3x, 296.9x, and 296.82) and 104,112 age- and sex-matched non-bipolar-disorder controls from 2001 to 2009 were selected from the Taiwan National Health Insurance Research Database. Patients who contracted any type of STI-including human immunodeficiency virus, syphilis, genital warts, gonorrhea, chlamydial infection, and trichomoniasis-during the follow-up period (from enrollment to the end of 2011) were identified. RESULTS Cox regression analysis with full adjustment for demographic data, psychiatric comorbidities, and bipolar disorder medications showed that bipolar disorder was an independent risk factor (hazard ratio [HR] = 4.11; 95% confidence interval [CI], 3.62-4.66) for contracting an STI. Patients with bipolar disorder and substance and/or alcohol use disorders were at highest risk of STI occurrence. Long-term use of mood stabilizers (HR = 0.54; 95% CI, 0.34-0.86) and atypical antipsychotics (HR = 0.82; 95% CI, 0.71-0.95) was associated with reduced risk for contracting STIs. CONCLUSIONS Adolescents and young adults with bipolar disorder exhibited an increased risk of subsequent STI during the follow-up period compared with those without bipolar disorder. Comorbidity of substance and alcohol use disorders further increased this risk. Long-term use of bipolar disorder medications (mood stabilizers and atypical antipsychotics) may reduce this risk.

Rationale: Bariatric surgery is the recommended treatment for morbid obesity because of its rapid and sustained body weight loss effect. Nutrient deficiency-related neurological complications after bariatric surgery are often disabling. Thus, early recognition of these complications is important. Neurological complications involving the central and peripheral nerve system after bariatric surgery were reported. However, the report on the clinical course of the concurrent involvement of central and peripheral nervous system is limited. We present a rare case of a patient who developed Wernicke encephalopathy concurrent with polyradiculoneuropathy after receiving bariatric surgery. Patient concerns: A 22-year-old man with a history of morbid obesity presented progressive bilateral lower limbs weakness, blurred vision, and gait disturbance 2 months after receiving laparoscopic sleeve gastrectomy. Bilateral lower limb numbness and cognition impairment were also noted. Diagnosis: Brain magnetic resonance imaging and electrophysiologic studies confirmed the diagnosis of Wernicke encephalopathy concurrent with acute polyradiculoneuropathy. Interventions: Vitamin B and folic acid were given since admission. He also received regular intensive rehabilitation program. Outcomes: The subject's cognitive impairment and diplopia improved 1 week after admission under medical treatments, yet lower limb weakness and gait disturbance were still noted. After a month of intensive inpatient rehabilitation, he was able to ambulate with a walker for 30 munder supervision. Lessons: Nutrient deficiency-related neurological complications after bariatric surgery are often disabling and even fatal. Prevention of neurological complications can be improved through close postsurgical follow-up of the nutritional status. Recognizing the signs and symptoms and evaluating the medical history are critical to the early diagnosis and treatment of this potentially serious yet treatable condition.

Objective To assess the independent or comorbid effect of conduct and mood disorders on the risk of suicide. Study design The Taiwan National Health Insurance Research Database was used to derive data for 3711 adolescents aged 12-17 years with conduct disorder and 14 844 age- and sex-matched controls between 2001 and 2009. The participants were followed up to the end of 2011, and those who attempted suicide during the follow-up period were identified. Results Adolescents with conduct disorder had a higher incidence of suicide (0.9% vs 0.1%; P .001) and attempted suicide at a younger age (17.38 ± 2.04 vs 20.52 ± 1.70 years of age) than did the controls. The Cox proportional hazards regression model, after adjustment for demographic data and psychiatric comorbidities, determined that conduct disorder was an independent risk factor for subsequent suicide attempts (hazard ratio, 5.17; 95% CI, 2.29-11.70). The sensitivity after those with other psychiatric comorbidities were excluded revealed a consistent finding (hazard ratio, 10.32; 95% CI, 3.71-28.71). Discussion Adolescents with conduct disorder had an increased risk of suicide attempts over the next decade. Future studies are required to clarify the underlying pathophysiology and elucidate whether prompt intervention for conduct disorder could reduce this risk.

This paper studies the amplitude-frequency characteristic of frontal steady-state visual evoked potential (SSVEP) and its feasibility as a control signal for brain computer interface (BCI). SSVEPs induced by different stimulation frequencies, from 13 ~ 31 Hz in 2 Hz steps, were measured in eight young subjects, eight elders and seven ALS patients. Each subject was requested to participate in a calibration study and an application study. The calibration study was designed to find the amplitude-frequency characteristics of SSVEPs recorded from Oz and Fpz positions, while the application study was designed to test the feasibility of using frontal SSVEP to control a two-command SSVEP-based BCI. The SSVEP amplitude was detected by an epoch-average process which enables artifact-contaminated epochs can be removed. The seven ALS patients were severely impaired, and four patients, who were incapable of completing our BCI task, were excluded from calculation of BCI performance. The averaged accuracies, command transfer intervals and information transfer rates in operating frontal SSVEP-based BCI were 96.1%, 3.43 s/command, and 14.42 bits/min in young subjects; 91.8%, 6.22 s/command, and 6.16 bits/min in elders; 81.2%, 12.14 s/command, and 1.51 bits/min in ALS patients, respectively. The frontal SSVEP could be an alternative choice to design SSVEP-based BCI.

Axillary hyperhidrosis combined with osmidrosis is a common problem, especially in Asian communities, that patients find annoying. Even though several surgical techniques have been reported to treat hyperhidrosis/osmidrosis permanently, patients would prefer a non-surgical approach. A microwave-based device was invented during this decade, and it has proven to be a safe and efficient way to treat axillary hyperhidrosis/osmidrosis without major complications. Mild complications reported are vacuum-associated marks, oedema, tenderness and temporary altered skin sensation. We herein report a rare case of brachial plexus injury with sensory and motor dysfunction that occurred after microwave-based treatment. The patient did not fully recover after 6 months of rehabilitation. Our case suggests that a lower initial energy level should be used for thin patients with less fat tissue on the underarm areas, regardless of the patient's sex.

Background Previous studies have suggested that the unaffected siblings of patients with attention-deficit hyperactivity disorder (ADHD) experience deficits in attention, impulsivity control, and behavior inhibition, which are associated with health-risk behaviors. However, risks to mental and physical health among the unaffected siblings of ADHD probands have rarely been investigated. Methods Using the Taiwan National Health Insurance Research Database, 5128 unaffected siblings of ADHD probands born between 1980 and 2000 were included in our study along with 20,512 age- and sex-matched controls, and they were followed from 1996 or birth until the end of 2011. Mental and physical health risks, including affective disorders, traumatic brain injury (TBI), and sexually transmitted infection were identified during the follow-up period. Results Logistic regression analyses with adjustments for demographic data showed that the unaffected siblings were more likely to develop unipolar depression (odds ratio [OR]: 1.76, 95% confidence interval [CI]: 1.39–2.22), bipolar disorder (OR: 2.10, 95% CI: 1. 09–4.05), and TBI (OR: 1.24, 95% CI: 1.14–1.36) than were the control group. Discussion The unaffected siblings of patients with ADHD were prone to developing unipolar depression, bipolar disorder, and TBI later in life.

Alcohol use disorder (AUD), which combines the criteria of both alcohol abuse and dependence, contributes as an important causal factor to multiple health and social problems. Given the limitation of current treatments, novel medications for AUD are needed to better control alcohol consumption and maintain abstinence. It has been well established that the intracellular signal transduction mediated by the second messengers cyclic AMP (cAMP) and cyclic GMP (cGMP) crucially underlies the genetic predisposition, rewarding properties, relapsing features, and systemic toxicity of compulsive alcohol consumption. On this basis, the upstream modulators phosphodiesterases (PDEs), which critically control intracellular levels of cyclic nucleotides by catalyzing their degradation, are proposed to play a role in modulating alcohol abuse and dependent process. Here, we highlight existing evidence that correlates cAMP and cGMP signal cascades with the regulation of alcohol-drinking behavior and discuss the possibility that PDEs may become a novel class of therapeutic targets for AUD.

This study assessed the total arsenic content and arsenic speciation in rice to determine the health risks associated with rice consumption in various age-gender subgroups in Taiwan. The average total arsenic levels in white rice and brown rice were 116.6 ± 39.2 and 215.5 ± 63.5 ng/g weight (n = 51 and 13), respectively. The cumulative cancer risk among males was 10.4/100,000. The highest fraction of inorganic/total arsenic content in white rice ranged from 76.9 to 88.2 % and from 81.0 to 96.5 % in brown rice. The current study found different arsenic speciation of rice in southern Taiwan, where the famous blackfoot disease has been reported compared with arsenic speciation from other Taiwan areas. Therefore, rice and other grains should be further monitored in southern Taiwan to evaluate whether arsenic contamination is well controlled in this area.

Background Liver transplant recipients suffer many complications, but few intraoperative interventions supported by high-quality evidence have been found effective to reduce their incidence or severity. Fluid balance has been proposed as an important aspect of perioperative care in high-risk recipients. We will conduct a systematic review aimed at evaluating the effects of restrictive perioperative fluid management strategies compared to liberal ones on clinically significant postoperative outcomes. Methods We will search through major databases (CINAHL Complete, EMB Reviews, EMBASE, MEDLINE, PubMed, and the gray literature (CADTH, Clinical Trials, National Guideline Clearing House, NICE, MedNar, Google Scholar and Open Grey)), from inception up to a date close to the review submission for publication, for eligible studies. Randomized controlled trials and comparative non-randomized studies (prospective or retrospective) comparing two fluid management strategies (or two outcomes with available data on fluid volume received for observational studies) on adult liver recipients will be included. Eligible studies will have to report at least one postoperative complication or mortality. Our primary outcome will be acute renal failure and our secondary exploratory outcomes will be all other postoperative complications and mortality. Study selection and data abstraction using an electronic standardized form will be performed by three authors. Risk of bias will be evaluated and data will be pooled if limited clinical diversity is observed. Discussion Human organs available for transplantation are scarce resources. Strategies to improve recipients’ survival are needed. We hypothesize that restrictive fluid management strategies will be associated with better postoperative outcomes than liberal fluid management strategies. This systematic review will improve our understanding of the available evidence and help us better inform future clinical trials. Systematic review registration This systematic review protocol is registered in PROSPERO (CRD42017054970). Electronic supplementary material The online version of this article (10.1186/s13643-018-0841-3) contains supplementary material, which is available to authorized users.