Feasibility of common bibliometrics in evaluating translational science.
A pilot study by 6 Clinical and Translational Science Awards (CTSAs) explored how bibliometrics can be used to assess research influence. Evaluators from 6 institutions shared data on publications (4202 total) they supported, and conducted a combined analysis with state-of-the-art tools. This paper presents selected results based on the tools from 2 widely used vendors for bibliometrics: Thomson Reuters and Elsevier. Both vendors located a high percentage of publications within their proprietary databases (>90%) and provided similar but not equivalent bibliometrics for estimating productivity (number of publications) and influence (citation rates, percentage of papers in the top 10% of citations, observed citations relative to expected citations). A recently available bibliometric from the National Institutes of Health Office of Portfolio Analysis, examined after the initial analysis, showed tremendous potential for use in the CTSA context. Despite challenges in making cross-CTSA comparisons, bibliometrics can enhance our understanding of the value of CTSA-supported clinical and translational research.


A Novel TNF-α-Targeting Aptamer for TNF-α-Mediated Acute Lung Injury and Acute Liver Failure.
Rationale: The TNF-α pathway plays as a double-edged sword that simultaneously regulates cell apoptosis and proliferation. The dysregulated TNF-α signaling can trigger cytokine storms that lead to profound cell death during the phase of acute tissue injury. On the other hand, an optimal level of TNF-α signaling is required for tissue repair following the acute injury phase. The TNF-α pathway is commonly upregulated in acute lung injury (ALI) and acute liver failure (ALF). Previous studies investigated the feasibility of adopting protein-based TNF-α blockers as disease modifiers in ALI and ALF, but none of these came out with a positive result. One of the potential reasons that resides behind the failure of the trials might be the long half-life of these inhibitors that led to undesired side effects. Developing alternative TNF-α blockers with manageable half-lives remain an unmet need in this regard. Methods: In the current study, we developed a novel TNF-α-targeting aptamer (aptTNF-α) and its PEG-derivate (aptTNF-α-PEG) with antagonistic functions. We investigated the in vivo antagonistic effects using mouse ALI and ALF models. Results: Our data showed that aptTNF-α possessed good in vitro binding affinity towards human/mouse TNF-α and successfully targeted TNF-α in vivo. In the mouse ALI model, aptTNF-α/aptTNF-α-PEG treatment attenuated the severity of LPS-induced ALI, as indicated by the improvement of oxygen saturation and lung injury scores, the reduction of protein-rich fluid leakage and neutrophil infiltration in the alveolar spaces, and the suppression of pro-inflammatory cytokines/chemokines expressions in the lung tissues. In the mouse ALF model, we further showed that aptTNF-α/aptTNF-α-PEG treatment not only attenuated the degree of hepatocyte damage upon acute injury but also potentiated early regeneration of the liver tissues. Conclusion: The results implicated potential roles of aptTNF-α/aptTNF-α-PEG in ALI and ALF. The data also suggested their translational potential as a new category of TNF-α blocking agent.


Bloodstream infections caused by ST2 Acinetobacter baumannii: risk factors, antibiotic regimens, and virulence over 6 years period in China.
Bloodstream infection (BSI) caused by multidrug-resistant Acinetobacter baumannii (MDR-AB) has been increasingly observed among hospitalized patients. The following study analyzed the epidemiology and microbiological characteristics of MDR-AB, as well as the clinical features, antimicrobial treatments, and outcomes in patients over a six years period in China. This retrospective study was conducted in a large tertiary hospital in China between January 2013 and December 2018. The clinical and microbiological data of all consecutive hospitalized patients with MDR-AB induced bloodstream infection were included and analyzed. A total of 108 BSI episodes were analyzed. All MDR isolates belonged to ST2, a sequence type that has spread all over the world. Overall, ST2 strains showed strong biofilm formation ability, high serum resistance, and high pathogenicity. As for the clinical characteristics of the patient, 30-day mortality was 69.4% (75/108). The three main risk factors included mechanical ventilation, intensive care unit (ICU) stay, and thrombocytopenia; three protective factors included a change of antimicrobial regimen within 48 h after positive blood culture, use of the antibacterial agent combination, and more inpatient days. The most effective antibacterial regimen was the combination of cefoperazone/sulbactam and tigecycline. BSI caused by ST2 A.baumannii represents a difficult challenge for physicians, considering the high mortality associated with this infection. The combination of cefoperazone/sulbactam and tigecycline may be an effective treatment option.


Glucocorticoid receptor and nuclear factor kappa-b affect three-dimensional chromatin organization.
The impact of signal-dependent transcription factors, such as glucocorticoid receptor and nuclear factor kappa-b, on the three-dimensional organization of chromatin remains a topic of discussion. The possible scenarios range from remodeling of higher order chromatin architecture by activated transcription factors to recruitment of activated transcription factors to pre-established long-range interactions. Using circular chromosome conformation capture coupled with next generation sequencing and high-resolution chromatin interaction analysis by paired-end tag sequencing of P300, we observed agonist-induced changes in long-range chromatin interactions, and uncovered interconnected enhancer-enhancer hubs spanning up to one megabase. The vast majority of activated glucocorticoid receptor and nuclear factor kappa-b appeared to join pre-existing P300 enhancer hubs without affecting the chromatin conformation. In contrast, binding of the activated transcription factors to loci with their consensus response elements led to the increased formation of an active epigenetic state of enhancers and a significant increase in long-range interactions within pre-existing enhancer networks. De novo enhancers or ligand-responsive enhancer hubs preferentially interacted with ligand-induced genes. We demonstrate that, at a subset of genomic loci, ligand-mediated induction leads to active enhancer formation and an increase in long-range interactions, facilitating efficient regulation of target genes. Therefore, our data suggest an active role of signal-dependent transcription factors in chromatin and long-range interaction remodeling.


Xenopus neuralized is a ubiquitin ligase that interacts with XDelta1 and regulates Notch signaling.
Notch signaling in Drosophila requires a RING finger (RF) protein encoded by neuralized. Here we show that the Xenopus homolog of neuralized (Xneur) is expressed where Notch signaling controls cell fate choices in early embryos. Overexpressing XNeur or putative dominant-negative forms in embryos inhibits Notch signaling. As expected for a RF protein, we show that XNeur fulfills the biochemical requirements of ubiquitin ligases. We also show that wild-type XNeur decreases the cell surface level of the Notch ligand, XDelta1, while putative inhibitory forms of XNeur increase it. Finally, we provide evidence that XNeur acts as a ubiquitin ligase for XDelta1 in vitro. We propose that XNeur plays a conserved role in Notch activation by regulating the cell surface levels of the Delta ligands, perhaps directly, via ubiquitination.


Dendritic Cells in Colorectal Cancer and a Potential for their Use in Therapeutic Approaches.
Multiple pathogenic mechanisms contribute to the development of colorectal cancer. This tumor is characterized by high chemoresistance and low immunogenicity due to the effective mechanisms of immunosuppression. Dendritic cells (DCs) play a key role in recognition of tumor antigens and induction of T-cell-primed anticancer response. However, in cancer microenvironment, the function of tumor-infiltrating DCs becomes impaired and switched from the immunostimulation to the immunosuppression. Colorectal cancer cells express anti-inflammatory cytokines such as IL-10 and TGF-β that could affect DC phenotype and support tumor escape from the immune surveillance. As a result, tumor-associated DCs display numerous defects in antigen-presenting capacity and have an altered pattern of expression of immune costimulatory molecules towards the immunoregulatory phenotype. Indeed, understanding of mechanisms, such as how tumor could impair activity of DCs, would help in the development of new DC-based vaccines against colorectal cancer.


Development of a core outcome set for lower limb orthopaedic surgical interventions in ambulant children and young people with cerebral palsy: a study protocol.
Musculoskeletal deformities and gait deviations are common features in ambulatory cerebral palsy (CP). Deformity correction through lower limb orthopaedic surgery is the standard form of care aimed at improving or preserving motor function. Current research on CP care does not always take into account individual patients' expectations and needs. There is a wide range of outcome domains and outcome measures used to assess outcome from treatment. This can lead to reporting bias and make it difficult to compare and contrast studies. A core outcome set (COS) would enhance the efficiency, relevance and overall quality of CP orthopaedic surgery research. The aim of this study is to establish a standardised COS for use in evaluating lower limb orthopaedic surgery for ambulatory children and young people with CP. A set of outcomes domains and outcome measures will be developed as follows: (1) a qualitative evidence synthesis to identify relevant outcomes from children and young people and family perspective; (2) a scoping review to identify relevant outcomes and outcome measures; (3) qualitative research to explore the experience of key stakeholders; (4) prioritisation of outcome domains will be achieved through a two-round Delphi process with key stakeholders; (5) a final COS will be developed at a consensus meeting with representation from key stakeholder groups. Ethical approval for this study was granted in the UK by the Oxfordshire Research Ethics Committee B (REC reference 19/SC/0357). Informed consent will be obtained from participants taking part in the qualitative research and Delphi process. Study findings will be published in an open access journal and presented at relevant national and international conferences. Charities and associations will be engaged to promote awareness of the project COS results. COMET registration: 1236. CRD42018089538.


Simeprevir plus sofosbuvir (12 and 8 weeks) in hepatitis C virus genotype 1-infected patients without cirrhosis: OPTIMIST-1, a phase 3, randomized study.
Effective antiviral therapy is essential for achieving sustained virological response (SVR) in hepatitis C virus (HCV)-infected patients. The phase 2 COSMOS study reported high SVR rates in treatment-naive and prior null-responder HCV genotype (GT) 1-infected patients receiving simeprevir+sofosbuvir±ribavirin for 12 or 24 weeks. OPTIMIST-1 (NCT02114177) was a multicenter, randomized, open-label study assessing the efficacy and safety of 12 and 8 weeks of simeprevir+sofosbuvir in HCV GT1-infected treatment-naive and treatment-experienced patients without cirrhosis. Patients were randomly assigned (1:1; stratified by HCV GT/subtype and presence or absence of NS3 Q80K polymorphism [GT1b, GT1a with Q80K, GT1a without Q80K]), prior HCV treatment history, and IL28B GT [CC, non-CC]) to simeprevir 150 mg once daily+sofosbuvir 400 mg once daily for 12 or 8 weeks. The primary efficacy endpoint was SVR rate 12 weeks after end of treatment (SVR12). Superiority in SVR12 was assessed for simeprevir+sofosbuvir at 12 and 8 weeks versus a composite historical control SVR rate. Enrolled were 310 patients, who were randomized and received treatment (n = 155 in each arm). SVR12 with simeprevir+sofosbuvir for 12 weeks (97% [150/155; 95% confidence interval 94%-100%]) was superior to the historical control (87%). SVR12 with simeprevir+sofosbuvir for 8 weeks (83% [128/155; 95% confidence interval 76-89%]) was not superior to the historical control (83%). The most frequent adverse events were nausea, headache, and fatigue (12-week arm: 15% [23/155], 14% [22/155], and 12% [19/155]; 8-week arm: 9% [14/155], 17% [26/155], and 15% [23/155], respectively). No patients discontinued treatment due to an adverse event. One (1%, 12-week arm) and three (2%, 8-week arm) patients experienced a serious adverse event (all unrelated to study treatment). Simeprevir+sofosbuvir for 12 weeks is highly effective in the treatment of HCV GT1-infected patients without cirrhosis, including those with Q80K. (Hepatology 2016;64:370-380).


Risk and protective factors for the development of ADHD symptoms in children and adolescents: Results of the longitudinal BELLA study.
Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in childhood worldwide, and causes significant impairments in overall functioning. In order to develop effective prevention and intervention programs, knowledge of the determinants that have an impact on the onset and development of ADHD symptoms is essential. So far, little is known about factors affecting ADHD symptoms in children and adolescents over time. Therefore, this study investigates potential psychosocial risk and protective factors for ADHD symptoms based on cross-sectional and longitudinal data of a German population-based study. Data on children and adolescents (n = 1,384 aged 11 to 17 years) were collected at three measurement points (baseline, 1-year and 2-year follow-ups) covering a period of two years. We used latent growth modelling to investigate effects of parental mental health problems (risk factor) and self-efficacy, family climate and social support (protective factors) on symptoms of ADHD based on cross-sectional as well as longitudinal data. Sociodemographic factors, pre- and postnatal factors, and comorbid symptoms of internalizing and externalizing mental health problems were considered as covariates. At baseline, male gender, younger age, stronger aggressive behavior, and stronger parental mental health problems were related to more ADHD symptoms. Longitudinal analyses showed that female gender, migration status, increasing symptoms of generalized anxiety, increasing aggressive behavior and increasing parental mental health problems were associated with stronger increase of ADHD symptoms over time. However, improving family climate was related to decreasing ADHD symptoms over time. We further found moderator effects for social support. The findings of the study provide important information concerning risk and protective factors in the context of ADHD. Hence, the results may be integrated into the planning and implementation of future prevention and early intervention strategies that target affected children and adolescents.


Cocaine receptors labeled by [3H]2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane.
The potent cocaine analog 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)-tropane (CFT, also designated WIN 35,428) was tritiated and evaluated as a molecular probe for cocaine receptors in caudate putamen membranes of cynomolgus monkeys. Kinetic, saturation, and competition experiments indicated that [3H]CFT, like [3H]cocaine, bound to at least two components. Association and dissociation of the radioligand at 0-4 degrees occurred in two phases; the t 1/2 for dissociation of the fast and slow components was 2.5 and 23 min, respectively. Saturation analysis revealed high and low affinity binding components with affinities (Kd) of 4.7 +/- 1.2 and 60 +/- 12 nM (means +/- SE) and densities (Bmax) of 50 +/- 18 and 290 +/- 20 pmol/g of tissue, respectively. [3H]CFT was displaced stereoselectively by the enantiomers of cocaine and by the diastereoisomers of the phenyltropane analog of cocaine. Most congeners displaced [3H]CFT fully, with shallow competition curves (nH, 0.69-0.81). In contrast, several monoamine uptake inhibitors structurally unrelated to cocaine (GBR 12909, Lu 19-005, and mazindol) displaced a maximum of about 90% specifically bound [3H]CFT, with steeper competition curves (nH, 0.89-1.3), suggesting that these drugs bind to a subpopulation of [3H]CFT-labeled sites. The rank order of potency observed in the present study is identical to the rank order of potency at binding sites labeled by [3H]cocaine: Lu 19-005 greater than mazindol greater than CFT greater than GBR 12909 greater than (-)-cocaine greater than bupropion greater than WIN 35,140 greater than (+)-cocaine. Moreover, there is a high positive correlation (r, 0.99, p less than 0.001) between the affinities of drugs at sites labeled by [3H]CFT and [3H]cocaine. The results show that [3H]CFT and [3H]cocaine bind to a similar spectrum of sites in monkey caudate putamen. Because of its higher affinity and slower dissociation rate, [3H]CFT appears to be a superior radioligand probe for these sites.


Adherence to self-care in patients with heart failure in the HeartCycle study.
The purpose of this study was to evaluate a novel online education and coaching program to promote self-care among patients with heart failure. In this program, education and coaching content is automatically tailored to the knowledge and behavior of the patient. The evaluation of the program took place within the scope of the HeartCycle study. This multi-center, observational study examined the ability of a third generation telehealth system to enhance the management of patients recently (<60 days) admitted to the hospital for worsening heart failure or outpatients with persistent New York Heart Association (NYHA) Functional Classification III/IV symptoms. Self-reported self-care behavior was assessed at baseline and study-end by means of the 9-item European Heart Failure Self-care Behavior scale. Adherence to daily weighing, blood pressure monitoring, and reporting of symptoms was determined by analyzing the system's database. Of 123 patients enrolled, the mean age was 66±12 years, 66% were in NYHA III and 79% were men. Self-reported self-care behavior scores (n=101) improved during the study for daily weighing, low-salt diet, physical activity (P<0.001), and fluid restriction (P<0.05). Average adherence (n=120) to measuring weight was 90%±16%, to measuring blood pressure was 89%±17% and to symptom reporting was 66%±32%. Self-reported self-care behavior scores improved significantly during the period of observation, and the objective evidence of adherence to daily weight and blood pressure measurements was high and remained stable over time. However, adherence to daily reporting of symptoms was lower and declined in the long-term.


Cigarette smoking, cytochrome P4501A1 polymorphisms, and breast cancer among African-American and white women.
Previous epidemiologic studies suggest that women with variant cytochrome P4501A1 (CYP1A1) genotypes who smoke cigarettes are at increased risk for breast cancer. We evaluated the association of breast cancer with CYP1A1 polymorphisms and cigarette smoking in a population-based, case-control study of invasive breast cancer in North Carolina. The study population consisted of 688 cases (271 African Americans and 417 whites) and 702 controls (285 African Americans and 417 whites). Four polymorphisms in CYP1A1 were genotyped using PCR/restriction fragment length polymorphism analysis: M1 (also known as CYP1A1*2A), M2 (CYP1A1*2C), M3 (CYP1A1*3), and M4 (CYP1A1*4) No associations were observed for CYP1A1 variant alleles and breast cancer, ignoring smoking. Among women who smoked for longer than 20 years, a modest positive association was found among women with one or more M1 alleles (odds ratio [OR] = 2.1, 95% confidence interval [CI] = 1.2-3.5) but not among women with non-M1 alleles (OR = 1.2, 95% CI = 0.9-1.6). Odds ratios for smoking longer than 20 years were higher among African-American women with one or more M3 alleles (OR = 2.5, 95% CI = 0.9-7.1) compared with women with non-M3 alleles (OR = 1.3, 95% CI = 0.8-2.2). ORs for smoking in white women did not differ appreciably based upon M2 or M4 genotypes. Cigarette smoking increases breast cancer risk in women with CYP1A1 M1 variant genotypes and in African-American women with CYP1A1 M3 variant genotypes, but the modifying effects of the CYP1A1 genotype are quite weak.


Health equity funds as the pathway to universal coverage in Cambodia: care seeking and financial risk protection.
Cambodia has developed the health equity fund (HEF) system to improve access to health services for the poor, and this strengthens the health system towards the universal health coverage goal. Given rising healthcare costs, Cambodia has introduced several innovations and accomplished considerable progress in improving access to health services and catastrophic health expenditures for the targeted population groups. Though this is improving in recent years, HEF households remain at the higher risk of catastrophic spending as measured by the higher share of HEF households with catastrophic health expenses being at 6.9% compared to the non-HEF households of 5.5% in 2017. Poverty targeting poses another challenge for the health system. Nevertheless, HEF appeared to be more significantly associated with decreased out-of-pocket expenditure per illness among those who sought care from public providers. Increasing population and cost coverages of the HEF and effectively attracting beneficiaries to the public sector will further enhance the financial protection and pave the pathway towards universal coverage. Our recommendations focus on leveraging the HEF experience for expanding coverage and increasing equitable access, as well as strengthening the quality of healthcare services.


Analytical expression and optimization of spatial acquisition for intersatellite optical communications.
In intersatellite optical communications it is important to obtain the most efficient performance of acquisition system with respect to acquisition time for a given probability. In this paper a novel approach to the analytical optimization of spatial acquisition is presented as an alternative of the conventional Monte Carlo simulation. First, an analytical expression of estimating mean acquisition time (MAT) is derived as a function of the desired acquisition probability, taking into account the distribution function of satellite position, field of uncertainty (FOU), beam divergence angle and dwell time. Accordingly, the analytical expression of multi-scan, which is always adopted by practical optical terminals to ensure the acquisition success, is also presented. Then, by minimizing the MAT of multi-scan, the optimum ratio of the FOU θU to the pointing error deviation σis obtained, which is θU/σ=1.3. An example for a practical intersatellite acquisition between a Low Earth Orbit Satellite and a Geostationary Earth Orbit Satellite is given. And the theoretical result calculated by the proposed analytical expression is approximately equal to the result by Monte Carlo simulation. The results can be used in designing acquisition system for the intersatellite optical communications.


Reduced risk of breast, endometrial and ovarian cancer in women with celiac disease.
Women with celiac disease (CD) may be at decreased risk of female hormone-related cancers given the observed reduction in breast cancer seen in some cohorts. Using biopsy data from all 28 pathology departments in Sweden, we identified 17,852 women with CD who were diagnosed between 1969 and 2007. We used Cox regression model to estimate their risk of breast, endometrial and ovarian cancer and then compared them with 88,400 age- and sex-matched controls. The results indicate that individuals with CD were at a lower risk for all three outcomes: breast cancer (hazard ratio, HR = 0.85; 95% CI = 0.72-1.01), endometrial cancer (HR = 0.60; 95% CI =0.41-0.86) and ovarian cancer (HR = 0.89; 95% CI =0.59-1.34). This inverse relationship was strengthened when we excluded the first year of follow-up beyond CD diagnosis (breast: HR = 0.82; 95% CI =0.68-0.99; endometrial: HR = 0.58; 0.39-0.87; ovarian cancer: HR = 0.72; 0.45-1.15). In conclusion, CD seems to be inversely related not only to breast cancer but also to endometrial and ovarian cancer. Potential explanations include shared risk factors and early menopause.


Inhibition of cytokine-mediated JNK signalling by purinergic P2Y11 receptors, a novel protective mechanism in endothelial cells.
Previous research from our laboratory has demonstrated a novel phenomenon whereby GPCRs play a role in inhibiting cytokine-mediated c-Jun N-terminal kinase (JNK) signalling. So far this novel phenomenon seems to have been vastly overlooked, with little research in the area. Therefore, in this study we explored this further; by assessing the potential of P2YRs to mediate inhibition of cytokine-mediated JNK signalling and related functional outcomes in human endothelial cells. We utilised primary endothelial cells, and employed the use of endogenous activators of P2YRs and well characterised pharmacological inhibitors, to assess signalling parameters mediated by P2YRs, Interleukin-1β (IL-1β), TNFα and JNK. Activation of P2YRs with adenosine tri-phosphate (ATP) resulted in a time- and concentration-dependent inhibition of IL-1β-mediated phosphorylation of JNK and associated kinase activity. The effect was specific for cytokine-mediated JNK signalling, as ATP was without effect on JNK induced by other non-specific activators (e.g. sorbitol, anisomycin), nor effective against other MAPK pathways such as p38 and the canonical NFκB cascade. Pharmacological studies demonstrated a role for the P2Y11 receptor in mediating this effect, but not the P2Y1 nor the adenosine receptors (A1, A2A, A2B & A3). The novel Gαq/11 inhibitor YM254890 and a protein kinase A (PKA) inhibitor H89 both partially reversed ATP-mediated inhibition of IL-1β-stimulated JNK indicating involvement of both Gαq/11 and Gαs mediated pathways. ATP also partially reversed IL-1β-mediated induction of cyclo‑oxygenase-2 (COX-2) and E-selectin. Collectively, these studies indicate the potential for activation of purinergic receptors to protect the endothelium from inflammatory driven JNK activation and may be a new target for inflammatory disease therapy.


Protective Effects of Hydrogen Gas on Experimental Acute Pancreatitis.
Acute pancreatitis (AP) is an inflammatory disease mediated by damage to acinar cells and pancreatic inflammation. In patients with AP, subsequent systemic inflammatory responses and multiple organs dysfunction commonly occur. Interactions between cytokines and oxidative stress greatly contribute to the amplification of uncontrolled inflammatory responses. Molecular hydrogen (H2) is a potent free radical scavenger that not only ameliorates oxidative stress but also lowers cytokine levels. The aim of the present study was to investigate the protective effects of H2 gas on AP both in vitro and in vivo. For the in vitro assessment, AR42J cells were treated with cerulein and then incubated in H2-rich or normal medium for 24 h, and for the in vivo experiment, AP was induced through a retrograde infusion of 5% sodium taurocholate into the pancreatobiliary duct (0.1 mL/100 g body weight). Wistar rats were treated with inhaled air or 2% H2 gas and sacrificed 12 h following the induction of pancreatitis. Specimens were collected and processed to measure the amylase and lipase activity levels; the myeloperoxidase activity and production levels; the cytokine mRNA expression levels; the 8-hydroxydeoxyguanosine, malondialdehyde, and glutathione levels; and the cell survival rate. Histological examinations and immunohistochemical analyses were then conducted. The results revealed significant reductions in inflammation and oxidative stress both in vitro and in vivo. Furthermore, the beneficial effects of H2 gas were associated with reductions in AR42J cell and pancreatic tissue damage. In conclusion, our results suggest that H2 gas is capable of ameliorating damage to the pancreas and AR42J cells and that H2 exerts protective effects both in vitro and in vivo on subjects with AP. Thus, the results obtained indicate that this gas may represent a novel therapy agent in the management of AP.


Nonpharmacologic approaches to the management of insomnia.
Insomnia is one of the more common complaints patients present to their physicians. Sleep problems affect up to one-third of all Americans, and the loss of workplace productivity and increased healthcare utilization result in costs approaching $100 billion a year. Patients with acute insomnia generally respond well to various sedative hypnotic medications, but chronic insomnia is a different challenge. Physicians and patients may raise concerns about the long-term use of sedative hypnotic medications. Even in light of these concerns, however, the chronic insomnia remains, ostensibly leaving the physician few choices. A number of promising nonpharmacologic strategies are available that physicians can easily implement. Through the use of self-rating instruments and a sleep log, physicians can bring the sleep problem into better focus and monitor the efficacy of clinical interventions. Certain behavioral techniques, such as sleep hygiene, stimulus control, and sleep restriction, can be effective remedies for chronic insomnia. The use of cranial electric stimulation for insomnia is also showing promising results. Through careful assessment and the adoption of simple nonpharmacologic strategies, the physician's interventions may result in a good night's sleep.


Early identification of non-remission in first-episode psychosis in a two-year outcome study.
To identify predictors of non-remission in first-episode, non-affective psychosis. During 4 years, we recruited 301 patients consecutively. Information about first remission at 3 months was available for 299 and at 2 years for 293 cases. Symptomatic and social outcomes were assessed at 3 months, 1 and 2 years. One hundred and twenty-nine patients (43%) remained psychotic at 3 months and 48 patients (16.4%) remained psychotic over 2 years. When we compared premorbid and baseline data for the three groups, the non-remitted (n = 48), remitted for <6 months (n = 38) and for more than 6 months (n = 207), duration of untreated psychosis (DUP) was the only variable that significantly differentiated the groups (median DUP: 25.5, 14.4 and 6.0 weeks, respectively). Three months univariate predictors of non-remission were being single, longer DUP, core schizophrenia, and less excitative and more negative symptoms at baseline. Two-year predictors were younger age, being single and male, deteriorating premorbid social functioning, longer DUP and core schizophrenia. In multivariate analyses DUP, negative and excitative symptoms predicted non-remission at 3 months, but only DUP predicted at 2 years. Long DUP predicted both 3 month and 2-year non-remission rates in first-episode psychosis.


Drug withdrawal conceptualized as a stressor.
Drug withdrawal is often conceptualized as an aversive state that motivates drug-seeking and drug-taking behaviors in humans. Stress is more difficult to define, but is also frequently associated with aversive states. Here we describe evidence for the simple theory that drug withdrawal is a stress-like state, on the basis of common effects on behavioral, neurochemical, and molecular endpoints. We also describe data suggesting a more complex relationship between drug withdrawal and stress. As one example, we will highlight evidence that, depending on drug class, components of withdrawal can produce effects that have characteristics consistent with mood elevation. In addition, some stressors can act as positive reinforcers, defined as having the ability to increase the probability of a behavior that produces it. As such, accumulating evidence supports the general principles of opponent process theory, whereby processes that have an affective valence are followed in time by an opponent process that has the opposite valence. Throughout, we identify gaps in knowledge and propose future directions for research. A better understanding of the similarities, differences, and overlaps between drug withdrawal and stress will lead to the development of improved treatments for addiction, as well as for a vast array of neuropsychiatric conditions that are triggered or exacerbated by stress.


Strong maternal Khoisan contribution to the South African coloured population: a case of gender-biased admixture.
The study of recently admixed populations provides unique tools for understanding recent population dynamics, socio-cultural factors associated with the founding of emerging populations, and the genetic basis of disease by means of admixture mapping. Historical records and recent autosomal data indicate that the South African Coloured population forms a unique highly admixed population, resulting from the encounter of different peoples from Africa, Europe, and Asia. However, little is known about the mode by which this admixed population was recently founded. Here we show, through detailed phylogeographic analyses of mitochondrial DNA and Y-chromosome variation in a large sample of South African Coloured individuals, that this population derives from at least five different parental populations (Khoisan, Bantus, Europeans, Indians, and Southeast Asians), who have differently contributed to the foundation of the South African Coloured. In addition, our analyses reveal extraordinarily unbalanced gender-specific contributions of the various population genetic components, the most striking being the massive maternal contribution of Khoisan peoples (more than 60%) and the almost negligible maternal contribution of Europeans with respect to their paternal counterparts. The overall picture of gender-biased admixture depicted in this study indicates that the modern South African Coloured population results mainly from the early encounter of European and African males with autochthonous Khoisan females of the Cape of Good Hope around 350 years ago.


Extrusion of barley and oat influence the fecal microbiota and SCFA profile of growing pigs.
The effect of extrusion of barley and oat on the fecal microbiota and the formation of SCFA was evaluated using growing pigs as model system. The pigs were fed a diet containing either whole grain barley (BU), oat groat (OU), or their respective extruded samples (BE and OE). 454 pyrosequencing showed that the fecal microbiota of growing pigs was affected by both extrusion and grain type. Extruded grain resulted in lower bacterial diversity and enrichment in operational taxonomic units (OTUs) affiliated with members of the Streptococcus, Blautia and Bulleidia genera, while untreated grain showed enrichment in OTUs affiliated with members of the Bifidobacterium and Lactobacillus genera, and the butyrate-producing bacteria Butyricicoccus, Roseburia, Coprococcus and Pseudobutyrivibrio. Untreated grain resulted in a significant increase of n-butyric, i-valeric and n-valeric acid, which correlated with an increase of Bifidobacterium and Lactobacillus. This is the first study showing that cereal extrusion affects the microbiota composition and diversity towards a state generally thought to be less beneficial for health, as well as less amounts of beneficial butyric acid.


Riding the wave of younger residents in long-term care.
Younger patients represent a growing percentage of nursing facility residents. Patients younger than 65 years of age comprise about 14% of the population in this setting. They are victims of traumatic brain or spinal cord injuries and diseases such as amyotrophic lateral sclerosis and Huntington's disease. These individuals present some novel challenges for pharmacists and other practitioners because they often are more informed and involved in their care, have younger family members (including small children), have addiction issues, and may have expected life spans much longer than the average elder nursing facility resident. By understanding these individuals and their special needs and issues, pharmacists can help maximize the quality of care younger residents receive, enhancing their quality of life.


[Case of thrombotic thrombocytopenic purpura with a positive Coomb test].
We report a case of thrombotic thrombocytopenic purpura (TTP) with a positive Coombs' test. A 59-year-old female was admitted to our hospital in February, 1997 with symptoms of heart failure. Ultrasound cardiography showed moderate pericardiac effusion and she was diagnosed as having pericarditis. After admission she had anorexia and her urine volume was reduced. Laboratory tests showed anemia and thrombocytopenia. Her Coombs' test result was positive. Her renal function gradually worsened and her conscious level was reduced. We diagnosed her as TTP and judged that she needed hemodialysis. We performed plasma exchange and started steroid therapy. The renal biopsy was compatible with TTP. After treatment, her level of consciousness improved, but her renal function did not improve. On the 51st hospital day she fell into acute respiratory distress syndrome (ARDS) and entered ICU. We considered ARDS caused by infection and continued treatment, but she died of shock and lactate acidosis. Activity of von Willebrand factor-cleaving protease in our case was 15% before the first PE, and 25 % just before death. A case of TTP without collagen disease usually shows a negative Coombs' test result. We think that this was a rare case in which autoimmune hemolytic anemia was supervened with TTP.


Human immunodeficiency virus-infected individuals contain provirus in small numbers of peripheral mononuclear cells and at low copy numbers.
In human immunodeficiency virus (HIV)-infected individuals, the proportion of circulating mononuclear cells (PBMCs) which carry HIV provirus and the number of HIV proviral sequences per infected PBMC have been matters for conjecture. Using a double polymerase chain reaction which allows the detection of single molecules of provirus and a method of quantifying the provirus molecules, we have measured provirus frequencies in infected individuals down to a level of one molecule per 10(6) PBMCs. As a general rule, only a small proportion of PBMCs contain provirus (median value of samples from 12 patients, one per 8,000 cells), and most if not all of the infected cells carry a single provirus molecule. The frequency of provirus-carrying cells correlated positively both with the progression of the disease and with the success with which virus could be isolated from the same patients by cocultivation methods. Of seven asymptomatic (Centers for Disease Control stage II) patients, all but one contained one provirus molecule per 6,000 to 80,000 cells; of five Centers for Disease Control stage IV patients, all but one contained one provirus molecule per 700 to 3,300 cells. When considered in conjunction with estimates of the frequency of PBMCs that express viral RNA, our results suggest that either (i) the majority of provirus-containing cells are monocytes or (ii) most provirus-containing lymphocytes are transcriptionally inactive. We also present nucleotide sequence data derived directly from provirus present in vivo which we show is not marred by the in vitro selection of potential virus variants or by errors introduced by Taq polymerase. We argue from these data that, of the provirus present in infected individuals, the proportion which is defective is not high in the regions sequenced.


Structure-based discovery of new maternal embryonic leucine zipper kinase inhibitors.
Maternal embryonic leucine zipper kinase (MELK), a serine/threonine protein kinase, has oncogenic properties and plays a key functional role in various cancer cells. Although MELK may not be a cancer addiction target, the development of specific MELK inhibitors would provide useful chemical tools for synthetic lethal investigation. Herein, we identified several hit compounds using a customized structure-based virtual screening, among which compounds 4 and 16 showed the most potent inhibition to MELK with IC50 values of 3.52 μM and 178.3 nM, respectively. In vitro cell-based assays revealed that 16 has no effect on the growth of various types of cancer cells, but has the potential to inhibit cancer cell migration and invasion. Western blotting analyses revealed that 16 suppresses the phosphorylation of focal adhesion kinase (FAK), a downstream molecule of MELK, which is a key kinase in regulating cancer cell migration and invasion.


Multiple effects of anthracene-9-carboxylic acid on the TMEM16B/anoctamin2 calcium-activated chloride channel.
Ca(2+)-activated Cl(-) currents (CaCCs) play important roles in many physiological processes. Recent studies have shown that TMEM16A/anoctamin1 and TMEM16B/anoctamin2 constitute CaCCs in several cell types. Here we have investigated for the first time the extracellular effects of the Cl(-) channel blocker anthracene-9-carboxylic acid (A9C) and of its non-charged analogue anthracene-9-methanol (A9M) on TMEM16B expressed in HEK 293T cells, using the whole-cell patch-clamp technique. A9C caused a voltage-dependent block of outward currents and inhibited a larger fraction of the current as depolarization increased, whereas the non-charged A9M produced a small, not voltage dependent block of outward currents. A similar voltage-dependent block by A9C was measured both when TMEM16B was activated by 1.5 and 13μM Ca(2+). However, in the presence of 1.5μM Ca(2+) (but not in 13μM Ca(2+)), A9C also induced a strong potentiation of tail currents measured at -100mV after depolarizing voltages, as well as a prolongation of the deactivation kinetics. On the contrary, A9M did not produce potentiation of tail currents, showing that the negative charge is required for potentiation. Our results provide the first evidence that A9C has multiple effects on TMEM16B and that the negative charge of A9C is necessary both for voltage-dependent block and for potentiation. Future studies are required to identify the molecular mechanisms underlying these complex effects of A9C on TMEM16B. Understanding these mechanisms will contribute to the elucidation of the structure and functional properties of TMEM16B channels.


Follow up study of haematological effects in workers exposed to 2-methoxyethanol.
To examine the association between 2-methoxyethanol (2-ME) exposure and haematological effects, as well as the recovery from these haematological effects with continuous reduction in exposure to 2-ME. Twenty nine exposed and 90 non-exposed workers were recruited. Haematological parameters, eight hour full shift personal exposure to 2-ME, and urinary 2-methoxyacetic acid (MAA) were repeatedly measured in three consecutive surveys within six months. Results of haematological examination in the first exposure survey showed that haemoglobin, packed cell volume, and red blood cell count in the male exposed workers were significantly lower than those in the comparison workers. The frequency of anaemia in the exposed group (42%) was significantly higher than that in the comparison group (3%). The haematological effects were significantly associated with the urinary MAA of exposed workers. The haematological effects had returned to normal in the first follow up survey 2.5 months later, when a reduction in 2-ME exposure was noted. Haematological results of the second follow up examination six months later remained normal. The mean airborne exposure of 2-ME in the three surveys dropped from 35.7 to 2.65, then to 0.55 ppm. The mean urinary MAA of exposed workers in the three surveys was reduced from 57.7 to 24.6, then to 13.5 mg/g creatinine (n = 29). The reduction in exposure through both inhalation and potential dermal contact with 2-ME might account for the haematological recovery. 2-ME is a haematological toxin which leads to anaemia in exposed workers. However, the toxic haematological effects of 2-ME persist for only a short period of time after cessation or reduction of exposure.


Multidiscipline Stroke Post-Acute Care Transfer System: Propensity-Score-Based Comparison of Functional Status.
Few studies have investigated the characteristics of stroke inpatients after post-acute care (PAC) rehabilitation, and few studies have applied propensity score matching (PSM) in a natural experimental design to examine the longitudinal impacts of a medical referral system on functional status. This study coupled a natural experimental design with PSM to assess the impact of a medical referral system in stroke patients and to examine the longitudinal effects of the system on functional status. The intervention was a hospital-based, function oriented, 12-week to 1-year rehabilitative PAC intervention for patients with cerebrovascular diseases. The average duration of PAC in the intra-hospital transfer group (31.52 days) was significantly shorter than that in the inter-hospital transfer group (37.1 days) (p < 0.001). The intra-hospital transfer group also had better functional outcomes. The training effect was larger in patients with moderate disability (Modified Rankin Scale, MRS = 3) and moderately severe disability (MRS = 4) compared to patients with slight disability (MRS = 2). Intensive post-stroke rehabilitative care delivered by per-diem payment is effective in terms of improving functional status. To construct a vertically integrated medical system, strengthening the qualified local hospitals with PAC wards, accelerating the inter-hospital transfer, and offering sufficient intensive rehabilitative PAC days are the most essential requirements.


Characterization of the Caenorhabditis elegans UDP-galactopyranose mutase homolog glf-1 reveals an essential role for galactofuranose metabolism in nematode surface coat synthesis.
Galactofuranose (Gal(f)), the furanoic form of d-galactose produced by UDP-galactopyranose mutases (UGMs), is present in surface glycans of some prokaryotes and lower eukaryotes. Absence of the Gal(f) biosynthetic pathway in vertebrates and its importance in several pathogens make UGMs attractive drug targets. Since the existence of Gal(f) in nematodes has not been established, we investigated the role of the Caenorhabditis elegans UGM homolog glf-1 in worm development. glf-1 mutants display significant late embryonic and larval lethality, and other phenotypes indicative of defective surface coat synthesis, the glycan-rich outermost layer of the nematode cuticle. The glf homolog from the protozoan Leishmania major partially complements C. elegans glf-1. glf-1 mutants rescued by L. major glf, which behave as glf-1 hypomorphs, display resistance to infection by Microbacterium nematophilum, a pathogen of rhabditid nematodes thought to bind to surface coat glycans. To confirm the presence of Gal(f) in C. elegans, we analyzed C. elegans nucleotide sugar pools using online electrospray ionization-mass spectrometry (ESI-MS). UDP-Gal(f) was detected in wild-type animals while absent in glf-1 deletion mutants. Our data indicate that Gal(f) likely has a pivotal role in maintenance of surface integrity in nematodes, supporting investigation of UGM as a drug target in parasitic species.


Highly Sensitive Lineage Discrimination of SARS-CoV-2 Variants through Allele-Specific Probe PCR.
Tools to detect SARS-CoV-2 variants of concern and track the ongoing evolution of the virus are necessary to support public health efforts and the design and evaluation of novel COVID-19 therapeutics and vaccines. Although next-generation sequencing (NGS) has been adopted as the gold standard method for discriminating SARS-CoV-2 lineages, alternative methods may be required when processing samples with low viral loads or low RNA quality. To this aim, an allele-specific probe PCR (ASP-PCR) targeting lineage-specific single nucleotide polymorphisms (SNPs) was developed and used to screen 1,082 samples from two clinical trials in the United Kingdom and Brazil. Probit regression models were developed to compare ASP-PCR performance against 1,771 NGS results for the same cohorts. Individual SNPs were shown to readily identify specific variants of concern. ASP-PCR was shown to discriminate SARS-CoV-2 lineages with a higher likelihood than NGS over a wide range of viral loads. The comparative advantage for ASP-PCR over NGS was most pronounced in samples with cycle threshold (CT) values between 26 and 30 and in samples that showed evidence of degradation. Results for samples screened by ASP-PCR and NGS showed 99% concordant results. ASP-PCR is well suited to augment but not replace NGS. The method can differentiate SARS-CoV-2 lineages with high accuracy and would be best deployed to screen samples with lower viral loads or that may suffer from degradation. Future work should investigate further destabilization from primer-target base mismatch through altered oligonucleotide chemistry or chemical additives.


Recombination of the Phase-Variable spnIII Locus Is Independent of All Known Pneumococcal Site-Specific Recombinases.
Streptococcus pneumoniae is one of the world's leading bacterial pathogens, causing pneumonia, septicemia, and meningitis. In recent years, it has been shown that genetic rearrangements in a type I restriction-modification system (SpnIII) can impact colony morphology and gene expression. By generating a large panel of mutant strains, we have confirmed a previously reported result that the CreX (also known as IvrR and PsrA) recombinase found within the locus is not essential for hsdS inversions. In addition, mutants of homologous recombination pathways also undergo hsdS inversions. In this work, we have shown that these genetic rearrangements, which result in different patterns of genome methylation, occur across a wide variety of serotypes and sequence types, including two strains (a 19F and a 6B strain) naturally lacking CreX. Our gene expression analysis, by transcriptome sequencing (RNAseq), confirms that the level of creX expression is impacted by these genomic rearrangements. In addition, we have shown that the frequency of hsdS recombination is temperature dependent. Most importantly, we have demonstrated that the other known pneumococcal site-specific recombinases XerD, XerS, and SPD_0921 are not involved in spnIII recombination, suggesting that a currently unknown mechanism is responsible for the recombination of these phase-variable type I systems.IMPORTANCEStreptococcus pneumoniae is a leading cause of pneumonia, septicemia, and meningitis. The discovery that genetic rearrangements in a type I restriction-modification locus can impact gene regulation and colony morphology led to a new understanding of how this pathogen switches from harmless colonizer to invasive pathogen. These rearrangements, which alter the DNA specificity of the type I restriction-modification enzyme, occur across many different pneumococcal serotypes and sequence types and in the absence of all known pneumococcal site-specific recombinases. This finding suggests that this is a truly global mechanism of pneumococcal gene regulation and the need for further investigation of mechanisms of site-specific recombination.


Refined models for the preferential interactions of tryptophan with phosphocholines.
A series of molecular models of the adducts formed between N-acetyl-l-tryptophan ethylamide and diacetyl-sn-glycero-3-phosphocholine have been generated. Using rOesy data that enabled us to place restrictions on the proximity of a number of key protons in the amino acid/phosphocholine pairs, a series of structures were generated following molecular dynamics and mechanics experiments using the CHARMM27 force field. These structures were then subjected to a series of clustering algorithms in order to classify the tight binding interactions between a single tryptophan and a phosphocholine. From these analyses, it is evident that: (i) binding is characterised by hydrogen bonding between the indole NH as donor and phosphate oxygen as acceptor, cation-carbonyl interactions between the choline ammonium and amide carbonyl groups and cation-pi interactions; (ii) cation-pi interactions are not always observed, particularly when their formation is at the expense of cation-carbonyl and hydrogen bonding interactions; (iii) on the basis of amino acid torsional parameters, it is possible to predict whether the phosphocholine headgroup will bind in a compact or elongated conformation. Extension of the procedures to characterise 2 : 1 Trp-PC binding revealed that the same intermolecular interactions are predominant; however, combinations of all three intermolecular interactions within the same adduct occur much more frequently due to the availability of donor/acceptor groups from both tryptophans in the 2 : 1 system.


Design of the Spine Patient outcomes Research Trial (SPORT).
The Spine Patient Outcomes Research Trial (SPORT) was designed to assess the relative efficacy and cost-effectiveness of surgical and nonsurgical approaches to the treatment of common conditions associated with low back and leg pain. To describe the rationale and design of the SPORT project and to discuss its strengths and limitations. Descriptive. First, the authors explain the rationale for embarking on SPORT, i.e., deficiencies in the existing scientific knowledge base for treatment of these conditions. Second, the authors describe the design of SPORT, including topics such as specific aims, participating sites, study population, recruitment and enrollment, study interventions, follow-up, outcomes, statistical analysis, and study governance and organization. Finally, issues that complicate the performance of randomized trials in surgery as they relate to the design and conduct of SPORT are discussed. The SPORT project is being conducted at 11 clinical centers around the United States. It involves the simultaneous conduct of three multicenter, randomized, controlled clinical trials. The study includes patients with the three most common diagnoses for which spine surgery is performed: intervertebral disc herniation, spinal stenosis, and degenerative spondylolisthesis, and it compares the most commonly used standard surgical and nonsurgical treatments for patients with these diagnoses. By the end of enrollment the authors anticipate a total of 500 patients with intervertebral disc herniation, 370 patients with spinal stenosis, and 300 patients with degenerative spondylolisthesis in the randomized trials. Patients who meet the eligibility criteria but decline to be randomized are invited to participate in an observational cohort study. Patients are being followed for a minimum of 24 months with visits scheduled at 6 weeks and at 3, 6, 12, and 24 months. The results of this study will provide high-quality scientific evidence to aid clinical decision-making and improve treatment outcomes for these common, costly, and, in some instances, debilitating conditions.


Arterial pole progenitors interpret opposing FGF/BMP signals to proliferate or differentiate.
During heart development, a subpopulation of cells in the heart field maintains cardiac potential over several days of development and forms the myocardium and smooth muscle of the arterial pole. Using clonal and explant culture experiments, we show that these cells are a stem cell population that can differentiate into myocardium, smooth muscle and endothelial cells. The multipotent stem cells proliferate or differentiate into different cardiovascular cell fates through activation or inhibition of FGF and BMP signaling pathways. BMP promoted myocardial differentiation but not proliferation. FGF signaling promoted proliferation and induced smooth muscle differentiation, but inhibited myocardial differentiation. Blocking the Ras/Erk intracellular pathway promoted myocardial differentiation, while the PLCgamma and PI3K pathways regulated proliferation. In vivo, inhibition of both pathways resulted in predictable arterial pole defects. These studies suggest that myocardial differentiation of arterial pole progenitors requires BMP signaling combined with downregulation of the FGF/Ras/Erk pathway. The FGF pathway maintains the pool of proliferating stem cells and later promotes smooth muscle differentiation.


Planned vaginal delivery of fetuses in breech presentation at term: prenatal determinants predictive of elevated risk of cesarean delivery during labor.
Identify the prenatal determinants associated with cesarean delivery during labor of term breech presentation for which vaginal delivery is planned. Prospective study of 174 French and Belgian maternity units. Relations between cesarean and prenatal determinants were estimated with a multilevel logistic model and expressed as adjusted ORs. A prediction score for cesarean section was proposed and diagnostic values were estimated for different cutoff values. Of 2,478 women meeting the inclusion criteria, 705 (28.5%) had cesarean deliveries. Nulliparity, complete breech, rupture of membranes before labor, fetal weight > or = 3800 g, biparietal diameter > 95 mm and university and public non-teaching hospital maternity units were significantly associated with cesarean delivery during labor. The rate of cesarean during labor was significantly higher in establishments where more than 80% of women had planned cesareans and in cases where mode of delivery had not been decided before labor. The prediction score values ranged from 9 to 21.4 (10th, 50th and 90th percentiles corresponded to 10.1, 12.2 and 14.7). The cesarean rate was 43% in women whose score was greater than the cutoff point of 12.9, and 15% for women whose score was below this value. Our findings indicate that once vaginal delivery has been decided upon, the risk of cesarean delivery during labor for breech presentation at term depends not only on the progress of labor, but also on prenatal determinants both maternal and obstetrical. It also depends on some characteristics of the maternity units. Obstetricians should either plan cesarean delivery or define stringent rules for indications of cesarean during labor.


Disorders in myelination in the twitcher mutant: immunohistochemical and biochemical studies.
The twitcher is an autosomal recessive mutant mouse characterized by absence of galactosylceramidase. The twitcher shows clinical and histological features similar to those of human Krabbe-type leukodystrophy. We here present the results of a neurochemical and immunohistochemical analysis of the twitcher. Electrophoretic analysis revealed that in the particulate fraction of the spinal cord, myelin basic proteins (MBP) and proteolipid protein were decreased, and in the sciatic nerve fibers, PO protein, X, Y and MBP were clearly decreased. 2',3'-Cyclic nucleotide 3'-phosphodiesterase (CNPase) activities of the pallium cerebri, brain stem and spinal cord of the twitcher were about 20% less than those of the control. However, in the sciatic nerve, the activity was half that of the control. Immunohistochemical studies were carried out by means of antisera against MBP and CNPase. There were clear patches indicating both MBP- and CNPase-negative reactions in the white matter of the central nervous system from the twitcher. The reaction on the section of sciatic nerve fibers from the twitcher showed a positive reaction only in a very limited number of fibers with both MBP and CNPase antisera. A clear astrocytic hypertrophy was detected by the antiserum against glial fibrillary acidic protein (GFAP). Even in the grey matter of the cerebral cortex, strong GFAP-positive astrocytes were clearly observed.


UVO-tunable superhydrophobic to superhydrophilic wetting transition on biomimetic nanostructured surfaces.
A novel strategy for a tunable sigmoidal wetting transition from superhydrophobicity to superhydrophilicity on a continuous nanostructured hybrid film via gradient UV-ozone (UVO) exposure is presented. Along a single wetting gradient surface (40 mm), we could visualize the superhydrophobic (thetaH2O > 165 degrees and low contact angle hysteresis) transition (165 degrees > thetaH2O > 10 degrees ) and superhydrophilic (thetaH2O < 10 degrees within 1 s) regions simply through the optical images of water droplets on the surface. The film is prepared through layer-by-layer assembly of negatively charged silica nanoparticles (11 nm) and positively charged poly(allylamine hydrochloride) with an initial deposition in a fractal manner. The extraordinary wetting transition on chemically modified nanoparticle layered surfaces with submicrometer- to micrometer-scale pores represents a competition between the chemical wettability and hierarchical roughness of surfaces as often occurs in nature (e.g., lotus leaves, insect wings, etc).


Effect of the anticoagulant, storage time and temperature of blood samples on the concentrations of 27 multiplex assayed cytokines - Consequences for defining reference values in healthy humans.
Cytokines are potentially useful biomarkers of sepsis and other inflammatory conditions. Many cytokines can be released by leukocytes and platelets after sampling. The sampling and processing techniques are consequently critically important to measure the in vivo levels. We therefore examined the effects of four different anticoagulants, EDTA, citrate, lepirudin, heparin compared to serum, on the levels of 27 different cytokines. The effects of storage temperature, freezing and thawing on the plasma cytokines were examined. Cytokines were analysed using a multiplex immunoassay. The cytokine levels in serum were significantly higher compared with plasma, consistent with release of cytokines in vitro during coagulation. In general, the lowest values for all cytokines were found in EDTA samples, stored on crushed ice, centrifuged within 4h and thereafter stored at -80°C. MCP-1 and MIP-1β levels were highest in heparin plasma and storage of blood for up to 4h at room temperature significantly increased the interleukin (IL)-2, IL-6, IL-8, IFN-γ and GM-CSF levels in EDTA plasma, indicating post-sampling release. In contrast, the IP-10 levels were unaffected by sample storage at both temperatures. Our results indicate that the cytokines were more stable in plasma than in whole blood after sampling. Thus, cytokines should be analysed in EDTA plasma samples stored on ice and centrifuged within 4h. Based on these data, the reference ranges of 27 cytokines in EDTA plasma in 162 healthy human donors were calculated.


Extensive middle cranial fossa arachnoid cysts and different clinical presentation in two patients.
Arachnoid cysts (ACs), particularly suprasellar cysts, cause a wide spectrum of endocrine disorders. Herein, we report two patients diagnosed with an extensive AC in the middle cranial fossa while being investigated for etiologies of precocious puberty and short stature. One of them required surgery due to his pubertal disorders associated with compression effects of cyst. After surgery, his puberty progression was regressed within one year. On the other hand, surgery was not planned for the second patient considering of his cranial imaging findings and the extremely low incidence of growth hormone (GH) deficiency caused by middle fossa AC (MFAC). We started treatment with recombinant human GH and no complication was found during treatment follow-up. Endocrine disorders associated with MFACs are extremely rare. By presenting with these two cases, we aimed to remain our fellow physcians that ACs can be possibly cause of endocrine disorders. Clinicians should be careful evaluating endocrine disorders because real cause may not be cyst itself but masked by it.


Periodontal inflammation: Integrating genes and dysbiosis.
Biofilm bacteria co-evolve and reach a symbiosis with the host on the gingival surface. The disruption of the homeostatic relationship between plaque bacteria and the host can initiate and promote periodontal disease progression. Recent advances in sequencing technologies allow researchers to profile disease-associated microbial communities and quantify microbial metabolic activities and host transcriptional responses. In addition to confirming the findings from previous studies, new putative pathogens and novel genes that have not previously been associated with periodontitis, emerge. For example, multiple studies have reported that Synergistetes bacteria are associated with periodontitis. Genes involved in epithelial barrier defense were downregulated in periodontitis, while excessive expression of interleukin-17 was associated with a hyperinflammatory response in periodontitis and with a unique microbial community. Bioinformatics-enabled gene ontology pathway analyses provide a panoramic view of the bacterial and host activities as they shift from periodontal health to disease. Additionally, host innate factors, such as genetic variants identified by either a candidate-gene approach or genome-wide association analyses, have an impact on subgingival bacterial colonization. Transgenic mice carrying candidate genetic variants, or with the deletion of candidate genes mimicking the deleterious loss-of-function variant effect, provide experimental evidence validating the biologic relevance of the novel markers associated with the microbial phenotype identified through a statistical approach. Further refinement in bioinformatics, data management approaches, or statistical tools, are required to gain insight into host-microbe interactions by harmonizing the multidimensional "big" data at the genomic, transcriptional, and proteomic levels.


Influence of dietary fish oil on conjugated linoleic acid and other fatty acids in milk fat from lactating dairy cows.
Lactating cows were fed menhaden fish oil to elevate concentrations of conjugated linoleic acid, transvaccenic acid, and n-3 fatty acids in milk. Twelve multiparous Holstein cows at 48+/-11 DIM were assigned randomly to a replicated 4 x 4 Latin square. Each treatment period was 35 d in length, with data collected d 15 to 35 of each period. On a dry matter (DM) basis, diets contained 25% corn silage, 25% alfalfa hay, and 50% of the respective concentrate mix. Fish oil was supplemented at 0, 1, 2, and 3% of ration DM. Linear decreases were observed for DM intake (28.8, 28.5, 23.4, and 20.4 kg/d) and milk fat (2.99, 2.79, 2.37, and 2.30%) for 0 to 3% dietary fish oil, respectively. Milk yield (31.7, 34.2, 32.3, and 27.4 kg/d) increased as dietary fish oil increased from 0 to 1% but decreased linearly from 1 to 3% dietary fish oil. Milk protein percentages (3.17, 3.19, 3.21, and 3.17) were similar for all treatments. When the 2% fish oil diet was fed, concentrations of conjugated linoleic acid and transvaccenic acid in milk fat increased to 356% (to 2.2 g/ 100 g of total fatty acids) and 502% (to 6.1 g/100 g), respectively, of amounts when 0% fish oil was fed. There were no additional increases in these fatty acids when cows were fed 3% fish oil. The n-3 fatty acids increased from a trace to over 1 g/100 g of milk fatty acids, when the 3% fish oil diet was fed. Fish oil supplementation to diets of dairy cows increased the conjugated linoleic acid, transvaccenic acid, and n-3 fatty acids in milk.


Self-assembly behaviour of hetero-nuclear Janus dumbbells.
We investigate the fluid structure and self-assembly of a system of Janus dumbbells by means of aggregation-volume-bias Monte Carlo simulations and Simulated Annealing techniques. In our approach, Janus dumbbells model asymmetric colloidal particles constituted by two tangent (touching) spheres (labelled as h and s) of different sizes and interaction properties: specifically, the h spheres interact with all other spheres belonging to different dumbbells via hard-sphere potentials, whereas two s spheres interact via a square-well potential. By introducing a parameter α ∈ [0,2] that controls the size ratio between the h and s spheres, we are able to investigate the overall phase behaviour of Janus dumbbells as a function of α. In a previous paper (O'Toole et al., Soft Matter, 2017, 13, 803) we focused on the region where the s sphere is larger than the h sphere (α > 1), documenting the presence of a variety of phase behaviours. Here we investigate a different regime of size ratios, predominantly where the hard sphere is larger than (or comparable to) the attractive one. Under these conditions, we observe the onset of many different self-assembled super-structures. Depending on the specific value of α we document the presence of spherical clusters (micelles) progressively evolving into more exotic structures including platelets, filaments, networks and percolating fluids, sponge structures and lamellar phases. We find no evidence of a gas-liquid phase separation for α ≤ 1.1, since under these conditions it is pre-empted by the development of self-assembled phases.


Severe coagulopathy associated with white-lipped green pit viper bite.
The authors report a case of Trimeresurus albolabris (white-lipped green pit viper) bite in a 6-year-old girl living in rural Yuen Long. Despite repeated use of Agkistrodon halys antivenin, the patient developed severe coagulopathy with defibrination syndrome on the fourth day of envenomation, which was also refractory to therapy with fresh frozen plasma. When treatment was switched to green pit viper antivenin, the coagulopathy resolved promptly. The case is illustrative of the potential lethality to children of snakebites in Hong Kong and suggests that the A halys antivenin may not be effective for the treatment of T albolabris bites.


Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines-2016 revision.
Allergic rhinitis (AR) affects 10% to 40% of the population. It reduces quality of life and school and work performance and is a frequent reason for office visits in general practice. Medical costs are large, but avoidable costs associated with lost work productivity are even larger than those incurred by asthma. New evidence has accumulated since the last revision of the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines in 2010, prompting its update. We sought to provide a targeted update of the ARIA guidelines. The ARIA guideline panel identified new clinical questions and selected questions requiring an update. We performed systematic reviews of health effects and the evidence about patients' values and preferences and resource requirements (up to June 2016). We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence-to-decision frameworks to develop recommendations. The 2016 revision of the ARIA guidelines provides both updated and new recommendations about the pharmacologic treatment of AR. Specifically, it addresses the relative merits of using oral H1-antihistamines, intranasal H1-antihistamines, intranasal corticosteroids, and leukotriene receptor antagonists either alone or in combination. The ARIA guideline panel provides specific recommendations for the choice of treatment and the rationale for the choice and discusses specific considerations that clinicians and patients might want to review to choose the management most appropriate for an individual patient. Appropriate treatment of AR might improve patients' quality of life and school and work productivity. ARIA recommendations support patients, their caregivers, and health care providers in choosing the optimal treatment.


Pump-probe imaging of historical pigments used in paintings.
A recently developed nonlinear optical pump-probe microscopy technique uses modulation transfer to sensitively extract excited-state dynamics of endogenous biological pigments, such as eumelanin and pheomelanin. In this work, we use this method to image and characterize several inorganic and organic pigments used in historical art. We show substantial differences in the near-IR pump-probe signatures from nominally similar pigments and suggest extensions to art restoration.


Analysis of experience-regulated transcriptome and imprintome during critical periods of mouse visual system development reveals spatiotemporal dynamics.
Visual system development is light-experience dependent, which strongly implicates epigenetic mechanisms in light-regulated maturation. Among many epigenetic processes, genomic imprinting is an epigenetic mechanism through which monoallelic gene expression occurs in a parent-of-origin-specific manner. It is unknown if genomic imprinting contributes to visual system development. We profiled the transcriptome and imprintome during critical periods of mouse visual system development under normal- and dark-rearing conditions using B6/CAST F1 hybrid mice. We identified experience-regulated, isoform-specific and brain-region-specific imprinted genes. We also found imprinted microRNAs were predominantly clustered into the Dlk1-Dio3 imprinted locus with light experience affecting some imprinted miRNA expression. Our findings provide the first comprehensive analysis of light-experience regulation of the transcriptome and imprintome during critical periods of visual system development. Our results may contribute to therapeutic strategies for visual impairments and circadian rhythm disorders resulting from a dysfunctional imprintome.


The cost-effectiveness and population outcomes of expanded HIV screening and antiretroviral treatment in the United States.
Although recent guidelines call for expanded routine screening for HIV, resources for antiretroviral therapy (ART) are limited, and all eligible persons are not currently receiving treatment. To evaluate the effects on the U.S. HIV epidemic of expanded ART, HIV screening, or interventions to reduce risk behavior. Dynamic mathematical model of HIV transmission and disease progression and cost-effectiveness analysis. Published literature. High-risk (injection drug users and men who have sex with men) and low-risk persons aged 15 to 64 years in the United States. Twenty years and lifetime (costs and quality-adjusted life-years [QALYs]). Societal. Expanded HIV screening and counseling, treatment with ART, or both. New HIV infections, discounted costs and QALYs, and incremental cost-effectiveness ratios. One-time HIV screening of low-risk persons coupled with annual screening of high-risk persons could prevent 6.7% of a projected 1.23 million new infections and cost $22,382 per QALY gained, assuming a 20% reduction in sexual activity after screening. Expanding ART utilization to 75% of eligible persons prevents 10.3% of infections and costs $20,300 per QALY gained. A combination strategy prevents 17.3% of infections and costs $21,580 per QALY gained. With no reduction in sexual activity, expanded screening prevents 3.7% of infections. Earlier ART initiation when a CD4 count is greater than 0.350 × 10(9) cells/L prevents 20% to 28% of infections. Additional efforts to halve high-risk behavior could reduce infections by 65%. The model of disease progression and treatment was simplified, and acute HIV screening was excluded. Expanding HIV screening and treatment simultaneously offers the greatest health benefit and is cost-effective. However, even substantial expansion of HIV screening and treatment programs is not sufficient to markedly reduce the U.S. HIV epidemic without substantial reductions in risk behavior. National Institute on Drug Abuse, National Institutes of Health, and Department of Veterans Affairs.


Genetic polymorphism and forensic parameters of nine short tandem repeat loci in Ngöbé and Emberá Amerindians of Panama.
Nine STR loci (CSF1PO, TPOX, TH01, F13A01, FESFPS, VWA, D16S539, D7S820, and D13S317) were analyzed in unrelated Ngöbé and Emberá Amerindians of Panama. The chi-square test demonstrated statistically significant differences (P < 0.001) in the allele frequencies for all markers except one (D16S539; P < 0.01). Both populations shared their alleles with the highest frequencies in seven loci. However, there were also noticeable differences at the TPOX locus, which showed its highest frequencies at alleles 11 (0.48) and 6 (0.54) for the Ngöé and Emberá, respectively. Interestingly, these alleles are present in one population and are absent in the other, suggesting that they could be distinctive for each population. These results demonstrate that, despite the fact that each population belongs to a different linguistic stock [Chibchan (Ngöbé) and Chocoan (Emberá)], both retain strong similarities in their allele-frequency distributions. Three loci (TPOX, VWA, and F13A01) in the Ngöbé and two loci (TH01 and TPOX) in the Emberá departed from Hardy-Weinberg equilibrium. The analysis of the STR markers demonstrates that, despite their low levels of genetic polymorphisms, most of them could be informative for forensic purposes, showing a combined power of discrimination of 0.9999 for both Amerindian populations. However, powers of exclusion in the Ngöbé were very low, particularly at the TH01 (0.04) and FESFPS (0.08) loci. The combined powers of exclusion were 0.9338 and 0.9890 for the Ngöbé and the Emberá, respectively. Furthermore, the combined typical paternity index in the Ngöbé was considerably low (2.58), and in the Emberá it was 40.44, which is also very low. The low genetic polymorphism levels suggest that theuse of additional loci supplementing the battery of the nine loci is recommended for paternity and forensic tests in both populations, particularly for the Ngöbé.


Cognitive plausibility in voice-based AI health counselors.
Voice-based personal assistants using artificial intelligence (AI) have been widely adopted and used in home-based settings. Their success has created considerable interest for its use in healthcare applications; one area of prolific growth in AI is that of voice-based virtual counselors for mental health and well-being. However, in spite of its promise, building realistic virtual counselors to achieve higher-order maturity levels beyond task-based interactions presents considerable conceptual and pragmatic challenges. We describe one such conceptual challenge-cognitive plausibility, defined as the ability of virtual counselors to emulate the human cognitive system by simulating how a skill or function is accomplished. An important cognitive plausibility consideration for voice-based agents is its ability to engage in meaningful and seamless interactive communication. Drawing on a broad interdisciplinary research literature and based on our experiences with developing two voice-based (voice-only) prototypes that are in the early phases of testing, we articulate two conceptual considerations for their design and use-conceptualizing voice-based virtual counselors as communicative agents and establishing virtual co-presence. We discuss why these conceptual considerations are important and how it can lead to the development of voice-based counselors for real-world use.


Dehydroascorbic acid transport by GLUT4 in Xenopus oocytes and isolated rat adipocytes.
Dehydroascorbic acid (DHA), the first stable oxidation product of vitamin C, was transported by GLUT1 and GLUT3 in Xenopus laevis oocytes with transport rates similar to that of 2-deoxyglucose (2-DG), but due to inherent difficulties with GLUT4 expression in oocytes it was uncertain whether GLUT4 transported DHA (Rumsey, S. C. , Kwon, O., Xu, G. W., Burant, C. F., Simpson, I., and Levine, M. (1997) J. Biol. Chem. 272, 18982-18989). We therefore studied DHA and 2-DG transport in rat adipocytes, which express GLUT4. Without insulin, rat adipocytes transported 2-DG 2-3-fold faster than DHA. Preincubation with insulin (0.67 micrometer) increased transport of each substrate similarly: 7-10-fold for 2-DG and 6-8-fold for DHA. Because intracellular reduction of DHA in adipocytes was complete before and after insulin stimulation, increased transport of DHA was not explained by increased internal reduction of DHA to ascorbate. To determine apparent transport kinetics of GLUT4 for DHA, GLUT4 expression in Xenopus oocytes was reexamined. Preincubation of oocytes for >4 h with insulin (1 micrometer) augmented GLUT4 transport of 2-DG and DHA by up to 5-fold. Transport of both substrates was inhibited by cytochalasin B and displayed saturable kinetics. GLUT4 had a higher apparent transport affinity (K(m) of 0.98 versus 5.2 mm) and lower maximal transport rate (V(max) of 66 versus 880 pmol/oocyte/10 min) for DHA compared with 2-DG. The lower transport rate for DHA could not be explained by binding differences at the outer membrane face, as shown by inhibition with ethylidene glucose, or by transporter trans-activation and therefore was probably due to substrate-specific differences in transporter/substrate translocation or release. These novel data indicate that the insulin-sensitive transporter GLUT4 transports DHA in both rat adipocytes and Xenopus oocytes. Alterations of this mechanism in diabetes could have clinical implications for ascorbate utilization.


Quantitative RARbeta2 hypermethylation: a promising prostate cancer marker.
Retinoic acid receptor beta2 (RARbeta2) is a tumor suppressor gene frequently hypermethylated in several human neoplasms. To further characterize this epigenetic alteration in prostate cancer progression, we examined tumor tissue from 118 patients with prostate carcinoma (PCa), 38 paired high-grade prostatic intraepithelial neoplasias (HGPIN), and non-neoplastic prostate tissue from 30 patients with benign prostate hyperplasia (BPH), using quantitative methylation-specific PCR. We found RARbeta2 hypermethylation in 97.5% of PCa, 94.7% of HGPIN, and 23.3% of BPH. Methylation levels were significantly higher in PCa compared with HGPIN and BPH (P < 0.00001). By establishing an empiric cutoff value, we were able to discriminate between neoplastic and non-neoplastic tissue, with 94.9% sensitivity and 100% specificity. Moreover, RARbeta2 methylation levels correlated with higher pathological stage (r = 0.30, P = 0.0009). This quantitative assay represents a novel and promising molecular marker that may augment current approaches for prostate cancer detection.


Posterolateral corner injuries of the knee: a serious injury commonly missed.
We retrospectively reviewed the hospital records of 68 patients who had been referred with an injury to the posterolateral corner of the knee to a specialist knee surgeon between 2005 and 2009. These injuries were diagnosed based on a combination of clinical testing and imaging and arthroscopy when available. In all, 51 patients (75%) presented within 24 hours of their injury with a mean presentation at eight days (0 to 20) after the injury. A total of 63 patients (93%) had instability of the knee at presentation. There was a mean delay to the diagnosis of injury to the posterolateral corner of 30 months (0 to 420) from the time of injury. In all, the injuries in 49 patients (72%) were not identified at the time of the initial presentation, with the injury to the posterolateral corner only recognised in those patients who had severe multiple ligamentous injuries. The correct diagnosis, including injury to the posterolateral corner, had only been made in 34 patients (50%) at time of referral to a specialist knee clinic. MRI correctly identified 14 of 15 injuries when performed acutely (within 12 weeks of injury), but this was the case in only four of 15 patients in whom it was performed more than 12 weeks after the injury. Our study highlights a need for greater diligence in the examination and investigation of acute ligamentous injuries at the knee with symptoms of instability, in order to avoid failure to identify the true extent of the injury at the time when anatomical repair is most straightforward.


Dynamic mechanisms of generation of oscillatory cluster patterns in a globally coupled chemical system.
We use simulations and dynamical systems tools to investigate the mechanisms of generation of phase-locked and localized oscillatory cluster patterns in a globally coupled Oregonator model where the activator receives global feedback from the inhibitor, mimicking experimental results observed in the photosensitive Belousov-Zhabotinsky reaction. A homogeneous two-cluster system (two clusters with equal cluster size) displays antiphase patterns. Heterogenous two-cluster systems (two clusters with different sizes) display both phase-locked and localized patterns depending on the parameter values. In a localized pattern the oscillation amplitude of the largest cluster is roughly an order of magnitude smaller than the oscillation amplitude of the smaller cluster, reflecting the effect of self-inhibition exerted by the global feedback term. The transition from phase-locked to localized cluster patterns occurs as the intensity of global feedback increases. Three qualitatively different basic mechanisms, described previously for a globally coupled FitzHugh-Nagumo model, are involved in the generation of the observed patterns. The swing-and-release mechanism is related to the canard phenomenon (canard explosion of limit cycles) in relaxation oscillators. The hold-and-release and hold-and-escape mechanisms are related to the release and escape mechanisms in synaptically connected neural models. The methods we use can be extended to the investigation of oscillatory chemical reactions with other types of non-local coupling.


Reversal of carbapenem-resistance in Shewanella algae by CRISPR/Cas9 genome editing.
Antibiotic resistance in pathogens is a growing threat to human health. Of particular concern is resistance to carbapenem, which is an antimicrobial agent listed as critically important by the World Health Organization. With the global spread of carbapenem-resistant organisms, there is an urgent need for new treatment options. Shewanella algae is an emerging pathogen found in marine environments throughout the world that has increasing resistance to carbapenem. The organism is also a possible antibiotic resistance reservoir in humans and in its natural habitat. The development of CRISPR/Cas9-based methods has enabled precise genetic manipulation. A number of attempts have been made to knock out resistance genes in various organisms. The study used a single plasmid containing CRISPR/Cas9 and recE/recT recombinase to reverse an antibiotic-resistant phenotype in S. algae and showed bla OXA-55 -like gene is essential for the carbapenem resistance. This result demonstrates a potential validation strategy for functional genome annotation in S. algae.


Granulocyte-colony stimulating factor (G-CSF) producing malignant pleural mesothelioma: Report of a case.
This report presents a case of malignant pleural mesothelioma (MPM) producing granulocyte colony-stimulating factor (G-CSF) that was treated by tumor resection. A 76-year-old male presented with a huge right-side chest wall tumor, along with a slight fever and chest wall pain. Laboratory findings showed an increased white blood cell count (64600 cells/μL) and C-reactive protein level (20.57 mg/dL). The patient underwent surgical removal of the tumor along with tissue from the chest wall and histopathological analysis led to a diagnosis of sarcomatous type of MPM. Immunohistochemical findings for both anti-human G-CSF and interleukin-6 monoclonal antibodies were positive. Although the general condition of the patient quickly improved after surgery, local recurrence occurred two months later and he died of respiratory failure seven months after the operation, though surgery provided symptom relief. G-CSF-producing MPMs usually show a poor prognosis, though less-invasive surgery may be considered for relief of symptoms.


Pharmacogenomic knowledge gaps and educational resource needs among physicians in selected specialties.
The use of pharmacogenomic testing in the clinical setting has the potential to improve the safety and effectiveness of drug therapy, yet studies have revealed that physicians lack knowledge about the topic of pharmacogenomics, and are not prepared to implement it in the clinical setting. This study further explores the pharmacogenomic knowledge deficit and educational resource needs among physicians. Surveys of primary care physicians, cardiologists, and psychiatrists were conducted. Few physicians reported familiarity with the topic of pharmacogenomics, but more reported confidence in their knowledge about the influence of genetics on drug therapy. Only a small minority had undergone formal training in pharmacogenomics, and a majority reported being unsure what type of pharmacogenomic tests were appropriate to order for the clinical situation. Respondents indicated that an ideal pharmacogenomic educational resource should be electronic and include such components as how to interpret pharmacogenomic test results, recommendations for prescribing, population subgroups most likely to be affected, and contact information for laboratories offering pharmacogenomic testing. Physicians continue to demonstrate pharmacogenomic knowledge gaps, and are unsure about how to use pharmacogenomic testing in clinical practice. Educational resources that are clinically oriented and easily accessible are preferred by physicians, and may best support appropriate clinical implementation of pharmacogenomics.


Clinical efficacy of launched JAK inhibitors in rheumatoid arthritis.
Tofacitinib and baricitinib are the first orally available, small-molecule inhibitors of Janus kinase (JAK) enzymes to be approved for the treatment of RA. Tofacitinib is a selective JAK1, 3 inhibitor with less activity against JAK2 and TYK2 and baricitinib is a selective, oral JAK1, 2 inhibitor with moderate activity against TYK2 and significantly less activity against JAK3. Both drugs have undergone extensive phase III clinical trials in RA and demonstrated rapid improvements in disease activity, function and patient-reported outcomes as well as disease modification. Tofacitinib 5 mg bd, was approved by the Federal Drug Administration in 2012 for the treatment of RA in patients who are intolerant or unresponsive to MTX. An extended release formulation for the treatment of RA was approved by Federal Drug Administration in 2016. In 2017 the European Medicines Agency approved tofacitinib 5 mg bd in combination with MTX and baricitinib 4 mg and 2 mg once daily for the treatment of moderate to severe active RA in adult patients who are intolerant or unresponsive to one or more conventional synthetic DMARDs.


Post-translational import of the prion protein into the endoplasmic reticulum interferes with cell viability: a critical role for the putative transmembrane domain.
Aberrant folding of the mammalian prion protein (PrP) is linked to prion diseases in humans and animals. We show that during post-translational targeting of PrP to the endoplasmic reticulum (ER) the putative transmembrane domain induces misfolding of PrP in the cytosol and interferes with its import into the ER. Unglycosylated and misfolded PrP with an uncleaved N-terminal signal sequence associates with ER membranes, and, moreover, decreases cell viability. PrP expressed in the cytosol, lacking the N-terminal ER targeting sequence, also adopts a misfolded conformation; however, this has no adverse effect on cell growth. PrP processing, productive ER import, and cellular viability can be restored either by deleting the putative transmembrane domain or by using a N-terminal signal sequence specific for co-translational ER import. Our study reveals that the putative transmembrane domain features in the formation of misfolded PrP conformers and indicates that post-translational targeting of PrP to the ER can decrease cell viability.


A Systematic Review of Access to Rehabilitation for People with Disabilities in Low- and Middle-Income Countries.
Rehabilitation seeks to optimize functioning of people with impairments and includes a range of specific health services-diagnosis, treatment, surgery, assistive devices, and therapy. Evidence on access to rehabilitation services for people with disabilities in low- and middle-income countries (LMICs) is limited. A systematic review was conducted to examine this in depth. In February 2017, six databases were searched for studies measuring access to rehabilitation among people with disabilities in LMICs. Eligible measures of access to rehabilitation included: use of assistive devices, use of specialist health services, and adherence to treatment. Two reviewers independently screened titles, abstracts, and full texts. Data was extracted by one reviewer and checked by a second. Of 13,048 screened studies, 77 were eligible for inclusion. These covered a broad geographic area. 17% of studies measured access to hearing-specific services; 22% vision-specific; 31% physical impairment-specific; and 44% measured access to mental impairment-specific services. A further 35% measured access to services for any disability. A diverse range of measures of disability and access were used across studies making comparability difficult. However, there was some evidence that access to rehabilitation is low among people with disabilities. No clear patterns were seen in access by equity measures such as age, locality, socioeconomic status, or country income group due to the limited number of studies measuring these indicators, and the range of measures used. Access to rehabilitation services was highly variable and poorly measured within the studies in the review, but generally shown to be low. Far better metrics are needed, including through clinical assessment, before we have a true appreciation of the population level need for and coverage of these services.


Dental composite restorations and psychosocial function in children.
Resin-based dental materials may intraorally release their chemical components and bisphenol A. The New England Children's Amalgam Trial found that children randomized to amalgam had better psychosocial outcomes than those assigned to composites for posterior tooth restorations. The objective of this study was to examine whether greater exposure to dental composites is associated with psychosocial problems in children. Analysis of treatment-level data from the New England Children's Amalgam Trial, a 2-group randomized safety trial comparing amalgam with the treatment plan of bisphenol A-glycidyl methacrylate (bisGMA)-based composite and urethane dimethacrylate-based polyacid-modified composite (compomer), among 534 children aged 6 to 10 years at baseline. Psychosocial function at follow-up (n = 434) was measured by using the self-reported Behavior Assessment System for Children (BASC-SR) and parent-reported Child Behavior Checklist (CBCL). Children with higher cumulative exposure to bisGMA-based composite had poorer follow-up scores on 3 of 4 BASC-SR global scales: Emotional Symptoms (β = 0.8, SE = 0.3, P = .003), Clinical Maladjustment (β = 0.7, SE = 0.3, P = .02), and Personal Adjustment (β = -0.8, SE = 0.2, P = .002). Associations were stronger with posterior-occlusal (chewing) surfaces, where degradation of composite was more likely. For CBCL change, associations were not statistically significant. At-risk or clinically significant scores were more common among children with greater exposure for CBCL Total Problem Behaviors (16.3% vs 11.2%, P-trend = .01) and numerous BASC-SR syndromes (eg, ≥ 13 vs 0 surface-years, Interpersonal Relations 13.7% vs 4.8%, P-trend = .01). No associations were found with compomer, nor with amalgam exposure levels among children randomized to amalgam. Greater exposure to bisGMA-based dental composite restorations was associated with impaired psychosocial function in children, whereas no adverse psychosocial outcomes were observed with greater urethane dimethacrylate-based compomer or amalgam treatment levels.


Volume-outcome relation for physicians and hospitals performing angioplasty for acute myocardial infarction in New York state.
An inverse relation exists between the number of coronary angioplasty procedures performed by physicians or hospitals and short-term mortality. It is not known, however, whether a similar relation holds for physicians and hospitals that perform primary angioplasty for acute myocardial infarction. We analyzed data from the 1995 New York State Coronary Angioplasty Reporting System Registry to determine the relation between the number of primary angioplasty procedures performed by physicians and hospitals and in-hospital mortality. Patients who underwent angioplasty procedures within 23 hours of onset of acute myocardial infarction without preceding thrombolytic therapy were included (n=1342). In-hospital mortality was reduced 57% among patients who underwent primary angioplasty by high-volume as opposed to low-volume physicians (adjusted relative risk 0.43; 95% CI 0.21 to 0.83). When patients with acute myocardial infarction were treated with primary angioplasty in high-volume hospitals rather than low-volume institutions, the relative risk reduction for in-hospital mortality was 44% (adjusted relative risk 0.56; 95% CI 0.29 to 1.1). Compared with patients treated at low-volume hospitals by low-volume physicians, patients treated at high-volume hospitals by high-volume physicians had a 49% reduction in the risk of in-hospital mortality (adjusted relative risk 0.51; 95% CI 0.26 to 0.99). Among hospitals in New York State, a higher volume of primary angioplasty procedures performed by physicians and/or hospitals was associated with a lower mortality rate.


Block copolymers confined in a nanopore: pathfinding in a curving and frustrating flatland.
We have studied structure formation in a confined block copolymer melt by means of dynamic density functional theory. The confinement is two dimensional, and the confined geometry is that of a cylindrical nanopore. Although the results of this study are general, our coarse-grained molecular model is inspired by an experimental lamella-forming polysterene-polybutadiene diblock copolymer system [K. Shin et al., Science 306, 76 (2004)], in which an exotic toroidal structure was observed upon confinement in alumina nanopores. Our computational study shows that a zoo of exotic structures can be formed, although the majority, including the catenoid, helix, and double helix that were also found in Monte Carlo nanopore studies, are metastable states. We introduce a general classification scheme and consider the role of kinetics and elongational pressure on stability and formation pathway of both equilibrium and metastable structures in detail. We find that helicity and threefold connections mediate structural transitions on a larger scale. Moreover, by matching the remaining parameter in our mesoscopic method, the Flory-Huggins parameter chi, to the experimental system, we obtain a structure that resembles the experimental toroidal structure in great detail. Here, the most important factor seems to be the roughness of the pore, i.e., small variations of the pore radius on a scale that is larger than the characteristic size in the system.