Ultrafast end-to-end protein structure prediction enables high-throughput exploration of uncharacterized proteins

Deep learning-based prediction of protein structure usually begins by constructing a multiple sequence alignment (MSA) containing homologs of the target protein. The most successful approaches combine large feature sets derived from MSAs, and considerable computational effort is spent deriving these input features. We present a method that greatly reduces the amount of preprocessing required for a target MSA, while producing main chain coordinates as a direct output of a deep neural network. The network makes use of just three recurrent networks and a stack of residual convolutional layers, making the predictor very fast to run, and easy to install and use. Our approach constructs a directly learned representation of the sequences in an MSA, starting from a one-hot encoding of the sequences. When supplemented with an approximate precision matrix, the learned representation can be used to produce structural models of comparable or greater accuracy as compared to our original DMPfold method, while requiring less than a second to produce a typical model. This level of accuracy and speed allows very large-scale three-dimensional modeling of proteins on minimal hardware, and we demonstrate this by producing models for over 1.3 million uncharacterized regions of proteins extracted from the BFD sequence clusters. After constructing an initial set of approximate models, we select a confident subset of over 30,000 models for further refinement and analysis, revealing putative novel protein folds. We also provide updated models for over 5,000 Pfam families studied in the original DMPfold paper

Physicians Infrequently Adhere to Hepatitis Vaccination Guidelines for Chronic Liver Disease

Background and Goals:Hepatitis A (HAV) and hepatitis B (HBV) vaccination in patients with chronic liver disease is an accepted standard of care. We determined HAV and HBV vaccination rates in a tertiary care referral hepatology clinic and the impact of electronic health record (EHR)-based reminders on adherence to vaccination guidelines.Methods:We reviewed the records of 705 patients with chronic liver disease referred to our liver clinic in 2008 with at least two follow-up visits during the subsequent year. Demographics, referral source, etiology, and hepatitis serology were recorded. We determined whether eligible patients were offered vaccination and whether patients received vaccination. Barriers to vaccination were determined by a follow-up telephone interview.Results:HAV and HBV serologic testing prior to referral and at the liver clinic were performed in 14.5% and 17.7%; and 76.7% and 74% patients, respectively. Hepatologists recommended vaccination for HAV in 63% and for HBV in 59.7% of eligible patients. Patient demographics or disease etiology did not influence recommendation rates. Significant variability was observed in vaccination recommendation amongst individual providers (30-98.6%), which did not correlate with the number of patients seen by each physician. Vaccination recommendation rates were not different for Medicare patients with hepatitis C infection for whom a vaccination reminder was automatically generated by the EHR. Most patients who failed to get vaccination after recommendation offered no specific reason for noncompliance; insurance was a barrier in a minority.Conclusions:Hepatitis vaccination rates were suboptimal even in an academic, sub-speciality setting, with wide-variability in provider adherence to vaccination guidelines. © 2013 Thudi et al

Water degrading effects on the bond behavior in FRP-strengthened masonry

Fiber reinforced polymers are being extensively used for external strengthening of masonry structures. However, durability of this strengthening technique under environmental conditions is still under inves- tigation. Previous studies indicate that moisture plays an important role in the durability of bond between FRP and substrate. Moisture can cause degradation in the bond behavior and also in the mechan- ical properties of the constituent materials. This paper presents and discusses the results of an experi- mental investigation on the effects of moisture on the bond behavior in FRP-strengthened masonry bricks. The degradation in the bond performance has been investigated by performing pull-off and pull-out tests on the conditioned specimens. The change in the mechanical properties of the materials has also been investigated. Comparative analysis has been performed and the results are presented and critically discussed.This work was partly funded by project FP7-ENV-2009-1-244123-NIKER of the 7th Framework Program of the European Commission, which is gratefully acknowledged. The first author also acknowledges the financial support of the Portuguese Science Foundation (Fundacao de Ciencia e Tecnologia, FCT), through grant SFRH/BD/80697/2011

A mechanistic spatio-temporal framework for modelling individual-to-individual transmission—With an application to the 2014-2015 West Africa Ebola outbreak

In recent years there has been growing availability of individual-level spatio-temporal disease data, particularly due to the use of modern communicating devices with GPS tracking functionality. These detailed data have been proven useful for inferring disease transmission to a more refined level than previously. However, there remains a lack of statistically sound frameworks to model the underlying transmission dynamic in a mechanistic manner. Such a development is particularly crucial for enabling a general epidemic predictive framework at the individual level. In this paper we propose a new statistical framework for mechanistically modelling individual-to-individual disease transmission in a landscape with heterogeneous population density. Our methodology is first tested using simulated datasets, validating our inferential machinery. The methodology is subsequently applied to data that describes a regional Ebola outbreak in Western Africa (2014-2015). Our results show that the methods are able to obtain estimates of key epidemiological parameters that are broadly consistent with the literature, while revealing a significantly shorter distance of transmission. More importantly, in contrast to existing approaches, we are able to perform a more general model prediction that takes into account the susceptible population. Finally, our results show that, given reasonable scenarios, the framework can be an effective surrogate for susceptible-explicit individual models which are often computationally challenging

A randomized, double blind, placebo and active comparator controlled pilot study of UP446, a novel dual pathway inhibitor anti-inflammatory agent of botanical origin

<p>Abstract</p> <p>Background</p> <p>Current use of prescribed or over the counter non-steroidal anti-inflammatory drugs (NSAIDs) for pain and osteoarthritis (OA) have untoward gastrointestinal and cardiovascular related side effects, as a result the need for a safe and effective alternative has become unequivocally crucial.</p> <p>Method</p> <p>A randomized, double blind, placebo and active controlled pilot study of a novel dual pathway, COX1/2 and LOX, inhibitor anti-inflammatory agent of botanical origin, UP446 was conducted. Sixty subjects (age 40-75) with symptomatic OA of the hip or knee were assigned to 4 treatment groups (n = 15); Group A0 (Placebo, CMC capsule), Group A1 (UP446 250 mg/day), Group A2 (UP446 500 mg/day) and Group A3 (Celecoxib, 200 mg/day). MOS-SF-36 and Western Ontario and McMaster University Osteoarthritis Index (WOMAC) data were collected at baseline and after 30, 60 and 90 days of treatment as a measure of efficacy. Erythrocyte sedimentation rate, C-reactive protein, plasma thrombin time (PTT), fructosamine, Hematology, clinical chemistry and fecal occult blood were monitored for safety.</p> <p>Results</p> <p>Statistically significant decrease in WOMAC pain score were observed for Group A1 at day 90, Group A2 at 30 and 90 days and Group A3 at 60 and 90 days. Statistically significant decrease in WOMAC stiffness score were observed for Group A1 and Group A2 at 30, 60 and 90 days; but not for Group A0 and Group A3. The mean change in WOMAC functional impairment scores were statistically significant for Group A1 and Group A2 respectively at 30 days (p = 0.006 and p = 0.006), at 60 days (p = 0.016 and p = 0.002) and at 90 days (p = 0.018 and p = 0.002), these changes were not significant for Group A0 and Group A3. Based on MOS -SF-36 questionnaires, statistically significant improvements in physical function, endurance and mental health scores were observed for all active treatment groups compared to placebo. No significant changes suggestive of toxicity in routine hematologies, serum chemistries, liver enzymes or PTT were noted in any of the treatment groups.</p> <p>Conclusion</p> <p>Based on current findings UP446 is safe and efficacious alternative to established anti-inflammatory medications for alleviating OA symptoms as measured by the WOMAC Index.</p

Development of Mathematical Models for the Analysis of Hepatitis Delta Virus Viral Dynamics

BACKGROUND: Mathematical models have shown to be extremely helpful in understanding the dynamics of different virus diseases, including hepatitis B. Hepatitis D virus (HDV) is a satellite virus of the hepatitis B virus (HBV). In the liver, production of new HDV virions depends on the presence of HBV. There are two ways in which HDV can occur in an individual: co-infection and super-infection. Co-infection occurs when an individual is simultaneously infected by HBV and HDV, while super-infection occurs in persons with an existing chronic HBV infection. METHODOLOGY/PRINCIPAL FINDINGS: In this work a mathematical model based on differential equations is proposed for the viral dynamics of the hepatitis D virus (HDV) across different scenarios. This model takes into consideration the knowledge of the biology of the virus and its interaction with the host. In this work we will present the results of a simulation study where two scenarios were considered, co-infection and super-infection, together with different antiviral therapies. Although, in general the predicted course of HDV infection is similar to that observed for HBV, we observe a faster increase in the number of HBV infected cells and viral load. In most tested scenarios, the number of HDV infected cells and viral load values remain below corresponding predicted values for HBV. CONCLUSIONS/SIGNIFICANCE: The simulation study shows that, under the most commonly used and generally accepted therapy approaches for HDV infection, such as lamivudine (LMV) or ribavirine, peggylated alpha-interferon (IFN) or a combination of both, LMV monotherapy and combination therapy of LMV and IFN were predicted to more effectively reduce the HBV and HDV viral loads in the case of super-infection scenarios when compared with the co-infection. In contrast, IFN monotherapy was found to reduce the HDV viral load more efficiently in the case of super-infection while the effect on the HBV viral load was more pronounced during co-infection. The results suggest that there is a need for development of high efficacy therapeutic approaches towards the specific inhibition of HDV replication. These approaches may additionally be directed to the reduction of the half-life of infected cells and life-span of newly produced circulating virions

Improvement in health-related quality of life in osteoporosis patients treated with teriparatide

<p>Abstract</p> <p>Background</p> <p>Individuals with osteoporosis and recent vertebral fractures suffer from pain and impaired health-related quality of life (HRQL). To determine whether patients with osteoporosis treated with teriparatide experienced improvement in HRQL and pain symptoms after several months of therapy.</p> <p>Methods</p> <p>We retrospectively studied a sample of osteoporosis patients treated with teriparatide in a Canadian rheumatology practice. We included patients that received teriparatide therapy with baseline and follow-up Mini-Osteoporosis Quality of Life Questionnaire (OQLQ) data. Follow-up data was measured at three or six months. We used a paired Student's t-test to compare baseline and follow-up measurements for each of the questionnaire's ten questions (five domains). Statistical analysis was also repeated to only include patients who suffered a prior vertebral fracture.</p> <p>Results</p> <p>57 patients were included in the study, including 47 women. The mean age was 63.8 years (standard deviation 12.1 years). About sixty five percent (37/57) had previously sustained one or more osteoporotic fractures and about 38.6% (22/57) had suffered a prior vertebral fracture. About 44% (25/57) of individuals were taking one or more types of pain medications regularly prior to starting therapy. At follow-up, significant improvements were observed in the OQLQ domains of pain symptoms. This was seen when all patients on teriparatide were included, and also when only patients with prior vertebral fractures were included. There was also an improvement in emotional functioning, relating to fear of falling at 3 months follow-up (p = 0.019). Respondents also reported improvement in the domain of activities of daily living, relating to vacuuming at 6 months follow-up (p = 0.036), and an improvement in the leisure domain, relating to ease of traveling in the prior vertebral fracture population at 3 months follow-up (p = 0.012). However, there was no significant improvement observed in the domains of physical functioning. Participants also reported a decrease in need for pain medications, with 26% (15/57) requiring analgesics at the time of follow-up.</p> <p>Conclusion</p> <p>Teriparatide use may be associated with improvements in HRQL in osteoporosis patients, in particular alleviation of pain symptoms. These results were especially evident in patients with a history of vertebral fractures. These findings should be confirmed in larger prospective studies with a suitable control group.</p

Anatomy of the Epidemiological Literature on the 2003 SARS Outbreaks in Hong Kong and Toronto: A Time-Stratified Review

Weijia Xing and colleagues reviewed the published epidemiological literature on SARS and show that less than a quarter of papers were published during the epidemic itself, suggesting that the research published lagged substantially behind the need for it

Disparities and risks of sexually transmissible infections among men who have sex with men in China: a meta-analysis and data synthesis.

BACKGROUND: Sexually transmitted infections (STIs), including Hepatitis B and C virus, are emerging public health risks in China, especially among men who have sex with men (MSM). This study aims to assess the magnitude and risks of STIs among Chinese MSM. METHODS: Chinese and English peer-reviewed articles were searched in five electronic databases from January 2000 to February 2013. Pooled prevalence estimates for each STI infection were calculated using meta-analysis. Infection risks of STIs in MSM, HIV-positive MSM and male sex workers (MSW) were obtained. This review followed the PRISMA guidelines and was registered in PROSPERO. RESULTS: Eighty-eight articles (11 in English and 77 in Chinese) investigating 35,203 MSM in 28 provinces were included in this review. The prevalence levels of STIs among MSM were 6.3% (95% CI: 3.5-11.0%) for chlamydia, 1.5% (0.7-2.9%) for genital wart, 1.9% (1.3-2.7%) for gonorrhoea, 8.9% (7.8-10.2%) for hepatitis B (HBV), 1.2% (1.0-1.6%) for hepatitis C (HCV), 66.3% (57.4-74.1%) for human papillomavirus (HPV), 10.6% (6.2-17.6%) for herpes simplex virus (HSV-2) and 4.3% (3.2-5.8%) for Ureaplasma urealyticum. HIV-positive MSM have consistently higher odds of all these infections than the broader MSM population. As a subgroup of MSM, MSW were 2.5 (1.4-4.7), 5.7 (2.7-12.3), and 2.2 (1.4-3.7) times more likely to be infected with chlamydia, gonorrhoea and HCV than the broader MSM population, respectively. CONCLUSION: Prevalence levels of STIs among MSW were significantly higher than the broader MSM population. Co-infection of HIV and STIs were prevalent among Chinese MSM. Integration of HIV and STIs healthcare and surveillance systems is essential in providing effective HIV/STIs preventive measures and treatments. TRIAL REGISTRATION: PROSPERO NO: CRD42013003721

Adherence to cardioprotective medications and mortality among patients with diabetes and ischemic heart disease

BACKGROUND: Patients with diabetes and ischemic heart disease (IHD) are at high risk for adverse cardiac outcomes. Clinical practice guidelines recommend multiple cardioprotective medications to reduce recurrent events. We evaluated the association between cardioprotective medication adherence and mortality among patients with diabetes and IHD. METHODS: In a retrospective cohort study of 3,998 patients with diabetes and IHD, we evaluated use of ACE inhibitors or angiotensin receptor blockers, β-blockers, and statin medications. Receipt of cardioprotective medications was based on filled prescriptions. Medication adherence was calculated as the proportion of days covered (PDC) for filled prescriptions. The primary outcome of interest was all-cause mortality. RESULTS: The majority of patients (92.8%) received at least 1 cardioprotective medication. Patients receiving any medications had lower unadjusted mortality rates compared to patients not receiving any medications (7.9% vs. 11.5%; p = 0.03). In multivariable analysis, receipt of any cardioprotective medication remained associated with lower all-cause mortality (OR 0.65; 95% CI 0.43–0.99). Among patients receiving cardioprotective medications, the majority (80.3%) were adherent (PDC ≥ 0.80). Adherent patients had lower unadjusted mortality rates (6.7% vs. 12.1%; p < 0.01). In multivariable analysis, medication adherence remained associated with lower all-cause mortality (OR 0.52; 95% CI 0.39–0.69) compared to non-adherence. In contrast, there was no mortality difference between patients receiving cardioprotective medications who were non-adherent compared to patients not receiving any medications (OR 1.01; 95% CI 0.64–1.61). CONCLUSION: In conclusion, medication adherence is associated with improved outcomes among patients with diabetes and IHD. Quality improvement interventions are needed to increase medication adherence in order for patients to maximize the benefit of cardioprotective medications