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Scientific data recording and reporting systems are of a great interest for endorsing reproducibility and transparency practices among the scientific community. Current research generates large datasets that can no longer be documented using paper lab notebooks (PLNs). In this regard, electronic laboratory notebooks (ELNs) could be a promising solution to replace PLNs and promote scientific reproducibility and transparency. We previously analyzed five ELNs and performed two survey-based studies to implement an ELN in a biomedical research institute. Among the ELNs tested, we found that Microsoft OneNote presents numerous features related to ELN best functionalities. In addition, both surveyed groups preferred OneNote over a scientifically designed ELN (PerkinElmer Elements). However, OneNote remains a general note-taking application and has not been designed for scientific purposes. We therefore provide a quick guide to adapt OneNote to an ELN workflow that can also be adjusted to other nonscientific ELNs. [ABSTRACT FROM AUTHOR]

Background: Patients experiencing adverse drug events (ADE) in many developing countries are in the best position to report these events to the authorities but need to be empowered to do so. Systematic evaluation of community engagement and patient support especially in rural areas would provide evidence for a program to monitor potential harm from medicines. The aim of this study was to assess the effects of a community dialogue and sensitization (CDS) program on the knowledge, attitude and practises of community members for reporting ADE. Methods: This an uncontrolled before-after study was conducted in two eastern Ugandan districts between September 2016 and August 2017 Results: After implementation of the community dialogue and sensitization (CDS) program, there was an overall 20% (95% CI:16% to 25%) increase in knowledge about ADE in the community compared to before the program began. Awareness levels increased by 50% (95% CI: 37% to 63%) among those with little or no education and by41% (95% CI: 31% to 52%) among young people (15–24 years). Furthermore, 5% (95% CI: 3% to 7%) more respondents recognized the need for reporting ADEs compared to before the program. Finally, there was a significant increase of 115% (95% CI:137% to 217%) in respondent recognition and reporting of ADEs compared to the beginning of the CDS program. Overall, this community found the CDS program acceptable and proposed aspects that could be improved for future use. Conclusion: Our evaluation showed that the CDS program increased knowledge and improved attitudes by catalyzing discussions among community members and healthcare professionals on health issues and monitoring safety of medicines compared to before the program. Successful implementation of the program depends on holistic health systems strengthening and adaptation to the community’s way of life. [ABSTRACT FROM AUTHOR]

Background: Clinical medication reviews (CMRs) are increasingly performed in older persons with multimorbidity and polypharmacy to reduce drug-related problems (DRPs). However, there is limited evidence that a CMR can improve clinical outcomes. Little attention has been paid to patients' preferences and needs. The aim of this study was to investigate the effect of a patient-centred CMR, focused on personal goals, on health-related quality of life (HR-QoL), and on number of health problems.Methods and Findings: This study was a randomised controlled trial (RCT) performed in 35 community pharmacies and cooperating general practices in the Netherlands. Community-dwelling older persons (≥70 years) with polypharmacy (≥7 long-term medications) were randomly assigned to usual care or to receive a CMR. Randomisation was performed at the patient level per pharmacy using block randomisation. The primary outcomes were HR-QoL (assessed with EuroQol [EQ]-5D-5L and EQ-Visual Analogue Scale [VAS]) and number of health problems (such as pain or dizziness), after 3 and 6 months. Health problems were measured with a self-developed written questionnaire as the total number of health problems and number of health problems with a moderate to severe impact on daily life. Between April 2016 and February 2017, we recruited 629 participants (54% females, median age 79 years) and randomly assigned them to receive the intervention (n = 315) or usual care (n = 314). Over 6 months, in the intervention group, HR-QoL measured with EQ-VAS increased by 3.4 points (95% confidence interval [CI] 0.94 to 5.8; p = 0.006), and the number of health problems with impact on daily life decreased by 12% (difference at 6 months -0.34; 95% CI -0.62 to -0.044; p = 0.024) as compared with the control group. There was no significant difference between the intervention group and control group for HR-QoL measured with EQ-5D-5L (difference at 6 months = -0.0022; 95% CI -0.024 to 0.020; p = 0.85) or total number of health problems (difference at 6 months = -0.30; 95% CI -0.64 to 0.054; p = 0.099). The main study limitations include the risk of bias due to the lack of blinding and difficulties in demonstrating which part of this complex intervention (for example, goal setting, extra attention to patients, reducing health problems, drug changes) contributed to the effects that we observed.Conclusions: In this study, we observed that a CMR focused on personal goals improved older patients' lives and wellbeing by increasing quality of life measured with EQ-VAS and decreasing the number of health problems with impact on daily life, although it did not significantly affect quality of life measured with the EQ-5D. Including the patient's personal goals and preferences in a medication review may help to establish these effects on outcomes that are relevant to older patients' lives.Trial Registration: Netherlands Trial Register; NTR5713. [ABSTRACT FROM AUTHOR]

The scientific and ethical importance of including women of reproductive age in biomedical research is widely acknowledged. Concerns about preventing fetal exposure to research interventions have motivated requirements for contraception among reproductive aged women in biomedical studies–often irrespective of risks and benefits or a woman’s actual potential for pregnancy, raising important questions about when such requirements are appropriate. The perspectives of women themselves on these issues are largely unexplored. We conducted 140 interviews, 70 in the U.S. and 70 in Malawi, with women either living with or at-risk for HIV, exploring their views about the practice of requiring contraception in clinical trials. A majority of women interviewed from both countries indicated overall support for the practice, with seven themes characterizing advantages and disadvantages raised: reproductive control, health effects, prevention of fetal harm, burden on women, deferral to authority, autonomy regarding enrollment and birth control method, and relationship concerns. While women in the US frequently raised prevention of fetal harm as a key advantage, many other positives noted by women in both countries were related to contraception use in general, not specific to a trial context. With regard to disadvantages, U.S. women tended to focus on biomedical risks such as side effects and impact on fertility, whereas Malawian women focused on the social risks of contraception requirements, including violations of trust in marital relations and suspicions of potential infidelity. Given the potential benefits and burdens highlighted, contraception in research should be sensitive to actual fetal risk assessments; directed where justified at optimizing effective pregnancy prevention; responsive to women’s reproductive preferences; and made available as an ancillary benefit even where risk thresholds do not justify requirement–in order to facilitate trials that are both ethical and robustly oriented around the interests and lives of women who will participate in them. [ABSTRACT FROM AUTHOR]

Introduction: Sandblasting is one of the oldest implant surface modifications to enhance osseointegration. Regarding its superiority over machined surface controversies still exist. Our objective was to compare implant failures (IF) and marginal bone level (MBL) changes between sandblasted and machined dental implants by a meta-analysis utilizing the available data. The PROSPERO registration number of the meta-analysis is CRD42018084190. Methods: The systematic search was performed in Cochrane, Embase and Pubmed. Inclusion criteria included participants with neither systemic diseases, nor excessive alcohol consumption, nor heavy smoking. We calculated pooled Risk Ratio (RRs) with confidence intervals of 95% (CIs) for dichotomous outcomes (implant failure) and weighted mean difference (WMD) CIs of 95% for continuous outcomes (marginal bone level change). We applied the random effect model with DerSimonian-Laird estimation. I2 and chi2 tests were used to quantify statistical heterogeneity and gain probability-values, respectively. Results: Literature search revealed 130 records without duplicates. Out of these, seven studies met the inclusion criteria and all were included in data synthesis, involving 362 sand-blasted and 360 machined implants. The results indicate that there is an 80% (RR = 0.2 95% CI:0.06–0.67; I2 = 0.0% p = 0.986) lower among sandblasted compared to machined implants after one year of use and 74% (RR = 0.26 95% CI:0.09–0.74; I2 = 0.0% p = 0.968) five years of use, respectively. In contrast, there is no significant difference in MBL (WMD:-0.10mm, 95% CI:-0.20, 0.01; p>0.05; I2 = 0.0%, p = 0.560 and WMD:-0.01mm, 95% CI:-0.12, 0.09; p>0.05; I2 = 26.2%, p = 0.258) between the two implant surfaces after one and five years of use. Conclusions: This meta-analysis reveals that sandblasting is superior over machined surface in implant failure but not in marginal bone level in healthy subjects. It also points out the need for further randomized clinical trials with large sample size for objective determination of the clinical benefits of certain implant surface modifications. [ABSTRACT FROM AUTHOR]

Background: The evidence supporting the benefit of femoral nerve block (FNB) for positioning before spinal anesthesia (SA) in patients suffering from a femur fracture remains inconclusive. In the present study, the authors intended to determine the efficacy and safety of FNB versus an intravenous analgesic (IVA) for positioning before SA in patients with a femur fracture. Method: PubMed, EMBASE, Cochrane, and Scopus databases were searched up to January 2018. We included randomized controlled studies (RCTs) and observational studies that compared FNB versus IVA for the positioning of patients with femur fracture receiving SA. The primary outcome was pain scores during positioning within 30 min before SA. Secondary outcomes were the time for SA, additional analgesic requirements, anesthesiologist’s satisfaction with the quality of positioning for SA, participant acceptance, and hemodynamic changes. A random-effects model was used to synthesize the data. We registered the study at PROSPERO with an ID of CRD42018091450. Results: Ten studies with 584 patients were eligible for inclusion. FNB achieved significantly lower pain scores than IVA during positioning within 30 min before SA (pooled standardized mean deviation (SMD): -1.27, 95% confidence interval (CI): -1.84 to -0.70, p < 0.05). A subgroup analysis showed that the analgesic effect was larger in patients in the sitting position for SA than a non-sitting position (sitting position vs non-sitting: pooled SMD: -1.75 (p < 0.05) vs -0.61 (not significant). A multivariate regression showed that the analgesic effect was also associated with age and the total equivalent amount as lidocaine after adjusting for gender (age: coefficient 0.048, p < 0.05; total equivalent amount as lidocaine: coefficient 0.005, p < 0.05). Patients receiving FNB also had a significantly shorter time for SA, greater anesthesiologist satisfaction, and higher patient acceptance than patients receiving IVA. The use of local anesthetics did not produce significant clinical hemodynamic change. Conclusion: Compared to IVA, FNB was an effective and safe strategy for the positioning of femur fracture patients for a spinal block, particularly patients who received SA in the sitting position. [ABSTRACT FROM AUTHOR]

Objectives: Duchenne muscular dystrophy (DMD) is a rare neuromuscular disorder that causes progressive weakness and early death. Gene therapy is an area of new therapeutic development. This qualitative study explored factors influencing parents’ and adult patients’ preferences about gene therapy. Methods: We report qualitative data from 17 parents of children with DMD and 6 adult patients. Participants responded to a hypothetical gene therapy vignette with features including non-curative stabilizing benefits to muscle, cardiac and pulmonary function; a treatment-related risk of death; and one-time dosing with time-limited benefit of 8–10 years. We used NVivo 11 to code responses and conduct thematic analyses. Results: All participants placed high value on benefits to skeletal muscle, cardiac, and pulmonary functioning, with the relative importance of cardiac and pulmonary function increasing with disease progression. More than half tolerated a hypothetical 1% risk of death when balanced against Duchenne progression and limited treatment options. Risk tolerance increased at later stages. Participants perceived a ‘right time’ to initiate gene therapy. Most preferred to wait until a highly-valued function was about to be lost. Conclusion: Participants demonstrated a complex weighing of potential benefits against harms and the inevitable decline of untreated Duchenne. Disease progression increased risk tolerance as participants perceived fewer treatment options and placed greater value on maintaining remaining function. In the context of a one-time treatment like gene therapy, our finding that preferences about timing of initiation are influenced by disease state suggest the importance of assessing ‘lifetime’ preferences across the full spectrum of disease progression. [ABSTRACT FROM AUTHOR]

Despite ongoing large-scale population-based whole-genome sequencing (WGS) projects such as the NIH NHLBI TOPMed program and the NHGRI Genome Sequencing Program, WGS-based association analysis of complex traits remains a tremendous challenge due to the large number of rare variants, many of which are non-trait-associated neutral variants. External biological knowledge, such as functional annotations based on the ENCODE, Epigenomics Roadmap and GTEx projects, may be helpful in distinguishing causal rare variants from neutral ones; however, each functional annotation can only provide certain aspects of the biological functions. Our knowledge for selecting informative annotations a priori is limited, and incorporating non-informative annotations will introduce noise and lose power. We propose FunSPU, a versatile and adaptive test that incorporates multiple biological annotations and is adaptive at both the annotation and variant levels and thus maintains high power even in the presence of noninformative annotations. In addition to extensive simulations, we illustrate our proposed test using the TWINSUK cohort (n = 1,752) of UK10K WGS data based on six functional annotations: CADD, RegulomeDB, FunSeq, Funseq2, GERP++, and GenoSkyline. We identified genome-wide significant genetic loci on chromosome 19 near gene TOMM40 and APOC4-APOC2 associated with low-density lipoprotein (LDL), which are replicated in the UK10K ALSPAC cohort (n = 1,497). These replicated LDL-associated loci were missed by existing rare variant association tests that either ignore external biological information or rely on a single source of biological knowledge. We have implemented the proposed test in an R package “FunSPU”. [ABSTRACT FROM AUTHOR]

This month in PLOS Medicine we launched a Special Issue on New Tools and Strategies for Tuberculosis Diagnosis, Care, and Elimination. In this issue's Editorial, the Guest Editors Claudia Denkinger, Richard Chaisson, and Mark Hatherill highlight some of the research that will publish and how these studies focusing on discovery, clinical trials and implementation research collectively add to the prospects for reaching the EndTB targets of the WHO by 2035. [ABSTRACT FROM AUTHOR]

Information about several papers discussed at a symposium held September 19 - 22, 2018 in Guangxi, China on health cooperation between China and the Association of Southeast Asian Nations (ASEAN) is presented. Topics include traditional medicine, management of hospitals and control of diseases, clonorchiasis and opisthorchiasis viverrini burden on the countries and research and development on liver flukes.

Background: Schizophrenia is a leading cause of disability, and a shift from facility- to community-based care has been proposed to meet the resource challenges of mental healthcare in low- and middle-income countries. We hypothesized that the addition of mobile texting would improve schizophrenia care in a resource-poor community setting compared with a community-based free-medicine program alone.Methods and Findings: In this 2-arm randomized controlled trial, 278 community-dwelling villagers (patient participants) were randomly selected from people with schizophrenia from 9 townships of Hunan, China, and were randomized 1:1 into 2 groups. The program participants were recruited between May 1, 2015, and August 31, 2015, and the intervention and follow-up took place between December 15, 2015, and July 1, 2016. Baseline characteristics of the 2 groups were similar. The patients were on average 46 years of age, had 7 years of education, had a duration of schizophrenia of 18 years with minimal to mild symptoms and nearly one-fifth loss of functioning, and were mostly living with family (95%) and had low incomes. Both the intervention and the control groups received a nationwide community-based mental health program that provided free antipsychotic medications. The patient participants in the intervention group also received LEAN (Lay health supporters, E-platform, Award, and iNtegration), a program that featured recruitment of a lay health supporter and text messages for medication reminders, health education, monitoring of early signs of relapses, and facilitated linkage to primary healthcare. The primary outcome was medication adherence (proportion of dosages taken) assessed by 2 unannounced home-based pill counts 30 days apart at the 6-month endpoint. The secondary and other outcomes included patient symptoms, functioning, relapses, re-hospitalizations, death for any reason, wandering away without notifying anyone, violence against others, damaging goods, and suicide. Intent-to-treat analysis was used. Missing data were handled with multiple imputations. In total, 271 out of 278 patient participants were successfully followed up for outcome assessment. Medication adherence was 0.48 in the control group and 0.61 in the intervention group (adjusted mean difference [AMD] 0.12 [95% CI 0.03 to 0.22]; p = 0.013; effect size 0.38). Among secondary and other outcomes we noted substantial reduction in the risk of relapse (26 [21.7%] of 120 interventional participants versus 40 [34.2%] of 117 controls; relative risk 0.63 [95% CI 0.42 to 0.97]; number needed to treat [NNT] 8.0) and re-hospitalization (9 [7.3%] of 123 interventional participants versus 25 [20.5%] of 122 controls; relative risk 0.36 [95% CI 0.17 to 0.73]; NNT 7.6). The program showed no statistical difference in all other outcomes. During the course of the program, 2 participants in the intervention group and 1 in the control group died. The limitations of the study include its lack of a full economic analysis, lack of individual tailoring of the text messages, the relatively short 6-month follow-up, and the generalizability constraint of the Chinese context.Conclusions: The addition of texting to patients and their lay health supporters in a resource-poor community setting was more effective than a free-medicine program alone in improving medication adherence and reducing relapses and re-hospitalizations. Future studies may test the effectiveness of customization of the texting to individual patients.Trial Registration: Chinese Clinical Trial Registry ChiCTR-ICR-15006053. [ABSTRACT FROM AUTHOR]

Inadequate access to medicines affected by un-controlled prices is a major concern in developing countries, including Pakistan, which lacks comprehensive data on medicine prices. Thus, the objective of this study was to evaluate the prices, availability and affordability of essential medicines in Lahore division, Pakistan. The survey was undertaken from November, 2016 till March, 2017 by including 50 medicines, 14 from the WHO/HAI core list and 36 supplementary medicines from national essential medicine list (NEML) at public (n = 16) and private (n = 16) health facilities. The prices, availability and affordability of selected medicines were measured using a variant of the WHO/HAI standard methodology available on HAI website and WHO/HAI manual. A questionnaire was used for data collection from Lahore division. The prices were compared to International reference prices (IRPs) and the daily wage of a lowest paid unskilled government worker was used to calculate medicine affordability. Data suggested poor availability of originator brands (OB) in public and private sector facilities, i.e., 6.8% and 55.0%, respectively. Similarly, low availability was observed for lowest price generics (LPGs), both in public (35.3%) and private sector (20.3%) facilities–far below the WHO global action plan targets of 80% availability of essential medicines by 2025. In private sector, 53% OB and 38% LPG medicines were found excessively priced. The cost of standard treatment with OBs was unaffordable, i.e., above a single daily wage (1.4 day’s wages) was demanded to purchase the standard treatment for the selected diseases in case of OBs medicines. Whereas, the cost of LPGs medicine required to purchase the standard treatment of the selected diseases was 0.6 day’s wage (median), below a single daily wage. In conclusion, access to essential medicines, especially at public sector facilities was affected by low availability, particularly of OBs in comparison to LPGs. Thus, the better availability of LPGs might be a rational basis of transition into a generic system of prescribing that may improve the availability and accessibility of essential medicines in Lahore division. Medicine prices in Lahore division were found higher in comparison to IRPs. Thus, the efforts must be made to formulate patient’s pocket friendly drug pricing policy that favors price cuts and improves affordability. [ABSTRACT FROM AUTHOR]

Background: A nonsputum blood test capable of predicting progression of healthy individuals to active tuberculosis (TB) before clinical symptoms manifest would allow targeted treatment to curb transmission. We aimed to develop a proteomic biomarker of risk of TB progression for ultimate translation into a point-of-care diagnostic.Methods and Findings: Proteomic TB risk signatures were discovered in a longitudinal cohort of 6,363 Mycobacterium tuberculosis-infected, HIV-negative South African adolescents aged 12-18 years (68% female) who participated in the Adolescent Cohort Study (ACS) between July 6, 2005 and April 23, 2007, through either active (every 6 months) or passive follow-up over 2 years. Forty-six individuals developed microbiologically confirmed TB disease within 2 years of follow-up and were selected as progressors; 106 nonprogressors, who remained healthy, were matched to progressors. Over 3,000 human proteins were quantified in plasma with a highly multiplexed proteomic assay (SOMAscan). Three hundred sixty-one proteins of differential abundance between progressors and nonprogressors were identified. A 5-protein signature, TB Risk Model 5 (TRM5), was discovered in the ACS training set and verified by blind prediction in the ACS test set. Poor performance on samples 13-24 months before TB diagnosis motivated discovery of a second 3-protein signature, 3-protein pair-ratio (3PR) developed using an orthogonal strategy on the full ACS subcohort. Prognostic performance of both signatures was validated in an independent cohort of 1,948 HIV-negative household TB contacts from The Gambia (aged 15-60 years, 66% female), longitudinally followed up for 2 years between March 5, 2007 and October 21, 2010, sampled at baseline, month 6, and month 18. Amongst these contacts, 34 individuals progressed to microbiologically confirmed TB disease and were included as progressors, and 115 nonprogressors were included as controls. Prognostic performance of the TRM5 signature in the ACS training set was excellent within 6 months of TB diagnosis (area under the receiver operating characteristic curve [AUC] 0.96 [95% confidence interval, 0.93-0.99]) and 6-12 months (AUC 0.76 [0.65-0.87]) before TB diagnosis. TRM5 validated with an AUC of 0.66 (0.56-0.75) within 1 year of TB diagnosis in the Gambian validation cohort. The 3PR signature yielded an AUC of 0.89 (0.84-0.95) within 6 months of TB diagnosis and 0.72 (0.64-0.81) 7-12 months before TB diagnosis in the entire South African discovery cohort and validated with an AUC of 0.65 (0.55-0.75) within 1 year of TB diagnosis in the Gambian validation cohort. Signature validation may have been limited by a systematic shift in signal magnitudes generated by differences between the validation assay when compared to the discovery assay. Further validation, especially in cohorts from non-African countries, is necessary to determine how generalizable signature performance is.Conclusions: Both proteomic TB risk signatures predicted progression to incident TB within a year of diagnosis. To our knowledge, these are the first validated prognostic proteomic signatures. Neither meet the minimum criteria as defined in the WHO Target Product Profile for a progression test. More work is required to develop such a test for practical identification of individuals for investigation of incipient, subclinical, or active TB disease for appropriate treatment and care. [ABSTRACT FROM AUTHOR]

Objective: This secondary analysis of data of a randomized controlled trial (RCT) retrospectively investigated the performance of pulse oximetry in identifying children with severe illnesses, with and without respiratory signs/symptoms, in a cohort of children followed for morbid episodes in an intervention trial assessing the efficacy of Intermittent Preventive Treatment for malaria in infants (IPTi) in Papua New Guinea (PNG) from June 2006 to May 2010. Setting: The IPTi study was conducted in a paediatric population visiting two health centres on the north coast of PNG in the Mugil area of the Sumkar District. Participants: A total of 669 children visited the clinic and a total of 1921 illness episodes were recorded. Inclusion criteria were: age between 3 and 27 months, full clinical record (signs/symptoms) and pulse oximetry used systematically to assess sick children at all visits. Children were excluded if they visited the clinic in the previous 14 days. Outcomes: The outcome measures were severe illness, severe pneumonia, pneumonia, defined by the Integrated Management of Childhood Illness (IMCI) definitions, and hospitalization. Results: Out of 1921 illness episodes, 1663 fulfilled the inclusion criteria. A total of 139 severe illnesses were identified, of which 93 were severe pneumonia. The ROC curves of pulse oximetry (continuous variable) showed an AUC of 0.63, 0.68 and 0.65 for prediction of severe illness, severe pneumonia and hospitalization, respectively. Pulse oximetry allowed better discrimination between severe and non-severe illness, severe and non-severe pneumonia, admitted and non-admitted patients, in children ≤12-months of age relative to older patients. For the threshold of peripheral arterial oxygen saturation ≤ 94% measured by pulse oximetry (SpO2), unadjusted odds ratios for severe illness, severe pneumonia and hospitalization were 6.1 (95% Confidence Interval (CI) 3.9–9.8), 8.5 (4.9–14.6) and 5.9 (3.4–10.3), respectively. Conclusion: Pulse oximetry was helpful in identifying children with severe illness in outpatient facilities in PNG. A SpO2 of 94% seems the most discriminative threshold. Considering its affordability and ease of use, pulse oximetry could be a valuable additional tool assisting the decision to admit for treatment. [ABSTRACT FROM AUTHOR]

The article discusses the challenges and opportunities for elimination and control of soil-transmitted helminth (STH) infection beyond 2020. These challenges include the inconsistent monitoring of program impact, the risk of anthelmintic drug resistance, and the occurrence of poor diagnostics to assess program needs by implementation stage. The need for active collaboration by government ministries, researchers, and donors to ensure progress toward eliminating STH infection is also tackled.

Objective: To evaluate the responsiveness in terms of correlation of the Hospital Universitario La Princesa Index (HUPI) comparatively to the traditional composite indices used to assess disease activity in rheumatoid arthritis (RA), and to compare the performance of HUPI-based response criteria with that of the EULAR response criteria. Methods: Secondary data analysis from the following studies: ACT-RAY (clinical trial), PROAR (early RA cohort) and EMECAR (pre-biologic era long term RA cohort). Responsiveness was evaluated by: 1) comparing change from baseline (Δ) of HUPI with Δ in other scores by calculating correlation coefficients; 2) calculating standardised effect sizes. The accuracy of response by HUPI and by EULAR criteria was analyzed using linear regressions in which the dependent variable was change in global assessment by physician (ΔGDA-Phy). Results: ΔHUPI correlation with change in all other indices ranged from 0.387 to 0.791); HUPI’s standardized effect size was larger than those from the other indices in each database used. In ACT-RAY, depending on visit, between 65 and 80% of patients were equally classified by HUPI and EULAR response criteria. However, HUPI criteria were slightly more stringent, with higher percentage of patients classified as non-responder, especially at early visits. HUPI response criteria showed a slightly higher accuracy than EULAR response criteria when using ΔGDA-Phy as gold standard. Conclusion: HUPI shows good responsiveness in terms of correlation in each studied scenario (clinical trial, early RA cohort, and established RA cohort). Response criteria by HUPI seem more stringent than EULAR’s. [ABSTRACT FROM AUTHOR]

The battle against malaria has been substantially impeded by the recurrence of drug resistance in Plasmodium falciparum, the deadliest human malaria parasite. To counter the problem, novel antimalarial drugs are urgently needed, especially those that target unique pathways of the parasite, since they are less likely to have side effects. The mitochondrial type II NADH dehydrogenase (NDH2) of P. falciparum, PfNDH2 (PF3D7_0915000), has been considered a good prospective antimalarial drug target for over a decade, since malaria parasites lack the conventional multi-subunit NADH dehydrogenase, or Complex I, present in the mammalian mitochondrial electron transport chain (mtETC). Instead, Plasmodium parasites contain a single subunit NDH2, which lacks proton pumping activity and is absent in humans. A significant amount of effort has been expended to develop PfNDH2 specific inhibitors, yet the essentiality of PfNDH2 has not been convincingly verified. Herein, we knocked out PfNDH2 in P. falciparum via a CRISPR/Cas9 mediated approach. Deletion of PfNDH2 does not alter the parasite’s susceptibility to multiple mtETC inhibitors, including atovaquone and ELQ-300. We also show that the antimalarial activity of the fungal NDH2 inhibitor HDQ and its new derivative CK-2-68 is due to inhibition of the parasite cytochrome bc1 complex rather than PfNDH2. These compounds directly inhibit the ubiquinol-cytochrome c reductase activity of the malarial bc1 complex. Our results suggest that PfNDH2 is not likely a good antimalarial drug target. [ABSTRACT FROM AUTHOR]

Introduction: Behavioral Activation is a behavioral-based treatment that has been proposed as suitable for smoking cessation, as it simultaneously addresses reinforcement-related variables and also mood management. The aim of this study was to compare the effects of a cognitive-behavioral smoking cessation treatment with components of behavioral activation (SCBSCT-BA) with a standard cognitive-behavioral treatment (SCBSCT), and a wait-list control group (WL). Method: The sample was comprised of 275 adults smokers (61.4% females, mean age = 45.36, SD = 10.96). After baseline assessment sessions, participants were randomized (ratio: 2.2.1.) to SCBSCT-BA, SCBSCT, or WL. Active groups received 8 weekly 1-hour face-to-face group sessions. Biochemically verified smoking abstinence and depressive symptoms were assessed at the end of treatment, and at 3-, 6-, and 12-month follow-ups. Results: Significant treatment effects in 7-dayspoint prevalence abstinence rates were found for both active groups at the end of treatment. Abstinence rates at 12-months follow-up were 30% for SCBSCT-BA, and 18% for SCBSCT. Using Multiple Imputation for missing data, regression analysis showed significantly greater ORs for the SCBSCT-BA condition (vs. SCBSCT) at the end of treatment and at 3-months follow-up. At 6-, and 12-months follow-ups, ORs for the SCBSCT-BA condition, although greater, did not reach statistical significance. Multilevel analysis showed that abstinence was related to reductions in depressive symptoms. Conclusions: SCBSCT-BA obtained positive results at short and medium term. Participants who quit smoking experienced a significant reduction in depressive symptoms. Findings support the benefit of adding BA to a cognitive-behavioral smoking cessation treatment. Trial registration: . [ABSTRACT FROM AUTHOR]

Background: Pharmacodynamic biomarkers are becoming increasingly valuable for assessing drug activity and target modulation in clinical trials. However, identifying quality biomarkers is challenging due to the increasing volume and heterogeneity of relevant data describing the biological networks that underlie disease mechanisms. A biological pathway network typically includes entities (e.g. genes, proteins and chemicals/drugs) as well as the relationships between these and is typically curated or mined from structured databases and textual co-occurrence data. We propose a hybrid Natural Language Processing and directed relationships-based network analysis approach using IBM Watson for Drug Discovery to rank all human genes and identify potential candidate biomarkers, requiring only an initial determination of a specific target-disease relationship. Methods: Through natural language processing of scientific literature, Watson for Drug Discovery creates a network of semantic relationships between biological concepts such as genes, drugs, and diseases. Using Bruton’s tyrosine kinase as a case study, Watson for Drug Discovery’s automatically extracted relationship network was compared with a prominent manually curated physical interaction network. Additionally, potential biomarkers for Bruton’s tyrosine kinase inhibition were predicted using a matrix factorization approach and subsequently compared with expert-generated biomarkers. Results: Watson’s natural language processing generated a relationship network matching 55 (86%) genes upstream of BTK and 98 (95%) genes downstream of Bruton’s tyrosine kinase in a prominent manually curated physical interaction network. Matrix factorization analysis predicted 11 of 13 genes identified by Merck subject matter experts in the top 20% of Watson for Drug Discovery’s 13,595 ranked genes, with 7 in the top 5%. Conclusion: Taken together, these results suggest that Watson for Drug Discovery’s automatic relationship network identifies the majority of upstream and downstream genes in biological pathway networks and can be used to help with the identification and prioritization of pharmacodynamic biomarker evaluation, accelerating the early phases of disease hypothesis generation. [ABSTRACT FROM AUTHOR]

Myasthenia gravis (MG) is an autoimmune disease. In recent years, considerable evidence has indicated that Gene Ontology (GO) functions, especially GO-biological processes, have important effects on the mechanisms and treatments of different diseases. However, the roles of GO functions in the pathogenesis and treatment of MG have not been well studied. This study aimed to uncover the potential important roles of risk-related GO functions and to screen significant candidate drugs related to GO functions for MG. Based on MG risk genes, 238 risk GO functions and 42 drugs were identified. Through constructing a GO function network, we discovered that positive regulation of NF-kappaB transcription factor activity (GO:0051092) may be one of the most important GO functions in the mechanism of MG. Furthermore, we built a drug-GO function network to help evaluate the latent relationship between drugs and GO functions. According to the drug-GO function network, 5 candidate drugs showing promise for treating MG were identified. Indeed, 2 out of 5 candidate drugs have been investigated to treat MG. Through functional enrichment analysis, we found that the mechanisms between 5 candidate drugs and associated GO functions may involve two vital pathways, specifically hsa05332 (graft-versus-host disease) and hsa04940 (type I diabetes mellitus). More interestingly, most of the processes in these two pathways were consistent. Our study will not only reveal a new perspective on the mechanisms and novel treatment strategies of MG, but also will provide strong support for research on GO functions. [ABSTRACT FROM AUTHOR]

Lymphatic malformation (LM) is a developmental anomaly of the lymphatic system that may lead to disfigurement, organ dysfunction and recurrent infection. Though several treatment modalities exist, pharmacotherapy is often associated with side effects and recurrence is common following surgical interventions. Moreover, despite the recent discovery of PIK3CA mutations in lymphatic endothelial cells of LM patients, the full spectrum of molecular pathways involved in LM pathogenesis is poorly understood. Here, we performed RNA sequencing on blood samples obtained from ten LM patients and nine healthy subjects and found 421 differentially expressed genes that stratify LM subjects from healthy controls. Using this LM gene signature, we identified novel pathway alterations in LM, such as oxidative phosphorylation, MEK/ERK, bone morphogenetic protein (BMP), and Wnt/β-catenin pathways, in addition to confirming the known alterations in cell cycle and the PI3K/AKT pathway. Furthermore, we performed computational drug repositioning analysis to predict existing therapies (e.g. sirolimus) and novel classes of drugs for LM. These findings deepen our understanding of LM pathogenesis and may facilitate non-invasive diagnosis, pathway analysis and therapeutic development. [ABSTRACT FROM AUTHOR]

Background: Newer direct-acting antiviral therapies are increasingly becoming the therapy of choice in patients with hepatitis C virus (HCV) infection. Here, we report the safety and effectiveness of sofosbuvir/velpatasvir (SOF/VEL) and ledipasvir/sofosbuvir (LDV/SOF) in real-world cohorts in Germany. Methods: Patients initiated on SOF/VEL 12 weeks or LDV/SOF 8, 12 or 24 weeks regimens in a single German centre were included in this study. Data on treatment outcomes and adverse events (AE) were analysed in patients with available sustained virologic response 12 weeks after cessation of treatment (SVR12) information overall and by subgroups. Results: This study included 115 patients who received SOF/VEL from July-2016 to July-2017, and 249 patients who received LDV/SOF from November-2014 to September-2015. Overall, SVR12 was achieved in 99% of patients on SOF/VEL ± ribavirin 12 weeks independent of HCV genotype, treatment history, or cirrhosis status, and in 96% of patients treated with LDV/SOF 8 weeks or LDV/SOF ± ribavirin 12 or 24 weeks. In genotype 1 treatment-naïve, non-cirrhotic patients, ≥99% achieved SVR12 across SOF/VEL and LDV/SOF regimens. Likewise, 100% of genotype 3-cirrhotic patients on SOF/VEL ± ribavirin regimens achieved SVR12. Grade 3/4 AE were reported in 13 (5.2%) patients on LDV/SOF and in 1 (<1%) patient on SOF/VEL. Conclusion: Overall, SOF/VEL and LDV/SOF achieved high SVR rates in a broad patient population. We showed the effectiveness of SOF/VEL as a pan-genotypic regimen, and regardless of treatment history or cirrhosis status. Use of such therapies improves outcomes and contributes towards the global efforts to eradicate HCV. [ABSTRACT FROM AUTHOR]

Background: The sites of mycobacterial infection in the lungs of tuberculosis (TB) patients have complex structures and poor vascularization, which obstructs drug distribution to these hard-to-reach and hard-to-treat disease sites, further leading to suboptimal drug concentrations, resulting in compromised TB treatment response and resistance development. Quantifying lesion-specific drug uptake and pharmacokinetics (PKs) in TB patients is necessary to optimize treatment regimens at all infection sites, to identify patients at risk, to improve existing regimens, and to advance development of novel regimens. Using drug-level data in plasma and from 9 distinct pulmonary lesion types (vascular, avascular, and mixed) obtained from 15 hard-to-treat TB patients who failed TB treatments and therefore underwent lung resection surgery, we quantified the distribution and the penetration of 7 major TB drugs at these sites, and we provide novel tools for treatment optimization.Methods and Findings: A total of 329 plasma- and 1,362 tissue-specific drug concentrations from 9 distinct lung lesion types were obtained according to optimal PK sampling schema from 15 patients (10 men, 5 women, aged 23 to 58) undergoing lung resection surgery (clinical study NCT00816426 performed in South Korea between 9 June 2010 and 24 June 2014). Seven major TB drugs (rifampin [RIF], isoniazid [INH], linezolid [LZD], moxifloxacin [MFX], clofazimine [CFZ], pyrazinamide [PZA], and kanamycin [KAN]) were quantified. We developed and evaluated a site-of-action mechanistic PK model using nonlinear mixed effects methodology. We quantified population- and patient-specific lesion/plasma ratios (RPLs), dynamics, and variability of drug uptake into each lesion for each drug. CFZ and MFX had higher drug exposures in lesions compared to plasma (median RPL 2.37, range across lesions 1.26-22.03); RIF, PZA, and LZD showed moderate yet suboptimal lesion penetration (median RPL 0.61, range 0.21-2.4), while INH and KAN showed poor tissue penetration (median RPL 0.4, range 0.03-0.73). Stochastic PK/pharmacodynamic (PD) simulations were carried out to evaluate current regimen combinations and dosing guidelines in distinct patient strata. Patients receiving standard doses of RIF and INH, who are of the lower range of exposure distribution, spent substantial periods (>12 h/d) below effective concentrations in hard-to-treat lesions, such as caseous lesions and cavities. Standard doses of INH (300 mg) and KAN (1,000 mg) did not reach therapeutic thresholds in most lesions for a majority of the population. Drugs and doses that did reach target exposure in most subjects include 400 mg MFX and 100 mg CFZ. Patients with cavitary lesions, irrespective of drug choice, have an increased likelihood of subtherapeutic concentrations, leading to a higher risk of resistance acquisition while on treatment. A limitation of this study was the small sample size of 15 patients, performed in a unique study population of TB patients who failed treatment and underwent lung resection surgery. These results still need further exploration and validation in larger and more diverse cohorts.Conclusions: Our results suggest that the ability to reach and maintain therapeutic concentrations is both lesion and drug specific, indicating that stratifying patients based on disease extent, lesion types, and individual drug-susceptibility profiles may eventually be useful for guiding the selection of patient-tailored drug regimens and may lead to improved TB treatment outcomes. We provide a web-based tool to further explore this model and results at http://saviclab.org/tb-lesion/. [ABSTRACT FROM AUTHOR]

Background: Advanced therapies are increasingly demanded by patients with the intent of treating some incurable conditions. Because family medicine professionals play an important role as health educators, their residency programs should incorporate new knowledge related to advanced therapies. To successfully implement these programs, how family medicine residents perceive these therapies should be investigated. The main components of perception, i.e. conceptual, procedural and attitudinal, refer to knowledge, skills and feelings, respectively. Methods and findings: We designed a specific questionnaire to assess the components of perceptions of advanced therapies in 300 medical residents enrolled in the Spanish National Family Medicine Residency Program. Each component consisted of 4 or 5 topics and each topic contained 6 items. Respondents scored highest in the procedural component (average 4.12±1.00), followed by the attitudinal (3.94±1.07) and conceptual component (3.04±1.43). Differences among the three components were statistically significant (p<0.00017). Family medicine residents perceived that procedures to implement advanced therapies are well established, especially their application. However, they felt their cognitive background was insufficient to respond efficiently to the expectations generated by these new therapeutic tools, especially in the regulatory framework. High awareness of the risks and limitations of these treatments was reflected by residents’ preference for clinically tested therapies. Although they appropriately situated treatment with these therapies within hospital care, they associated the biofabrication of novel products with research centers, although these therapeutic tools can be produced in different facilities. Conclusions: These results are potentially useful for designing future training programs and health policies for family medicine residents, and suggest the need to implement specific training programs in advanced therapies at the conceptual, procedural and attitudinal level. [ABSTRACT FROM AUTHOR]

Background: Maternal pertussis vaccination has been introduced in several countries to prevent pertussis morbidity and mortality in infants too young to be vaccinated. Our review aimed to systematically collect and summarize the available evidence on the effectiveness of interventions used to improve pertussis vaccination uptake in pregnant women. Methods: We conducted a systematic search of MEDLINE/PubMed, PMC and CINAHL. Before and after studies and those with a concurrent control group were considered for inclusion. Standardized effect sizes were described as the ratio of the odds to be vaccinated in the intervention group compared with the standard care group and absolute benefit increase (ABI) were calculated. Results: Six studies were included in the review, of which three were randomized controlled trials (RCTs). Strategies to improve uptake were focused on healthcare providers, pregnant women, or enhancing vaccine access. Healthcare provider interventions included provider reminder, education, feedback and standing orders. Interventions directed at pregnant women focused solely on education. Observational studies showed: (1) the provision of maternal pertussis vaccination by midwives at the place of antenatal care has improved uptake of pertussis vaccine during pregnancy from 20% to 90%; (2) introduction of an automated reminder within the electronic medical record was associated with an improvement in the pertussis immunization rate from 48% to 97%; (3) an increase in prenatal pertussis vaccine uptake from 36% to 61% after strategies to increase provider awareness of recommendations were introduced. In contrast to these findings, interventions in all three RCTs (2 involved education of pregnant women, 1 had multi-component interventions) did not demonstrate improved vaccination uptake. Conclusions: Based on the existing research, we recommend incorporating midwife delivered maternal immunization programs at antenatal clinics, use of a provider reminder system to target unvaccinated pregnant women and include maternal pertussis immunization as part of standard antenatal care. [ABSTRACT FROM AUTHOR]

Background: The objective of the present study was to evaluate effectiveness, complications and cost-effectiveness of any surgical or non-surgical treatment for radius or ulna fractures in elderly patients. Secondary objectives were to analyze present treatment traditions of distal radius fractures (DRF) in Sweden and to calculate resource usage for its treatment. Methods and findings: The assessment contains a systematic review of clinical and health economic studies comparing treatment options for radius or ulna fractures. The results regarding the effectiveness of the treatments are summarized in meta-analyses. In addition, the assessment contains a cost analysis for different treatment options commonly used for DRF care, and an analysis of registry data on the incidence and treatment of DRF. In total 31 randomized controlled trials were included in meta-analyses. When comparing functional outcome for plate fixation versus non-surgical treatment for DRF, there were no clinically important differences at one-year follow-up (mean difference [MD], -3.29, 95% CI, -7.03; 0.44). Similar results were found when comparing plating and percutaneous methods with respect to functional outcome (standardized mean difference [SMD], -0.07, 95% CI, -0.21; 0.07) and grip strength (MD, -3.47, 95% CI, -11.21; 4.28). There were no differences for minor complications, (risk difference [RD], -0.01, 95% CI, -0.07; 0.05) whereas major complications were less common for the percutaneous group, (RD, 0.02, 95% CI, 0.02; 0.03). Given the low number of studies, the evidence above was rated as moderate certainty. The cost for plate fixation versus plaster cast was estimated to 1698 compared to 137 US dollars. For DRF, plate fixation increased in Sweden between 2005 and 2013, and was the most common surgical method in 2013. Conclusions: Surgical treatment of moderately displaced distal radius fractures in elderly patients offers no clear benefit compared to non-surgical treatment. Plating procedures have become more common during the second millennium and involve higher costs and higher risk of major complications than percutaneous options. [ABSTRACT FROM AUTHOR]

Data are the foundation of science, and there is an increasing focus on how data can be reused and enhanced to drive scientific discoveries. However, most seemingly “open data” do not provide legal permissions for reuse and redistribution. The inability to integrate and redistribute our collective data resources blocks innovation and stymies the creation of life-improving diagnostic and drug selection tools. To help the biomedical research and research support communities (e.g. libraries, funders, repositories, etc.) understand and navigate the data licensing landscape, the (Re)usable Data Project (RDP) () assesses the licensing characteristics of data resources and how licensing behaviors impact reuse. We have created a ruleset to determine the reusability of data resources and have applied it to 56 scientific data resources (e.g. databases) to date. The results show significant reuse and interoperability barriers. Inspired by game-changing projects like Creative Commons, the Wikipedia Foundation, and the Free Software movement, we hope to engage the scientific community in the discussion regarding the legal use and reuse of scientific data, including the balance of openness and how to create sustainable data resources in an increasingly competitive environment. [ABSTRACT FROM AUTHOR]

Allosteric ligands bind to receptors at sites that are distinct from those endogenous agonists and orthosteric pharmacological agents interact with. Both an allosteric and orthosteric ligand bind simultaneously to the receptor to form a ternary complex, where each ligand influences binding affinity of the other to the receptor, either positively or negatively. Allosteric modulators are an intensively studied group of receptor ligands because of their potentially greater selectivity over orthosteric ligands, with the possibility of fine tuning of the effects of endogenous neurotransmitters and hormones. The affinity of an unlabelled allosteric ligand is commonly estimated by measuring its effects on binding of a radio-labelled orthosteric tracer. This scenario is complicated by many folds when one studies the kinetics of interactions of two allosteric agents, added simultaneously, on binding of an orthosteric tracer. In this paper, we provide, for the first time, theoretical basis for analysis of such complex interactions. We have expanded our analysis to include the possibility of having two allosteric modulators interact with the same or different sites on the receptor. An added value of our analysis is to provide a tool to distinguish between the two situations. Finally, we also modelled binding of two molecules of one allosteric modulator to one receptor. [ABSTRACT FROM AUTHOR]

Christian Lienhardt and Payam Nahid launch the Collection on Advances in Clinical Trial Design for Development of New Tuberculosis Treatments. [ABSTRACT FROM AUTHOR]

In a Collection Review, Patrick Phillips and colleagues discuss developments in clinical trial design for the evaluation of TB therapeutics. [ABSTRACT FROM AUTHOR]

Human protein biomarker discovery relies heavily on pre-clinical models, in particular established cell lines and patient-derived xenografts, but confirmation studies in primary tissue are essential to demonstrate clinical relevance. We describe in this study the process that was followed to clinically translate a 5-protein response signature predictive for the activity of an anti-HER3 monoclonal antibody (lumretuzumab) originally measured in fresh frozen xenograft tissue. We detail the development, qualification, and validation of the multiplexed targeted mass spectrometry assay used to assess the signature performance in formalin-fixed, paraffin-embedded human clinical samples collected in a phase Ib trial designed to evaluate lumretuzumab in patients with metastatic breast cancer. We believe that the strategy delineated here provides a path forward to avoid the time- and cost-consuming step of having to develop immunological reagents against unproven targets. We expect that mass spectrometry-based platforms may become part of a rational process to rapidly test and qualify large number of candidate biomarkers to identify the few that stand a chance for further development and validation. [ABSTRACT FROM AUTHOR]

Background: Ultrasound (US) guidance has yet to prove its applicability in radial arterial blood gas analysis (ABGA) punctures. The main objective of our study was to compare the number of first-attempt successes (NFAS) for radial arterial puncture in difficult patients with or without US guidance. The Secondary aims were to compare the number of punctures (NOP), puncture time, and patient pain. Methods: In this single-center, randomized controlled trial, patients who required a radial ABGA and in whom the arterial puncture was assessed as difficult (because of non-palpable radial arteries or two previous puncture failures by a nurse) were assigned to the US group or no-US (NUS) group (procedure performed by a trained physician). Results: Thirty-six patients were included in the US group and 37 in the NUS groups. The NFAS was 7 (19%) in the NUS group and 19 (53%) in the US group. The relative risk of success in the US group was 2.79 (95% CI,1.34 to 5.82), p = 0.01. In the NUS and US groups, respectively, the median NOP was 3 [2; 6] vs. 1 [1; 2], estimated difference −2.0 (95%CI, −3.4 to −0.6), p < 0.01; the respective puncture time was 3.1 [1.6; 5.4] vs. 1.4 [0.6; 3.1] min, estimated difference −1.45 (95%CI, −2.57 to −0.39), p = 0.01; the respective median patient pain was 6 [4; 8] vs. 2 [1; 4], estimated difference −4.0 (95%CI, −5.8 to −2.3); p < 0.01. Conclusion: US guidance by a trained physician significantly improves the rate of success in difficult radial ABGA patients. [ABSTRACT FROM AUTHOR]

Introduction: Patients with chronic kidney disease (CKD) depend on advice from healthcare professionals to avoid using unsuitable over-the-counter (OTC) drugs. Recently, qualified, registered nonpharmacist salespersons became licensed to sell OTC drugs in Japan. However, registered salespersons' knowledge and awareness of precautions regarding unsuitable OTC drugs for use in patients with CKD are unclear. Objectives: This study aimed to clarify the awareness, knowledge, and implementation of precautions by registered salespersons regarding OTC drugs used by patients with CKD. Additionally, we evaluated the change of registered salespersons' knowledge and awareness of this topic generated by a pharmacist intervention. Methods: A questionnaire survey and pharmacist intervention were applied to 175 registered salespersons. The intervention comprised a 50-minute lecture imparted by a pharmacist who was trained in nephrology. The knowledge, awareness, and implementation of precautions by participants with respect to nonsteroidal anti-inflammatory drugs (NSAIDs) and antacids were evaluated before and after the intervention. Results: Approximately half of the registered salespersons reported previous experience with selling OTC drugs that were inappropriate for patients with CKD (NSAIDs, 48.0%; antacids, 39.7%). Few participants recognized the need to check renal function when selling those drugs to such patients (NSAIDs, 25.7%; antacids, 47.5%). The registered salespersons' awareness and knowledge were significantly higher after the intervention than before it. Conclusion: The results indicate that before the intervention, the registered salespersons had low levels of awareness and knowledge regarding OTC drug use in patients with CKD despite having prior experience selling unsuitable OTC drugs. However, the pharmacist intervention improved the registered salespersons' awareness and knowledge. The educational program for registered salespersons might be necessary to prevent inappropriate OTC drug use by patients with CKD. [ABSTRACT FROM AUTHOR]

We test and compare different incentives in motivating water conservation using a randomized controlled trial. In a field experiment carried out with Singaporean households, regular feedback was given, with informative, normative and monetary incentives provided to different groups. Evidence shows that all households saved an average of 4 Litres of water per person per day, with no difference in treatment effect found across various groups. Perhaps unsurprisingly, the water saving effect is also found to be more significant with high baseline users, who saved up to 5.9 Litres per person per day. High baseline households also respond more positively to the non-monetary incentives. [ABSTRACT FROM AUTHOR]

Background: Breast milk is important to infant health, yet shorter breastfeeding duration is reported for preterm infants. Both breast and bottle feeds are given in the neonatal unit, with full oral feeding often the last milestone to be achieved prior to discharge home. Unlike standard bottle teats, a vacuum release teat requires the application of negative intra-oral pressure to release milk, and so may facilitate breastfeeding in preterm infants. The objective of this study was to determine the effect of vacuum release teat use on timing of achievement of the first full oral feed and on first completion of 24 h full oral feeds. Feeding method at discharge home, 2 weeks, 6 weeks and 12 weeks corrected gestational age were also examined. Methods: A randomized controlled trial was completed with mothers of preterm infants born 24–33 weeks gestation in the neonatal unit of a tertiary women's hospital. Infants were randomized to one of two parallel groups using a vacuum release teat or standard teat for oral feeds when the mother was not available to breastfeed. Test weights were completed for all oral feeds. It was not possible to blind participants, care givers and outcome assessors to group assignment due to the nature of the study. Results: The groups did not differ with regard to timing of achievement of first full oral feed or 24 h of full oral feeds. Significantly more infants in the vacuum release teat group were exclusively fed breast milk at discharge from hospital and breastfed at 3 months corrected gestational age. Conclusions: Use of a vacuum release teat when the mother is not available to breastfeed may promote preterm breastfeeding skills, resulting in higher rates of exclusivity and longer breastfeeding duration. Trial registration: The trial is registered with the Australian New Zealand Clinical Trials Registry . [ABSTRACT FROM AUTHOR]

Background and objectives: This study explored whether, for people with chronic obstructive pulmonary disease (COPD), changes to the 24-hour composition of physical activity (PA), sedentary behaviour (SB) and sleep were associated with changes in symptoms and health-related quality of life (HRQoL); and how time re-allocations between these behaviours were associated with changes in outcomes. Methods: This study pools data on people with COPD drawn from two previous studies: a randomised controlled trial of cognitive behavioural therapy and pulmonary rehabilitation and a usual care cohort. Participants recalled behaviours and completed symptom and HRQoL assessments at baseline (T0) and four months (T1). Linear mixed-effects models (pooled control/intervention samples) predicted changes in outcomes from T0 to T1 with a change to the 24-hour behaviour composition; compositional isotemporal substitution predicted change in outcomes when re-allocating time between behaviours. Results: Valid data were obtained for 95 participants (forced expiratory volume in one second %predicted = 49.6±15.3) at T0 and T1. A change in the 24-hour behaviour composition was associated with a change in anxiety (p<0.01) and mastery (p<0.01), but not breathlessness, depression or fatigue. When modelling time re-allocation with compositional isotemporal substitution, more time re-allocated to higher intensity PA or sleep was associated with favourable changes in outcomes; re-allocating time to SB or light PA was associated with unfavourable changes in outcomes. The direction of association, however, could not be determined. Conclusion: To improve the overall health and wellbeing of people with COPD, intervention approaches that optimise the composition of PA, SB and sleep may be beneficial. [ABSTRACT FROM AUTHOR]

Introduction: In outcome research, incomplete follow-up is a major, yet potentially correctable source of bias. Cross-sectional surveys may theoretically increase completeness of follow-up, but low response rates are reported typically. We investigated whether a pre-notification letter improved patient availability for follow-up phone interviews and thereby improved cross-sectional survey yield. Methods: A consecutive series of vascular patients was randomly divided into a trial and a validation population. The trial population was then randomized 1:1 to one of two cross-sectional contact strategies: Strategy 1 consisted of direct contact attempts by up to 12 systematically timed phone calls, whereas Strategy 2 used a personalized pre-notification letter to arrange for scheduled phone call interviews. Response rates, average time and efforts needed per patient and overall survey duration were compared. Subsequently, trial findings were externally validated in the validation population. Results: Of 728 consecutive patients, 370 were allocated to the trial population. Trial patients contacted by strategy 1 (n = 183) had a similar profile when compared to trial patients contacted by strategy 2 (n = 187). Follow-up periods following surgery (54.3 versus 53.6 months) and all-cause mortality rates (21.3% versus 18.7%) were comparable between the trial groups. Cross-sectional information on survival outcomes was almost complete after both contact strategies (99.5% versus 98.9%, P = 1.0). In 144/187 strategy 2 patients (77%) interviews were scheduled successfully necessitating significantly less contact attempts (median of 1.3 versus 2.3 per patient, P<0.0001). However, invested time per patient was similar between the groups (median of 10.1 versus 9.6 minutes), and survey strategy 1 completed earlier (median time to contact 4 versus 11 days, P<0.0001). Therefore, strategy 1 was validated in the validation population (n = 358): a low lost to follow-up rate below 1% (P = 1.0) was reconfirmed necessitating an average of 2.3 contact attempts per patient. Conclusions: Both contact strategies were equally successful in contacting almost all patients cross-sectionally. If systematically timed, direct phone calls were less complicated to organize and faster completed. Given the low time and effort per patient, outcome studies should invest in systematic follow-up surveys to minimize attrition bias. [ABSTRACT FROM AUTHOR]

There have been many in silico studies based on a Boolean network model to investigate network sensitivity against gene or interaction mutations. However, there are no proper tools to examine the network sensitivity against many different types of mutations, including user-defined ones. To address this issue, we developed RMut, which is an R package to analyze the Boolean network-based sensitivity by efficiently employing not only many well-known node-based and edgetic mutations but also novel user-defined mutations. In addition, RMut can specify the mutation area and the duration time for more precise analysis. RMut can be used to analyze large-scale networks because it is implemented in a parallel algorithm using the OpenCL library. In the first case study, we observed that the real biological networks were most sensitive to overexpression/state-flip and edge-addition/-reverse mutations among node-based and edgetic mutations, respectively. In the second case study, we showed that edgetic mutations can predict drug-targets better than node-based mutations. Finally, we examined the network sensitivity to double edge-removal mutations and found an interesting synergistic effect. Taken together, these findings indicate that RMut is a flexible R package to efficiently analyze network sensitivity to various types of mutations. RMut is available at . [ABSTRACT FROM AUTHOR]

Background: To the extent that outcomes are mediated through negative perceptions of generics (the nocebo effect), observational studies comparing brand-name and generic drugs are susceptible to bias favoring the brand-name drugs. We used authorized generic (AG) products, which are identical in composition and appearance to brand-name products but are marketed as generics, as a control group to address this bias in an evaluation aiming to compare the effectiveness of generic versus brand medications.Methods and Findings: For commercial health insurance enrollees from the US, administrative claims data were derived from 2 databases: (1) Optum Clinformatics Data Mart (years: 2004-2013) and (2) Truven MarketScan (years: 2003-2015). For a total of 8 drug products, the following groups were compared using a cohort study design: (1) patients switching from brand-name products to AGs versus generics, and patients initiating treatment with AGs versus generics, where AG use proxied brand-name use, addressing negative perception bias, and (2) patients initiating generic versus brand-name products (bias-prone direct comparison) and patients initiating AG versus brand-name products (negative control). Using Cox proportional hazards regression after 1:1 propensity-score matching, we compared a composite cardiovascular endpoint (for amlodipine, amlodipine-benazepril, and quinapril), non-vertebral fracture (for alendronate and calcitonin), psychiatric hospitalization rate (for sertraline and escitalopram), and insulin initiation (for glipizide) between the groups. Inverse variance meta-analytic methods were used to pool adjusted hazard ratios (HRs) for each comparison between the 2 databases. Across 8 products, 2,264,774 matched pairs of patients were included in the comparisons of AGs versus generics. A majority (12 out of 16) of the clinical endpoint estimates showed similar outcomes between AGs and generics. Among the other 4 estimates that did have significantly different outcomes, 3 suggested improved outcomes with generics and 1 favored AGs (patients switching from amlodipine brand-name: HR [95% CI] 0.92 [0.88-0.97]). The comparison between generic and brand-name initiators involved 1,313,161 matched pairs, and no differences in outcomes were noted for alendronate, calcitonin, glipizide, or quinapril. We observed a lower risk of the composite cardiovascular endpoint with generics versus brand-name products for amlodipine and amlodipine-benazepril (HR [95% CI]: 0.91 [0.84-0.99] and 0.84 [0.76-0.94], respectively). For escitalopram and sertraline, we observed higher rates of psychiatric hospitalizations with generics (HR [95% CI]: 1.05 [1.01-1.10] and 1.07 [1.01-1.14], respectively). The negative control comparisons also indicated potentially higher rates of similar magnitude with AG compared to brand-name initiation for escitalopram and sertraline (HR [95% CI]: 1.06 [0.98-1.13] and 1.11 [1.05-1.18], respectively), suggesting that the differences observed between brand and generic users in these outcomes are likely explained by either residual confounding or generic perception bias. Limitations of this study include potential residual confounding due to the unavailability of certain clinical parameters in administrative claims data and the inability to evaluate surrogate outcomes, such as immediate changes in blood pressure, upon switching from brand products to generics.Conclusions: In this study, we observed that use of generics was associated with comparable clinical outcomes to use of brand-name products. These results could help in promoting educational interventions aimed at increasing patient and provider confidence in the ability of generic medicines to manage chronic diseases. [ABSTRACT FROM AUTHOR]

Among various approaches to the repeated measures analysis in crossover clinical trials, the general linear models (GLMs) with correlated errors attract substantial attention due to their simplicity in model specification, implementation, and interpretation. The goal of this research note is to conduct simulation studies to numerically investigate the impact of model misspecification in the GLMs with correlated errors in the analysis of crossover trials. A series of synthetic two-treatment and three-treatment crossover trials were designed, and simulation studies were conducted to assess how treatment effect estimation, type I error rates, and power can be affected by misspecified period effects, carryover effects, and variance-covariance structures in the GLMs. Numerical studies confirm that (i) the GLMs with terms for both carryover and period effects and with an unstructured variance-covariance matrix can provide unbiased treatment effect estimates and control of Type I error rates and that (ii) misspecification in either period effects, carryover effects, or covariance structures in the GLMs can induce inflated type I error, declined power, or biased treatment effect estimates. Although methodologic contribution of this research note is minimal, we provide practical recommendations and advice to pharmaceutical sponsors and other investigational drugs and device applicants in designing and analyzing crossover trials using the GLMs with correlated errors. [ABSTRACT FROM AUTHOR]

Background: Recent evidence suggests that higher rifampicin doses may improve tuberculosis (TB) treatment outcome. Methods: In this observational cohort study we evaluated all TB patients who were treated with high-dose rifampicin (> 10 mg/kg daily) in our reference centre, from January 2008 to May 2018. Indications, achieved plasma rifampicin exposures, safety and tolerability were evaluated. Results: Eighty-eight patients were included. The main indications were low plasma concentrations (64.7%) and severe illness (29.5%), including central nervous system TB. Adjusted rifampicin dosages ranged from 900 mg to a maximum of 2400 mg (corresponding to 32 mg/kg) per day. Patients with severe illness received high-dose rifampicin immediately, the others had a higher dosage guided by therapeutic drug monitoring. Four patients developed hepatotoxicity, of which two were proven due to isoniazid. Re-introduction of high-dose rifampicin was successful in all four. Eighty-seven patients tolerated high-dose rifampicin well throughout treatment. Only one patient required a dose reduction due to gastro-intestinal disturbance. Conclusion: High-dose rifampicin, used in specific groups of patients in our clinical setting, is safe and well-tolerated for the whole treatment duration. Measurement of drug exposures could be used as a tool/guide to increase rifampicin dosage if a reduced medication absorption or a poor treatment outcome is suspected. We suggest to administer high-dose rifampicin to patients with severe manifestations of TB or low rifampicin exposure to improve treatment outcome. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is an infectious bacterial disease that kills approximately 1.3 million people every year. Despite global efforts to reduce both the incidence and mortality associated with TB, the emergence of drug resistant strains has slowed any progress made towards combating the spread of this deadly disease. The current TB drug regimen is inadequate, takes months to complete and poses significant challenges when administering to patients suffering from drug resistant TB. New treatments that are faster, simpler and more affordable are urgently required. Arguably, a good strategy to discover new drugs is to start with an old drug. Here, we have screened a library of 1200 FDA approved drugs from the Prestwick Chemical library using a GFP microplate assay. Drugs were screened against GFP expressing strains of Mycobacterium smegmatis and Mycobacterium bovis BCG as surrogates for Mycobacterium tuberculosis, the causative agent of TB in humans. We identified several classes of drugs that displayed antimycobacterial activity against both M. smegmatis and BCG, however each organism also displayed some selectivity towards certain drug classes. Variant analysis of whole genomes sequenced for resistant mutants raised to florfenicol, vanoxerine and pentamidine highlight new pathways that could be exploited in drug repurposing programmes. [ABSTRACT FROM AUTHOR]

Falls are commonly reported post-stroke. Ankle-foot orthoses (AFOs) are often provided to improve safety and walking, but the effect of their use in the reduction of falls after stroke is unknown. A randomized controlled trial (RCT) on the effects of AFO-provision after stroke was performed. Effects on clinical scales, 3D-gait kinematics and muscle-activity were previously reported. This paper aims to study the effects of AFO-provision on occurrence and circumstances of falls/near falls. The RCT included unilateral hemiparetic stroke patients. AFOs were provided either early (study week 1) or delayed (study week 9). Both groups were compared in the first eight weeks of the study and diaries were used to register falls/near falls and their circumstances. Follow-up measurements were performed in week 9–52, in which both groups were provided with AFOs. Functional Ambulation Categories and Berg Balance Scale were assessed to determine walking independence and balance, respectively. Last known scores were noted in case of an incident. Thirty-three subjects were included (16 early, 17 delayed). In week 1–8, the early group, who were provided with AFOs, fell significantly more frequently compared with the delayed group, 11 versus 4 times, respectively (Incidence Rate Ratio = 2.9, p = 0.039). Out of the falls recorded in the early group, 63.6% occurred without wearing AFOs. Most of these falls occurred during transfers (36.4%) and standing (27.3%), and notably it were the subjects who did not have independent walking ability. No differences were found for near falls in week 1–8, or for falls/near falls in week 9–52. Six severe consequences (including fractures) were reported from a fall. To conclude, the subjects provided with AFOs early after stroke reported a higher number of falls, compared to the subjects that had not yet been provided with AFOs. However, in the subjects provided with AFOs, 63.6% of the falls occurred whilst without wearing the AFO. Furthermore, the majority of these incidents took place whilst subjects had no independent walking ability. This raises an interesting question of the importance of careful instructions to patients and their relatives, and the influence of potential cognitive impairments on the ability of the subjects to take on these instructions. [ABSTRACT FROM AUTHOR]

Background: The Healthy Living Pharmacy (HLP) project, launched in England, UK in 2009 was a novel approach of introducing public health services within community pharmacy to tackle local health inequalities. A national roll-out followed a reported successful pilot; subsequent local evaluations ensued. Objectives: To summarise reported outcomes and investigate contextual factors that indicate the presence, absence and maturity of implementation determinants, thus offering useful lessons to stakeholders in implementing future initiatives to achieve successful outcomes. Methods: A systematic review was conducted to identify all publications reporting on the HLP project. All HLP articles and conference abstracts were considered for inclusion and were assessed for methodological quality. The Consolidated Framework for Implementation Research (CFIR) was utilised to identify potential implementation determinants reported. Each article was then analysed to identify reported economic, humanistic or clinical outcomes. Results: The review included six peer-reviewed journal articles and 12 conference abstracts. Joanna Briggs Institute Qualitative Assessment and Review Instrument indicated deficiencies in methodological quality. Through adoption of the CFIR framework, the implementation determinants relevant to the implementation of HLP into community pharmacy were identified. A resonating issue emerged in that the absence of adopting an evidence-based implementation process limited the ability to capture meaningful outcome data. This resulted in a lack of evidence to support sustainability and the failure to address many of the well cited barriers, e.g. lack of awareness amongst patients, public and other healthcare professionals, and weak support for future investment in resource for training and dissemination. Conclusions: Healthcare systems are increasingly called on to adopt evidence-based interventions that improve quality, control costs, and maximize value, thus offering opportunity to accelerate the implementation of clinical pharmacy services and programs aimed at improving patient care. Interventions, such as the HLP project require focused efforts on implementation and evaluation of those implementation efforts to produce effective and lasting changes in complex health care systems. [ABSTRACT FROM AUTHOR]

We present a selection design that couples S-adenosylmethionine–dependent methylation to growth. We demonstrate its use in improving the enzyme activities of not only N-type and O-type methyltransferases by 2-fold but also an acetyltransferase of another enzyme category when linked to a methylation pathway in Escherichia coli using adaptive laboratory evolution. We also demonstrate its application for drug discovery using a catechol O-methyltransferase and its inhibitors entacapone and tolcapone. Implementation of this design in Saccharomyces cerevisiae is also demonstrated. [ABSTRACT FROM AUTHOR]

Open Educational Resources (OER) have been lauded for their ability to reduce student costs and improve equity in higher education. Research examining whether OER provides learning benefits have produced mixed results, with most studies showing null effects. We argue that the common methods used to examine OER efficacy are unlikely to detect positive effects based on predictions of the access hypothesis. The access hypothesis states that OER benefits learning by providing access to critical course materials, and therefore predicts that OER should only benefit students who would not otherwise have access to the materials. Through the use of simulation analysis, we demonstrate that even if there is a learning benefit of OER, standard research methods are unlikely to detect it. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 fusion protein, encoded by the Philadelphia chromosome, have drastically improved the outcomes for patients with chronic myeloid leukemia (CML). Although several real-time quantitative polymerase chain reaction (RQ-PCR) kits for the detection of BCR-ABL1 transcripts are commercially available, their accuracy and efficiency in laboratory practice require reevaluation. We have developed a new in-house RQ-PCR method to detect minimal residual disease (MRD) in CML cases. MRD was analyzed in 102 patients with CML from the DOMEST study, a clinical trial to study the rationale for imatinib mesylate discontinuation in Japan. The BCR-ABL1/ABL1 ratio was evaluated using the international standard (IS) ratio, where IS < 0.1% was defined as a major molecular response. At enrollment, BCR-ABL1 transcripts were undetectable in all samples using a widely-applied RQ-PCR method performed in the commercial laboratory, BML (BML Inc., Tokyo, Japan); however, the in-house method detected the BCR-ABL1 transcripts in five samples (5%) (mean IS ratio: 0.0062 ± 0.0010%). After discontinuation of imatinib, BCR-ABL1 transcripts were detected using the in-house RQ-PCR in 21 patients (21%) that were not positive using the BML method. Nineteen samples were also tested using a commercially available RQ-PCR assay kit with a detection limit of IS ratio, 0.0032 (ODK-1201, Otsuka Pharmaceutical Co., Tokyo, Japan). This method detected low levels of BCR-ABL1 transcripts in 14 samples (74%), but scored negative for five samples (26%) that were positive using the in-house method. From the perspective of the in-house RQ-PCR method, number of patients confirmed loss of MMR was 4. These data suggest that our new in-house RQ-PCR method is effective for monitoring MRD in CML. [ABSTRACT FROM AUTHOR]

Introduction: Prescription drug abuse is a major public health problem in rural and suburban areas of the United States, however its emergence in large urban settings with endemic injection drug use remains understudied. We examined temporal trends in injection drug use initiation and mortality among people who inject drugs (PWID) in Baltimore, Maryland. Methods: Data were derived from the baseline assessment of PWID enrolled in a community-based cohort study with longitudinal follow-up for mortality assessment. PWID were recruited from 2005–2008 (N = 1,008) and 2015–2018 (N = 737). We compared characteristics by birth cohort (before/after 1980) and type of drug initiated (prescription opioids, prescription non-opioids, non-injection illicit drugs, or injection drugs). We calculated standardized mortality ratios (SMR) using the US general population as the reference. Results: PWID born after 1980 were more likely to initiate drug use with prescription opioids and non-opioids and had higher levels of polysubstance prior to injection initiation, compared to individuals born before 1980. Overall mortality was high: 2.59 per 100 person-years (95% CI: 2.27–2.95 per 100 person-years). Compared to the US population, the highest SMRs were observed among participants between 40–44 years of age, with especially high mortality among women in this age group (SMR:29.89, 95% CI: 15.24–44.54). Conclusions: Mirroring national trends, the profile of PWID in Baltimore has changed with increased prescription drug abuse and high levels of polysubstance use among younger PWID. Interventions need to reach those using prescription drugs early after initiation of use in order to reduce transition to injecting. Urgent attention is warranted to address premature mortality, particularly among middle-aged and female PWID. [ABSTRACT FROM AUTHOR]

Background: Propensity score (PS) methods are commonly used to control for confounding in comparative effectiveness studies. Electronic health records (EHRs) contain much unstructured data that could be used as proxies for potential confounding factors. The goal of this study was to assess whether the unstructured information can also be used to construct PS models that would allow to properly deal with confounding. We used an example of coxibs (Cox-2 inhibitors) vs. traditional NSAIDs and the risk of upper gastro-intestinal bleeding as example, since this association is often confounded due to channeling of coxibs to patients at higher risk of upper gastro-intestinal bleeding. Methods: In a cohort study of new users of nonsteroidal anti-inflammatory drugs (NSAIDs) from the Dutch Integrated Primary Care Information (IPCI) database, we identified all patients who experienced an upper gastrointestinal bleeding (UGIB). We used a large-scale regularized regression to fit two PS models using all structured and unstructured information in the EHR. We calculated hazard ratios (HRs) to estimate the risk of UGIB among selective cyclo-oxygenase-2 (COX-2) inhibitor users compared to nonselective NSAID (nsNSAID) users. Results: The crude hazard ratio of UGIB for COX-2 inhibitors compared to nsNSAIDs was 0.50 (95% confidence interval 0.18–1.36). Matching only on age resulted in an HR of 0.36 (0.11–1.16), and of 0.35 (0.11–1.11) when further adjusted for sex. Matching on PS only, the first model yielded an HR of 0.42 (0.13–1.38), which reduced to 0.35 (0.96–1.25) when adjusted for age and sex. The second model resulted in an HR of 0.42 (0.13–1.39), which dropped to 0.31 (0.09–1.08) after adjustment for age and sex. Conclusions: PS models can be created using unstructured information in EHRs. An incremental benefit was observed by matching on PS over traditional matching and adjustment for covariates. [ABSTRACT FROM AUTHOR]

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