Search

Background: Medication errors have long been associated with low-quality medical care services and significant additional medical costs. Objective: The aim of this study was to culturally adapt and validate the questionnaire on knowledge, attitudes and behaviors in the administration of intravenous medication, as well as to explore these factors in a hospital setting. Methods: The study was divided into two phases: 1) validation and cross-cultural adaptation, and 2) cross-sectional study. A total of 276 hospital-based nursing professionals participated in the study. Results: A Cronbach’s alpha value of 0.849 was found, indicating good internal consistency. In the multivariate analysis, statistically significant differences were found between knowledge and attitudes, demonstrating that having greater suitable knowledge correlates with having a more positive attitude. It was also discovered that having a positive attitude as well as the necessary knowledge increases the possibility of engaging in adequate behaviors. Conclusions: The knowledge, attitudes and behavior questionnaire has a satisfactory internal consistency in order to be applied to the Spanish context. Implications for nursing management: Knowledge acquisition and positive attitude are both factors which promote adequate behavior, which in turn seems to have an impact on medication errors prevention. Health institutions must encourage continuous education for their employees. [ABSTRACT FROM AUTHOR]

Adverse drug effects (ADEs) are one of the leading causes of death in developed countries and are the main reason for drug recalls from the market, whereas the ADEs that are associated with action on the cardiovascular system are the most dangerous and widespread. The treatment of human diseases often requires the intake of several drugs, which can lead to undesirable drug-drug interactions (DDIs), thus causing an increase in the frequency and severity of ADEs. An evaluation of DDI-induced ADEs is a nontrivial task and requires numerous experimental and clinical studies. Therefore, we developed a computational approach to assess the cardiovascular ADEs of DDIs. This approach is based on the combined analysis of spontaneous reports (SRs) and predicted drug-target interactions to estimate the five cardiovascular ADEs that are induced by DDIs, namely, myocardial infarction, ischemic stroke, ventricular tachycardia, cardiac failure, and arterial hypertension. We applied a method based on least absolute shrinkage and selection operator (LASSO) logistic regression to SRs for the identification of interacting pairs of drugs causing corresponding ADEs, as well as noninteracting pairs of drugs. As a result, five datasets containing, on average, 3100 potentially ADE-causing and non-ADE-causing drug pairs were created. The obtained data, along with information on the interaction of drugs with 1553 human targets predicted by PASS Targets software, were used to create five classification models using the Random Forest method. The average area under the ROC curve of the obtained models, sensitivity, specificity and balanced accuracy were 0.837, 0.764, 0.754 and 0.759, respectively. The predicted drug targets were also used to hypothesize the potential mechanisms of DDI-induced ventricular tachycardia for the top-scoring drug pairs. The created five classification models can be used for the identification of drug combinations that are potentially the most or least dangerous for the cardiovascular system. [ABSTRACT FROM AUTHOR]

Background: Diabetes prevention programmes delay or prevent the onset of type 2 diabetes in people with pre-diabetes. To increase accessibility, national guidelines recommend delivering diabetes prevention programmes in primary care settings, including community pharmacy. This study aimed to explore the English community pharmacy setting as an option for delivering diabetes prevention services. Methods: Two focus groups and nine semi-structured interviews were conducted with stakeholders including, community pharmacists, general practitioners and commissioners. The topic guide was framed using the COM-B theoretical model for behaviour change to elicit practitioners’ capability, opportunity and motivation to engage with providing or referring to community pharmacy diabetes prevention services. Data were analysed thematically, and barriers/facilitators mapped to the COM-B framework. Results: Five themes were identified: ‘Pre-diabetes management and associated challenges’, ‘The community pharmacy setting’, ‘Awareness of community pharmacy services’, ‘Relationships and communication’ and ‘Delivery of community pharmacy services’. Community pharmacy was highlighted as an accessible setting for delivering screening and follow-on lifestyle interventions. Key factors for enhancing the capability of community pharmacy teams to deliver the interventions included training and appropriate use of skill mix. Delivering diabetes prevention services in collaboration with general practices was identified as key to the provision of integrated primary care services. Whilst financial incentives were identified as a motivating factor for delivery, service promotion to patients, public and healthcare professionals was perceived as crucial for enhancing engagement. Conclusions: This research highlights a role for community pharmacy in diabetes prevention. New service models should seek to integrate community pharmacy services in primary care to facilitate patient engagement and better communication with general practices. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization (WHO) currently recommends height or age-based dosing as alternatives to weight-based dosing for mass drug administration lymphatic filariasis (LF) elimination programs. The goals of our study were to compare these alternative dosing strategies to weight-based dosing and to develop and evaluate new height-based dosing pole scenarios. Methodology/Principal findings: Age, height and weight data were collected from >26,000 individuals in five countries during a cluster randomized LF clinical trial. Weight-based dosing for diethylcarbamazine (DEC; 6 mg/kg) and ivermectin (IVM; 200 ug/kg) with tablet numbers derived from a table of weight intervals was treated as the “gold standard” for this study. Following WHO recommended age-based dosing of DEC and height-based dosing of IVM would have resulted in 32% and 27% of individuals receiving treatment doses below those recommended by weight-based dosing for DEC and IVM, respectively. Underdosing would have been especially common in adult males, who tend to have the highest LF prevalence in many endemic areas. We used a 3-step modeling approach to develop and evaluate new dosing pole cutoffs. First, we analyzed the clinical trial data using quantile regression to predict weight from height. We then used weight predictions to develop new dosing pole cutoff values. Finally, we compared different dosing pole cutoffs and age and height-based WHO dosing recommendations to weight-based dosing. We considered hundreds of scenarios including country- and sex-specific dosing poles. A simple dosing pole with a 6-tablet maximum for both DEC and IVM reduced the underdosing rate by 30% and 21%, respectively, and was nearly as effective as more complex pole combinations for reducing underdosing. Conclusions/Significance: Using a novel modeling approach, we developed a simple dosing pole that would markedly reduce underdosing for DEC and IVM in MDA programs compared to current WHO recommended height or age-based dosing. [ABSTRACT FROM AUTHOR]

Background: Therapeutic footwear becomes the first treatment line in the prevention of diabetic foot ulcer and future complications of diabetes. Previous studies and the International Working Group on the Diabetic Foot have described therapeutic footwear as a protective factor to reduce the risk of re-ulceration. In this study, we aimed to analyze the efficacy of a rigid rocker sole to reduce the recurrence rate of plantar ulcers in patients with diabetic foot. Methods: Between June 2016 and December 2017, we conducted a randomized controlled trial in a specialized diabetic foot unit. Participants and intervention: Fifty-one patients with diabetic neuropathy who had a recently healed plantar ulcer were randomized consecutively into the following two groups: therapeutic footwear with semi-rigid sole (control) or therapeutic footwear with a rigid rocker sole (experimental). All patients included in the study were followed up for 6 months (one visit each 30 ± 2 days) or until the development of a recurrence event. Main outcome and measure: Primary outcome measure was recurrence of ulcers in the plantar aspect of the foot. Findings: A total of 51 patients were randomized to the control and experimental groups. The median follow-up time was 26 [IQR—4.4—26.1] weeks for both groups. On an intention-to-treat basis, 16 (64%) and 6 (23%) patients in the control and experimental groups had ulcer recurrence, respectively. Among the group with >60% adherence to therapeutic footwear, multivariate analysis showed that the rigid rocker sole improved ulcer recurrence-free survival time in diabetes patients with polyneuropathy and DFU history (P = 0.019; 95% confidence interval, 0.086–0.807; hazard ratio, 0.263). Conclusions: We recommend the use of therapeutic footwear with a rigid rocker sole in patients with diabetes with polyneuropathy and history of diabetic foot ulcer to reduce the risk of plantar ulcer recurrence. Trial registration: ClinicalTrials.gov . [ABSTRACT FROM AUTHOR]

Background: Effective education in basic life support (BLS) may improve the early initiation of high-quality cardiopulmonary resuscitation and automated external defibrillation (CPR-AED). Aim: To compare the learning outcome in terms of practical skills and knowledge of BLS after participating in learning activities related to BLS, with and without web-based education in cardiovascular diseases (CVD). Methods: Laymen (n = 2,623) were cluster randomised to either BLS education or to web-based education in CVD before BLS training. The participants were assessed by a questionnaire for theoretical knowledge and then by a simulated scenario for practical skills. The total score for practical skills in BLS six months after training was the primary outcome. The total score for practical skills directly after training, separate variables and self-assessed knowledge, confidence and willingness, directly and six months after training, were the secondary outcomes. Results: BLS with web-based education was more effective than BLS without web-based education and obtained a statistically significant higher total score for practical skills at six months (mean 58.8, SD 5.0 vs mean 58.0, SD 5.0; p = 0.03) and directly after training (mean 59.6, SD 4.8 vs mean 58.7, SD 4.9; p = 0.004). Conclusion: A web-based education in CVD in addition to BLS training enhanced the learning outcome with a statistically significant higher total score for performed practical skills in BLS as compared to BLS training alone. However, in terms of the outcomes, the differences were minor, and the clinical relevance of our findings has a limited practical impact. [ABSTRACT FROM AUTHOR]

Objectives: To examine 1) the publication rate of registered otology trials in ClinicalTrials.gov, 2) the public availability of the results, 3) the study characteristics associated with publication, and 4) the time to publication after trial completion. Background: Publication bias, the publication or non-publication of research findings, depending on the nature and direction of results, is accountable for wrong treatment decisions. The extent of publication bias in otology trials has not been evaluated. Methods: All registered otology trials were extracted from ClinicalTrials.gov with completion date up to December 2015. A search strategy was used to identify corresponding publications up to June 2017, providing at least 18 months to publish the results after trial completion. Characteristics were obtained from ClinicalTrials.gov and corresponding publications. Regression models were used to examine study characteristics associated with publication or non-publication. Results: From the 419 trials identified on ClinicalTrials.gov, 225 (53.7%) corresponding publications were found in PubMed. Among these, 109 (48.4%) publications were cited on ClinicalTrials.gov and 124 (55.1%) articles reported the National Clinical Trial registry number. For 36 (8.6%) trials, results were only reported in ClinicalTrials.gov. Trials with a biological intervention were more likely to be published than studies involving drugs (odds ratio (OR) 10.41, 95% confidence interval (CI) 1.26–86.22, P = 0.030). Trials funded by industry were less likely to be published (OR 0.46, CI 0.25–0.84, P = 0.011). The median trial duration was 20 months (interquartile range (IQR) 26 months), and median time from trial completion to publication was 24 months (IQR 22 months). Conclusion: In 37.7% of the registered otology trials the results remained unpublished, even several years after trial completion. With little citations on ClinicalTrials.gov and low reporting of the Clinical Trial registry number, the accessibility is limited. Our findings show that there is room for improvement in accuracy of trial registration and publication of results, in order to diminish publication bias in otology studies. [ABSTRACT FROM AUTHOR]

Geraint Davies and colleagues discuss the potential for innovative early-phase clinical trial methods and technologies to reduce risk and speed up drug development for tuberculosis. [ABSTRACT FROM AUTHOR]

In this non-randomized extension study of a randomized controlled trial we converted 87 stable long-term kidney transplant recipients (KTR) from either ciclosporin (CSA, n = 28) or tacrolimus (TAC, n = 59) to TAC modified release (TAC MR4) to study the characteristics of TAC trough levels after conversion with the primary endpoint graft function after 12 months. TAC MR4 consumption was calculated by level-to-dose ([ng/mL]/[mg/d]) and concentration-to-dose ([mg/kg])/d) ratios. Influences of ABCB1 single nucleotide polymorphisms (2677G>T/A, 1236C>T, 3435C>T) on TAC metabolism were studied. Graft function of KTR converted from CSA to TAC MR4 significantly declined over 12 months, and remained unchanged after conversion from TAC to TAC MR4. Conversion from CSA to TAC MR4 resulted in supra therapeutic- and conversion from TAC to TAC MR4 in low trough levels. We could not find associations of ABCB1 genotypes and TAC MR4 trough levels. Adverse events and errors with TAC/TAC MR4 intake were common. In stable long-term KTR conversion from TAC to TAC MR4 is feasible. For conversion from CSA we suggest a rate of 1:40 for a rough estimation of TAC MR4 target doses. Trial registration: PEP Study: Ethics committee N° 393/2004, EudraCT 2004-004209-98. PEP-X Study: Ethics committee amendment application N° 154/01/2008. ClinicalTrials.gov . [ABSTRACT FROM AUTHOR]

Background: Onchocerciasis currently afflicts an estimated 15 million people and is the second leading infectious cause of blindness world-wide. The development of a macrofilaricide to cure the disease has been hindered by the lack of appropriate small laboratory animal models. This study therefore, was aimed at developing and validating the Mongolian gerbil, as an Onchocerca ochengi (the closest in phylogeny to O. volvulus) adult male worm model. Methodology/Principal findings: Mongolian gerbils (Meriones unguiculatus) were each implanted with 20 O. ochengi male worms (collected from infected cattle), in the peritoneum. Following drug or placebo treatments, the implanted worms were recovered from the animals and analyzed for burden, motility and viability. Worm recovery in control gerbils was on average 35%, with 89% of the worms being 100% motile. Treatment of the gerbils implanted with male worms with flubendazole (FBZ) resulted in a significant reduction (p = 0.0021) in worm burden (6.0% versus 27.8% in the control animals); all recovered worms from the treated group had 0% worm motility versus 91.1% motility in control animals. FBZ treatment had similar results even after four different experiments. Using this model, we tested a related drug, oxfendazole (OFZ), and found it to also significantly (p = 0.0097) affect worm motility (22.7% versus 95.0% in the control group). Conclusions/Significance: We have developed and validated a novel gerbil O. ochengi adult male worm model for testing new macrofilaricidal drugs in vivo. It was also used to determine the efficacy of oxfendazole in vivo. [ABSTRACT FROM AUTHOR]

Tolvaptan is the only drug approved to slow cyst growth and preserve kidney function in patients with autosomal dominant polycystic kidney disease (ADPKD). However, its limited efficacy combined with significant side effects underscores the need to identify new and safe therapeutic drug targets to slow progression to end stage kidney disease. We identified Discoidin Domain Receptor 1 (DDR1) as receptor tyrosine kinase upregulated in vivo in 3 mouse models of ADPKD using a novel mass spectrometry approach to identify kinases upregulated in ADPKD. Previous studies demonstrating critical roles for DDR1 to cancer progression, its potential role in the pathogenesis of a variety of other kidney disease, along with the possibility that DDR1 could provide new insight into how extracellular matrix impacts cyst growth led us to study the role of DDR1 in ADPKD pathogenesis. However, genetic deletion of DDR1 using CRISPR/Cas9 failed to slow cyst growth or preserve kidney function in both a rapid and slow mouse model of ADPKD demonstrating that DDR1 does not play a role in PKD pathogenesis and is thus a not viable drug target. In spite of the negative results, our studies will be of interest to the nephrology community as it will prevent others from potentially conducting similar experiments on DDR1 and reinforces the potential of performing unbiased screens coupled with in vivo gene editing using CRISPR/Cas9 to rapidly identify and confirm new potential drug targets for ADPKD. [ABSTRACT FROM AUTHOR]

Background: Self-medication is the use of any drug or medication to treat an illness or ailment without the supervision of a licensed medical doctor/health care providers. Self-medication practice in Eastern Ethiopia is quite common. However, there is little information with regard to magnitude and associated factors. The objective of this study was to assess the magnitude of self-medication practice and associated factors among adult community members of Jigjiga town, Eastern Ethiopia. Methods: A community based cross-sectional study was conducted from June 27- July 12, 2017. Multistage sampling method was used and the number of kebeles and Sub-kebeles were selected using simple random sampling technique. Finally, sampled households in the Sub-kebeles were selected using systematic random sampling. Data were collected using face to face interview with 547 adult (≥18 years) participants. It was entered and cleaned using EPI-Data version 3.02 and exported to Statistical Package for Social Science (SPSS) Version 23 for further analysis. Bi-variable and multivariable logistic regression models were carried out to identify factors associated with the self-medication. Result: The magnitude of self-medication was found to be 37.5% (95% CI: (33.6%–41.7%). Educational status of secondary school [(AOR = 0.46; 95% CI: (0.22–0.98)], high income [(AOR = 3.00; 95% CI: (1.77–5.06)], advised by neighbors, friends or relatives to take drug for their complaint [(AOR = 2.59; 95% CI: (1.62–4.14)], used old prescription /past experience to bought drugs [(AOR = 12.19; 95% CI: (6.65–22.35)], follow advertisements of drugs by television [(AOR = 0.21; 95% CI: (0.05–0.85)], and perception about Hospital drugs (clinics, health centers and hospitals) do not work [(AOR = 2.36; 95% CI: (1.39–3.99)] were significantly associated with self-medication. Conclusion: High income, advice by neighbors, friends or relatives to take drug for their complaint, old prescription/past experience use to bought drugs, and perception of hospital drugs do not work was positively associated with self-medication. Therefore, health education should be given to the community on the importance of hospital drugs (clinics, health centers and hospitals) to shift their perception. [ABSTRACT FROM AUTHOR]

Motivation: Disease progression originates from the concept that an individual disease may go through different changes as it evolves, and such changes can cause new diseases. It is important to find a progression between diseases since knowing the prior-posterior relationship beforehand can prevent further complications or evolutions to other diseases. Furthermore, the series of progressions can be represented in the form of a chain, which enables us to readily infer successive influences from one disease to another after many passages through other diseases. Methods: In this paper, we propose a systematic approach for finding a disease progression chain from a source disease to a target one via exploring a disease network. The network is constructed based on various sets of biomedical data. To find the most influential progression chains, the k-shortest path search algorithm is employed. The most representative algorithms such as A*, Dijkstra, and Yen’s are incorporated into the proposed method. Results: A disease network consisting of 3,302 diseases was constructed based on four sources of biomedical data: disease-protein relations, biological pathways, clinical history, and biomedical literature information. The last three sets of data contain prior-posterior information, and they endow directionality on the edges of the network. The results were interesting and informative: for example, when colitis and respiratory insufficiency were set as a source disease and a target one, respectively, five progression chains were found within several seconds (when k = 5). Each chain was provided with a progression score, which indicates the strength of plausibility relative to others. Similarly, the proposed method can be expanded to any pair of source-target diseases in the network. This can be utilized as a preliminary tool for inferring complications or progressions between diseases. [ABSTRACT FROM AUTHOR]

Background: Few randomized controlled trials have assessed the effects of laughter therapy on health-related quality of life (QOL) in cancer patients. This study aimed to evaluate these effects as an exploratory endpoint in cancer patients as part of a randomized controlled trial conducted at a single institution in Japan. Methods: The Initiative On Smile And CAncer (iOSACA) study was an open-label randomized controlled trial conducted in 2017 in which participants aged 40–64 years with cancer were randomly assigned to either an intervention group (laughter therapy) or control group (no laughter therapy). Each participant in the intervention group underwent a laughter therapy session once every two weeks for seven weeks (total of four sessions). Each session involved a laughter yoga routine followed by Rakugo or Manzai traditional Japanese verbal comedy performances. We assessed QOL as a secondary endpoint in this intention-to-treat population using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). The questionnaire was completed at baseline (Week 0) and at Weeks 3 and 7. Mixed-effects models for repeated measures were developed to compare time-dependent changes in each QOL domain from baseline between the intervention and control groups. Results: Four participants retracted consent and one participant was retrospectively excluded from analysis due to unmet inclusion criteria. The analysis was conducted using 56 participants, with 26 in the intervention group and 30 in the control group. Questionnaire completion rates were high (>90%), with similar QOL scores reported at baseline in both groups. The mixed-effects models showed that the intervention group had significantly better cognitive function and less pain than the control group for a short period. Conclusion: Laughter therapy may represent a beneficial, noninvasive complementary intervention in the clinical setting. Further studies are needed to verify the hypotheses generated from this exploratory study. [ABSTRACT FROM AUTHOR]

Gastrointestinal side effects are among the most common classes of adverse reactions associated with orally absorbed drugs. These effects decrease patient compliance with the treatment and induce undesirable physiological effects. The prediction of drug action on the gut wall based on in vitro data solely can improve the safety of marketed drugs and first-in-human trials of new chemical entities. We used publicly available data of drug-induced gene expression changes to build drug-specific small intestine epithelial cell metabolic models. The combination of measured in vitro gene expression and in silico predicted metabolic rates in the gut wall was used as features for a multilabel support vector machine to predict the occurrence of side effects. We showed that combining local gut wall-specific metabolism with gene expression performs better than gene expression alone, which indicates the role of small intestine metabolism in the development of adverse reactions. Furthermore, we reclassified FDA-labeled drugs with respect to their genetic and metabolic profiles to show hidden similarities between seemingly different drugs. The linkage of xenobiotics to their transcriptomic and metabolic profiles could take pharmacology far beyond the usual indication-based classifications. [ABSTRACT FROM AUTHOR]

Background: In 2017, more than 1.1 million children were living with type 1 diabetes mellitus (T1DM) globally. The goal in paediatric diabetes therapy is reaching optimal glycaemic control as early as possible in order to avoid complications and early mortality without compromising the quality of life (QoL) of children. Several different insulin regimens are available for T1DM patients to reach this goal. Aims: This review set out to analyse whether continuous subcutaneous insulin infusion (CSII) regimens are superior to multiple daily injection (MDI) therapy in T1DM youth regarding QoL. Additionally, it assessed glycaemic control and adverse events as secondary outcomes and discussed potential future public health implications and justifications for using CSII as a first-line therapy in diabetic youth. Methods: A systematic review and random effects meta-analysis was performed on studies investigating the association between QoL and diabetes treatment regimen. Differences in adverse event rates between groups were analysed using a Mann-Whitney U test. Lastly, differences in glycaemic control were assessed using a random effects meta-analysis. Results: QoL and glycaemic control was significantly better in CSII subjects at baseline and follow-up. No significant differences in adverse events were found between study groups. No significant changes over time could be shown for either QoL or glycaemic control. Conclusion: CSII proved to provide similar or slightly better outcomes in all analysed fields. This is consistent with previous research. However, to make credible recommendations, better-designed studies are needed to investigate the impact of CSII in children. [ABSTRACT FROM AUTHOR]

Objectives: Despite the relationship between physical activity (PA) and learning outcomes, the school system has not been able to support the inclusion of PA throughout the day. A solution to this problem integrates PA into the academic classroom. The objective of this review is to determine the impact of active classrooms compared to traditional sedentary classrooms on educational outcomes of school-aged children. Design: We searched ERIC, PubMed, PsychINFO, and Web of Science, reference lists of included studies for randomised controlled studies. Independent reviewers screened the texts of potentially eligible studies and assessed the risk of bias. Data were pooled using random-effects models on standardized mean differences. Results: This review identified 25 studies examining educational outcomes, including approximately 6,181 students. Risk of bias was assessed as either some or high risk of bias for most of the studies and outcomes. Pooled data from 20 studies and 842 participants measuring academic performance shows a small positive effect of active classrooms compared with traditional, sedentary classrooms (SMD = 0.28, 95% CI: 0.09 to 0.47). Conclusions: Physically active classrooms may slightly improve academic achievement compared to the traditional sedentary lessons. Future research is needed to ensure that studies are adequately powered, employ appropriate methods of randomization, and measure a wide range of important student outcomes across the full spectrum of the school-age. [ABSTRACT FROM AUTHOR]

Introduction: ARV-based pre-exposure prophylaxis (PrEP) has the potential to avert many new HIV infections, yet little is known about how to reach women at high risk for HIV infection and motivate them to initiate PrEP. Clinical trials have succeeded in recruiting at-risk participants, evidenced by control arm HIV incidence ≥3% (defined by the World Health Organization as “substantial risk”). We examined experiences from HIV prevention trials to document recruitment strategies and identify practical, potentially effective strategies for reaching women in real-world PrEP delivery. Methods: We conducted semi-structured qualitative phone interviews with 31 staff from five countries who had worked on one or more of seven ARV-based HIV prevention clinical trials. Questions explored recruitment strategies used to reach women at risk of HIV and to successfully communicate about PrEP (inclusive of oral and vaginal formulations). We structurally coded data in NVivo and analyzed codes to derive themes. We conducted results interpretation webinars with research and programmatic stakeholders to validate findings and develop recommendations. Results: Clinical trial researchers employed a range of recruitment strategies to recruit at-risk women. They recommended engaging the local community and potential PrEP users via community events, meetings with gatekeepers, and use of community advisory boards; and they encouraged interpersonal communication like presentations in waiting rooms and door-to-door recruitment to address personal concerns and prevent misinformation. Participants also stressed the importance of addressing the challenges that already exist within the health system to create a more enabling environment and delivering positive messages through a variety of communication channels to normalize PrEP. Conclusions: Findings from this study provide important insights into potentially effective ways for countries currently rolling out oral PrEP to reach at-risk women with information about PrEP and promote uptake. [ABSTRACT FROM AUTHOR]

Background: Medicines regulatory harmonization has been recommended as one way to improve access to quality-assured medicines in low- and middle-income countries. The rationale is that by lowering barriers to entry more manufacturers will be enticed to enter the market, while the capacity at the national medicines regulatory authorities is strengthened. The African Medicines Regulatory Harmonization Initiative, agreed in 2009, is developing regional platforms with harmonized regulatory procedures for the registration of medicines. The first region to implement medicines regulatory harmonization was the East African Community (EAC). The harmonization was based on the existing EAC Free Trade Agreement, which officially launched the free movement of goods and services in 2010. Methods and findings: In this study we conducted semi-structured interviews and performed document reviews. The main target group for our interviews was pharmaceutical companies. We interviewed 18 companies, including 64% of the total companies who had experienced the EAC joint product assessment procedure, and two EAC-based national medicines regulatory authorities. We found that generally pharmaceutical companies are supportive of the African-based MRH efforts and appreciative of the progress being achieved. However, many companies are now hesitant to use the joint product assessment procedure until efficiency improvements are made. Common frustrations were the length of time to receive the actual marketing authorization; unexpectedly higher quality standards than national procedures; and challenges in getting all EAC countries to recognize EAC approvals. Smaller, less attractive markets have not yet become more attractive from a corporate perspective, and there is no free trade of pharmaceuticals in the EAC region. Conclusions: Pharmaceutical companies agree that medicines regulatory harmonization is the way forward. However, regulatory medicines harmonization must actually result in quicker access to the harmonized markets for quality-assured medicines. At this time, improvements are required to the current EAC processes to meet the vision of harmonization. [ABSTRACT FROM AUTHOR]

Objectives: The Code of Ethics of pharmacy practitioners in Australia recognises the obligation to provide care to patients in a culturally safe and responsive manner. The aim of this exploratory study was to examine how Australian community pharmacists understand and experience the concept of ‘culture’ in their everyday practice environment. Methods: Voluntary, semi-structured interviews were conducted at community pharmacy placement sites in South-East Queensland, Australia. Pharmacists were asked to recall an incident that evoked their cultural awareness during the course of their practice. The question stated, verbatim: “We are preparing our students to be pharmacists in a highly multicultural community. Can you think of an incident where you learnt something about another person’s culture or it made you more aware of your own culture? Please briefly describe the incident.” Reportable responses were collected from 59 of the 92 visited pharmacists. These responses were audio-recorded and transcribed. The data were collated and analysed through iterative, reflexive, thematic analysis using constant comparison. Results and significance: The responses provided a rich selection of lived experiences within Australian multicultural pharmacy practice, describing professional dilemmas, fears and the strategies employed to overcome practice challenges. Six main response categories were identified: (i) Language/communication challenges, (ii) Cultural attitudes and behaviours, (iii) Exposure to culture due to pharmacy location, (iv) Religion, gender, and age, (v) Prejudiced/perceived racist attitudes and discrimination towards ‘other’ cultures, (vi) Perceived ‘sameness’ of different cultures. The study has provided valuable insights into community pharmacists’ experiences of culture in their day-to-day professional practice, also highlighting the associated strategies used to maintain a high standard of practice. There is merit in ensuring that the pharmacy curriculum and professional development programs are designed to respond to the ethical obligation of pharmacists to practise in a culturally safe, responsive manner that acknowledges and incorporates the importance of culture, cultural differences and intercultural relations, while addressing culturally unique needs in a skilled and professional manner. [ABSTRACT FROM AUTHOR]

Both basic and translational research are continuously evolving, but the principles that underpin research integrity remain constant. These include rational, hypothesis-driven, and adequately planned and controlled science, which is carried out openly, honestly, and ethically. An important component of this should be minimising experimental irreproducibility. Biological systems, in particular, are inherently variable due to the nature of cells and tissues, as well as the complex molecules within them. As a result, it is important to understand and identify sources of variability and to strive to minimise their influence. In many instances, the application of metrology (the science of measurement) can play an important role in ensuring good quality research, even within biological systems that aren’t always amenable to many of the metrological concepts applied in other fields. Here, we introduce the basic concepts of metrology in relation to biological systems and promote the application of these principles to help avoid potentially costly mistakes in both basic and translational research. We also call on funders to encourage the uptake of metrological principles, as well as provide funding and support for later engagement with regulatory bodies. [ABSTRACT FROM AUTHOR]

Many complex diseases such as cancer are associated with multiple pathological manifestations. Moreover, the therapeutics for their treatments often lead to serious side effects. Thus, it is needed to develop multi-indication therapeutics that can simultaneously target multiple clinical indications of interest and mitigate the side effects. However, conventional one-drug-one-gene drug discovery paradigm and emerging polypharmacology approach rarely tackle the challenge of multi-indication drug design. For the first time, we propose a one-drug-multi-target-multi-indication strategy. We develop a novel structural systems pharmacology platform 3D-REMAP that uses ligand binding site comparison and protein-ligand docking to augment sparse chemical genomics data for the machine learning model of genome-scale chemical-protein interaction prediction. Experimentally validated predictions systematically show that 3D-REMAP outperforms state-of-the-art ligand-based, receptor-based, and machine learning methods alone. As a proof-of-concept, we utilize the concept of drug repurposing that is enabled by 3D-REMAP to design dual-indication anti-cancer therapy. The repurposed drug can demonstrate anti-cancer activity for cancers that do not have effective treatment as well as reduce the risk of heart failure that is associated with all types of existing anti-cancer therapies. We predict that levosimendan, a PDE inhibitor for heart failure, inhibits serine/threonine-protein kinase RIOK1 and other kinases. Subsequent experiments and systems biology analyses confirm this prediction, and suggest that levosimendan is active against multiple cancers, notably lymphoma, through the direct inhibition of RIOK1 and RNA processing pathway. We further develop machine learning models to predict cancer cell-line’s and a patient’s response to levosimendan. Our findings suggest that levosimendan can be a promising novel lead compound for the development of safe, effective, and precision multi-indication anti-cancer therapy. This study demonstrates the potential of structural systems pharmacology in designing polypharmacology for precision medicine. It may facilitate transforming the conventional one-drug-one-gene-one-disease drug discovery process and single-indication polypharmacology approach into a new one-drug-multi-target-multi-indication paradigm for complex diseases. [ABSTRACT FROM AUTHOR]

Background: Systematic reviews of randomised controlled trials (RCTs) have suggested that maternal vitamin D (25[OH]D) and calcium supplementation increase birth weight. However, limitations of many trials were highlighted in the reviews. Our aim was to combine genetic and RCT data to estimate causal effects of these two maternal traits on offspring birth weight.Methods and Findings: We performed two-sample mendelian randomisation (MR) using genetic instrumental variables associated with 25(OH)D and calcium that had been identified in genome-wide association studies (GWAS; sample 1; N = 122,123 for 25[OH]D and N = 61,275 for calcium). Associations between these maternal genetic variants and offspring birth weight were calculated in the UK Biobank (UKB) (sample 2; N = 190,406). We used data on mother-child pairs from two United Kingdom birth cohorts (combined N = 5,223) in sensitivity analyses to check whether results were influenced by fetal genotype, which is correlated with the maternal genotype (r ≈ 0.5). Further sensitivity analyses to test the reliability of the results included MR-Egger, weighted-median estimator, 'leave-one-out', and multivariable MR analyses. We triangulated MR results with those from RCTs, in which we used randomisation to supplementation with vitamin D (24 RCTs, combined N = 5,276) and calcium (6 RCTs, combined N = 543) as an instrumental variable to determine the effects of 25(OH)D and calcium on birth weight. In the main MR analysis, there was no strong evidence of an effect of maternal 25(OH)D on birth weight (difference in mean birth weight -0.03 g [95% CI -2.48 to 2.42 g, p = 0.981] per 10% higher maternal 25[OH]D). The effect estimate was consistent across our MR sensitivity analyses. Instrumental variable analyses applied to RCTs suggested a weak positive causal effect (5.94 g [95% CI 2.15-9.73, p = 0.002] per 10% higher maternal 25[OH]D), but this result may be exaggerated because of risk of bias in the included RCTs. The main MR analysis for maternal calcium also suggested no strong evidence of an effect on birth weight (-20 g [95% CI -44 to 5 g, p = 0.116] per 1 SD higher maternal calcium level). Some sensitivity analyses suggested that the genetic instrument for calcium was associated with birth weight via exposures that are independent of calcium levels (horizontal pleiotropy). Application of instrumental variable analyses to RCTs suggested that calcium has a substantial effect on birth weight (178 g [95% CI 121-236 g, p = 1.43 × 10-9] per 1 SD higher maternal calcium level) that was not consistent with any of the MR results. However, the RCT instrumental variable estimate may have been exaggerated because of risk of bias in the included RCTs. Other study limitations include the low response rate of UK Biobank, which may bias MR estimates, and the lack of suitable data to test whether the effects of genetic instruments on maternal calcium levels during pregnancy were the same as those outside of pregnancy.Conclusions: Our results suggest that maternal circulating 25(OH)D does not influence birth weight in otherwise healthy newborns. However, the effect of maternal circulating calcium on birth weight is unclear and requires further exploration with more research including RCT and/or MR analyses with more valid instruments. [ABSTRACT FROM AUTHOR]

Identification of drug-target interactions (DTIs) plays a key role in drug discovery. The high cost and labor-intensive nature of in vitro and in vivo experiments have highlighted the importance of in silico-based DTI prediction approaches. In several computational models, conventional protein descriptors have been shown to not be sufficiently informative to predict accurate DTIs. Thus, in this study, we propose a deep learning based DTI prediction model capturing local residue patterns of proteins participating in DTIs. When we employ a convolutional neural network (CNN) on raw protein sequences, we perform convolution on various lengths of amino acids subsequences to capture local residue patterns of generalized protein classes. We train our model with large-scale DTI information and demonstrate the performance of the proposed model using an independent dataset that is not seen during the training phase. As a result, our model performs better than previous protein descriptor-based models. Also, our model performs better than the recently developed deep learning models for massive prediction of DTIs. By examining pooled convolution results, we confirmed that our model can detect binding sites of proteins for DTIs. In conclusion, our prediction model for detecting local residue patterns of target proteins successfully enriches the protein features of a raw protein sequence, yielding better prediction results than previous approaches. Our code is available at . [ABSTRACT FROM AUTHOR]

Different pediatric physiologically-based pharmacokinetic (PBPK) models have been described incorporating developmental changes that influence plasma drug concentrations. Drug disposition into cerebrospinal fluid (CSF) is also subject to age-related variation and can be further influenced by brain diseases affecting blood-brain barrier integrity, like meningitis. Here, we developed a generic pediatric brain PBPK model to predict CSF concentrations of drugs that undergo passive transfer, including age-appropriate parameters. The model was validated for the analgesics paracetamol, ibuprofen, flurbiprofen and naproxen, and for a pediatric meningitis population by empirical optimization of the blood-brain barrier penetration of the antibiotic meropenem. Plasma and CSF drug concentrations derived from the literature were used to perform visual predictive checks and to calculate ratios between simulated and observed area under the concentration curves (AUCs) in order to evaluate model performance. Model-simulated concentrations were comparable to observed data over a broad age range (3 months– 15 years postnatal age) for all drugs investigated. The ratios between observed and simulated AUCs (AUCo/AUCp) were within 2-fold difference both in plasma (range 0.92–1.09) and in CSF (range 0.64–1.23) indicating acceptable model performance. The model was also able to describe disease-mediated changes in neonates and young children (<3m postnatal age) related to meningitis and sepsis (range AUCo/AUCp plasma: 1.64–1.66, range AUCo/AUCp CSF: 1.43–1.73). Our model provides a new computational tool to predict CSF drug concentrations in children with and without meningitis and can be used as a template model for other compounds that passively enter the CNS. [ABSTRACT FROM AUTHOR]

The dosage of pharmaceuticals is determined through the process of clinical development and approval review based on clinical trial results; however, the information obtained from clinical trials before approval is limited. Some pharmaceutical products are used at doses lower than those approved for post-marketing use. The aim of this study was to reveal the actual state of lower-dose prescriptions for post-marketing clinical use of pharmaceuticals. We investigated the factors related to the deviation based on therapeutic area, detailed statement of the approved dosage, clinical data package, and post-marketing requirement. Among the new molecular entities approved in Japan between January 2005 and December 2014, we identified products that are orally administered and have the same daily dose for different indications, if any. For these products, we collected information on the actual daily dose from the medical information databases of Medical Data Vision Co., LTD. and JammNet Co., LTD. Products whose dose was lower than the approved dose (maintenance dose excluding the initial dose) in ≥ 30% prescriptions in 2015 were defined here as “lower-dose prescription drugs.” We identified 27 lower-dose prescription drugs out of 113 products investigated. The results of the multivariate analysis revealed that factors related to the Anatomical Therapeutic Chemical classification and the detailed statement of the approved dosage significantly influenced the occurrence of lower-dose prescription, whereas the factors related to clinical data package and post-marketing requirements did not. These results suggest the limitation in determining an optimal dosage for the actual clinical use of a drug based on the information obtained from clinical trials conducted before approval, emphasizing the importance of reexamining the optimal dosage that is applicable to a greater number of patients after marketing, if necessary. We believe that the utilization of real-world data could be of help in this regard. [ABSTRACT FROM AUTHOR]

Background: The health service delivery framework collaborative care is an effective intervention for depression. However, uncertainties remain about how to optimise its delivery at scale. Structured case management is a core component of collaborative care; its delivery via the telephone may improve access. Aims: To examine using meta-regression if telephone delivered case management diminishes the clinical effectiveness of collaborative care on depressive symptoms and anti-depressant use relative to face-to-face delivery methods. Methods: Randomised controlled trials were eligible if they included collaborative care interventions for adults with depression identified using self-report measures or diagnostic interviews and reported depression outcomes. Sociodemographics, intervention characteristics, depressive symptoms, and anti-depressant use were extracted. Random effects univariable and multivariable meta-regression analyses were used to examine the moderating effect of telephone delivered case-management on outcomes. Results: Ninety-four trials were identified comprising of 103 comparisons across 24, 132 participants with depression outcomes and 67 comparisons from 15,367 participants with anti-depressant use outcomes. Telephone delivered case management did not diminish the effects of collaborative care on depressive symptoms (β = -0.01, 95% CI -0.12 to 0.10; p = 0.86). Telephone delivered case management decreased anti-depressant medication use (relative risk 0.76, 95% CI 0.63 to 0.92; p = 0.005); this effect remained when assessed simultaneously alongside other study-level moderators of collaborative care. Conclusion: Using remote platforms such as the telephone to deliver case management may be a feasible way to implement collaborative care with no loss of effectiveness on depressive symptoms. However, adherence to anti-depressant medication may decrease when telephone case management is used. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia is a severe condition that affects approximately 1% of the population. Certain elements of antipsychotic treatment can only be examined in large population, thus the need for population-based real-world analyses has been increasing. Patients and methods: Hungarian National Health Fund database includes all healthcare data of the population of Hungary. All patients diagnosed with schizophrenia between 01.01.2006 and 31.12.2015 were included in the study. We analyzed all patients with newly initiated second-generation antipsychotic during the inclusion period (01.01.2012–31.12.2013). Patients were followed for 2 years. All-cause treatment discontinuation served as the primary outcome of the study. Patients with newly initiated long-acting injectable treatments were further investigated in stratified analyses based on their previous treatment. Results: 106,624 patients had schizophrenia diagnosis during the study period. 12,232 patients met the inclusion criteria for newly initiating second-generation antipsychotic during the inclusion period. The proportion of patients still on treatment after 1 year for oral treatments varied between 17% (oral risperidone) and 31% (oral olanzapine) while the analogous data for long acting injectables were between 32% (risperidone long acting) and 64% (paliperidone long acting one monthly). The 2-year data were similarly in favor of long-actings. Median time to discontinuation in the oral group varied between 57 days (clozapine) and 121 days (olanzapine). The median time to discontinuation for long-actings was significantly longer: between 176 and 287 days; in case of paliperidone long acting, median was not reached during the observation period. Patients receiving long-acting treatment switched from another long-acting remained on the newly initiated treatment significantly longer than those switched from orals. Conclusion: Our results indicate the superiority of second generation long-acting antipsychotics with regard to rates of treatment discontinuation and periods of persistence to the assigned medication. [ABSTRACT FROM AUTHOR]

Advances in machine learning and deep learning methods, together with the increasing availability of large-scale pharmacological, genomic, and chemical datasets, have created opportunities for identifying potentially useful relationships within biochemical networks. Knowledge embedding models have been found to have value in detecting knowledge-based correlations among entities, but little effort has been made to apply them to networks of biochemical entities. This is because such networks tend to be unbalanced and sparse, and knowledge embedding models do not work well on them. However, to some extent, the shortcomings of knowledge embedding models can be compensated for if they are used in association with graph embedding. In this paper, we combine knowledge embedding and graph embedding to represent biochemical entities and their relations as dense and low-dimensional vectors. We build a cascade learning framework which incorporates semantic features from the knowledge embedding model, and graph features from the graph embedding model, to score the probability of linking. The proposed method performs noticeably better than the models with which it is compared. It predicted links and entities with an accuracy of 93%, and its average hits@10 score has an average of 8.6% absolute improvement compared with original knowledge embedding model, 1.1% to 9.7% absolute improvement compared with other knowledge and graph embedding algorithm. In addition, we designed a meta-path algorithm to detect path relations in the biomedical network. Case studies further verify the value of the proposed model in finding potential relationships between diseases, drugs, genes, treatments, etc. Amongst the findings of the proposed model are the suggestion that VDR (vitamin D receptor) may be linked to prostate cancer. This is backed by evidence from medical databases and published research, supporting the suggestion that our proposed model could be of value to biomedical researchers. [ABSTRACT FROM AUTHOR]

Introduction: Poor translation of efficacy data derived from animal models can lead to clinical trials unlikely to benefit patients–or even put them at risk–and is a potential contributor to costly and unnecessary attrition in drug development. Objectives: To develop a tool to assess, validate and compare the clinical translatability of animal models used for the preliminary assessment of efficacy. Design and results: We performed a scoping review to identify the key aspects used to validate animal models. Eight domains (Epidemiology, Symptomatology and Natural History–SNH, Genetic, Biochemistry, Aetiology, Histology, Pharmacology and Endpoints) were identified. We drafted questions to evaluate the different facets of human disease simulation. We designed the Framework to Identify Models of Disease (FIMD) to include standardised instructions, a weighting and scoring system to compare models as well as factors to help interpret model similarity and evidence uncertainty. We also added a reporting quality and risk of bias assessment of drug intervention studies in the Pharmacological Validation domain. A web-based survey was conducted with experts from different stakeholders to gather input on the framework. We conducted a pilot study of the validation in two models for Type 2 Diabetes (T2D)–the ZDF rat and db/db mouse. Finally, we present a full validation and comparison of two animal models for Duchenne Muscular Dystrophy (DMD): the mdx mouse and GRMD dog. We show that there are significant differences between the mdx mouse and the GRMD dog, the latter mimicking the human epidemiological, SNH, and histological aspects to a greater extent than the mouse despite the overall lack of published data. Conclusions: FIMD facilitates drug development by serving as the basis to select the most relevant model that can provide meaningful data and is more likely to generate translatable results to progress drug candidates to the clinic. [ABSTRACT FROM AUTHOR]

Background: In recent years, criticism of the percentage range approach for individualised exercise prescription has intensified and we were concerned that sub-optimal exercise dose (especially intensity) may be in part responsible for the variability in the effectiveness of cardiac rehabilitation (CR) programmes in the United Kingdom (UK). The aim was to investigate the fidelity of a structured Phase III CR programme, by monitoring and quantifying exercise training intensity. Design: Observational study. Methods: The programme comprised 16 sessions over 8 weeks, where patients undertook an interval, circuit training approach within national guidelines for exercise prescription (40–70% heart rate reserve [HRR]). All patients wore an Apple Watch (Series 0 or 2, Watch OS2.0.1, Apple Inc., California, USA). We compared the mean % heart rate reserve (%HRR) achieved during the cardiovascular training component (%HRR-CV) of a circuit-based programme, with the %HRR during the active recovery phases (%HRR-AR) in a randomly selected cohort of patients attending standard CR. We then compared the mean %HRR-CV achieved with the minimal exercise intensity threshold during supervised exercise (40% HRR) recommended by national governing bodies. Results: Thirty cardiac patients (83% male; mean age [SD] 67 [] years; BMI 28.3 [4.6] kg∙m-2) were recruited. We captured 332 individual training sessions. The mean %HRR-CV and %HRR-AR were 37 (10) %, and 31 (13) %, respectively. There was weak evidence to support the alternative hypothesis of a difference between the %HRR-CV and 40% HRR. There was very strong evidence to accept the alternative hypothesis that the mean %HRR-AR was lower than the mean %HRR-CV, median standardised effect size 1.1 (95%CI: 0.563 to 1.669), with a moderate to large effect. Conclusion: Mean exercise training intensity was below the lower limit of the minimal training intensity guidelines for a Phase III CR programme. These findings may be in part responsible for previous reports highlighting the significant variability in effectiveness of UK CR services and poor CRF improvements observed from several prior investigations. [ABSTRACT FROM AUTHOR]

Objectives: To assess the impact of specialist contraceptive support after abortion on effective contraceptive use at six months and subsequent abortions within two years. Methods: Multicentre randomised controlled trial among women undergoing induced abortion in three London boroughs. Allocation was through electronically concealed stratified randomisation by centre, blinding clinicians and participants to arm allocation until interventions. Control group received standard care, comprising advice to follow up with their general practitioner or contraceptive clinic as needed. Intervention group additionally received specialist contraceptive support via telephone or face-to-face consultation at 2–4 weeks and 3 months post-abortion. Primary outcome was rate of effective contraceptive use at six months post-abortion. Secondary outcomes were subsequent abortions within two years. Results: 569 women were recruited between October 2011 and February 2013, randomised to intervention (282) and control (287) groups; 290 (142 intervention, 148 control) were available for primary outcome analysis. Intention-to-treat analysis showed no significant difference between the two groups in effective contraceptive use after abortion (62%, vs 54%, p = 0·172), long-acting contraceptive use (42% versus 32%, p = 0·084), and subsequent abortion (similar rates, at 1 year: 10%, p = 0·895, between 1–2 years: 6%, p = 0·944). Per-protocol analysis showed those who received the complete intervention package were significantly more likely to use effective contraception (67% versus 54%, p = 0·048), in particular long-acting contraception (49% versus 32%, p = 0·010) and showed a non-significant reduction in subsequent abortions within 2 years (at 1 year: 5% versus 10%, p = 0·098; and between 1–2 years: 3% versus 6%, p = 0·164, respectively). Conclusions: Structured specialist support post-abortion did not result in significant use of effective contraception at six months or reduction in subsequent abortions within two years. Participants engaging with the intervention showed positive effect on effective contraception at six months post-abortion. The potential benefit of such intervention may become evident through further studies with increased patient participation. [ABSTRACT FROM AUTHOR]

Background: Mass azithromycin distributions have been shown to reduce mortality among pre-school children in sub-Saharan Africa. It is unclear what mediates this mortality reduction, but one possibility is that antibiotics function as growth promoters for young children. Methods and findings: 24 rural Ethiopian communities that had received biannual mass azithromycin distributions over the previous four years were enrolled in a parallel-group, cluster-randomized trial. Communities were randomized in a 1:1 ratio to either continuation of biannual oral azithromycin (20mg/kg for children, 1 g for adults) or to no programmatic antibiotics over the 36 months of the study period. All community members 6 months and older were eligible for the intervention. The primary outcome was ocular chlamydia; height and weight were measured as secondary outcomes on children less than 60 months of age at months 12 and 36. Study participants were not masked; anthropometrists were not informed of the treatment allocation. Anthropometric measurements were collected for 282 children aged 0–36 months at the month 12 assessment and 455 children aged 0–59 months at the month 36 assessment, including 207 children who had measurements at both time points. After adjusting for age and sex, children were slightly but not significantly taller in the biannually treated communities (84.0 cm, 95%CI 83.2–84.8, in the azithromycin-treated communities vs. 83.7 cm, 95%CI 82.9–84.5, in the untreated communities; mean difference 0.31 cm, 95%CI -0.85 to 1.47, P = 0.60). No adverse events were reported. Conclusions: Periodic mass azithromycin distributions for trachoma did not demonstrate a strong impact on childhood growth. Trial registration: The TANA II trial was registered on clinicaltrials.gov . [ABSTRACT FROM AUTHOR]

Most clinically used opioids are thought to induce analgesia through activation of the mu opioid receptor (MOR). However, disparities have been observed between the efficacy of opioids in activating the MOR in vitro and in inducing analgesia in vivo. In addition, some clinically used opioids do not produce cross-tolerance with each other, and desensitization produced in vitro does not match tolerance produced in vivo. These disparities suggest that some opioids could be acting through other targets in vivo, but this has not been comprehensively tested. We thus screened 9 clinically relevant opioids (buprenorphine, hydrocodone, hydromorphone, morphine, O-desmethyl-tramadol, oxycodone, oxymorphone, tapentadol, tramadol) against 9 pain-related receptor targets (MOR, delta opioid receptor [DOR], kappa opioid receptor [KOR], nociceptin receptor [NOP], cannabinoid receptor type 1 [CB1], sigma-1 receptor [σ1R], and the monoamine transporters [NET/SERT/DAT]) expressed in cells using radioligand binding and functional activity assays. We found several novel interactions, including monoamine transporter activation by buprenorphine and σ1R binding by hydrocodone and tapentadol. Tail flick anti-nociception experiments with CD-1 mice demonstrated that the monoamine transporter inhibitor duloxetine selectively promoted buprenorphine anti-nociception while producing no effects by itself or in combination with the most MOR-selective drug oxymorphone, providing evidence that these novel interactions could be relevant in vivo. Our findings provide a comprehensive picture of the receptor interaction profiles of clinically relevant opioids, which has not previously been performed. Our findings also suggest novel receptor interactions for future investigation that could explain some of the disparities observed between opioid performance in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Introduction: Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory bone disorder primarily affecting children and adolescents. It can lead to chronic pain, bony deformities and fractures. The pathophysiology of CNO is incompletely understood. Scientific evidence suggests dysregulated expression of pro- and anti-inflammatory cytokines to be centrally involved. Currently, treatment is largely based on retrospective observational studies and expert opinion. Treatment usually includes nonsteroidal anti-inflammatory drugs and/or glucocorticoids, followed by a range of drugs in unresponsive cases. While randomised clinical trials are lacking, retrospective and prospective non-controlled studies suggest effectiveness of TNF inhibitors and bisphosphonates. The objective of the Bayesian consensus meeting was to quantify prior expert opinion. Methods: Twelve international CNO experts were randomly chosen to be invited to a Bayesian prior elicitation meeting. Results: Results showed that a typical new patient treated with pamidronate would have an 84% chance of improvement in their pain score relative to baseline at 26 weeks and an 83% chance on adalimumab. Experts thought there was a 50% chance that a new typical patient would record a pain score of 28mm (pamidronate) to 30mm (adalimumab) or better at 26 weeks. There was a modest trend in prior opinion to indicate an advantage of pamidronate vs adalimumab, with a 68% prior chance that pamidronate is superior to adalimumab by some margin. However, it is clear that there is considerable uncertainty about the precise relative merits of the two treatments. Conclusions: The rarity of CNO leads to challenges in conducting randomised controlled trials with sufficient power to provide a definitive outcome. We address this using a Bayesian design, and here describe the process and outcome of the elicitation exercise to establish expert prior opinion. This opinion will be tested in the planned prospective CNO study. The process for establishing expert consensus opinion in CNO will be helpful for developing studies in other rare paediatric diseases. [ABSTRACT FROM AUTHOR]

Despite the high success rates of preformed metal crowns (PMCs) in children no randomized clinical trials compare methods of placement and none describe its use in Africa. Our aim was to compare survival and cost-effectiveness of PMCs placed by conventional techniques (CT) and biological Hall techniques (HT) using a prospective randomized control trial in a general dental practice from Khartoum. One hundred and nine and 103 PMCs were placed in randomly selected children (5-8years) with 1–2 carious primary molars using HT and CT respectively and followed for 2 years. Socioeconomic status, periodontal health, occlusion, anxiety, and procedure time were compared using student t-test. Kaplan–Meier survival rates and incremental cost effectiveness ratio (ICER) were compared between CT and HT. CT and HT groups were similar for age, gender, socio-economic status. Survival rates were high (over 90%) for both study arms and not statistically different (p>0.05). Anxiety scores were significantly higher in CT arm after 12 months compared to HT (p<0.001). Clinically, gingival and plaque indices were similar between groups (p>0.05) but occlusions were raised in nearly all subjects in the HT arm (p<0.05). Periodontal health improved, and occlusions adjusted over time in both arms. There were 3 (2.7%) and 6 (5.8%) minor failures, 7 (6.4%) and 6 (5.8%) major failures in HT and CT arms respectively. Mean procedure time was lower in HT (9.1 min) than CT (33.9 min); p<0.001. Mean PMC cost was US$2.45 and US$7.81 for HT and CT respectively. The ICER was US$136.56 more for each PMC placed by CT per life year. We show that PMCs have high survival outcomes in disadvantaged populations similar to results from developed countries. As HT can be carried out by less experienced dental operators and therapists, this biological approach provides a promising cost-effective option to manage caries in developing countries with limited resources. Trial registration: The trial is registered at clinicaltrials.gov. ClinicalTrial.gov Trial Registration: [ABSTRACT FROM AUTHOR]

Hookworms remain a major health burden in the developing world, with hundreds of millions currently afflicted by these blood-feeding parasites. There exists a vital need for the discovery of novel drugs and identification of parasite drug targets for the development of chemotherapies. New drug development requires the identification of compounds that target molecules essential to parasite survival and preclinical testing in robust, standardized animal models of human disease. This process can prove costly and time consuming using conventional, low-throughput methods. We have developed a novel high-throughput screen (HTS) to identify anthelmintics for the treatment of soil-transmitted helminths. Our high-throughput, plate reader-based assay was used to rapidly assess compound toxicity to Ancylostoma ceylanicum L1 larva. Using this method, we screened 39,568 compounds from several small molecule screening libraries at 10 μM and identified 830 bioactive compounds that inhibit egg hatching of the human hookworm A. ceylanicum by >50%. Of these, 132 compounds inhibited hookworm egg hatching by >90% compared to controls. The nematicidal activities of 268 compounds were verified by retesting in the egg hatching assay and were also tested for toxicity against the human HeLa cell line at 10 μM. Fifty-nine compounds were verified to inhibit A. ceylanicum egg hatching by >80% and were <20% toxic to HeLa cells. Half-maximal inhibitory concentration (IC50) values were determined for the 59 hit compounds and ranged from 0.05–8.94 μM. This stringent advancement of compounds was designed to 1) systematically assess the nematicidal activity of novel compounds against the egg stage of A. ceylanicum hookworms in culture and 2) define their chemotherapeutic potential in vivo by evaluating their toxicity to human cells. Information gained from these experiments may directly contribute to the development of new drugs for the treatment of human hookworm disease. [ABSTRACT FROM AUTHOR]

Sharing of injection drug use paraphernalia is a dyadic process linked to the transmission of HIV and hepatitis C virus (HCV). Despite this, limited research exists identifying specific dyadic interpersonal factors driving injecting partners’ engagement in needle/syringe and ancillary injecting equipment sharing among young adults. Using semi-structured in-depth interview data collected between 2014 and 2015 from twenty-seven people who inject drugs (PWID), we applied an inductive approach to identify key injection drug-related interpersonal factors and developed a conceptual model integrating the findings based on interdependence theory. Interactions between injecting partners resulted in varying levels of injecting-related trust, cooperation, intimacy, and power. These factors interacted to collectively influence the type and level of risk perceived and enacted by injecting partners. The relationship between these injecting-related interpersonal factors, on the one hand, and risk perception on the other was dynamic and fluctuated between actions that protect the self (person-centered) and those that protect the partnership (partnership-centered). These findings indicate that the interpersonal context exerts substantial influence that shapes risk perception in all types of injecting partnerships. Partnership-focused prevention strategies should consider the dynamics of trust, cooperation, intimacy, and power, in characterizing dyadic risk perceptions and in understanding risky injecting practices among PWID. [ABSTRACT FROM AUTHOR]

Objective: To assess the effectiveness of surgical vs conservative interventions on pain and function in patients with subacromial impingement syndrome. Design: Systematic review and meta-analysis of randomized controlled trials. Setting: Clinical setting. Participants: Patients 18 years and older with subacromial impingement syndrome. Intervention/Comparison: Surgical intervention plus postoperative physiotherapy / placebo surgery plus physiotherapy or physiotherapy only. Main outcome measures: Pain and function. Results: 11 RCTs (n = 919) were included. The pooled results displayed no statistically or clinically different between surgery plus physiotherapy vs physiotherapy alone on pain levels at 3-, 6-months, 5- and 10 years follow up (moderate quality, 3 RCTs, 300 patients, WMD -0.39, 95% CI: -1.02 to 0.23, p = 0.22; moderate quality, 3 RCTs, 310 patients, WMD -0.36, 95% CI: -1.02 to 0.29, p = 0.27; low quality, 1 RCT, 109 patients, WMD -0.30, 95% CI: -1.54 to 0.94, p = 0.64; low quality, 1 RCT, 90 patients, WMD -1.00, 95% CI: -0.24 to 2.24, p = 0.11) respectively. Similarly, the pooled results were not statistically or clinically different between groups for function at 3-, 6-month and 1-year follow ups (very low quality, 2 RCTs, 184 patients, SMD 0.11, 95% CI: -0.57 to 0.79, p = 0.75; moderate quality, 3 RCTs, 310 patients, SMD 0.15, 95% CI: -0.14 to 0.43, p = 0.31; very low quality, 2 RCTs, 197 patients, SMD 0.11, 95% CI: -0.46 to 0.69, p = 0.70) respectively. Conclusion: The effects of surgery plus physiotherapy compared to physiotherapy alone on improving pain and function are too small to be clinically important at 3-, 6-months, 1-, 2-, 5- and ≥ 10-years follow up. [ABSTRACT FROM AUTHOR]

Background: Affordability is a key barrier to access to medicines. Generic medicines policies can address this barrier and promote access. Successful uptake of generic medicines depends, in part, on ensuring that these products are interchangeable with reference products. Typically, bioequivalence certification is established in order to demonstrate such interchangeability. Objective: To study the implementation of the bioequivalence certification policy in Chile. Methods: We used Chilean Market Regulatory Authority data for analysis to study the number of products that obtained bioequivalence certification, the time until bioequivalence certification and associated factors to obtain bioequivalence. Results: As of January 2017, out of 2,336 products with a valid market authorization containing at least one of the 167 APIs that required BE certification, 1,026 products actually have BE certification (1,026/2,336, 43.9% compliance). Where data were available, the time between submission of the market authorization as a bioequivalent product to final authorization by the national medicine regulatory authority for most products varied between 4–6 months. The fraction of all BE products containing a given API out of the total marketed products containing that API varies considerably, e.g. for the API olmesartan there was only a single BE product marketed, the API diclofenac had none. Conclusions: Although the implementation of Chile’s bioequivalence policy increased the number of bioequivalent products, over 50% of generic products requiring bioequivalence that did not obtain this certification. Also for some of the API none or very few BE products are marketed which limits the success of a substitution policy. Further studies are required to identify the apparent lack of incentives to obtain bioequivalence certification. Studies of sales volumes and prices of the products are needed to identify whether generic products without bioequivalence certification either become bioequivalent or eventually exit the market. [ABSTRACT FROM AUTHOR]

During intertemporal decisions, the value of future rewards decreases as a function of the delay of its receipt (temporal discounting, TD). Since high discount rates have been associated with a series of problematic behaviours and clinical conditions, current research has focused on possible modulators of TD. Specifically, a reduction of individual discount rates has been shown during episodic future thinking (EFT), wherein time intervals are anchored to personal future events. However, it is not entirely clear whether this effect is mediated by a change in the representation of future events (i.e., from abstract to concrete) or by a positive-emotion modulation. Here, we investigated this issue by manipulating the valence of the EFT (i.e., using negative, neutral and positive episodic tags), and by collecting explicit and implicit measures of behaviour. The results showed a significant reduction of TD in all the three emotional conditions compared to the baseline, with differences among them, thus suggesting the existence of a cumulative effect of the concreteness and affective components of the EFT. The analyses of implicit measures additionally revealed that this effect was mediated by a simultaneous increase/decrease of attraction toward the delayed/immediate alternative. Finally, these effects appeared to be modulated by participants’ baseline discounting preferences. These findings provide important insights on clinical applications in reward-related disorders. [ABSTRACT FROM AUTHOR]

In light of increased co-prescription of multiple drugs, the ability to discern and predict drug-drug interactions (DDI) has become crucial to guarantee the safety of patients undergoing treatment with multiple drugs. However, information on DDI profiles is incomplete and the experimental determination of DDIs is labor-intensive and time-consuming. Although previous studies have explored various feature spaces for in silico screening of interacting drug pairs, their use of conventional cross-validation prevents them from achieving generalizable performance on drug pairs where neither drug is seen during training. Here we demonstrate for the first time targets of adversely interacting drug pairs are significantly more likely to have synergistic genetic interactions than non-interacting drug pairs. Leveraging genetic interaction features and a novel training scheme, we construct a gradient boosting-based classifier that achieves robust DDI prediction even for drugs whose interaction profiles are completely unseen during training. We demonstrate that in addition to classification power—including the prediction of 432 novel DDIs—our genetic interaction approach offers interpretability by providing plausible mechanistic insights into the mode of action of DDIs. [ABSTRACT FROM AUTHOR]

Recent large cancer studies have measured somatic alterations in an unprecedented number of tumours. These large datasets allow the identification of cancer-related sets of genetic alterations by identifying relevant combinatorial patterns. Among such patterns, mutual exclusivity has been employed by several recent methods that have shown its effectiveness in characterizing gene sets associated to cancer. Mutual exclusivity arises because of the complementarity, at the functional level, of alterations in genes which are part of a group (e.g., a pathway) performing a given function. The availability of quantitative target profiles, from genetic perturbations or from clinical phenotypes, provides additional information that can be leveraged to improve the identification of cancer related gene sets by discovering groups with complementary functional associations with such targets. In this work we study the problem of finding groups of mutually exclusive alterations associated with a quantitative (functional) target. We propose a combinatorial formulation for the problem, and prove that the associated computational problem is computationally hard. We design two algorithms to solve the problem and implement them in our tool UNCOVER. We provide analytic evidence of the effectiveness of UNCOVER in finding high-quality solutions and show experimentally that UNCOVER finds sets of alterations significantly associated with functional targets in a variety of scenarios. In particular, we show that our algorithms find sets which are better than the ones obtained by the state-of-the-art method, even when sets are evaluated using the statistical score employed by the latter. In addition, our algorithms are much faster than the state-of-the-art, allowing the analysis of large datasets of thousands of target profiles from cancer cell lines. We show that on two such datasets, one from project Achilles and one from the Genomics of Drug Sensitivity in Cancer project, UNCOVER identifies several significant gene sets with complementary functional associations with targets. Software available at: . [ABSTRACT FROM AUTHOR]

Background: The recently established association between higher levels of DNA-incorporated thioguanine nucleotides and lower relapse risk in childhood acute lymphoblastic leukaemia (ALL) calls for reassessment of prolonged 6-thioguanine (6TG) treatment, while avoiding the risk of hepatotoxicity. Objectives: To assess the incidence of hepatotoxicity in patients treated with 6TG, and to explore if a safe dose of continuous 6TG can be established. Data sources: Databases, conference proceedings, and reference lists of included studies were systematically searched for 6TG and synonyms from 1998–2018. Methods: We included studies of patients with ALL or inflammatory bowel disorder (IBD) treated with 6TG, excluding studies with 6TG as part of an intensive chemotherapy regimen. We uploaded a protocol to PROSPERO (registration number CRD42018089424). Database and manual searches yielded 1823 unique records. Of these, 395 full-texts were screened for eligibility. Finally, 134 reports representing 42 studies were included. Results and conclusions: We included data from 42 studies of ALL and IBD patients; four randomised controlled trials (RCTs) including 3,993 patients, 20 observational studies including 796 patients, and 18 case reports including 60 patients. Hepatotoxicity in the form of sinusoidal obstruction syndrome (SOS) occurred in 9–25% of the ALL patients in two of the four included RCTs using 6TG doses of 40–60 mg/m2/day, and long-term hepatotoxicity in the form of nodular regenerative hyperplasia (NRH) was reported in 2.5%. In IBD patients treated with 6TG doses of approximately 23 mg/m2/day, NRH occurred in 14% of patients. At a 6TG dose of approximately 12 mg/m2/day, NRH was reported in 6% of IBD patients, which is similar to the background incidence. According to this review, doses at or below 12 mg/m2/day are rarely associated with notable hepatotoxicity and can probably be considered safe. [ABSTRACT FROM AUTHOR]

Objectives: This study investigated how the essential elements of informed consent are realised during the consent process and examined the challenges in obtaining genuine informed consent in Korea. Methods: Through purposive sampling, we recruited 21 subjects from those participating in anticancer drug research since 2013. We undertook 1:1 in-depth interviews and analysed the data by framework analysis. Results: Themes raised throughout the interviews were categorised into ‘disclosure’ and ‘understanding’ of clinical information and ‘decision’. Provider-centred information, both verbal and written, was delivered to each participant. There were few tools that the research staff might evaluate study participants’ level of understanding of the provided information during the clinical trial. Although participants did not understand basic clinical trial concepts as much as desired, they may not seek to solve difficulties through communication with trial researchers. Doubts were raised about whether participants had sufficient capacity and free will to provide informed consent. Conclusion: There is a concern that informed consent can fall short of genuine in Korea. To ensure informed consent meets the international standard, greater efforts should be made to establish an explicit standard operational protocol for obtaining informed consent. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to screen lead compounds and medication candidates from drug library (ZINC database) which has potential agonist effect targeting STING protein. Methods and materials: A series of computer-aided virtual screening techniques were utilized to identify potential agonists of STING. Structure-based screening using Libdock was carried out followed by ADME (absorption, distribution, metabolism, excretion) and toxicity prediction. Molecular docking was performed to demonstrate the binding affinity and mechanism between ligands and STING dimers. Molecular dynamic simulation was utilized to evaluate the stability of ligand-receptor complex. Finally, animal experiment was conducted to validate the effectiveness of selected compounds. Results: Three novel natural compounds 1,2,3 (ZINC000015149223, ZINC000011616633 and ZINC000001577210, respectively) from the ZINC15 database were found binding to STING with more favorable interaction energy. Also, they were predicted with less ames mutagenicity, rodent carcinogenicity, non-developmental toxic potential and tolerant with cytochrome P450 2D6 (CYP2D6). The ligand chemical structure analysis showed the three compounds were inborn axisymmetric, such chemical structures account for combining and activating process of STING protein dimers. The dynamic simulation analysis demonstrated that ZINC000015149223-, ZINC000011616633- and ZINC000001577210-STING dimer complex had more favorable potential energy compared with amidobenzimidazole (ABZI) and they can exist in natural environments stably. Animal experiments also demonstrated that these three compounds could suppress tumor growth. Conclusion: This study demonstrates that ZINC000015149223, ZINC000011616633 and ZINC000001577210 are potential agonists targeting STING protein. These compounds are safe drug candidates and have a great significance in STING agonists development. [ABSTRACT FROM AUTHOR]

Directly observed therapy (DOT) is almost universally used for the treatment of TB. Several meta-analyses using different methods have assessed the effectiveness of DOT compared to self-administered therapy (SAT). The results of these meta-analyses often conflict with some concluding DOT is superior and others that there is little or no difference. Meta-analyses can guide policymaking, but such analyses must be reliable. To assess the validity of a previous meta-analysis, we tried to reproduce it. We encountered problems with the previous analysis that did not allow for a meaningful reproduction. We describe the issues we encountered here. We then performed a new meta-analysis comparing the treatment outcomes of adults given treatment with SAT versus DOT. Outcomes in the new analysis are loss to follow-up, treatment failure, cure, treatment completed, and all-cause mortality. All data, documentation, and code used to generate our results is provided. Our new analysis included four randomized and three observational studies with 1603 and 1626 individuals respectively. The pooled relative risks (RR) are as follows: Lost to follow-up (RR = 1.2, 95% CI 0.9, 1.7), Treatment Failure (RR = 1.1, 95% CI 0.6, 2), Cure (RR = 0.9, 95% CI 0.8, 1.1), Treatment Completion (RR = 1, 95% CI 0.9, 1.1), Mortality (RR = 0.9, 95% CI 0.6, 1.3). Based on data from our new meta-analysis, the magnitude of the difference between DOT and SAT for all reported outcomes is small, and none of the differences are statistically significant. [ABSTRACT FROM AUTHOR]

Background: The performance of a new diagnostic test is typically evaluated against a comparator which is assumed to correspond closely to some true state of interest. Judgments about the new test’s performance are based on the differences between the outputs of the test and comparator. It is commonly assumed that a small amount of uncertainty in the comparator’s classifications will negligibly affect the measured performance of a diagnostic test. Methods: Simulated datasets were generated to represent typical diagnostic scenarios. Comparator noise was introduced in the form of random misclassifications, and the effect on the apparent performance of the diagnostic test was determined. An actual dataset from a clinical trial on a new diagnostic test for sepsis was also analyzed. Results: We demonstrate that as little as 5% misclassification of patients by the comparator can be enough to statistically invalidate performance estimates such as sensitivity, specificity and area under the receiver operating characteristic curve, if this uncertainty is not measured and taken into account. This distortion effect is found to increase non-linearly with comparator uncertainty, under some common diagnostic scenarios. For clinical populations exhibiting high degrees of classification uncertainty, failure to measure and account for this effect will introduce significant risks of drawing false conclusions. The effect of classification uncertainty is magnified further for high performing tests that would otherwise reach near-perfection in diagnostic evaluation trials. A requirement of very high diagnostic performance for clinical adoption, such as a 99% sensitivity, can be rendered nearly unachievable even for a perfect test, if the comparator diagnosis contains even small amounts of uncertainty. This paper and an accompanying online simulation tool demonstrate the effect of classification uncertainty on the apparent performance of tests across a range of typical diagnostic scenarios. Both simulated and real datasets are used to show the degradation of apparent test performance as comparator uncertainty increases. Conclusions: Overall, a 5% or greater misclassification rate by the comparator can lead to significant underestimation of true test performance. An online simulation tool allows researchers to explore this effect using their own trial parameters () and the source code is freely available (). [ABSTRACT FROM AUTHOR]

High-throughput drug screening has facilitated the discovery of drug combinations in cancer. Many existing studies adopted a full matrix design, aiming for the characterization of drug pair effects for cancer cells. However, the full matrix design may be suboptimal as it requires a drug pair to be combined at multiple concentrations in a full factorial manner. Furthermore, many of the computational tools assess only the synergy but not the sensitivity of drug combinations, which might lead to false positive discoveries. We proposed a novel cross design to enable a more cost-effective and simultaneous testing of drug combination sensitivity and synergy. We developed a drug combination sensitivity score (CSS) to determine the sensitivity of a drug pair, and showed that the CSS is highly reproducible between the replicates and thus supported its usage as a robust metric. We further showed that CSS can be predicted using machine learning approaches which determined the top pharmaco-features to cluster cancer cell lines based on their drug combination sensitivity profiles. To assess the degree of drug interactions using the cross design, we developed an S synergy score based on the difference between the drug combination and the single drug dose-response curves. We showed that the S score is able to detect true synergistic and antagonistic drug combinations at an accuracy level comparable to that using the full matrix design. Taken together, we showed that the cross design coupled with the CSS sensitivity and S synergy scoring methods may provide a robust and accurate characterization of both drug combination sensitivity and synergy levels, with minimal experimental materials required. Our experimental-computational approach could be utilized as an efficient pipeline for improving the discovery rate in high-throughput drug combination screening, particularly for primary patient samples which are difficult to obtain. [ABSTRACT FROM AUTHOR]