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Early industrialization and the development of cheap production processes for paper have led to an exponential accumulation of paper-based documents during the last two centuries. Archives and libraries harbor vast amounts of ancient and modern documents and have to undertake extensive endeavors to protect them from abiotic and biotic deterioration. While services for mechanical preservation such as ex post de-acidification of historic documents are already commercially available, the possibilities for long-term protection of paper-based documents against fungal attack (apart from temperature and humidity control) are very limited. Novel processes for mechanical enhancement of damaged cellulosic documents use Ionic Liquids (IL) as essential process components. With some of these ILs having azole-functionalities similar to well-known fungicides such as Clotrimazole, the possibility of antifungal activities of these ILs was proposed but has not yet been experimentally confirmed. We evaluated the potency of four ILs with potential application in paper restoration for suppression of fungal growth on five relevant paper-infesting molds. The results revealed a general antifungal activity of all ILs, which increased with the size of the non-polar group. Physiological experiments and ultimate elemental analysis allowed to determine the minimal inhibitory concentration of each IL as well as the residual IL concentration in process-treated paper. These results provide valuable guidelines for IL-applications in paper restoration processes with antifungal activity as an added benefit. With azoles remaining in the paper after the process, simultaneous repair and biotic protection in treated documents could be facilitated. [ABSTRACT FROM AUTHOR]

Poor research reporting is a major contributing factor to low study reproducibility, financial and animal waste. The ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines were developed to improve reporting quality and many journals support these guidelines. The influence of this support is unknown. We hypothesized that papers published in journals supporting the ARRIVE guidelines would show improved reporting compared with those in non-supporting journals. In a retrospective, observational cohort study, papers from 5 ARRIVE supporting (SUPP) and 2 non-supporting (nonSUPP) journals, published before (2009) and 5 years after (2015) the ARRIVE guidelines, were selected. Adherence to the ARRIVE checklist of 20 items was independently evaluated by two reviewers and items assessed as fully, partially or not reported. Mean percentages of items reported were compared between journal types and years with an unequal variance t-test. Individual items and sub-items were compared with a chi-square test. From an initial cohort of 956, 236 papers were included: 120 from 2009 (SUPP; n = 52, nonSUPP; n = 68), 116 from 2015 (SUPP; n = 61, nonSUPP; n = 55). The percentage of fully reported items was similar between journal types in 2009 (SUPP: 55.3 ± 11.5% [SD]; nonSUPP: 51.8 ± 9.0%; p = 0.07, 95% CI of mean difference -0.3–7.3%) and 2015 (SUPP: 60.5 ± 11.2%; nonSUPP; 60.2 ± 10.0%; p = 0.89, 95%CI -3.6–4.2%). The small increase in fully reported items between years was similar for both journal types (p = 0.09, 95% CI -0.5–4.3%). No paper fully reported 100% of items on the ARRIVE checklist and measures associated with bias were poorly reported. These results suggest that journal support for the ARRIVE guidelines has not resulted in a meaningful improvement in reporting quality, contributing to ongoing waste in animal research. [ABSTRACT FROM AUTHOR]

In recent years there has been increased attention to child neurodevelopment in studies on medication safety in pregnancy. Neurodevelopment is a multifactorial outcome that can be assessed by various assessors, using different measures. This has given rise to a debate on the validity of various measures of neurodevelopment. The aim of this review was twofold. Firstly we aimed to give an overview of studies on child neurodevelopment after prenatal exposure to central nervous system acting medications using psychotropics and analgesics as examples, giving special focus on the use and validity of outcome measures. Secondly, we aimed to give guidance on how to conduct and interpret medication safety studies with neurodevelopment outcomes. We conducted a systematic review in the MEDLINE, Embase, PsycINFO, Web of Science, Scopus, and Cochrane databases from inception to April 2019, including controlled studies on prenatal exposure to psychotropics or analgesics and child neurodevelopment, measured with standardised psychometric instruments or by diagnosis of neurodevelopmental disorder. The review management tool Covidence was used for data-extraction. Outcomes were grouped as motor skills, cognition, behaviour, emotionality, or “other”. We identified 110 eligible papers (psychotropics, 82 papers, analgesics, 29 papers). A variety of neurodevelopmental outcome measures were used, including 27 different psychometric instruments administered by health care professionals, 15 different instruments completed by parents, and 13 different diagnostic categories. In 23 papers, no comments were made on the validity of the outcome measure. In conclusion, establishing neurodevelopmental safety includes assessing a wide variety of outcomes important for the child’s daily functioning including motor skills, cognition, behaviour, and emotionality, with valid and reliable measures from infancy through to adolescence. Consensus is needed in the scientific community on how neurodevelopment should be assessed in medication safety in pregnancy studies. Review registration number: CRD42018086101 in the PROSPERO database. [ABSTRACT FROM AUTHOR]

An estimated 30–70% of available medications in low-income countries and conflict states are of low quality or counterfeit. Reasons for this vary but most are rooted in regulatory agencies being poorly equipped to oversee quality of pharmaceutical stocks. This paper presents the development and validation of a method for point-of-care drug stock quality testing in these environs. The method is termed Baseline Spectral Fingerprinting and Sorting (BSF-S). BSF-S leverages the phenomena that all compounds in solution have nearly unique spectral profiles in the UV spectrum. Further, BSF-S recognizes that variations in sample concentrations are introduced when preparing samples in the field. BSF-S compensates for this variability by incorporating the ELECTRE-TRI-B sorting algorithm, which contains parameters that are trained in the laboratory using authentic, proxy low quality and counterfeit samples. The method was validated in a case study using fifty samples that include factually authentic Praziquantel and inauthentic samples prepared in solution by an independent pharmacist. Study researchers were blinded to which solution contained the authentic samples. Each sample was tested by the BSF-S method described in this paper and sorted to authentic or low quality/counterfeit categories with high levels of specificity and sensitivity. In combination with a companion device under development using ultraviolet light emitting diodes, the BSF-S method is intended to be a portable and low-cost method for testing medications for authenticity at or near the point-of-care in low income countries and conflict states. [ABSTRACT FROM AUTHOR]

Background: Despite several decades of evidence supporting the benefits of taking medications in various diseases and healthcare settings, a significant proportion of prescribed treatments are not taken. This review sought to synthesise qualitative research exploring experiences of medication taking around the world, and to determine whether there were consistent messages arising from these studies. Methods and findings: 5 databases (MEDLINE, PsycINFO, EMBASE, SCOPUS, CINAHL) were systematically searched to identify published research papers using qualitative methodologies, which explored medication-taking experiences in patients, citizens, carers, relatives and clinicians. Data were extracted independently by at least two clinician reviewers. Implications for practice from individual papers were charted and coded using thematic content analysis. These were then cross-tabulated with research paper categories to explore emergent patterns with particular implications for practice. 192 papers from 34 different countries were included in the review. Implications for practice fitted into 11 categories: increase family involvement, increase clinician involvement, promote personalised management, address practical barriers, provide ongoing support, promote self-management, adopt a patient-centred approach, improve patient education, address system barriers, increase access to non-prescribing clinicians and improve clinician training. These implications for practice were generally evenly spread across research paper categories. Conclusions: Implications for practice from the published qualitative literature exploring medication-taking are notably consistent across research methods, disease categories and geographical settings. More recent clinical trials of interventions to improve adherence have started to draw on these findings by focussing on improving clinical interactions and involving patients in healthcare decisions. Promoting patient education and self-management have been widely advocated, and improvements at a system level have been frequently cited in studies from developing countries and those relating to communicable diseases. Regardless of the setting, clinicians and policymakers around the world can focus efforts to improve medication-taking by considering a number of consistently emerging findings. [ABSTRACT FROM AUTHOR]

The negative consequences of Substandard and falsified (SF) medicines are widely documented nowadays and there is still an urgent need to find them in more efficient ways. Several screening tools have been developed for this purpose recently. In this study, three screening tools were used on 292 samples of ciprofloxacin and metronidazole collected in Cameroon. Each sample was then analyzed by HPLC and disintegration tests. Seven additional samples from the nitro-imidazole (secnidazole, ornidazole, tinidazole) and the fluoroquinolone (levofloxacin, ofloxacin, norfloxacin, moxifloxacin) families were analyzed to mimic falsified medicines. Placebo samples that contained only inert excipients were also tested to mimic falsified samples without active pharmaceutical ingredient (API). The three screening tools implemented were: a simplified visual inspection checklist, a low-cost handheld near infrared (NIR) spectrophotometer and paper analytical devices (PADs). Overall, 61.1% of the samples that failed disintegration and assay tests also failed the visual inspection checklist test. For the handheld NIR, one-class classifier models were built to detect the presence of ciprofloxacin and metronidazole, respectively. The APIs were correctly identified in all the samples with sensitivities and specificities of 100%. However, the importance of a representative and up-to-date spectral database was underlined by comparing models built with different calibration set spanning different variability spaces. The PADs were used only on ciprofloxacin samples and detected the API in all samples in which the presence of ciprofloxacin was confirmed by HPLC. However, these PADs were not specific to ciprofloxacin since they reacted like ciprofloxacin to other fluoroquinolone compounds. The advantages and drawbacks of each screening tool were highlighted. They are promising means in the frame of early detection of SF medicines and they can increase the speed of decision about SF medicines in the context of pharmaceutical post-marketing surveillance. [ABSTRACT FROM AUTHOR]

The unique expression patterns of circRNAs linked to the advancement and prognosis of cancer underscore their considerable potential as valuable biomarkers. Repurposing existing drugs for new indications can significantly reduce the cost of cancer treatment. Computational prediction of circRNA-cancer and drug-cancer relationships is crucial for precise cancer therapy. However, prior computational methods fail to analyze the interaction between circRNAs, drugs, and cancer at the systematic level. It is essential to propose a method that uncover more valuable information for achieving cancer-centered multi-association prediction. In this paper, we present a novel computational method, AutoEdge-CCP, to unveil cancer-associated circRNAs and drugs. We abstract the complex relationships between circRNAs, drugs, and cancer into a multi-source heterogeneous network. In this network, each molecule is represented by two types information, one is the intrinsic attribute information of molecular features, and the other is the link information explicitly modeled by autoGNN, which searches information from both intra-layer and inter-layer of message passing neural network. The significant performance on multi-scenario applications and case studies establishes AutoEdge-CCP as a potent and promising association prediction tool. Author summary: CircRNAs serve as crucial biomarkers and drug targets in cancer therapy. Predicting cancer-associated circRNAs and drugs contributes to uncover intricate molecular mechanisms driving tumorigenesis, thus offering novel insights into cancer diagnosis, treatment, and research. However, prevailing predictive methods often neglect the comprehensive interactions within circRNAs, drugs, and cancer, leading to an incomplete understanding of their complex interplay. In response, we introduce AutoEdge-CCP, a framework that models circRNA-cancer-drug interactions within a multi-source heterogeneous network. Each molecule combines intrinsic attribute information describing molecular features with interaction information derived through autoGNN, revealing pivotal circRNAs and drugs associated with cancer. Experimental results across multi-scenario attest to AutoEdge-CCP's superior performance compared to competing methods, particularly in predicting novel circRNAs and drugs associated with cancer. Additionally, visualization of edge embeddings and case studies provide interpretable insights into the prediction outcomes. [ABSTRACT FROM AUTHOR]

Quality circles or peer review groups, and similar structured small groups of 6–12 health care professionals meet regularly across Europe to reflect on and improve their standard practice. There is debate over their effectiveness in primary health care, especially over their potential to change practitioners’ behaviour. Despite their popularity, we could not identify broad surveys of the literature on quality circles in a primary care context. Our scoping review was intended to identify possible definitions of quality circles, their origins, and reported effectiveness in primary health care, and to identify gaps in our knowledge. We searched appropriate databases and included any relevant paper on quality circles published until December 2017. We then compared information we found in the articles to that we found in books and on websites. Our search returned 7824 citations, from which we identified 82 background papers and 58 papers about quality circles. We found that they originated in manufacturing industry and that many countries adopted them for primary health care to continuously improve medical education, professional development, and quality of care. Quality circles are not standardized and their techniques are complex. We identified 19 papers that described individual studies, one paper that summarized 3 studies, and 1 systematic review that suggested that quality circles can effectively change behaviour, though effect sizes varied, depending on topic and context. Studies also suggested participation may affirm self-esteem and increase professional confidence. Because reports of the effect of quality circles on behaviour are variable, we recommend theory-driven research approaches to analyse and improve the effectiveness of this complex intervention. [ABSTRACT FROM AUTHOR]

Cholera rapid diagnostic tests (RDT) could play a central role in outbreak detection and surveillance in low-resource settings, but their modest performance has hindered their broad adoption. The addition of an enrichment step may improve test specificity. We describe the results of a prospective diagnostic evaluation of the Crystal VC RDT (Span Diagnostics, India) with enrichment step and of culture, each compared to polymerase chain reaction (PCR), during a cholera outbreak in South Sudan. RDTs were performed on alkaline peptone water inoculated with stool and incubated for 4–6 hours at ambient temperature. Cholera culture was performed from wet filter paper inoculated with stool. Molecular detection of Vibrio cholerae O1 by PCR was done from dry Whatman 903 filter papers inoculated with stool, and from wet filter paper supernatant. In August and September 2015, 101 consecutive suspected cholera cases were enrolled, of which 36 were confirmed by PCR. The enriched RDT had 86.1% (95% CI: 70.5–95.3) sensitivity and 100% (95% CI: 94.4–100) specificity compared to PCR as the reference standard. The sensitivity of culture versus PCR was 83.3% (95% CI: 67.2–93.6) for culture performed on site and 72.2% (95% CI: 54.8–85.8) at the international reference laboratory, where samples were tested after an average delay of two months after sample collection, and specificity was 98.5% (95% CI: 91.7–100) and 100% (95% CI: 94.5–100), respectively. The RDT with enrichment showed performance comparable to that of culture and could be a sustainable alternative to culture confirmation where laboratory capacity is limited. [ABSTRACT FROM AUTHOR]

The response of a cell population is often delayed relative to drug injection, and individual cells in a population of cells have a specific age distribution. The application of transit compartment models (TCMs) is a common approach for describing this delay. In this paper, we propose a TCM in which damaged cells caused by a drug are given by a single fractional derivative equation. This model describes the delay as a single equation composed of fractional and ordinary derivatives, instead of a system of ODEs expressed in multiple compartments, applicable to the use of the PK concentration in the model. This model tunes the number of compartments in the existing model and expresses the delay in detail by estimating an appropriate fractional order. We perform model robustness, sensitivity analysis, and change of parameters based on the amount of data. Additionally, we resolve the difficulty in parameter estimation and model simulation using a semigroup property, consisting of a system with a mixture of fractional and ordinary derivatives. This model provides an alternative way to express the delays by estimating an appropriate fractional order without determining the pre-specified number of compartments. [ABSTRACT FROM AUTHOR]

Atherosclerosis, a chronic inflammatory disorder of the arterial wall, is a complex process whose dynamics are affected by multiple factors. The disease control consists of restraining it by administering statins. Slowing down or halting the plaque growth depends on the patient age at which the statin treatment begins and on the thickness of the intima-media (IMT) at that time. In this paper, we propose a mathematical model to estimate the sets of atherosclerosis states, from which the use of statins can restrain the disease. Our model is control-theoretic, and the estimated sets are the viability kernels, in the parlance of viability theory. To our best knowledge, this way of modelling the atherosclerosis progression is original. We compute two viability kernels, each for a different statin-treatment dose. Each kernel is composed of the vector [age, IMT] from which the disease can be restrained. By extension, the disease can't be restrained from the kernel complements, this being mainly because of the disease and patient-age advancement. The kernels visualise tradeoffs between early and late treatments, which helps the clinician to decide when to start the statin treatment and which statin dose may be sufficient. [ABSTRACT FROM AUTHOR]

Background and objectives: High out-of-pocket expenditures (OOPE) increases the probability that households will become impoverished or will forgo needed care. The aim of this paper is to study household medicines expenditure and its associated determining factors to develop policies to protect households from financial hardship. Methods: The present cross-sectional and population-level study used the Bangladesh 2016–17 National Household Income and Expenditure Survey (HIES). The final sample size was 46,080 households. We analyzed the probability of OOPE for medicines, the share of total OOPE due to medicines out of total OOPE in health (reported as a ratio between zero and one), the OOPE amount for medicines reported (in United States Dollars), and the share of OOPE amount on medicines out of total household expenditure (reported as a ratio between zero and one). Predictors of analyzed outcomes were identified using three regression models. Results: Out of those households who spent on healthcare, the probability of having any OOPE on medicines was 87.9%. Of those who spent on medicines, the median monthly expenditure was US$3.03. The poorest households spent 9.97% of their total household expenditure as OOPE on medicines, nearly double that of the wealthiest households (5.86%). The characteristic which showed the most significant correlation to a high OOPE on medicines was the presence of chronic diseases, especially cancer. Twenty six percent of all surveyed households spend more than 10% of their OOPE on medicines. Conclusions: Our study shows that financial protection should be targeted at the poorest quintiles and such protection should include enrollment of rural households. Further, outpatient medicines benefits should include those for non-communicable diseases (NCDs). [ABSTRACT FROM AUTHOR]

Objective: Studies suggest that parenteral MTX may be more efficacious than the oral form at equivalent doses for the treatment of rheumatoid arthritis. We carried out a meta-analysis to compare the efficacy of oral versus parenteral MTX in RA. Methods: PubMed, Web of Science and Embase were systematically searched from inception to June 8th 2017 and reviewed following PRISMA 2009 guidelines, by two independent reviewers. To be included, trials had to study adults with RA randomized to the same dose of either oral or parenteral MTX. The primary endpoint was ACR20 at 6 months. Intention-to-treat analysis results were used when possible. Data from direct comparisons between oral and parenteral methotrexate quantitatively analyzed using maximum likelihood random effects meta-analysis. Relative treatment effects were generated as an odds ratio [OR] (OR>1 indicated a benefit for parenteral therapy). Results: The search yielded 357 papers or abstracts. After review of titles or abstracts and full text papers, we found 4 that met inclusion criteria with 703 patients randomized. Dose of MTX started at 15mg/week and increased up to 25mg/week. The summary OR for achieving ACR20 using parenteral vs. oral MTX was 3.02 (95% CI 1.41, 6.46), with no significant difference in the risk for all adverse events. Conclusion: Parenteral MTX therapy had significantly higher odds than oral MTX of achieving reduction in disease activity. We propose that parenteral MTX is more effective than weekly oral MTX; its widespread use may lead to better control of disease and a decrease in demand for biologic agents. [ABSTRACT FROM AUTHOR]

Data from clinical trials investigating on-demand medication often consist of an intentionally varying number of measurements per patient. These measurements are often observations of discrete events of when the medication was taken, including for example data on symptom severity. In addition to the varying number of observations between patients, the data have another important feature: they are characterized by a hierarchical structure in which the events are nested within patients. Traditionally, the observed events of patients are aggregated into means and subsequently analyzed using, for example, a repeated measures ANOVA. This procedure has drawbacks. One drawback is that these patient means have different standard errors, first, because the variance of the underlying events differs between patients and second, because the number of events per patient differs. In this paper, we argue that such data should be analyzed by applying a multilevel analysis using the individual observed events as separate nested observations. Such a multilevel approach handles this drawback and it also enables the examination of varying drug effects across patients by estimating random effects. We show how multilevel analyses can be applied to on-demand medication data from a clinical trial investigating the efficacy of a drug for women with low sexual desire. We also explore linear and quadratic time effects that can only be performed when the individual events are considered as separate observations and we discuss several important statistical topics relevant for multilevel modeling. Taken together, the use of a multilevel approach considering events as nested observations in these types of data is advocated as it is more valid and provides more information than other (traditional) methods. [ABSTRACT FROM AUTHOR]

Introduction: Previous research has shown that statin adherence for the primary prevention of CVD is lower compared to secondary prevention populations. Therefore the aim of this systematic review was to review predictors of statin adherence for the primary prevention of CVD. Methods: A systematic search of papers published between Jan 1984 and May 2017 was conducted in PubMed, PsycINFO, EMbase and CINAHL databases. A study was eligible for inclusion if; 1) it was a study of the general population or of patients with familial hypercholesterolemia, hypertension, diabetes or arthritis; 2) statins were prescribed; 3) adherence was defined and measured as the extent to which patients followed their statin regimen during the period of prescription, and 4) it was an original trial or observational study (excluding case reports). A study was subsequently excluded if 1) results were not presented separately for primary prevention; 2) it was a trial of an intervention (for example patient education). Papers were reviewed by two researchers and consensus agreed with a third. A quality assessment (QA) tool was used to formally assess each included article. To evaluate the effect of predictors, data were quantitatively and qualitatively synthesised. Results: In total 19 studies met the inclusion criteria and nine were evaluated as high quality using the QA tool. The proportion of patients classed as “adherent” ranged from 17.8% to 79.2%. Potential predictors of statin adherence included traditional risk factors for CVD such as age, being male, diabetes and hypertension. Income associated with adherence more strongly in men than women, and highly educated men were more likely and highly educated women less likely to be adherent. Alcohol misuse and high BMI associated with non-adherence. There was no association between polypharmacy and statin adherence. The evidence base for the effect of other lifestyle factors and health beliefs on statin adherence was limited. Conclusion: Current evidence suggests that patients with more traditional risk factors for CVD are more likely to be adherent to statins. The implications for future research are discussed. [ABSTRACT FROM AUTHOR]

Background: HIV transmitted drug resistance (TDR) remains at moderate level in Latin America and the Caribbean (LAC). However, different epidemiologic scenarios could influence national and sub-regional TDR levels and trends. Methods and Findings: We performed a systematic review of currently available publications on TDR in antiretroviral treatment-naïve adults in LAC. Ninety-eight studies published between January 2000 and June 2015 were included according to critical appraisal criteria and classified by sub-region: Brazil (50), Mesoamerica (17), Southern Cone (16), Andean (8) and Caribbean (7). From these, 81 studies encompassing 11,441 individuals with data on DR mutation frequency were included in a meta-analysis. Overall TDR prevalence in LAC was 7.7% (95% CI: 7.2%-8.2%). An increasing trend was observed for overall TDR when comparing 2000–2005 (6.0%) and 2006–2015 (8.2%) (p<0.0001), which was associated with significant NNRTI TDR increase (p<0.0001). NRTI TDR decreased (4.5% vs. 2.3%, p<0.0001). NNRTI TDR increase was associated mainly with K101E, K103N and G190A. NRTI TDR decrease was associated mainly with M184V, K70R and T215Y. All sub-regions reached moderate overall TDR levels. The rapid increase in TDR to all antiretroviral classes in the Caribbean is notable, as well as the significant increase in NNRTI TDR reaching moderate levels in the Southern Cone. NRTI TDR was dominant in 2000–2005, mainly in the Caribbean, Mesoamerica and Brazil. This dominance was lost in 2006–2015 in all sub-regions, with the Southern Cone and the Caribbean switching to NNRTI dominance. PI TDR remained mostly constant with a significant increase only observed in the Caribbean. Conclusions: Given the high conceptual and methodological heterogeneity of HIV TDR studies, implementation of surveys with standardized methodology and national representativeness is warranted to generate reliable to inform public health policies. The observed increasing trend in NNRTI TDR supports the need to strengthen TDR surveillance and programme monitoring and evaluation in LAC. [ABSTRACT FROM AUTHOR]

Background: The life quality of about two-thirds of patients with COVID-19 is affected by related olfactory dysfunctions. The negative impact of olfactory dysfunction ranged from the decreased pleasure of eating to impaired quality of life. This research aimed to provide a comprehensive understanding of the effects of corticosteroid treatments by comparing that to other currently available treatments and interventions. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist's 27-point checklist was used to conduct this review. PubMed (Public/Publisher MEDLINE), PubMed Central and EMBASE (Excerpta Medica Database) databases were conveniently selected and Boolean search commands were used for a comprehensive literature search. Five core search terms were "effects of treatments", " COVID-19-related olfactory dysfunction", "corticosteroids", "treatments" and "interventions". The reporting qualities of the included studies were appraised using JBI (Joanna Briggs Institute) appraisal tools. The characteristics of the 21 experimental studies with a total sample (of 130,550) were aggregated using frequencies and percentages and presented descriptively. The main interventions and their effects on the duration of the COVID-19-related olfactory dysfunction were narratively analyzed. Results: Among patients with COVID-19, the normal functions of the olfactory lobe were about 23 days earlier to gain with the treatments of fluticasone and triamcinolone acetonide nasal spray compared with that of mometasone furoate nasal spray and oral corticosteroid. The smell loss duration was reduced by fluticasone and triamcinolone acetonide nasal spray 9 days earlier than the inflawell syrup and 16 days earlier than the lavender syrup. The nasal spray of corticosteroids ended the COVID-19-related smell loss symptoms 2 days earlier than the zinc supplementation, about 47 days earlier than carbamazepine treatment and was more effective than palmitoylethanolamide (PEA) and luteolin and omega-3 supplementations and olfactory training. Treatment with oral corticosteroid plus olfactory training significantly improved Threshold, Discrimination and Identification (TDI) scores compared with olfactory training alone. A full dose of the COVID-19 vaccination was not uncertain to reduce the COVID-19-related smell loss duration. Conclusion: Corticosteroid treatment is effective in reducing the duration of COVID-19-related smell loss and olfactory training, the basic, essential and effective intervention, should be used as a combination therapy. [ABSTRACT FROM AUTHOR]

In this paper we study antibiotic-induced C. difficile infection (CDI), caused by the toxin-producing C. difficile (CD), and implement clinically-inspired simulated treatments in a computational framework that synthesizes a generalized Lotka-Volterra (gLV) model with SIR modeling techniques. The gLV model uses parameters derived from an experimental mouse model, in which the mice are administered antibiotics and subsequently dosed with CD. We numerically identify which of the experimentally measured initial conditions are vulnerable to CD colonization, then formalize the notion of CD susceptibility analytically. We simulate fecal transplantation, a clinically successful treatment for CDI, and discover that both the transplant timing and transplant donor are relevant to the the efficacy of the treatment, a result which has clinical implications. We incorporate two nongeneric yet dangerous attributes of CD into the gLV model, sporulation and antibiotic-resistant mutation, and for each identify relevant SIR techniques that describe the desired attribute. Finally, we rely on the results of our framework to analyze an experimental study of fecal transplants in mice, and are able to explain observed experimental results, validate our simulated results, and suggest model-motivated experiments. [ABSTRACT FROM AUTHOR]

The interaction radius r plays an important role in the collective behavior of many multi-agent systems because it defines the interaction network among agents. For the topic of intervention on collective behavior of multi-agent systems, does r also affect the intervention performance? In this paper we study whether it is easier to change the convergent heading of the group by adding some special agents (called shills) into the Vicsek model when r is larger (or smaller). Two kinds of shills are considered: fixed-heading shills (like leaders that never change their headings) and evolvable-heading shills (like normal agents but with carefully designed initial headings). We know that with the increase of r, two contradictory effects exist simultaneously: the influential area of a single shill is enlarged, but its influence strength is weakened. Which factor dominates? Through simulations and theoretical analysis we surprisingly find that r affects the intervention performance differently in different cases: when fixed-heading shills are placed together at the center of the group, larger r gives a better intervention performance; when evolvable-heading shills are placed together at the center, smaller r is better; when shills (either fixed-heading or evolvable-heading) are distributed evenly inside the group, the effect of r on the intervention performance is not significant. We believe these results will inspire the design of intervention strategies for many other multi-agent systems. [ABSTRACT FROM AUTHOR]

Nigeria has the highest burden of NTDs in sub-Saharan Africa. Commitments to reach the control and elimination of many Neglected Tropical Diseases (NTDs), particularly those amenable to preventive chemotherapy (onchocerciasis, schistosomiasis, soil transmitted helminths, lymphatic filariasis and trachoma) by 2020 are detailed in the London declaration. Strategies to reach targets build on existing approaches, one of which is the use of community directed intervention (CDI) methods to deliver the mass administration of medicines (MAM). However, treatment using this approach has been inconsistent and there are questions about the acceptability and adaptability of these interventions during periods of programmatic, social, and political change. This paper explores the current strengths and weaknesses of CDI approaches in MAM delivery. We consider the acceptability and adaptability of existing MAM approaches to ensure equity in access to essential treatments. Using qualitative methods, we explore implementer perspectives of MAM delivery. We purposively selected programme implementers to ensure good programmatic knowledge and representation from the different levels of health governance in Nigeria. Data collection took place across two States (Kaduna and Ogun). Our results indicate that CDI approaches have underpinned many historic successes in NTD programme acceptance in Nigeria, specifically in Kaduna and Ogun State. However, our results also show that in some contexts, factors that underpin the success of CDI have become disrupted presenting new challenges for programme implementers. Capturing the tacit knowledge of health implementers at varying levels of the health system, we present the current and changing context of MAM delivery in Kaduna and Ogun States and consolidate a platform of evidence to guide future programme delivery and research studies. We situate our findings within the broader NTD literature, specifically, in identifying how our findings align to existing reviews focused on factors that shape individual acceptance of MAM. Author summary: Nigeria has the highest number of people affected by neglected tropical diseases in sub-Saharan Africa. Many of these diseases (onchocerciasis, lymphatic filariasis, schistosomiasis and soil transmitted helminths) can be prevented and treated using mass administration of medicines (MAM), which involves giving everyone in communities medicines based on their height. MAM has been going on for a long time in Nigeria and has achieved many successes, however, the programmatic, social, political and economic context in Nigeria is rapidly changing and there is limited evidence about the ability of current MAM approaches to ensure everyone who needs these medicines is able to access them during this time of change. We asked MAM programme implementers at different levels of the health system in Nigeria to tell us what they thought the key strengths and weaknesses of the current programme were and what they would do to make it better to ensure that everyone who needs the medicines would still be able to access them. They told us that the commitment of health workers and community leaders to telling communities about the medicines and encouraging them to accept them as well as the knowledge of the disability these diseases can cause had supported programme success. However, they also told us that in some areas, such as those with security concerns or where communities feel fatigued by the programme, the way communities respond is changing. To address the change in community responses our study participants felt that we need to support programme implementers with the time, tools and resources to build stronger more trusting relationships with communities to ensure everyone can access medicines. [ABSTRACT FROM AUTHOR]

Background: Daodi-herb is a part of Chinese culture, which has been naturally selected by traditional Chinese medicine clinical practice for many years. Sweet wormwood herb is a kind of Daodi-herb, and comes from Artemisia annua L. Artemisinin is a kind of effective antimalarial drug being extracted from A. annua. Because of artemisinin, Sweet wormwood herb earns a reputation. Based on the Pharmacopoeia of the People's Republic of China (PPRC), Sweet wormwood herb can be used to resolve summerheat-heat, and prevent malaria. Besides, it also has other medical efficacies. A. annua, a medicinal plant that is widely distributed in the world contains many kinds of chemical composition. Research has shown that compatibility of artemisinin, scopoletin, arteannuin B and arteannuic acid has antimalarial effect. Compatibility of scopoletin, arteannuin B and arteannuic acid is conducive to resolving summerheat-heat. Chemical constituents in A. annua vary significantly according to geographical locations. So, distribution of A. annua may play a key role in the characteristics of efficacy and chemical constituents of Sweet wormwood herb. It is of great significance to study this relationship. Objectives: We mainly analyzed the relationship between the chemical constituents (arteannuin B, artemisinin, artemisinic acid, and scopoletin) with special efficacy in A. annua that come from different provinces in china, and analyzed the relationship between chemical constituents and spatial distribution, in order to find out the relationship between efficacy, chemical constituents and distribution. Methods: A field survey was carried out to collect A. annua plant samples. A global positioning system (GPS) was used for obtaining geographical coordinates of sampling sites. Chemical constituents in A. annua were determined by liquid chromatography tandem an atmospheric pressure ionization-electrospray mass spectrometry. Relationship between chemical constituents including proportions, correlation analysis (CoA), principal component analysis (PCA) and cluster analysis (ClA) was displayed through Excel and R software version2.3.2(R), while the one between efficacy, chemical constituents and spatial distribution was presented through ArcGIS10.0, Excel and R software. Results: According to the results of CoA, arteannuin B content presented a strong positive correlation with artemisinic acid content (p = 0), and a strong negative correlation with artemisinin content (p = 0). Scopoletin content presented a strong positive correlation with artemisinin content (p = 0), and a strong negative correlation with artemisinic acid content (p = 0). According to the results of PCA, the first two principal components accounted for 81.57% of the total accumulation contribution rate. The contribution of the first principal component is about 45.12%, manly including arteannuin B and artemisinic acid. The contribution of the second principal component is 36.45% of the total, manly including artemisinin and scopoletin. According to the ClA by using the principal component scores, 19 provinces could be divided into two groups. In terms of provinces in group one, the proportions of artemisinin are all higher than 80%. Based on the results of PCA, ClA, percentages and scatter plot analysis, chemical types are defined as "QHYS type", "INT type" and "QHS type." Conclusion: As a conclusion, this paper shows the relationship between efficacy, chemical constituents and distribution. Sweet wormwood herb with high arteannuin B and artemisinic acid content, mainly distributes in northern China. Sweet wormwood herb with high artemisinin and scopoletin content has the medical function of preventing malaria, which mainly distributes in southern China. In this paper, it is proved that Sweet wormwood Daodi herb growing in particular geographic regions, has more significant therapeutical effect and higher chemical constituents compared with other same kind of CMM. And also, it has proved the old saying in China that Sweet wormwood Daodi herb which has been used to resolve summerheat-heat and prevent malaria, which distributed in central China. But in modern time, Daodi Sweet wormwood herb mainly has been used to extract artemisinin and prevent malaria, so the Daod-region has transferred to the southern China. [ABSTRACT FROM AUTHOR]

Although harmful consumption of alcohol and other drugs (both illicit and pharmaceutical) significantly contribute to global burden of disease, not all harms are captured within existing morbidity data sources. Indeed, harms occurring in the community may be missed or under-reported. This paper describes the National Ambulance Surveillance System, a unique Australian system for monitoring and mapping acute harms related to alcohol and other drug consumption. Data are sourced from paramedic electronic patient care records provided by ambulance services from across Australia. Coding occurs in a purpose-built system, by a team of specialised research assistants. Alcohol, and specific illicit and pharmaceutical drugs, rather than broad drug classes, are manually coded and the dataset is reviewed and cleaned prior to analysis. The National Ambulance Surveillance System is an ongoing, dynamic surveillance system of alcohol and other drug-related harms across Australia. The data includes more than 140 output variables per attendance, including individual substances, demographics, temporal, geospatial, and clinical data (e.g., Glasgow Coma Scale score, naloxone provision and response, outcome of attendance). The National Ambulance Surveillance System is an internationally unique population-level surveillance system of acute harms arising from alcohol and other drug consumption. Dissemination of National Ambulance Surveillance System data has been used to inform and evaluate policy approaches and potential points of intervention, as well as guide workforce development needs and clinical practice at the local and national level. This methodology could be replicated in other countries. [ABSTRACT FROM AUTHOR]

Background: Although clozapine is the gold-standard for treatment refractory schizophrenia, it has the worst metabolic profile of all antipsychotics. This is partly mediated by clozapine’s impact on glucagon-like peptide (GLP-1). There is an absence of robust evidence for effective treatments for clozapine associated weight gain and metabolic syndrome. Metformin, with its role in increasing GLP-1 may aid weight loss among people on clozapine. Methods: We conducted a systematic-review and meta-analysis of metformin versus placebo for change in weight and metabolic syndrome for people on clozapine without diabetes mellitus. We searched the Cochrane Schizophrenia Group’s trial register, Pubmed and Embase, as well as the following Chinese databases: the Chinese Biomedical Literature Service System and China Knowledge Resource Integrated Database. This was supplemented by hand searches of key papers. Results: Eight studies, of which three were from Chinese databases, with 478 participants were included. We found that metformin was superior to placebo in terms of weight loss (-3.12kg, 95%CI -4.88kg to -1.37kg) and BMI (-1.18kg/m2, 95%CI -1.76kg/m2 to -0.61kg/m2). Metformin significantly improved three of the five components of metabolic syndrome; waist circumference, fasting glucose and triglycerides. Sensitivity analysis on study quality and duration did not greatly impact results. Conclusions: Metformin led to clinically meaningful weight loss among people on clozapine, and may reduce the rates of metabolic syndrome. Inclusion of metformin into the treatment protocols of people on clozapine, as tolerated, should be considered. Trial Registration: PROSPERO registration number: CRD42015029723 [ABSTRACT FROM AUTHOR]

Background: How can we explain the uneven decline of syphilis around the world following the introduction of penicillin? In this paper we use antenatal syphilis prevalence (ASP) to investigate how syphilis prevalence varied worldwide in the past century, and what risk factors correlate with this variance. Methods: 1) A systematic review using PubMed and Google Scholar was conducted to identify countries with published data relating to ASP estimates from before 1952 until the present. Eleven countries were identified (Canada, Denmark, Finland, India, Japan, Norway, Singapore, South Africa, United States of America (USA), United Kingdom (UK) and Zimbabwe). The ASP epidemic curve for each population was depicted graphically. In South Africa and the USA, results are reported separately for the black and white populations. 2) National antenatal syphilis prevalence estimates for 1990 to 1999 and 2008 were taken from an Institute for Health Metrics and Evaluation database on the prevalence of syphilis in low risk populations compiled for the Global Burden of Diseases study and from a recent review paper respectively. National ASPs were depicted graphically and regional median ASPs were calculated for both time periods. 3) Linear regression was used to test for an association between ASP in 1990–1999 and 2008 and four risk factors (efficacy of syphilis screening/treatment, health expenditure, GDP per capita and circumcision prevalence). WHO world regions were included as potential explanatory variables. Results: In most populations, ASP dropped to under 1% before 1960. In Zimbabwe and black South Africans, ASP was high in the pre-penicillin period, dropped in the post-penicillin period, but then plateaued at around 6% until the end of the 20th century when ASP dropped to just above 1%. In black Americans, ASP declined in the post penicillin period, but plateaued at 3–5% thereafter. ASP was statistically significantly higher in sub-Saharan Africa in 1990–1999 and 2008 than in the other world regions (P < 0.001). On multivariate analysis in both time periods, ASP was only associated with residence in sub-Saharan Africa. Conclusions: Further research is necessary to elucidate the reasons for the higher prevalence of syphilis in sub-Saharan Africa. [ABSTRACT FROM AUTHOR]

Objectives: Our hospital replaced the format for delivering portable antimicrobial prescribing guidance from a paper-based pocket guide to a smartphone application (app). We used this opportunity to assess the relationship between its use and the attitudes and behaviours of antimicrobial prescribers. Methods: We used 2 structured cross-sectional questionnaires issued just prior to and 3 months following the launch of the smartphone app. Ordinal Likert scale responses to both frequencies of use and agreement statements permitted quantitative assessment of the relationship between variables. Results: The smartphone app was used more frequently than the pocket guide it replaced (p < 0.01), and its increased use was associated with sentiments that the app was useful, easy to navigate and its content relevant. Users who used the app more frequently were more likely to agree that the app encouraged them to challenge inappropriate prescribing by their colleagues (p = 0.001) and were more aware of the importance of antimicrobial stewardship (p = 0.005). Reduced use of the app was associated with agreement that senior physicians’ preferences for antimicrobial prescribing would irrespectively overrule guideline recommendations (p = 0.0002). Conclusions: Smartphone apps are an effective and acceptable format to deliver guidance on antimicrobial prescribing. Our findings suggest that they may empower users to challenge incorrect prescribing, breaking well-established behaviours, and thus supporting vital stewardship efforts in an era of increased antimicrobial resistance. Future work will need to focus on the direct impact on drug prescriptions as well as identifying barriers to implementing smartphone apps in other clinical settings. [ABSTRACT FROM AUTHOR]

Background: Low-dose aspirin has been shown to reduce the incidence of cancer, but its role in the treatment of cancer is uncertain. Objectives: We conducted a systematic search of the scientific literature on aspirin taken by patients following a diagnosis of cancer, together with appropriate meta-analyses. Methods: Searches were completed in Medline and Embase in December 2015 using a pre-defined search strategy. References and abstracts of all the selected papers were scanned and expert colleagues were contacted for additional studies. Two reviewers applied pre-determined eligibility criteria (cross-sectional, cohort and controlled studies, and aspirin taken after a diagnosis of cancer), assessed study quality and extracted data on cancer cause-specific deaths, overall mortality and incidence of metastases. Random effects meta-analyses and planned sub-group analyses were completed separately for observational and experimental studies. Heterogeneity and publication bias were assessed in sensitivity analyses and appropriate omissions made. Papers were examined for any reference to bleeding and authors of the papers were contacted and questioned. Results: Five reports of randomised trials were identified, together with forty two observational studies: sixteen on colorectal cancer, ten on breast and ten on prostate cancer mortality. Pooling of eleven observational reports of the effect of aspirin on cause-specific mortality from colon cancer, after the omission of one report identified on the basis of sensitivity analyses, gave a hazard ratio (HR) of 0.76 (95% CI 0.66, 0.88) with reduced heterogeneity (P = 0.04). The cause specific mortality in five reports of patients with breast cancer showed significant heterogeneity (P<0.0005) but the omission of one outlying study reduced heterogeneity (P = 0.19) and led to an HR = 0.87 (95% CI 0.69, 1.09). Heterogeneity between nine studies of prostate cancer was significant, but again, the omission of one study led to acceptable homogeneity (P = 0.26) and an overall HR = 0.89 (95% CI 0.79–0.99). Six single studies of other cancers suggested reductions in cause specific mortality by aspirin, and in five the effect is statistically significant. There were no significant differences between the pooled HRs for the three main cancers and after the omission of three reports already identified in sensitivity analyses heterogeneity was removed and revealed an overall HR of 0.83 (95% CI 0.76–0.90). A mutation of PIK3CA was present in about 20% of patients, and appeared to explain most of the reduction in colon cancer mortality by aspirin. Data were not adequate to examine the importance of this or any other marker in the effect of aspirin in the other cancers. On bleeding attributable to aspirin two reports stated that there had been no side effect or bleeding attributable to aspirin. Authors on the other reports were written to and 21 replied stating that no data on bleeding were available. Conclusions and Implications: The study highlights the need for randomised trials of aspirin treatment in a variety of cancers. While these are awaited there is an urgent need for evidence from observational studies of aspirin and the less common cancers, and for more evidence of the relevance of possible bio-markers of the aspirin effect on a wide variety of cancers. In the meantime it is urged that patients in whom a cancer is diagnosed should be given details of this research, together with its limitations, to enable each to make an informed decision as to whether or not to take low-dose aspirin. Systematic Review Protocol Number: CRD42015014145 [ABSTRACT FROM AUTHOR]

Media plays an important role in informing the general public about scientific ideas. We examine whether the word “evolve,” sometimes considered controversial by the general public, is frequently used in the popular press. Specifically, we ask how often articles discussing antibiotic resistance use the word “evolve” (or its lexemes) as opposed to alternative terms such as “emerge” or “develop.” We chose the topic of antibiotic resistance because it is a medically important issue; bacterial evolution is a central player in human morbidity and mortality. We focused on the most widely-distributed newspapers written in English in the United States, United Kingdom, Canada, India, and Australia. We examined all articles that focused primarily on the evolution of antibiotic resistance, were published in 2014 or earlier, and were accessible in online archives, for a total of 1639 articles. The total years examined per newspaper ranged from 5 to 37 years with a median of 27 years, and the overall range was 1978–2014. We quantified how many articles included the term “evolve” and analyzed how this varied with newspaper, country, and time. We found that an overall rate of 18% of articles used the term “evolve” but with significant variation among countries. Newspapers in the United Kingdom had the highest rate (24%), more than double of those in India (9%), the country with the lowest rate. These frequencies were lower than those found in scientific papers from both evolutionary journals and biomedical journals. There were no statistically significant changes in frequency and no trends when “evolve” usage was compared against variables such as newspaper circulation, liberal/conservative bias, time, and state evolution acceptance in U.S. newspapers. This study highlights the globally low usage of the word “evolve” in the popular press. We suggest this low usage may affect public understanding and acceptance of evolutionary concepts. [ABSTRACT FROM AUTHOR]

Background: The administration of intravenous (IV) medications is a technically complicated and error-prone process. Especially, in the hematopoietic stem cell transplantation (HSCT) setting where toxic drugs are frequently used and patients are in critical immunocompromised conditions, medication errors (ME) can have catastrophic reactions and devastating outcomes such as death. Studies on ME are challenging due to poor methodological approaches and complicated interpretations. Here, we tried to resolve this problem using reliable methods and by defining new denominators, as a crucial part of an epidemiological approach. Methods: This was an observational, cross-sectional study. A total of 525 episodes of IV medication administration were reviewed by a pharmacist using the disguised direct observation method to evaluate the preparation and administration processes of 32 IV medications in three HSCT wards. We reported errors in 3 ratios; 1) Total Opportunities for Error (TOE; the number of errors/sum of all administered doses observed plus omitted medications), 2) Proportional Error Ratio (the number of errors for each drug or situation/total number of detected errors) and, 3) Corrected Total Opportunities for Errors (CTOE; the number of errors/ Sum of Potential Errors (SPE)). Results: A total of 1,568 errors were observed out of 5,347 total potential errors. TOE was calculated as 2.98 or 298% and CTOE as 29.3%. Most of the errors occurred at the administration step. The most common potential errors were the use of an incorrect volume of the reconstitution solvent during medication preparation and lack of monitoring in the administration stage. Conclusion: Medication errors frequently occur during the preparation and administration of IV medications in the HSCT setting. Using precise detection methods, denominators, and checklists, we identified the most error-prone steps during this process, for which there is an urgent need to implement effective preventive measures. Our findings can help plan targeted preventive measures and investigate their effectiveness, specifically in HSCT settings. [ABSTRACT FROM AUTHOR]

Introduction: Opioids are one of the most important and effective drug classes in pain medicine with a key role in most medical fields. The increase of opioid prescription over time has led to higher numbers of prescription opioid misuse, abuse and opioid-related deaths in most developed OECD (Organisation for Economic Co-operation and Development) countries around the world. Whilst reliable data on the prevalence of opioid treatment is accessible for many countries, data on Germany specifically is still scarce. Considering Germany being the largest country in the European Union, the lack of evidence-based strategies from long-term studies is crucial. The aim of this work is to review and summarise relevant published literature on the prevalence of opioid prescription in Germany to adequately inform health policy strategies. Methods: A systematic review of the epidemiology of opioid prescription in Germany was conducted, searching PubMed and Web of Science. Eligibility criteria were defined prior to conducting the search. Literature concerning Germany, published in English and German was included and the search was replicated by three independent researchers. Two levels of screening were employed. Disagreement was resolved by face-to-face discussion, leading to a consensus judgement. Results: Our electronic search yielded 735 articles. Reviewing titles and abstracts yielded 19 relevant articles. Three authors examined each article’s full text more closely and determined that twelve papers should be included. Of the twelve identified studies—with publication dates ranging from 1985 to 2016—six were retrospective cross-sectional studies and six were retrospective repeated-measures cross-sectional studies. Sample sizes ranged from 92,842 to ≈ 11,000,000 participants. Data sources of included studies showed vast heterogeneity. The reviewed literature suggested an increase in the number of patients with opioid prescriptions and defined daily doses of opioids per recipient in Germany over time. The majority of opioid prescriptions was used for patients with non-cancer pain. Opioid use was more common in older people, women and in the north of Germany. Fentanyl was shown to be the most prescribed strong opioid in outpatient settings in Germany, despite not being the first-line choice for chronic pain conditions. All data published before 2000—but none of the more recent studies—suggested an insufficient treatment of pain using opioids. There were no signs for a current opioid epidemic in Germany. Conclusions: Despite some limitations of the review and the heterogeneity of studies, it can be stated that the number of opioid prescriptions overall as well as the number of people receiving opioid treatment have increased over time. Most prescriptions were found to be for strong opioids and patients with non-cancer pain. Even though patterns of opioid prescription follow trends observed in other developed countries, there are no signs of an opioid epidemic in Germany. Therefore, this review could currently not find a need for urgent health policy interventions regarding opioid prescription practices. However, critical gaps in the literature remain and more research is needed to make more reliable judgements. [ABSTRACT FROM AUTHOR]

As antimicrobial resistance increases, it is crucial to develop new treatment strategies to counter the emerging threat. In this paper, we consider combination therapies involving conventional antibiotics and debridement, coupled with a novel anti-adhesion therapy, and their use in the treatment of antimicrobial resistant burn wound infections. Our models predict that anti-adhesion–antibiotic–debridement combination therapies can eliminate a bacterial infection in cases where each treatment in isolation would fail. Antibiotics are assumed to have a bactericidal mode of action, killing bacteria, while debridement involves physically cleaning a wound (e.g. with a cloth); removing free bacteria. Anti-adhesion therapy can take a number of forms. Here we consider adhesion inhibitors consisting of polystyrene microbeads chemically coupled to a protein known as multivalent adhesion molecule 7, an adhesin which mediates the initial stages of attachment of many bacterial species to host cells. Adhesion inhibitors competitively inhibit bacteria from binding to host cells, thus rendering them susceptible to removal through debridement. An ordinary differential equation model is developed and the antibiotic-related parameters are fitted against new in vitro data gathered for the present study. The model is used to predict treatment outcomes and to suggest optimal treatment strategies. Our model predicts that anti-adhesion and antibiotic therapies will combine synergistically, producing a combined effect which is often greater than the sum of their individual effects, and that anti-adhesion–antibiotic–debridement combination therapy will be more effective than any of the treatment strategies used in isolation. Further, the use of inhibitors significantly reduces the minimum dose of antibiotics required to eliminate an infection, reducing the chances that bacteria will develop increased resistance. Lastly, we use our model to suggest treatment regimens capable of eliminating bacterial infections within clinically relevant timescales. [ABSTRACT FROM AUTHOR]

Background: A new contraceptive microarray patch (MAP) for women is in development. Input on this method from potential end-users early in the product development process is important to guide design decisions. This paper presents the qualitative component of a broader study exploring initial acceptability of the MAP and selected product features. The qualitative research was intended to identify product features that are most salient to end-users and to contextualize preferences around them with subsequent research planned to assess quantitatively the relative importance of those features. Methods: We conducted 16 focus group discussions and 20 in-depth interviews with women and 20 IDIs with family planning providers in New Delhi, India, and Ibadan, Nigeria. Input from the MAP developer served to identify plausible features of the MAP to include in the focus group discussions and in-depth interviews. Interviews were audio-recorded, transcribed into English, coded, and analyzed to examine key dimensions of MAP features. Results: Many participants viewed the MAP as potentially easy to use. Interest in self-application after learning correct use was high, especially in India. Participants favored formulations affording protection from pregnancy for three or six months, if not longer. Interest in a shorter-acting MAP was particularly low in Nigeria. Non-desirable MAP features included a potential localized skin rash and pain at application. Views on patch size and location of application were related to the potential for rash and pain, with a desire to permit discreet use and minimize pain. Results indicate that the side effect profile, effectiveness, and pricing are also important factors for acceptability and uptake of a future product. Conclusion: Study findings indicate that a contraceptive MAP is of potential interest to women and that specific MAP attributes will be important to acceptability. [ABSTRACT FROM AUTHOR]

Biofilm-related infections of bones pose a significant therapeutic issue. In this article we present in vitro results of the efficacy of gentamicin released from a collagen sponge carrier against Staphylococcus aureus, Pseudomonas aeruginosa and Klebsiella pneumoniae biofilms preformed on hydroxyapatite surface. The results indicate that high local concentrations of gentamicin released from a sponge eradicate the biofilm formed not only by gentamicin-sensitive strains but, to some extent, also by those that display a resistance pattern in routine diagnostics. The data presented in this paper is of high clinical translational value and may find application in the treatment of bone infections. [ABSTRACT FROM AUTHOR]

Background: This study reports on physicians’ experiences with chronic pain management. For over a decade prescription opioids have been a primary treatment for chronic pain in North America. However, the current opioid epidemic has complicated long-standing practices for chronic pain management which historically involved prescribing pain medication. Caring for patients with chronic pain occurs within a context in which a growing proportion of patients suffer from chronic rather than acute conditions alongside rising social inequities. Methods: Our team undertook an ethnographic approach known as institutional ethnography in the province of Ontario, Canada in order to explore the social organization of chronic pain management from the standpoint of primary care physicians. This paper reports on a subset of this study data, specifically interviews with 19 primary care clinicians and 8 nurses supplemented by 40 hours of observations. The clinicians in our sample were largely primary care physicians and nurses working in urban, rural and Northern settings. Findings: In their reflections on providing care for patients with chronic pain, many providers describe being most challenged by the work involved in helping patients who also struggled with poverty, mental health and addiction. These frustrations were often complicated by concerns that they could lose their license for inappropriate prescribing, thus shifting their work from providing treatment and care to policing their patients for malingering and opioid abuse. Interpretation: Our findings show that care providers find the treatment of patients with chronic pain–especially those patients also experiencing poverty–to be challenging at best, and at worst frustrating and overwhelming. In many instances, their narratives suggested experiences of depersonalization, loss of job satisfaction and emotional exhaustion in relation to providing care for these patients, key dimensions of burnout. In essence, the work that they performed in relation to their patients’ social rather than medical needs seems to contribute to these experiences. Their experiences were further exacerbated by the fact that restricting and reducing opioid dosing in patients with chronic pain has become a major focus of care provision. [ABSTRACT FROM AUTHOR]

Hepatitis A virus (HAV), an enigmatic and ancient pathogen, is a major causative agent of acute viral hepatitis worldwide. Although there are effective vaccines, antivirals against HAV infection are still required, especially during fulminant hepatitis outbreaks. A more in-depth understanding of the antigenic characteristics of HAV and the mechanisms of neutralization could aid in the development of rationally designed antiviral drugs targeting HAV. In this paper, 4 new antibodies—F4, F6, F7, and F9—are reported that potently neutralize HAV at 50% neutralizing concentration values (neut50) ranging from 0.1 nM to 0.85 nM. High-resolution cryo-electron microscopy (cryo-EM) structures of HAV bound to F4, F6, F7, and F9, together with results of our previous studies on R10 fragment of antigen binding (Fab)-HAV complex, shed light on the locations and nature of the epitopes recognized by the 5 neutralizing monoclonal antibodies (NAbs). All the epitopes locate within the same patch and are highly conserved. The key structure-activity correlates based on the antigenic sites have been established. Based on the structural data of the single conserved antigenic site and key structure-activity correlates, one promising drug candidate named golvatinib was identified by in silico docking studies. Cell-based antiviral assays confirmed that golvatinib is capable of blocking HAV infection effectively with a 50% inhibitory concentration (IC50) of approximately 1 μM. These results suggest that the single conserved antigenic site from complete HAV capsid is a good antiviral target and that golvatinib could function as a lead compound for anti-HAV drug development. [ABSTRACT FROM AUTHOR]

Antimicrobial biopolymers provide a biodegradable, sustainable, safe, and cheap approach to drug delivery and wound dressing to control bacterial infection and improve wound healing respectively. Here, we report a one-step method of making antimicrobial alginate polymer from sodium alginate and aqueous extract of Wakame using antibiotic aminoglycosides. Thin layer chromatography of commercially available sodium alginate and Wakame extract showed similar oligosaccharide profiles. Screening of six aminoglycosides showed that kanamycin disulfate and neomycin sulfate produces the highest amount of biopolymer; however, kanamycin disulfate produces the most malleable and form fitting biopolymer. Image texture analysis of biopolymers showed similar quantification parameters for all the six aminoglycosides. Weight of alginate polymer as a function of aminoglycoside concentration follows a growth model of prion protein, consistent with the aggregating nature of both processes. Slow release of antibiotics and the resulting zone of inhibition against E. coli DH5α were observed by agar well diffusion assay. Inexpensive method of production and slow release of antibiotics will enable diverse applications of antimicrobial alginate biopolymer reported in this paper. [ABSTRACT FROM AUTHOR]

Selenium nanoparticle modified surfaces attract increasing attention in the field of tissue engineering. Selenium exhibits strong anticancer, antibacterial and anti-inflammatory properties and it maintains relatively low off-target cytotoxicity. In our paper, we present the fabrication, characterization and cytocompatibility of titanium oxide (TiO2) nanotube surface decorated with various surface densities of chemically synthesized selenium nanoparticles. To evaluate antibacterial and anti-cancer properties of such nanostructured surface, gram negative bacteria E. coli, cancerous osteoblast like MG-63 cells and non-cancerous fibroblast NIH/3T3 were cultured on designed surfaces. Our results suggested that selenium nanoparticles improved antibacterial properties of titanium dioxide nanotubes and confirmed the anticancer activity towards MG-63 cells, with increasing surface density of nanoparticles. Further, the selenium decorated TiO2 nanotubes suggested deteriorating effect on the cell adhesion and viability of non-cancerous NIH/3T3 cells. Thus, we demonstrated that selenium nanoparticles decorated TiO2 nanotubes synthesized using sodium selenite and glutathione can be used to control bacterial infections and prevent the growth of cancerous cells. However, the higher surface density of nanoparticles adsorbed on the surface was found to be cytotoxic for non-cancerous NIH/3T3 cells and thus it might complicate the integration of biomaterial into the host tissue. Therefore, an optimal surface density of selenium nanoparticles must be found to effectively kill bacteria and cancer cells, while remaining favorable for normal cells. [ABSTRACT FROM AUTHOR]

Objectives: Although systematic evaluation has confirmed the efficacy of fresh fecal microbiota transplantation (FMT) for treatment of recurrent and/or refractory and/or relapse C. difficile infection (RCDI), it lacks the support of well-designed randomized controlled trials (RCTs), and the latest guidelines do not optimize the management of FMT. In this paper, we focus on an in-depth study of fresh FMT and fecal infusion times to guide clinical practice. Methods: We reviewed studies in PubMed, Medline, Embase, the Cochrane library and Cochrane Central written in English. The retrieval period was from the establishment of the databases to September 20th, 2018. The retrieval objects were published RCTs of RCDI treated by fresh FMT. The intervention group was fresh FMT group, while the control group included antibiotic therapy or placebo or frozen FMT or capsule. The primary and secondary outcomes were the clinical remission of diarrhea without relapse after 8–17 weeks and the occurrence of severe adverse events, respectively. Subgroup analysis analyzed the effect of single and multiple fecal infusions. Two authors independently completed the information extraction and assessed risk of bias and overall quality of the evidence. Results: 8 randomized controlled trials met the inclusion criteria, involving 537 patients (273 in the fresh FMT group and 264 in the control group). The recurrence rate of clinical diarrhea in the fresh FMT group was 11.0% (30/273), which was significantly lower than the control group (24.6%, 65/264; P < 0.05); the pooled relative risk (RR) was 0.38 (95%CI:0.16–0.87; I2 = 67%; P = 0.02) in the fresh FMT group, and the clinical heterogeneity was significant and random effects model was used; However, there was no significant difference neither for the effect of antibiotic treatment/frozen feces transplanted by enema (RR = 1.07; 95%CI: 0.64–1.80; I2 = 0%; P = 0.79) or capsule/frozen feces transplanted by colonoscopy (RR = 0.42; 95%CI: 0.05–3.94; I2 = 43%; P = 0.45) compared with fresh FMT. The subgroup analysis showed that FMT by multiple infusions could effectively and significantly (RR = 0.24; 95%CI:0.10–0.58; I2 = 0%; P = 0.001) improve the clinical diarrhea remission rate. Most mild to moderate adverse events caused by FMT were self-limited and could be quickly alleviated; no severe adverse events happened because of FMT. Conclusions: Overall, the use of fresh feces for bacterial transplantation was the best efficiency for RCDI compared to antibiotic therapy or placebo. The fecal transmission method by enema was not ideal, but capsules or frozen feces transported by colonoscopy could be an alternative treatment compared to fresh FMT. For patients with severe RCDI, multiple fecal transplants can effectively improve their diarrhea remission rate. The focus of future research should be on how to standardize the production of capsules or frozen feces to better guide the clinical management of RCDI patients by FMT. [ABSTRACT FROM AUTHOR]

Background: Although empirical evidence suggests that the adherence club model is more effective in retaining people living with HIV in antiretroviral treatment care and sustaining medication adherence compared to standard clinic care, it is poorly understood exactly how and why this works. In this paper, we examined and made explicit how, why and for whom the adherence club model works at a public health facility in South Africa. Methods: We applied an explanatory theory-building case study approach to examine the validity of an initial programme theory developed a priori. We collected data using a retrospective cohort quantitative design to describe the suppressive adherence and retention in care behaviours of patients on ART using Kaplan-Meier methods. In conjunction, we employed an explanatory qualitative study design using non-participant observations and realist interviews to gain insights into the important mechanisms activated by the adherence club intervention and the relevant contextual conditions that trigger the different mechanisms to cause the observed behaviours. We applied the retroduction logic to configure the intervention-context-actor-mechanism-outcome map to formulate generative theories. Results: A modified programme theory involving targeted care for clinically stable adult patients (18 years+) receiving antiretroviral therapy was obtained. Targeted care involved receiving quick, uninterrupted supply of antiretroviral medication (with reduced clinic visit frequencies), health talks and counselling, immediate access to a clinician when required and guided by club rules and regulations within the context of adequate resources, and convenient (size and position) space and proper preparation by the club team. When grouped for targeted care, patients feel nudged, their self-efficacy is improved and they become motivated to adhere to their medication and remain in continuous care. Conclusion: This finding has implications for understanding how, why and under what health system conditions the adherence club intervention works to improve its rollout in other contexts. [ABSTRACT FROM AUTHOR]

Background: Preclinical evidence suggests statins may have anti-tumor properties. Large observational studies are also consistent with improved survival and cancer-specific outcomes among cancer patients on statins. We sought to evaluate the randomized controlled trials of statins in addition to usual anti-cancer therapy. Methods: A systematic search of MEDLINE, Embase, CINAHL, Cochrane Library, Web of Science, Papers First and Clinicaltrials.gov was performed from inception through to July 4, 2017 to identify randomized clinical trials that investigated statin therapy in cancer patients. Our primary outcome was overall survival and our secondary outcome was progression-free survival. We calculated summary hazard ratio’s (HR) and 95% confidence intervals (CI) based on random-effects models using aggregate data. PROSPERO (CRD42017065503). Results: Ten studies with 1,881 individuals were included with 1,572 deaths and a median follow-up of 23 months. All trials included patients with advanced (stage 3 or higher) disease. There was minimal between-study statistical heterogeneity (I2 = 1.8%, for OS; I2 = 0%, for PFS). The pooled HR for overall survival in patients randomized to statins plus standard anti-cancer therapy versus standard therapy alone was 0.94 (95% CI, 0.85 to 1.04). In the 9 studies that reported progression-free survival (1,798 participants), the pooled HR for statin plus standard therapy versus standard therapy alone was 0.97 (95% CI, 0.87 to 1.07). Conclusions: In patients with advanced cancer and a prognosis <2 years, the addition of statins to standard anti-cancer therapy does not appear to improve overall survival or progression-free survival. Future research should assess if cancer patients with better prognosis benefit from longer-term statin therapy. [ABSTRACT FROM AUTHOR]

Objective: The aim of this paper is to investigate how doctors working in primary health care in Latin American address patients with common mental disorders and to investigate how stigma can affect their clinical decisions. Methods: Using a cross-sectional design, we applied an online self-administered questionnaire to a sample of 550 Primary Care Physicians (PCPs) from Bolivia, Brazil, Cuba and Chile. The questionnaire collected information about sociodemographic variables, training and experience with mental health care. Clinicians’ stigmatizing attitudes towards mental health were measured using the Mental Illness Clinicians' Attitudes Scale (MICA v4). The clinical decisions of PCPs were assessed through three clinical vignettes representing typical cases of depression, anxiety and somatization. Results: A total of 387 professionals completed the questionnaires (70.3% response rate). The 63.7% of the PCPs felt qualified to diagnose and treat people with common mental disorders. More than 90% of the PCPs from Bolivia, Cuba and Chile agreed to treat the patients presented in the three vignettes. We did not find significant differences between the four countries in the scores of the MICA v4 stigma levels, with a mean = 36.3 and SD = 8.3 for all four countries. Gender (p = .672), age (p = .171), training (p = .673) and years of experience (p = .28) were unrelated to stigma. In the two multivariate regression models, PCPs with high levels of stigma were more likely to refer them to a psychiatrist the patients with depression (OR = 1.03, 95% CI, 0.99 to 1.07 p<0.05) and somatoform symptoms somatoform (OR = 1.03, 95% CI, 1.00 to 1.07, p<0.05) to a psychiatrist. Discussion: The majority of PCPs in the four countries were inclined to treat patients with depression, anxiety and somatoform symptoms. PCPs with more levels of stigma were more likely to refer the patients with depression and somatoform symptoms to a psychiatrist. Stigmatizing attitudes towards mental disorders by PCPs might be important barriers for people with mental health problems to receive the treatment they need in primary care. [ABSTRACT FROM AUTHOR]

Opioids are widely used for treating different types of pains, but overuse and abuse of prescription opioids have led to opioid epidemic in the United States. Besides analgesic effects, chronic use of opioid can also cause tolerance, dependence, and even addiction. Effective treatment of opioid addiction remains a big challenge today. Studies on addictive effects of opioids focus on striatum, a main component in the brain responsible for drug dependence and addiction. Some transcription regulators have been associated with opioid addiction, but relationship between analgesic effects of opioids and dependence behaviors mediated by them at the molecular level has not been thoroughly investigated. In this paper, we developed a new computational strategy that identifies novel targets and potential therapeutic molecular compounds for opioid dependence and addiction. We employed several statistical and machine learning techniques and identified differentially expressed genes over time which were associated with dependence-related behaviors after exposure to either morphine or heroin, as well as potential transcription regulators that regulate these genes, using time course gene expression data from mouse striatum. Moreover, our findings revealed that some of these dependence-associated genes and transcription regulators are known to play key roles in opioid-mediated analgesia and tolerance, suggesting that an intricate relationship between opioid-induce pain-related pathways and dependence may develop at an early stage during opioid exposure. Finally, we determined small compounds that can potentially target the dependence-associated genes and transcription regulators. These compounds may facilitate development of effective therapy for opioid dependence and addiction. We also built a database () for all opioid-induced dependence-associated genes and transcription regulators that we discovered, as well as the small compounds that target those genes and transcription regulators. [ABSTRACT FROM AUTHOR]

Huanglongbing (HLB, also known as citrus greening) is considered to be the most devastating disease that has significantly damaged the citrus industry globally. HLB is caused by the Candidatus Liberibacter asiaticus (CLas), the fastidious phloem-restricted gram-negative bacterium, vectored by the asian citrus psyllid. To date, there is no effective control available against CLas. To alleviate the effects of HLB on the industry and protect citrus farmers, there is an urgent need to identify or develop inhibitor molecules to suppress or eradicate CLas from infected citrus plant. In this paper, we demonstrate for the first time an in planta efficacy of two antimicrobial compounds against CLas viz. 2S albumin (a plant based protein; ~12.5 kDa), Nano-Zinc Oxide (Nano-ZnO; ~ 4.0 nm diameter) and their combinations. Aqueous formulations of these compounds were trunk-injected to HLB affected Mosambi plants (Citrus sinensis) grafted on 3-year old rough lemon (C. jambhiri) rootstock with known CLas titer maintained inside an insect-free screen house. The effective concentration of 2S albumin (330 ppm) coupled with the Nano-ZnO (330 ppm) at 1:1 ratio was used. The dynamics of CLas pathogen load of treated Mosambi plants was assessed using TaqMan-qPCR assay every 30 days after treatment (DAT) and monitored till 120 days. We observed that 2S albumin-Nano-ZnO formulation performed the best among all the treatments decreasing CLas population by 96.2%, 97.6%, 95.6%, and 97% of the initial bacterial load (per 12.5 ng of genomic DNA) at 30, 60, 90, and 120 DAT, respectively. Our studies demonstrated the potency of 2S albumin-Nano-ZnO formulation as an antimicrobial treatment for suppressing CLas in planta and could potentially be developed as a novel anti CLas therapeutics to mitigate the HLB severity affecting the citrus industry worldwide. [ABSTRACT FROM AUTHOR]

In this paper, we examine the inequality in the dynamics of the total fertility rate within 21 sub-Saharan African countries by wealth quintiles. We also examine the associated inequality within each country in the proximate determinants of fertility–marriage, contraception, and breastfeeding. Applying Bongaarts’ proximate determinants of fertility framework, for 14/21 countries we analyze, we find that those in the richest wealth quintiles have had a more rapid decline in fertility rates than those in the poorest wealth quintiles. The rapid decline for those in the richest wealth quintiles is attributable to delayed marriage and modest increases in contraceptive use. Although the poorest lag in fertility decline, postpartum abstinence and breastfeeding are the most important factors for them for fertility regulation. Further encouraging maternal health programs that focus on natural methods of fertility regulation will work in favor of the poorest in sub-Saharan Africa in moving through the demographic transition. [ABSTRACT FROM AUTHOR]

Introduction: This study systematically reviews costing studies of seasonal influenza-like illness (ILI) in high-income countries. Existing reviews on the economic impact of ILI do not report information on drug consumption and its costs, nor do they provide data on the overall cost per episode. Methods: The PRISMA-P checklist was used to design the research protocol. Studies included were cost of illness analysis (COI) and modeling studies that estimated the cost of ILI episodes. Records were searched from January 2000 to December 2016 in electronic bibliographic databases including Medline, Embase, Science Direct, the Cochrane Library, the Centre for Reviews and Disseminations of the University of York, and Google scholar. References from the included studies were hand-searched for completion. Abstract screening, full-text analysis and data extraction were performed by two reviewers independently and discrepancies were resolved by discussion with a third reviewer. A standardized, pre-piloted form was used for data extraction. All costs were converted to 2015 US$ Purchasing Power Parities. Results: The literature search identified 5,104 records. After abstract and title screening, 76 studies were analyzed full-text and 27 studies were finally included in the review. Full estimates of the cost per episode range from US$19 in Korea to US$323 in Germany. Particularly, the cost per episode of laboratory confirmed influenza cases was estimated between US$64 and US$73. Inpatient and outpatient services account for the majority of the costs. Differences in the estimates may reflect country-specific characteristics, as well as other study-specific features including study design, identification strategy of ILI cases, study populations and types of costs included in the analysis. Children usually register higher costs, whereas evidence for the elderly is less conclusive. Patients risk-profile, co-morbidities and complications are the other important cost-drivers. None of the papers considered appropriateness in resource use (e.g. abuse of antibiotics). Despite cost of illness studies have ultimately a descriptive role, evidence on (in)appropriateness is useful for policy-makers. [ABSTRACT FROM AUTHOR]

Pain and inflammation are complex clinical conditions that are present in a wide variety of disorders. Most drugs used to treat pain and inflammation have potential side effects, which makes it necessary to search for new sources of bioactive molecules. In this paper, we describe the ability of LASSBio-1586, an N-acylhydrazone derivative, to attenuate nociceptive behavior and the inflammatory response in mice. Antinociceptive activity was evaluated through acetic acid-induced writhing and formalin-induced nociception tests. In these experimental models, LASSBio-1586 significantly (p<0.05) reduced nociceptive behavior. Several methods of acute and chronic inflammation induced by different chemical (carrageenan, histamine, croton oil, arachidonic acid) and physical (cotton pellet) agents were used to evaluate the anti-inflammatory effect of LASSBio-1586. LASSBio-1586 exhibited potent anti-inflammatory activity in all tests (p<0.05). Study of the mechanism of action demonstrated the possible involvement of the nitrergic, serotonergic and histamine signaling pathways. In addition, a molecular docking study was performed, indicating that LASSBio-1586 is able to block the COX-2 enzyme, reducing arachidonic acid metabolism and consequently decreasing the production of prostaglandins, which are important inflammatory mediators. In summary, LASSBio-1586 exhibited relevant antinociceptive and anti-inflammatory potential and acted on several targets, making it a candidate for a new multi-target oral anti-inflammatory drug. [ABSTRACT FROM AUTHOR]

The aim of this paper was to compare the cardiorespiratory effects of the two combinations (medetomidine-tiletamine-zolazepam (MTZ) or dexmedetomidine-tiletamine-zolazepam (DTZ)) used for Asiatic black bear (Ursus thibetanus) immobilization. A retrospective analysis was carried out, reviewing the anesthetic records of captive bears. Sixty-six records were reviewed. The bears were immobilized, and general anesthesia was maintained with isoflurane vaporized in 100% oxygen. The mean sedation time and score were evaluated. The cardiorespiratory parameters were recorded every 10 minutes from intubation until extubation. Mean sedation time was 26.1 ± 14.5 minutes for the MTZ group and 25.6 ± 19.4 minutes for the DTZ group. The heart rate and the respiratory rate were higher in the bears immobilized with DTZ (66 ± 19 beats/min; 13 ± 5.2 breaths/min) as compared with the bears immobilized with MTZ (57 ± 14.5 beats/min; 10 ± 4.7 breaths/min) whereas the mean arterial pressure did not differ significantly between the groups. The body temperature was in the normal range throughout the procedures in all bears (MTZ 36.3 ± 0.9°C; DTZ 37 ± 1°C). In conclusion, the two protocols used in this study have been proven to be safe and reliable for the immobilization of Asiatic black bears, and the DTZ combination seemed to be associated with less cardiorespiratory depression than the MTZ one. [ABSTRACT FROM AUTHOR]

Clinical and subclinical mastitis affects 30% of cows and is regarded as the most significant economic burden on the dairy farm reducing milk yield and quality and increasing culling rate. A proprietary Acoustic Pulse Therapy (APT) device was developed specifically for treating dairy cows. The APT device was designed to produce deep penetrating acoustic pulses that are distributed over a large treated area at a therapeutic level. This paper presents findings from a clinical assessment of this technology for the treatment of dairy cows with subclinical and clinical mastitis. In subclinical mastitis, a group of 116 cows from 3 herds were identified with subclinical intramammary infection and enrolled in the study; 78 cows were assigned to the treatment group and 38 cows to the control group. Significant differences (P<0.001) were found where 70.5% of the cows in the treatment group returned to normal milk production, compared with only 18.4% of the control group. Daily milk yields of the treated cows increased significantly (P<0.05) and the percentage of cows with log somatic cell count under 5.6 cells/mL was significantly higher (P<0.001). Milk of the infected quarters appeared normal with lactose greater than 4.8%, but this difference was not significant. Of the treated cows with identified bacteria, 52.6% of the quarters were cured, while in the control group only 25.0% (P<0.001). Specifically, all cows identified with Escherichia coli in the treatment group were cured, with 66.6% cured with no intervention in the control. Spontaneous cure of glands infected with coagulase negative staphylococci (CNS) and Streptococci was low while treatment successfully increased the cure of CNS from 13.3% to 53.8% and that of Streptococci from 18.2% to 36.4%. Of the 4 cows identified with Staphylococcus aureus, 3 were cured. The clinical mastitis study group included 29 infected cows that were submitted either to a gold standard antibiotic treatment subgroup of 16 cows (n = 16) or to an APT treatment subgroup of 13 cows (n = 13). A cure of 18.7% was shown for the antibiotic treatment, of which logSCC returned to <5.6 cell/mL and 56.2% were culled. A cure of 76.9% was shown for the APT treatment with only one cow culled (7.7%). [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second leading cause of cancer mortality by 2030. PDAC remains resistant to the majority of systemic chemotherapies. In this paper, we explore if epigenetic sensitization can improve chemotherapy response in PDAC. Multiple PDAC cell lines were tested with serial concentrations of the epigenetic modulators 5-azacitidine (Aza) and guadecitabine (SGI-110). Guadecitabine was effective at inhibiting the expression of DNA Methyltransferase 1 (DNMT1) and in decreasing cell viability at nanomolar concentrations. We also report that guadecitabine has increased efficacy following a delay period or as we reference, a ‘rest period’. Sensitization with guadecitabine improved response to the chemotherapeutic agent–Irinotecan- as measured by decreased cell viability and accompanied by an increase in caspase activity. Additional studies are needed to understand the mechanism of action. [ABSTRACT FROM AUTHOR]