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Abstract To bridge the gap between oxygen reduction electrocatalysts development and their implementation in real proton exchange membrane fuel cell electrodes, an important aspect to be understood is the interaction between the carbon support, the active sites, and the proton conductive ionomer as it greatly affects the local transportations to the catalyst surface. Here we show that three Pt/C catalysts, synthesized using the polyol method with different carbon supports (low surface area Vulcan, high surface area Ketjenblack, and biomass-derived highly ordered mesoporous carbon), revealed significant variations in ionomer-catalyst interactions. The Pt/C catalysts supported on ordered mesoporous carbon derived from biomass showed the best performance under the gas diffusion electrode configuration. Through a unique approach of operando X-ray Absorption Spectroscopy combined with gas sorption analysis, we were able to demonstrate the beneficial effect of mesopore presence for optimal ionomer-catalyst interaction at both molecular and structural level.

Abstract Objective A common low back pain treatment is epidural injection of corticosteroids. The nominal target of anti-inflammatory corticosteroid drugs is the glucocorticoid receptor (GR). In vitro studies show many clinically used steroids also activate the mineralocorticoid receptor (MR) with substantial potency. Based on preclinical studies, this may have pro-inflammatory and pro-nociceptive effects that counter the desired GR effects. Of two outpatient pain clinics associated with the University of Cincinnati Department of Anesthesiology, one primarily used methylprednisolone while the other used mainly triamcinolone for epidural steroid injections. We hypothesized that triamcinolone would give better outcomes because in vitro, ratio of MR/GR potency is about 10 fold less favorable for methylprednisolone. Methods We conducted a retrospective chart review of adults receiving lumbar epidural steroid injection for low back pain due to degenerative disc disease at the two pain clinics. For subjects treated at the first clinic, we obtained basic demographics, smoking history, 2 primary outcomes (patient-rated percent improvement in pain levels, and injection outcome rated as poor, partial, or good), and pain ratings (0–10 scale) before and after injection. For analysis, a subset of subjects from the second clinic was matched as closely as possible (sex, age, race, and ethnicity) to those from the first clinic. Results Eighty-six subjects from the first clinic were identified, of whom fifty-five met inclusion criteria. Review of 83 potentially matched subjects from the second clinic yielded 37 subjects. From this combined set of subjects, 44 receiving triamcinolone and 48 receiving methylprednisolone were obtained. Matching was effective in avoiding significant differences between the two drug groups in age, weight, sex, race, and body mass index, however, the incidence of smoking (current and former) was significantly higher in the methylprednisolone group (who were primarily from clinic 1). The injection responses codified on a 0–2 scale, where 0 indicated a poor response, 1 a partial response with a second injection recommended, and 2 a good response where no further treatment was recommended at the 1 month follow up point, were not significantly different between the groups (Mann–Whitney, p = 0.44) although the triamcinolone group overall had slightly better responses. However, the patient-reported percent improvement after the injection was significantly better for the triamcinolone than for methylprednisolone (60% ± 5.3 vs. 42% ± 4.9), as was the pain ratings (0–10 scale) after the injection (5.0 ± 0.5 vs. 6.3 ± 0.3). A marked demographic difference between the two clinics in smoking rates was not controlled for in subject matching but accounting for smoking status did not affect the observed differences between the two steroids. Conclusions Differences in the two primary outcomes, patient-reported percent improvement and pain ratings after epidural steroid injection, were consistent with the hypothesis that more GR-selective steroids may give better outcomes though the differences were modest. We propose that one factor in choosing steroids should be their relative potency in also activating the pro-inflammatory mineralocorticoid receptor. Graphical Abstract

The Barremian-aged Wessex Formation of the Isle of Wight, UK, offers a globally significant glimpse into the sauropod dinosaur faunas of the early Cretaceous. These deposits have yielded specimens of several neosauropod lineages, such as rebbachisaurids, titanosauriforms (including some of the earliest titanosaur remains), and possible flagellicaudatans. Here, we report an undescribed sauropod partial hindlimb from the Wessex Formation (NHMUK PV R16500) and analyse its phylogenetic affinities. This hindlimb preserves the left tibia, astragalus and pes, lacking only a few phalanges. NHMUK PV R16500 can be diagnosed based on two autapomorphies: an unusually high distal end to midshaft transverse width ratio in metatarsals III and IV, and the presence of small bump-like projections located in the centre of the proximal articular surfaces of the unguals of pedal digits I and II. The phylogenetic affinities of NHMUK PV R16500 are uncertain: although our analyses recover it as an early-branching somphospondylan, a single character change moves it to close to Flagellicaudata when extended implied weighting is applied. The possibility of flagellicaudatan affinities for NHMUK PV R16500 implies a potential ghost lineage that survived the Jurassic/Cretaceous boundary; however, we present evidence that the somphospondylan position is more probable and should be preferred.

Mutations in UBQLN2 cause ALS and frontotemporal dementia (FTD). The pathological signature in UBQLN2 cases is deposition of highly unusual types of inclusions in the brain and spinal cord that stain positive for UBQLN2. However, what role these inclusions play in pathogenesis remains unclear. Here we show cellular prion protein (PrPC) is found in UBQLN2 inclusions in both mouse and human neuronal induced pluripotent (IPSC) models of UBQLN2 mutations, evidenced by the presence of aggregated forms of PrPC with UBQLN2 inclusions. Turnover studies indicated that the P497H UBQLN2 mutation slows PrPC protein degradation and leads to mislocalization of PrPC in the cytoplasm. Immunoprecipitation studies indicated UBQLN2 and PrPC bind together in a complex. The abnormalities in PrPC caused by UBQLN2 mutations may be relevant in disease pathogenesis.

Uterotonics are essential in preventing postpartum hemorrhage (PPH), the leading direct cause of maternal death worldwide. However, uterotonics are often substandard in low- and middle-income countries, contributing to poor maternal health outcomes. This study examines the health and economic impact of substandard uterotonics in Ghana. A decision-tree model was built to simulate vaginal and cesarean section births across health facilities, uterotonic quality and utilization, PPH risk and diagnosis, and resulting health and economic outcomes. We utilized delivery data from Ghana's maternal health survey, risks of health outcomes from a Cochrane review, and E-MOTIVE trial data for health outcomes related to oxytocin quality. We compared scenarios with and without substandard uterotonics, as well as scenarios altering uterotonic use and care-seeking behaviors. We found that substandard uterotonic use contributes to $18.8 million in economic burden annually, including $6.3 million and $4.8 million in out-of-pocket expenditures in public and private sectors, respectively. Annually, the National Health Insurance Scheme bears $1.6 million in costs due to substandard uterotonic use. Substandard uterotonics contribute to $6 million in long-term productivity losses from maternal mortality annually. Improving the quality of uterotonics could reduce 20,000 (11%) PPH cases, 5,000 (11%) severe PPH cases, and 100 (11%) deaths due to PPH annually in Ghana. Ensuring the quality of uterotonics would result in millions of dollars in cost savings and improve maternal health outcomes for the government and families in Ghana. Cost savings from improving uterotonic quality would provide financial protection and help Ghana advance toward Universal Health Coverage.

Background: Data on the performance of newer biologics in patients with fistulizing Crohn’s disease (CD) are limited. Objective: Our study’s objective was to evaluate the response to ustekinumab (UST) and vedolizumab (VDZ) in patients with fistulizing CD. Design: Retrospective cohort. Methods: We used natural language processing of electronic medical record data to identify a retrospective cohort of individuals with fistulizing CD at a single academic tertiary-care referral center and then performed a chart review. Individuals were eligible for inclusion if a fistula was present at the time of UST or VDZ initiation. Outcomes included medication discontinuation, surgical intervention, development of a new fistula, and fistula closure. Groups were compared with unadjusted analyses and competing risk analyses using multi-state survival models. Results: In all, 68 patients were included (48 UST and 20 VDZ). Most patients had one fistula (79%) and had prior anti-tumor necrosis factor-α treatment (98% in UST group, 80% in VDZ group, p = 0.01). VDZ was significantly more likely to be discontinued than UST ( p

The prevalence of substandard and falsified medicines in low- and middle-income countries (LMICs) is a major global public health concern. Multiple screening technologies for post-market surveillance of medicine quality have been developed but there exists no clear guidance on which technology is optimal for LMICs. This study examined the return on investment (ROI) of implementing a select number of screening technologies for post-market surveillance of amoxicillin quality in a case study of Kenya. An agent-based model, Examining Screening Technologies using Economic Evaluations for Medicines (ESTEEM), was developed to estimate the costs, benefits, and ROI of implementing screening technologies for post-market surveillance of substandard and falsified amoxicillin for treatment of pediatric pneumonia in Kenya. The model simulated sampling, testing, and removal of substandard and falsified amoxicillin from the Kenyan market using five screening technologies: (1) Global Pharma Health Fund's GPHF-Minilab, (2) high-performance liquid chromatography (HPLC), (3) near-infrared spectroscopy (NIR), (4) paper analytical devices / antibiotic paper analytical devices (PADs/aPADs), and (5) Raman spectroscopy. The study team analyzed the population impact of utilizing amoxicillin for the treatment of pneumonia in children under age five in Kenya. We found that the GPHF-Minilab, NIR, and PADs/aPADs were similar in their abilities to rapidly screen for and remove substandard and falsified amoxicillin from the Kenyan market resulting in a higher ROI compared to HPLC. NIR and PADs/aPADs yielded the highest ROI at $21 (90% Uncertainty Range (UR) $5-$51) each, followed by GPHF-Minilab ($16, 90%UR $4 - $38), Raman ($9, 90%UR $2 - $21), and HPLC ($3, 90%UR $0 - $7). This study highlights screening technologies that can be used to reduce costs, speed up the removal of poor-quality medicines, and consequently improve health and economic outcomes in LMICs. National medicine regulatory authorities should adopt these fast, reliable, and low-cost screening technologies to better detect substandard and falsified medicines, reserving HPLC for confirmatory tests.

Abstract Background Many countries are striving to become malaria-free, but global reduction in case estimates has stagnated in recent years. Substandard and falsified medicines may contribute to this lack of progress. Zambia aims to eliminate their annual burden of 1.2 million pediatric malaria cases and 2500 child deaths due to malaria. We examined the health and economic impact of poor-quality antimalarials in Zambia. Methods An agent-based model, Substandard and Falsified Antimalarial Research Impact (SAFARI), was modified and applied to Zambia. The model was developed to simulate population characteristics, malaria incidence, patient care-seeking, disease progression, treatment outcomes, and associated costs of malaria for children under age five. Zambia-specific demographic, epidemiological, and cost inputs were extracted from the literature. Simulations were run to estimate the health and economic impact of poor-quality antimalarials, the effect of potential artemisinin resistance, and six additional malaria focused policy interventions. Results We simulated annual malaria cases among Zambian children under five. At baseline, we found 2610 deaths resulting in $141.5 million in annual economic burden of malaria. We estimated that elimination of substandard and falsified antimalarials would result in an 8.1% (n = 213) reduction in under-five deaths, prevent 937 hospitalizations, and realize $8.5 million in economic savings, annually. Potential artemisinin resistance could further increase deaths by 6.3% (n = 166) and cost an additional $9.7 million every year. Conclusions Eliminating substandard and falsified antimalarials is an important step towards a malaria-free Zambia. Beyond the dissemination of insecticide-treated bed nets, indoor residual spraying, and other malaria control measures, attention must also be paid to assure the quality of antimalarial treatments.

BackgroundHighly connected individuals disseminate information effectively within their social network. To apply this concept to inflammatory bowel disease (IBD) care and lay the foundation for network interventions to disseminate high-quality treatment, we assessed the need for improving the IBD practices of highly connected clinicians. We aimed to examine whether highly connected clinicians who treat IBD patients were more likely to provide high-quality treatment than less connected clinicians.MethodsWe used network analysis to examine connections among clinicians who shared patients with IBD in the Veterans Health Administration between 2015-2018. We created a network comprised of clinicians connected by shared patients. We quantified clinician connections using degree centrality (number of clinicians with whom a clinician shares patients), closeness centrality (reach via shared contacts to other clinicians), and betweenness centrality (degree to which a clinician connects clinicians not otherwise connected). Using weighted linear regression, we examined associations between each measure of connection and two IBD quality indicators: low prolonged steroids use, and high steroid-sparing therapy use.ResultsWe identified 62,971 patients with IBD and linked them to 1,655 gastroenterologists and 7,852 primary care providers. Clinicians with more connections (degree) were more likely to exhibit high-quality treatment (less prolonged steroids beta -0.0268, 95%CI -0.0427, -0.0110, more steroid-sparing therapy beta 0.0967, 95%CI 0.0128, 0.1805). Clinicians who connect otherwise unconnected clinicians (betweenness) displayed more prolonged steroids use (beta 0.0003, 95%CI 0.0001, 0.0006). The presence of variation is more relevant than its magnitude.ConclusionsClinicians with a high number of connections provided more high-quality IBD treatments than less connected clinicians, and may be well-positioned for interventions to disseminate high-quality IBD care. However, clinicians who connect clinicians who are otherwise unconnected are more likely to display low-quality IBD treatment. Efforts to improve their quality are needed prior to leveraging their position to disseminate high-quality care.

We explore the potential of the Gaussian mixture model (GMM), an unsupervised machine-learning method, to identify coherent physical structures in the interstellar medium. The implementation we present can be used on any kind of spatially and spectrally resolved data set. We provide a step-by-step guide to use these models on different sources and data sets. Following the guide, we run the models on NGC 1977, RCW 120, and RCW 49 using the [C ii ] 158 μ m mapping observations from the SOFIA telescope. We find that the models identified six, four, and five velocity coherent physical structures in NGC 1977, RCW 120, and RCW 49, respectively, which are validated by analyzing the observed spectra toward these structures and by comparison to earlier findings. In this work we demonstrate that GMM is a powerful tool that can better automate the process of spatial and spectral analysis to interpret mapping observations.

Abstract Background Global efforts to address the burden of malaria have stagnated in recent years with malaria cases beginning to rise. Substandard and falsified anti-malarial treatments contribute to this stagnation. Poor quality anti-malarials directly affect health outcomes by increasing malaria morbidity and mortality, as well as threaten the effectiveness of treatment by contributing to artemisinin resistance. Research to assess the scope and impact of poor quality anti-malarials is essential to raise awareness and allocate resources to improve the quality of treatment. A probabilistic agent-based model was developed to provide country-specific estimates of the health and economic impact of poor quality anti-malarials on paediatric malaria. This paper presents the methodology and case study of the Substandard and Falsified Antimalarial Research Impact (SAFARI) model developed and applied to Uganda. Results The total annual economic impact of malaria in Ugandan children under age five was estimated at US$614 million. Among children who sought medical care, the total economic impact was estimated at $403 million, including $57.7 million in direct costs. Substandard and falsified anti-malarials were a significant contributor to this annual burden, accounting for $31 million (8% of care-seeking children) in total economic impact involving $5.2 million in direct costs. Further, 9% of malaria deaths relating to cases seeking treatment were attributable to poor quality anti-malarials. In the event of widespread artemisinin resistance in Uganda, we simulated a 12% yearly increase in costs associated with paediatric malaria cases that sought care, inflicting $48.5 million in additional economic impact annually. Conclusions Improving the quality of treatment is essential to combat the burden of malaria and prevent the development of drug resistance. The SAFARI model provides country-specific estimates of the health and economic impact of substandard and falsified anti-malarials to inform governments, policy makers, donors and the malaria community about the threat posed by poor quality medicines. The model findings are useful to illustrate the significance of the issue and inform policy and interventions to improve medicinal quality.

Summary: Hepatic lipid accumulation in obesity correlates with the severity of hyperinsulinemia and systemic insulin resistance. Obesity-induced hepatocellular lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic afferent vagal nerve firing, increases GABA release from liver slices, and causes hyperinsulinemia. Preventing hepatic GABA release or eliminating the ability of the liver to communicate to the hepatic vagal nerve ameliorates the hyperinsulinemia and insulin resistance associated with diet-induced obesity. In people with obesity, hepatic expression of GABA transporters is associated with glucose infusion and disposal rates during a hyperinsulinemic euglycemic clamp. Single-nucleotide polymorphisms in hepatic GABA re-uptake transporters are associated with an increased incidence of type 2 diabetes mellitus. Herein, we identify GABA as a neuro-hepatokine that is dysregulated in obesity and whose release can be manipulated to mute or exacerbate the glucoregulatory dysfunction common to obesity.

ObjectiveTo assess the importance of ensuring medicine quality in order to achieve universal health coverage (UHC).MethodsWe developed a systems map connecting medicines quality assurance systems with UHC goals to illustrate the ensuing impact of quality-assured medicines in the implementation of UHC. The association between UHC and medicine quality was further examined in the context of essential medicines in low- and middle-income countries (LMICs) by analyzing data on reported prevalence of substandard and falsified essential medicines and established indicators for UHC. Finally, we examined the health and economic savings of improving antimalarial quality in four countries in sub-Saharan Africa: the Democratic Republic of the Congo (DRC), Nigeria, Uganda, and Zambia.FindingsA systems perspective demonstrates how quality assurance of medicines supports dimensions of UHC. Across 63 LMICs, the reported prevalence of substandard and falsified essential medicines was found to be negatively associated with both an indicator for coverage of essential services (p = 0.05) and with an indicator for government effectiveness (p = 0.04). We estimated that investing in improving the quality of antimalarials by 10% would result in annual savings of $8.3 million in Zambia, $14 million in Uganda, $79 million in two DRC regions, and $598 million in Nigeria, and was more impactful compared to other potential investments we examined. Costs of substandard and falsified antimalarials per malaria case ranged from $7 to $86, while costs per death due to poor-quality antimalarials ranged from $14,000 to $72,000.ConclusionMedicines quality assurance systems play a critical role in reaching UHC goals. By ensuring the quality of essential medicines, they help deliver effective treatments that lead to less illness and result in health care savings that can be reinvested towards UHC.

BackgroundData on external validation of models developed to distinguish Crohn's disease (CD) from intestinal tuberculosis (ITB) are limited. This study aimed to validate and compare models using clinical, endoscopic, and/or pathology findings to differentiate CD from ITB.MethodsData from newly diagnosed ITB and CD patients were retrospectively collected from 5 centers located in Thailand or Hong Kong. The data was applied to Lee, et al., Makharia, et al., Jung, et al., and Limsrivilai, et al. model.ResultsFive hundred and thirty patients (383 CD, 147 ITB) with clinical and endoscopic data were included. The area under the receiver operating characteristic curve (AUROC) of Limsrivilai's clinical-endoscopy (CE) model was 0.853, which was comparable to the value of 0.862 in Jung's model (p = 0.52). Both models performed significantly better than Lee's endoscopy model (AUROC: 0.713, pConclusionsScoring systems with more parameters and diagnostic modalities performed better; however, application to clinical practice is still limited owing to high rate of misdiagnosis of ITB as CD. Models integrating more modalities such as imaging and serological tests are needed.

Abstract Background In September 2009, a mumps outbreak originated in New York and spread to Northeastern USA and Canada. This study compares the performance of different diagnostic testing methods used in Ontario and describes molecular characteristics of the outbreak strain. Methods Between September 2009 and February 2010, specimens from suspect cases were submitted to Public Health Ontario Laboratory for mumps serology, culture and/or real-time reverse-transcriptase PCR (rRT-PCR) testing. rRT-PCR-positive specimens underwent genotyping at Canada’s National Microbiology Laboratory. Whole genome sequencing was performed on four outbreak and three sporadic viral culture isolates. Results Six hundred ninety-eight patients had IgM serology testing, of which 255 (37%) had culture and rRT-PCR. Among those, 35/698 (5%) were IgM positive, 39/255 (15%) culture positive and 47/255 (18%) rRT-PCR-positive. Buccal swabs had the highest rRT-PCR positivity (21%). The outbreak isolates were identical to that in the New York outbreak occurring at the same time. Nucleotide and amino acid identity with the Jeryl Lynn vaccine strain ranged from 85.0-94.5% and 82.4-99.4%, depending on the gene and coding sequences. Homology of the HN protein, the main immunogenic mumps virus protein, was found to be 94.5 and 95.3%, when compared to Jeryl Lynn vaccine major and minor components, respectively. Conclusions Despite higher sensitivity than serology, rRT-PCR testing is underutilized. Further work is needed to better understand the suboptimal match of the HN gene between the outbreak strain and the Jeryl Lynn vaccine strain.

Abstract Background The clinical course of ulcerative colitis (UC) and the effects of treatment are assessed through patient-reported signs and symptoms (S&S), and endoscopic evidence of inflammation. The Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms (UC-PRO/SS) measure was developed to standardize the quantification of gastrointestinal S&S of UC in clinical trials through direct report from patient ratings. Design The UC-PRO/SS was developed by collecting data from concept elicitation (focus groups, and individual interviews), then refined through a process of cognitive interviews of 57 UC patients. Measurement properties, including item-level statistics, scaling structure, reliability, and validity, were evaluated in an observational, four-week study of adults with mild to severe UC (N = 200). Results Findings from qualitative focus groups and interviews identified nine symptom items covering bowel and abdominal symptoms. The final UC-PRO/SS daily diary includes two scales: Bowel S&S (six items) and Abdominal Symptoms (three items), each scored separately. Each scale showed evidence of adequate reliability (α = 80 and 0.66, respectively); reproducibility (intraclass correlation coefficient = 0.81, 0.71) and validity, including moderate-to-high correlations with the Partial Mayo Score (0.79; 0.45) and Inflammatory Bowel Disease Questionnaire (IBDQ) total score (− 0.70; − 0.61). Scores discriminated by level of disease severity, as defined by the Partial Mayo Score, Patient Global Rating, and Clinician Global Rating (p

Abstract Background The clinical course of Crohn’s disease (CD) and the effect of its treatment are monitored through patient-reported signs and symptoms (S&S), and endoscopic evidence of inflammation. The Crohn’s Disease Patient-reported Outcomes Signs and Symptoms (CD-PRO/SS) measure was developed to standardize the quantification of gastrointestinal S&S of CD through direct report from patient ratings. Methods The CD-PRO/SS was developed based on data from concept elicitation (focus groups, interviews; n = 29), then refined through cognitive interviews of CD patients (n = 20). Measurement properties, including item-level statistics, scaling structure, reliability, and validity, were examined using secondary analyses of baseline and two-week clinical trial data of adults with moderate-to-severe CD (n = 238). Results Findings from qualitative interviews identified nine S&S items covering bowel and abdominal symptoms. The final CD-PRO/SS daily diary includes two scales: Bowel S&S (three items) and Abdominal Symptoms (three items), each scored separately. Each scale showed evidence of adequate reliability (α = 0.74 and 0.67, respectively); reproducibility (intraclass correlation coefficient > 0.80), and validity, with the last including moderate correlations with the Inflammatory Bowel Disease Questionnaire bowel symptom score and select items (ranging from r = 0.43–0.54). Scores distinguished patients categorized by patient global ratings of disease severity (p

Twelve years after cardiologists and cardiac surgeons from all over the world issued the ‘Drakensberg Declaration on the Control of Rheumatic Fever and Rheumatic Heart Disease in Africa’, calling on the world community to address the prevention and treatment of rheumatic heart disease (RHD) through improving living conditions, to develop pilot programmes at selected sites for control of rheumatic fever and RHD, and to periodically review progress made and challenges that remain, RHD still accounts for a major proportion of cardiovascular diseases in children and young adults in low- and middle-income countries, where more than 80% of the world population live. Globally equal in prevalence to human immunodeficiency virus infection, RHD affects 33 million people worldwide. Prevention efforts have been important but have failed to eradicate the disease. At the present time, the only effective treatment for symptomatic RHD is open heart surgery, yet that life-saving cardiac surgery is woefully absent in many endemic regions. In this declaration, we propose a framework structure to create a co-ordinated and transparent international alliance to address this inequality.

IntroductionSubstandard and falsified medications pose significant risks to global health. Nearly one in five antimalarials circulating in low- and middle-income countries are substandard or falsified. We assessed the health and economic impact of substandard and falsified antimalarials on children under five in Nigeria, where malaria is endemic and poor-quality medications are commonplace.MethodsWe developed a dynamic agent-based SAFARI (Substandard and Falsified Antimalarial Research Impact) model to capture the impact of antimalarial use in Nigeria. The model simulated children with background characteristics, malaria infections, patient care-seeking, disease progression, treatment outcomes, and incurred costs. Using scenario analyses, we simulated the impact of substandard and falsified medicines, antimalarial resistance, as well as possible interventions to improve the quality of treatment, reduce stock-outs, and educate caregivers about antimalarial quality.ResultsWe estimated that poor quality antimalarials are responsible for 12,300 deaths and $892 million ($890-$893 million) in costs annually in Nigeria. If antimalarial resistance develops, we simulated that current costs of malaria could increase by $839 million (11% increase, $837-$841 million). The northern regions of Nigeria have a greater burden as compared to the southern regions, with 9,700 deaths and $698 million ($697-$700 million) in total economic losses annually due to substandard and falsified antimalarials. Furthermore, our scenario analyses demonstrated that possible interventions-such as removing stock-outs in all facilities ($1.11 billion), having only ACTs available for treatment ($594 million), and 20% more patients seeking care ($469 million)-can save hundreds of millions in costs annually in Nigeria.ConclusionsThe results highlight the significant health and economic burden of poor quality antimalarials in Nigeria, and the impact of potential interventions to counter them. In order to reduce the burden of malaria and prevent antimalarials from developing resistance, policymakers and donors must understand the problem and implement interventions to reduce the impact of ineffective and harmful antimalarials.

Enteric viral pathogens causing gastroenteritis include adenovirus and rotavirus, among others. Rotavirus is the leading cause of severe diarrhea in infants and young children worldwide. Among the adenoviruses known to cause gastroenteritis are those of species F (serotypes 40, 41). Here, we describe the development and validation of a laboratory-developed gastrointestinal triplex rRT-PCR (triplex) assay that targets adenovirus and rotavirus. Stool specimens were tested from patients across Ontario. Specimens were previously tested for adenovirus and/or rotavirus by electron microscopy (EM) or immunochromatographic test (ICT). Triplex sensitivity, specificity, positive and negative predictive values compared to Seegene assay (a commercial assay used here as the standard reference method) were 100%, 97.8%, 86.0%, 100% for adenovirus, and 99.1%, 98.4%, 96.3%. 99.6% for rotavirus, respectively. The triplex assay had a 95.2% and 97.3% overall percent agreements (OPAs) when compared to EM for adenovirus or rotavirus detection, respectively, and an OPA of 90.9% when compared to rotavirus ICT for rotavirus detection. Triplex assay exhibited similar performance to the Seegene assay for both adenovirus and rotavirus and detected more adenovirus and rotavirus than traditional testing methods. The high performance along with lower cost and reduced turnaround time makes the triplex assay a desirable testing method for a clinical microbiology laboratory.

ABSTRACT Recurrent Clostridium difficile infection (rCDI) frequently complicates recovery from CDI. Accurately predicting rCDI would allow judicious allocation of limited resources, but published models have met with limited success. Thus, biomarkers predictive of recurrence have been sought. This study tested whether PCR ribotype independently predicted rCDI. Stool samples from nonpregnant inpatients ≥18 years of age with diarrhea were included from October 2010 to January 2013 after the patients tested positive for C. difficile in the clinical microbiology laboratory. Per guidelines, the rCDI was defined as a positive test for C. difficile at >2 weeks but ≤8 weeks from the index episode. For each sample, a single colony of C. difficile was isolated by anaerobic culture, confirmed to be toxigenic by PCR, and ribotyped. Simple logistic regression and multiple logistic regression were used to model the primary outcome of rCDI, incorporating a wide range of clinical parameters. In total, 927 patients with 968 index episodes of CDI were included, with 110 (11.4%) developing rCDI. Age and use of proton pump inhibitors or concurrent antibiotics did not increase the risk of rCDI. Low serum bilirubin levels and ribotype 027 were associated with increased risk of rCDI on unadjusted analysis, with health care-associated CDI being inversely associated. In the final multivariable model, ribotype 027 was the strongest independent predictor of rCDI (odds ratio, 2.17; 95% confidence interval, 1.33 to 3.56; P = 0.002). Ribotype 027 is an independent predictor of rCDI. IMPORTANCE CDI is a major public health issue, with over 400,000 cases per year in the United States alone. Recurrent CDI is common, occurring in approximately one in five individuals after a primary episode. Although interventions exist that could reduce the risk of recurrence, deployment in all patients is limited by cost, invasiveness, and/or an undetermined long-term safety profile. Thus, clinicians need risk stratification tools to properly allocate treatments. Because prior research on clinical predictors has failed to yield a reliable, reproducible, and effective predictive model to assist treatment decisions, accurate biomarkers of recurrence would be of great value. This study tested whether PCR ribotype independently predicted rCDI, and the data build upon prior research in showing that ribotype 027 is associated with rCDI.

Patients with inflammatory bowel disease(IBD) are frequently exposed to computed tomography (CT). Each CT exposes patients to radiation that cumulatively could increase the risk of malignancy, particularly in younger patients. We aim to study the effect of age on CT use in IBD patients seen in the Emergency Department (ED) or the hospital.We conducted a retrospective cohort study of IBD patients identified in Truven Health Marketscan databases between 2009-2013. The main outcome was use of CT during an ED or inpatient visit. Effect of age on CT use was characterized using logistic regression accounting for important covariables.There were 66,731 patients with IBD with 144,147 ED or inpatient visits in this cohort with a diagnosis code of IBD. At first visit, 5.8% percent were below age 18. CT was utilized in 26.6% of visits. In multivariable analysis, adjusting for medications, recent surgery, and gender, patients 18-35 were more likely to undergo CT (OR 2.35, 95%CI: 2.20-2.52) compared to those

[This corrects the article DOI: 10.1371/journal.pone.0158017.].