Neopterin and procalcitonin are suitable biomarkers for exclusion of severe Plasmodium falciparum disease at the initial clinical assessment of travellers with imported malaria

Background. Most clinicians in developed, non-malaria endemic countries have limited or no experience in making clinical assessments of malaria disease severity and subsequent decisions regarding the need for parenteral therapy or high-level monitoring in febrile patients with imported malaria. In the present study, the diagnostic accuracy of plasma soluble Triggering Receptor Expressed on Myeloid cells 1 (TREM-1), neopterin and procalcitonin levels as biomarkers for severe Plasmodium falciparum disease was evaluated in 104 travellers with imported malaria (26 patients with non-P. falciparum malaria, 64 patients with uncomplicated P. falciparum malaria and 14 patients with severe P. falciparum malaria). Methods. TREM-1, neopterin and procalcitonin were determined in serum using commercially available ELISA or EIA tests. The diagnostic performance of these biomarkers for severe disease was compared with plasma lactate, a well-validated parameter for disease severity in patients with malaria, as reference. Severe malaria was defined according to the modified WHO criteria. Results. No significant differences in TREM-1 levels were detected between the different patient groups. Patients with severe P. falciparum malaria had significantly higher neopterin and procalcitonin levels on admission when compared to patients with uncomplicated P. falciparum malaria or non-P. falciparum malaria. Receiver Operating Characteristic (ROC) curve analysis showed that neopterin had the highest Area-Under-the-ROC curve (AUROC 0.85) compared with plasma lactate (AUROC 0.80) and procalcitonin (AUROC 0.78). At a cut-off point of 10.0 ng/ml, neopterin had a positive and negative predictive value of 0.38 and 0.98 whereas procalcitonin, at a cut-off point of 0.9 ng/ml, had a positive and negative predictive value of 0.30 and 1.00. Conclusion. Although the diagnostic value of neopterin and procalcitonin is limited, the high negative predictive value of both neopterin and procalcitonin may be helpful for a rapid exclusion of severe malaria disease on admission. This may be a valuable tool for physicians only occasionally dealing with ill-returned travellers from malaria-endemic regions and who need to decide on subsequent oral anti-malarial treatment or timely referral to a specialized centre for high-level monitoring and intensified parenteral treatment

Lives saved by Global Fund-supported HIV/AIDS, tuberculosis and malaria programs: estimation approach and results between 2003 and end-2007

<p>Abstract</p> <p>Background</p> <p>Since 2003, the Global Fund has supported the scale-up of HIV/AIDS, tuberculosis and malaria control in low- and middle-income countries. This paper presents and discusses a methodology for estimating the lives saved through selected service deliveries reported to the Global Fund.</p> <p>Methods</p> <p>Global Fund-supported programs reported, by end-2007, 1.4 million HIV-infected persons on antiretroviral treatment (ARV), 3.3 million new smear-positive tuberculosis cases detected in DOTS (directly observed TB treatment, short course) programs, and 46 million insecticide-treated mosquito nets (ITNs) delivered. We estimated the corresponding lives saved using adaptations of existing epidemiological estimation models.</p> <p>Results</p> <p>By end-2007, an estimated 681,000 lives (95% uncertainty range 619,000-774,000) were saved and 1,097,000 (993,000-1,249,000) life-years gained by ARV. DOTS treatment would have saved 1.63 million lives (1.09 - 2.17 million) when compared against no treatment, or 408,000 lives (265,000-551,000) when compared against non-DOTS treatment. ITN distributions in countries with stable endemic <it>falciparum </it>malaria were estimated to have achieved protection from malaria for 26 million of child-years at risk cumulatively, resulting in 130,000 (27,000-232,000) under-5 deaths prevented.</p> <p>Conclusions</p> <p>These results illustrate the scale of mortality effects that supported programs may have achieved in recent years, despite margins of uncertainty and covering only selected intervention components. Evidence-based evaluation of disease impact of the programs supported by the Global Fund with international and in-country partners must be strengthened using population-level data on intervention coverage and demographic outcomes, information on quality of services, and trends in disease burdens recorded in national health information systems.</p

Demand-side financing for maternal and newborn health: what do we know about factors that affect implementation of cash transfers and voucher programmes?

BackgroundDemand-side financing (DSF) interventions, including cash transfers and vouchers, have been introduced to promote maternal and newborn health in a range of low- and middle-income countries. These interventions vary in design but have typically been used to increase health service utilisation by offsetting some financial costs for users, or increasing household income and incentivising 'healthy behaviours'. This article documents experiences and implementation factors associated with use of DSF in maternal and newborn health.MethodsA secondary analysis (using an adapted Supporting the Use of Research Evidence framework - SURE) was performed on studies that had previously been identified in a systematic review of evidence on DSF interventions in maternal and newborn health.ResultsThe article draws on findings from 49 quantitative and 49 qualitative studies. The studies give insights on difficulties with exclusion of migrants, young and multiparous women, with demands for informal fees at facilities, and with challenges maintaining quality of care under increasing demand. Schemes experienced difficulties if communities faced long distances to reach participating facilities and poor access to transport, and where there was inadequate health infrastructure and human resources, shortages of medicines and problems with corruption. Studies that documented improved care-seeking indicated the importance of adequate programme scope (in terms of programme eligibility, size and timing of payments and voucher entitlements) to address the issue of concern, concurrent investments in supply-side capacity to sustain and/or improve quality of care, and awareness generation using community-based workers, leaders and women's groups. ConclusionsEvaluations spanning more than 15 years of implementation of DSF programmes reveal a complex picture of experiences that reflect the importance of financial and other social, geographical and health systems factors as barriers to accessing care. Careful design of DSF programmes as part of broader maternal and newborn health initiatives would need to take into account these barriers, the behaviours of staff and the quality of care in health facilities. Research is still needed on the policy context for DSF schemes in order to understand how they become sustainable and where they fit, or do not fit, with plans to achieve equitable universal health coverage

Effects of demand-side financing on utilisation, experiences and outcomes of maternity care in low- and middle-income countries: a systematic review.

Demand-side financing, where funds for specific services are channelled through, or to, prospective users, is now employed in health and education sectors in many low- and middle-income countries. This systematic review aimed to critically examine the evidence on application of this approach to promote maternal health in these settings. Five modes were considered: unconditional cash transfers, conditional cash transfers, short-term payments to offset costs of accessing maternity services, vouchers for maternity services, and vouchers for merit goods. We sought to assess the effects of these interventions on utilisation of maternity services and on maternal health outcomes and infant health, the situation of underprivileged women and the healthcare system

Software for the frontiers of quantum chemistry:An overview of developments in the Q-Chem 5 package

This article summarizes technical advances contained in the fifth major release of the Q-Chem quantum chemistry program package, covering developments since 2015. A comprehensive library of exchange–correlation functionals, along with a suite of correlated many-body methods, continues to be a hallmark of the Q-Chem software. The many-body methods include novel variants of both coupled-cluster and configuration-interaction approaches along with methods based on the algebraic diagrammatic construction and variational reduced density-matrix methods. Methods highlighted in Q-Chem 5 include a suite of tools for modeling core-level spectroscopy, methods for describing metastable resonances, methods for computing vibronic spectra, the nuclear–electronic orbital method, and several different energy decomposition analysis techniques. High-performance capabilities including multithreaded parallelism and support for calculations on graphics processing units are described. Q-Chem boasts a community of well over 100 active academic developers, and the continuing evolution of the software is supported by an “open teamware” model and an increasingly modular design

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.JW is supported by a Cancer Research UK Cambridge Cancer Centre Clinical Research Training Fellowship. Funding for the NIHR BioResource – Rare diseases project was provided by the National Institute for Health Research (NIHR, grant number RG65966). ERM acknowledges support from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre), Cancer Research UK Cambridge Cancer Centre and Medical Research Council Infrastructure Award. The University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. DGE is an NIHR Senior Investigator and is supported by the all Manchester NIHR Biomedical Research Centre