Laboratory Evaluation and Field Testing of Dengue NS1 and IgM/IgG Rapid Diagnostic Tests in an Epidemic Context in Senegal.

In Senegal, the burden of dengue is increasing and expanding. As case management and traditional diagnostic techniques can be difficult to implement, rapid diagnostic tests (RDTs) deployed at point of care are ideal for investigating active outbreaks. The aim of this study was to evaluate the diagnostic performance of the Dengue NS1 and Dengue IgM/IgG RDTs on the serum/plasma samples in a laboratory setting and in the field. During laboratory evaluation, performance of the NS1 RDT was assessed using NS1 ELISA as the gold standard. Sensitivity and specificity were 88% [75-95%] and 100% [97-100%], respectively. Performance of the IgM/IG RDT was assessed using the IgM Antibody Capture (MAC) ELISA, indirect IgG, and PRNT as gold standards. The IgM and IgG test lines respectively displayed sensitivities of 94% [83-99%] and 70% [59-79%] and specificities of 91% [84-95%] and 91% [79-98%]. In the field, the Dengue NS1 RDT sensitivity and specificity was 82% [60-95%] and 75% [53-90%], respectively. The IgM and IgG test lines displayed sensitivities of 86% [42-100%] and 78% [64-88%], specificities of 85% [76-92%] and 55% [36-73%], respectively. These results demonstrate that RDTs are ideal for use in a context of high prevalence or outbreak setting and can be implemented in the absence of a confirmatory test for acute and convalescent patients.

Prevalence of neutralising antibodies against SARS-CoV-2 in acute infection and convalescence: A systematic review and meta-analysis.

BACKGROUND: Individuals infected with SARS-CoV-2 develop neutralising antibodies. We investigated the proportion of individuals with SARS-CoV-2 neutralising antibodies after infection and how this proportion varies with selected covariates. METHODOLOGY/PRINCIPAL FINDINGS: This systematic review and meta-analysis examined the proportion of individuals with SARS-CoV-2 neutralising antibodies after infection and how these proportions vary with selected covariates. Three models using the maximum likelihood method assessed these proportions by study group, covariates and individually extracted data (protocol CRD42020208913). A total of 983 reports were identified and 27 were included. The pooled (95%CI) proportion of individuals with neutralising antibodies was 85.3% (83.5-86.9) using the titre cut off >1:20 and 83.9% (82.2-85.6), 70.2% (68.1-72.5) and 54.2% (52.0-56.5) with titres >1:40, >1:80 and >1:160, respectively. These proportions were higher among patients with severe COVID-19 (e.g., titres >1:80, 84.8% [80.0-89.2], >1:160, 74.4% [67.5-79.7]) than those with mild presentation (56.7% [49.9-62.9] and 44.1% [37.3-50.6], respectively) and lowest among asymptomatic infections (28.6% [17.9-39.2] and 10.0% [3.7-20.1], respectively). IgG and neutralising antibody levels correlated poorly. CONCLUSIONS/SIGNIFICANCE: 85% of individuals with proven SARS-CoV-2 infection had detectable neutralising antibodies. This proportion varied with disease severity, study setting, time since infection and the method used to measure antibodies.

Self-sampling of capillary blood for SARS-CoV-2 serology.

Serological testing is emerging as a powerful tool to progress our understanding of COVID-19 exposure, transmission and immune response. Large-scale testing is limited by the need for in-person blood collection by staff trained in venepuncture, and the limited sensitivity of lateral flow tests. Capillary blood self-sampling and postage to laboratories for analysis could provide a reliable alternative. Two-hundred and nine matched venous and capillary blood samples were obtained from thirty nine participants and analysed using a COVID-19 IgG ELISA to detect antibodies against SARS-CoV-2. Thirty eight out of thirty nine participants were able to self-collect an adequate sample of capillary blood (≥ 50 µl). Using plasma from venous blood collected in lithium heparin as the reference standard, matched capillary blood samples, collected in lithium heparin-treated tubes and on filter paper as dried blood spots, achieved a Cohen's kappa coefficient of > 0.88 (near-perfect agreement, 95% CI 0.738-1.000). Storage of capillary blood at room temperature for up to 7 days post sampling did not affect concordance. Our results indicate that capillary blood self-sampling is a reliable and feasible alternative to venepuncture for serological assessment in COVID-19.

IgG Seroconversion and Pathophysiology in Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

We investigated the dynamics of seroconversion in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. During March 29-May 22, 2020, we collected serum samples and associated clinical data from 177 persons in London, UK, who had SARS-CoV-2 infection. We measured IgG against SARS-CoV-2 and compared antibody levels with patient outcomes, demographic information, and laboratory characteristics. We found that 2.0%-8.5% of persons did not seroconvert 3-6 weeks after infection. Persons who seroconverted were older, were more likely to have concurrent conditions, and had higher levels of inflammatory markers. Non-White persons had higher antibody concentrations than those who identified as White; these concentrations did not decline during follow-up. Serologic assay results correlated with disease outcome, race, and other risk factors for severe SARS-CoV-2 infection. Serologic assays can be used in surveillance to clarify the duration and protective nature of humoral responses to SARS-CoV-2 infection.

Global funding trends for malaria research in sub-Saharan Africa: a systematic analysis.

BACKGROUND: Total domestic and international funding for malaria is inadequate to achieve WHO global targets in burden reduction by 2030. We describe the trends of investments in malaria-related research in sub-Saharan Africa and compare investment with national disease burden to identify areas of funding strength and potentially neglected populations. We also considered funding for malaria control. METHODS: Research funding data related to malaria for 1997-2013 were sourced from existing datasets, from 13 major public and philanthropic global health funders, and from funding databases. Investments (reported in US$) were considered by geographical area and compared with data on parasite prevalence and populations at risk in sub-Saharan Africa. 45 sub-Saharan African countries were ranked by amount of research funding received. FINDINGS: We found 333 research awards totalling US$814·4 million. Public health research covered $308·1 million (37·8%) and clinical trials covered $275·2 million (33·8%). Tanzania ($107·8 million [13·2%]), Uganda ($97·9 million [12·0%]), and Kenya ($92·9 million [11·4%]) received the highest sum of research investment and the most research awards. Malawi, Tanzania, and Uganda remained highly ranked after adjusting for national gross domestic product. Countries with a reasonably high malaria burden that received little research investment or funding for malaria control included Central African Republic (ranked 40th) and Sierra Leone (ranked 35th). Congo (Brazzaville) and Guinea had reasonably high malaria mortality, yet Congo (Brazzaville) ranked 38th and Guinea ranked 25th, thus receiving little investment. INTERPRETATION: Some countries receive reasonably large investments in malaria-related research (Tanzania, Kenya, Uganda), whereas others receive little or no investments (Sierra Leone, Central African Republic). Research investments are typically highest in countries where funding for malaria control is also high. Investment strategies should consider more equitable research and operational investments across countries to include currently neglected and susceptible populations. FUNDING: Royal Society of Tropical Medicine and Hygiene and Bill & Melinda Gates Foundation.

Campylobacter bacteremia in London: A 44-year single-center study.

PURPOSE: Campylobacter species are a well-recognized but rare cause of bloodstream infection. METHODS: Here we reviewed 41 cases of Campylobacter bloodstream infection occurring at a single center in London over 44years, comprising 0.2% of all recorded episodes during this time period. RESULTS: Patients had a mean age of 46years and, contrasting with previous reports, nearly 50% of our patients did not have significant comorbidities. Ciprofloxacin resistance increased over the study period with 35% of isolates overall being resistant compared with only 3% exhibiting macrolide resistance. Despite a minority of patients receiving appropriate empirical antibiotic therapy, overall mortality was only 7%. CONCLUSION: Campylobacter bacteremia remains a rare but significant cause of morbidity with a low associated mortality. Underlying immunosuppressive conditions are common but by no means universal. In our setting, macrolides would be favored as empirical agents to treat suspected Campylobacter enteritis, including cases with associated bacteremia.

Investments in cancer research awarded to UK institutions and the global burden of cancer 2000-2013: a systematic analysis.

OBJECTIVES: To systematically categorise cancer research investment awarded to United Kingdom (UK) institutions in the period 2000-2013 and to estimate research investment relative to disease burden as measured by mortality, disability-adjusted life years (DALYs) and years lived with disability (YLDs). DESIGN: Systematic analysis of all open-access data. SETTING AND PARTICIPANTS: Public and philanthropic funding to all UK cancer research institutions, 2000-2013. MAIN OUTCOME MEASURES: Number and financial value of cancer research investments reported in 2013 UK pounds (UK£). Mortality, DALYs and YLDs data were acquired from the Global Burden of Disease Study. A compound metric was adapted to estimate research investment relative to disease burden as measured by mortality, DALYs and YLDs. RESULTS: We identified 4299 funded studies with a total research investment of £2.4 billion. The highest fundings by anatomical sites were haematological, breast, prostate, colorectal and ovarian cancers. Relative to disease burden as determined by a compound metric combining mortality, DALYs and YLDs, gender-specific cancers were found to be highest funded-the five sites that received the most funding were prostate, ovarian, breast, mesothelioma and testicular cancer; the least well-funded sites were liver, thyroid, lung, upper gastrointestinal (GI) and bladder. Preclinical science accounted for 66.2% of award numbers and 62.2% of all funding. The top five areas of primary research focus by funding were pathogenesis, drug therapy, diagnostic, screening and monitoring, women's health and immunology. The largest individual funder was the Medical Research Council. In combination, the five lowest funded site-specific cancers relative to disease burden account for 47.9%, 44.3% and 20.4% of worldwide cancer mortality, DALYs and YLDs. CONCLUSIONS: Research funding for cancer is not allocated according to relative disease burden. These findings are in line with earlier published studies. Funding agencies and industry should openly document their research investments to improve better targeting of research investment.

Research Investments in Global Health: A Systematic Analysis of UK Infectious Disease Research Funding and Global Health Metrics, 1997-2013.

BACKGROUND: Infectious diseases account for a significant global burden of disease and substantial investment in research and development. This paper presents a systematic assessment of research investments awarded to UK institutions and global health metrics assessing disease burden. METHODS: We systematically sourced research funding data awarded from public and philanthropic organisations between 1997 and 2013. We screened awards for relevance to infection and categorised data by type of science, disease area and specific pathogen. Investments were compared with mortality, disability-adjusted life years (DALYs) and years lived with disability (YLD) across three time points. FINDINGS: Between 1997-2013, there were 7398 awards with a total investment of £3.7 billion. An increase in research funding across 2011-2013 was observed for most disease areas, with notable exceptions being sexually transmitted infections and sepsis research where funding decreased. Most funding remains for pre-clinical research (£2.2 billion, 59.4%). Relative to global mortality, DALYs and YLDs, acute hepatitis C, leishmaniasis and African trypanosomiasis received comparatively high levels of funding. Pneumonia, shigellosis, pertussis, cholera and syphilis were poorly funded across all health metrics. Tuberculosis (TB) consistently attracts relatively less funding than HIV and malaria. INTERPRETATION: Most infections have received increases in research investment, alongside decreases in global burden of disease in 2013. The UK demonstrates research strengths in some neglected tropical diseases such as African trypanosomiasis and leishmaniasis, but syphilis, cholera, shigellosis and pneumonia remain poorly funded relative to their global burden. Acute hepatitis C appears well funded but the figures do not adequately take into account projected future chronic burdens for this condition. These findings can help to inform global policymakers on resource allocation for research investment.

Mapping Investments and Published Outputs in Norovirus Research: A Systematic Analysis of Research Funded in the United States and United Kingdom During 1997-2013.

BACKGROUND: Norovirus accounts for a considerable portion of the global disease burden. Mapping national or international investments relating to norovirus research is limited. METHODS: We analyzed the focus and type of norovirus research funding awarded to institutions in the United States and United Kingdom during 1997-2013. Data were obtained from key public and philanthropic funders across both countries, and norovirus-related research was identified from study titles and abstracts. Included studies were further categorized by the type of scientific investigation, and awards related to vaccine, diagnostic, and therapeutic research were identified. Norovirus publication trends are also described using data from Scopus. RESULTS: In total, US and United Kingdom funding investment for norovirus research was £97.6 million across 349 awards; 326 awards (amount, £84.9 million) were received by US institutions, and 23 awards (£12.6 million) were received by United Kingdom institutions. Combined, £81.2 million of the funding (83.2%) was for preclinical research, and £16.4 million (16.8%) was for translational science. Investments increased from £1.7 million in 1997 to £11.8 million in 2013. Publication trends showed a consistent temporal increase from 48 in 1997 to 182 in 2013. CONCLUSIONS: Despite increases over time, trends in US and United Kingdom funding for norovirus research clearly demonstrate insufficient translational research and limited investment in diagnostics, therapeutics, or vaccine research.

Non-surgical interventions for pelvic organ prolapse in rural Nepal: a prospective monitoring and evaluation study.

OBJECTIVES: Pelvic organ prolapse (POP) is a major cause of morbidity in Nepal, particularly affecting women in the rural communities. Women with POP in Nepal may suffer from symptoms for decades. At present, the Government of Nepal advocates surgical intervention but access to surgical care is inadequate. This report evaluated the feasibility of a non-surgical public health programme in rural Nepal, and describes risk factors associated with POP in this setting. DESIGN: Prospective monitoring and evaluation study of a new public health programme. SETTING: Baglung district, rural Nepal. PARTICIPANTS: Women with gynaecological symptoms of POP. MAIN OUTCOME MEASURES: Risk factors for disease progression were assessed using Fisher's exact test, Pearson's χ(2)-test and logistic regression analysis. RESULTS: Of the 74 women included in this analysis, 70.8% were diagnosed with stage 2 POP or greater. The majority of women did not have any further children following the onset of POP symptoms (63.5%). Duration of symptoms ranged from 2 months to 60 years, with 73.4% of women suffering for over 5 years and 28.4% suffering for over 20 years. Univariate analyses identified age at screening, age at onset of symptoms, the duration of symptoms and an associated rectocele as factors associated with increasing POP severity (p < 0.05). Kegel exercises were taught to 25 (33.8%) women with POP and ring pessaries were offered to 47 (63.5%) women with POP. CONCLUSIONS: Non-surgical interventions may provide an opportunity to address the significant burden of POP in rural Nepal.

Comparing research investment to United Kingdom institutions and published outputs for tuberculosis, HIV and malaria: a systematic analysis across 1997-2013.

BACKGROUND: The "Unfinished Agenda" of infectious diseases is of great importance to policymakers and research funding agencies that require ongoing research evidence on their effective management. Journal publications help effectively share and disseminate research results to inform policy and practice. We assess research investments to United Kingdom institutions in HIV, tuberculosis and malaria, and analyse these by numbers of publications and citations and by disease and type of science. METHODS: Information on infection-related research investments awarded to United Kingdom institutions across 1997-2010 were sourced from funding agencies and individually categorised by disease and type of science. Publications were sourced from the Scopus database via keyword searches and filtered to include only publications relating to human disease and containing a United Kingdom-based first and/or last author. Data were matched by disease and type of science categories. Investment (United Kingdom pounds) and publications were compared to generate an 'investment per publication' metric; similarly, an 'investment per citation' metric was also developed as a measure of the usefulness of research. RESULTS: Total research investment for all three diseases was £1.4 billion, and was greatest for HIV (£651.4 million), followed by malaria (£518.7 million) and tuberculosis (£239.1 million). There were 17,271 included publications, with 9,322 for HIV, 4,451 for malaria, and 3,498 for tuberculosis. HIV publications received the most citations (254,949), followed by malaria (148,559) and tuberculosis (100,244). According to UK pound per publication, tuberculosis (£50,691) appeared the most productive for investment, compared to HIV (£61,971) and malaria (£94,483). By type of science, public health research was most productive for HIV (£27,296) and tuberculosis (£22,273), while phase I-III trials were most productive for malaria (£60,491). According to UK pound per citation, tuberculosis (£1,797) was the most productive area for investment, compared to HIV (£2,265) and malaria (£2,834). Public health research was the most productive type of science for HIV (£2,265) and tuberculosis (£1,797), whereas phase I-III trials were most productive for malaria (£1,713). CONCLUSIONS: When comparing total publications and citations with research investment to United Kingdom institutions, tuberculosis research appears to perform best in terms of efficiency. There were more public health-related publications and citations for HIV and tuberculosis than other types of science. These findings demonstrate the diversity of research funding and outputs, and provide new evidence to inform research investment strategies for policymakers, funders, academic institutions, and healthcare organizations.

Mapping pneumonia research: A systematic analysis of UK investments and published outputs 1997-2013.

BACKGROUND: The burden of pneumonia continues to be substantial, particularly among the poorest in global society. We describe here the trends for UK pneumonia R&D investment and published outputs, and correlate with 2013 global mortality. METHODS: Data related to awards to UK institutions for pneumonia research from 1997 to 2013 were systematically sourced and categorised by disease area and type of science. Investment was compared to mortality figures in 2010 and 2013 for pneumonia, tuberculosis and influenza. Investment was also compared to publication data. RESULTS: Of all infectious disease research between 2011 and 2013 (£917.0 million), £28.8 million (3.1%) was for pneumonia. This was an absolute and proportionate increase from previous time periods. Translational pneumonia research (33.3%) received increased funding compared with 1997-2010 where funding was almost entirely preclinical (87.5%, here 30.9%), but high-burden areas such as paediatrics, elderly care and antimicrobial resistance received little investment. Annual investment remains volatile; publication temporal trends show a consistent increase. When comparing investment to global burden with a novel 'investment by mortality observed' metric, tuberculosis (£48.36) and influenza (£484.21) receive relatively more funding than pneumonia (£43.08), despite investment for pneumonia greatly increasing in 2013 compared to 2010 (£7.39). Limitations include a lack of private sector data and the need for careful interpretation of the comparisons with burden, plus categorisation is subjective. CONCLUSIONS: There has been a welcome increase for pneumonia funding awarded to UK institutions in 2011-2013 compared with 1997-2010, along with increases for more translational research. Published outputs relating to pneumonia rose steadily from 1997 to 2013. Investment relative to mortality for pneumonia has increased, but it remains low compared to other respiratory infections and clear inequities remain. Analyses that measure investments in pneumonia can provide an insight into funding trends and research gaps. RESEARCH IN CONTEXT: Pneumonia continues to be a high-burden illness around the globe. This paper shows that although research funding is increasing in the UK (between 1997 and 2013), it remains poorly funded compared to other important respiratory infectious diseases such as tuberculosis and influenza. Publications about pneumonia have been steadily increasing over time, indicating continuing academic and clinical interest in the topic. Though global mortality of pneumonia is declining, it should still be an area of high priority for funders, policymakers and researchers.

Investments in sexually transmitted infection research, 1997-2013: a systematic analysis of funding awarded to UK institutions.

BACKGROUND: We report the first study that analyses public and philanthropic investments awarded to UK institutions for research related to sexually transmitted infections (STIs). METHODS: We systematically searched award data from the major funders for information on all infectious disease research funding awarded in 1997-2013. The STI-related projects were identified and categorised by pathogen, disease and type of science along the research pipeline from preclinical to translational research. FINDINGS: We identified 7393 infection-related awards with total investment of GBP 3.5 billion. Of these, 1238 awards (16.7%) covering funding of GBP 719.1 million (20.5%) were for STI research. HIV as an STI received GBP 465 million across 719 studies; non-HIV STIs received GBP 139 million across 378 studies. The Medical Research Council provided greatest investment (GBP 193 million for HIV, GBP 45 million for non-HIV STIs). Preclinical awards totalled GBP 233 million (37.1%), whilst translational research received GBP 286 million (39.7%). Substantial proportions of HIV investment addressed global health research (GBP 265 million), vaccinology (GBP 110 million) and therapeutics (GBP 202 million). For other STIs, investments focused on diagnostics (GBP 45 million) and global health (GBP 27 million). Human Papilloma Virus research received GBP 58 million and chlamydia GBP 24 million. Funding for non-HIV STIs has declined in the three most recent years of this data set. CONCLUSIONS: The investment for HIV research awarded to UK institutions correlates with the high global burden, but other STIs are relatively neglected, including gonorrhoea and syphilis. Future STI funding should be better aligned with burden while addressing the emerging risk of antimicrobial resistance in Neisseria gonorrhoeae and outbreaks of other pathogens.

Systematic analysis of funding awarded to institutions in the United Kingdom for infectious disease research, 1997-2010.

OBJECTIVES: This study aimed to assess the research investments made to UK institutions for all infectious disease research and identify the direction of spend by institution. DESIGN: Systematic analysis. Databases and websites were systematically searched for information on relevant studies funded for the period 1997-2010. SETTING: UK institutions carrying out infectious disease research. PARTICIPANTS: None. MAIN OUTCOME MEASURES: Twenty academic institutions receiving greatest sum investments across infection are included here, also NHS sites, Sanger Institute, Health Protection Agency and the Medical Research Council. We measured total funding, median award size, disease areas and position of research along the R&D value chain. RESULTS: Included institutions accounted for £2.1 billion across 5003 studies. Imperial College and University of Oxford received the most investment. Imperial College led the most studies. The Liverpool and London Schools of Tropical Medicine had highest median award size, whereas the NHS sites combined had many smaller studies. Sum NHS funding appears to be declining over time, whilst university income is relatively stable. Several institutions concentrate almost exclusively on pre-clinical research. In some areas, there is clearly a leading institution, e.g. Aberdeen and mycology research or UCL and antimicrobial resistance. CONCLUSION: UK institutions carry out research across a wide range of infectious disease areas. This analysis can identify centres of excellence and help inform future resource allocation for research priorities. Institutions can use this analysis for establishing expertise within their groups, identifying external collaborators and informing local research strategy.