Investing in health R&D: where we are, what limits us, and how to make progress in Africa.

Global research and development (R&D) pipelines for diseases that disproportionately affect African countries appear to be inadequate, with governments struggling to prioritise investment in R&D. This article provides insights into the sources of investment in health science research, available research capacity and level of research output in Africa. The African region comprises 15% of the world's population, yet only accounted for 1.1% of global investments in R&D in 2016. There were substantial disparities within the continent, with Egypt, Nigeria and South Africa contributing 65.7% of the total R&D spending. In most countries of the Organisation for Economic Co-operation and Development, the largest source of R&D funding is the private sector. R&D in Africa is mainly funded by the public sector, with significant proportions of financing in many countries coming from international funding. Challenges that limit private sector investment include unstable political environments, poor governance and corruption. Evidence suggests various research output and research capacity limitations in Africa when considering a global context. Metrics that reflect this include university rankings, number of researchers, number of publications, clinical trials networks and pharmaceutical manufacturing capacity. Within the continent there are substantial regional disparities. Incentivising investment is crucial to foster current and future research output and research capacity. This paper outlines some of the many commendable initiatives under way. Innovative and collaborative financing mechanisms can stimulate further investment. Given the vast inequalities across Africa in R&D, strategies need to reflect the different capacities of countries to address this disparity.

Incentivising innovation in antibiotic drug discovery and development: progress, challenges and next steps.

Political momentum and funding for combatting antimicrobial resistance (AMR) continues to build. Numerous major international and national initiatives aimed at financially incentivising the research and development (R&D) of antibiotics have been implemented. However, it remains unclear how to effectively strengthen the current set of incentive programmes to further accelerate antibiotic innovation. Based on a literature review and expert input, this study first identifies and assesses the major international, European Union, US and UK antibiotic R&D funding programmes. These programmes are then evaluated across market and public health criteria necessary for comprehensively improving the antibiotic market. The current set of incentive programmes are an important initial step to improving the economic feasibility of antibiotic development. However, there appears to be a lack of global coordination across all initiatives, which risks duplicating efforts, leaving funding gaps in the value chain and overlooking important AMR goals. This study finds that incentive programmes are overly committed to early-stage push funding of basic science and preclinical research, while there is limited late-stage push funding of clinical development. Moreover, there are almost no pull incentives to facilitate transition of antibiotic products from early clinical phases to commercialisation, focus developer concentration on the highest priority antibiotics and attract large pharmaceutical companies to invest in the market. Finally, it seems that antibiotic sustainability and patient access requirements are poorly integrated into the array of incentive mechanisms.

Contemporary cardiac surgery for adults with congenital heart disease.

OBJECTIVE: Advances in early management of congenital heart disease (CHD) have led to an exponential growth in adults with CHD (ACHD). Many of these patients require cardiac surgery. This study sought to examine outcome and its predictors for ACHD cardiac surgery. METHODS: This is an observational cohort study of prospectively collected data on 1090 consecutive adult patients with CHD, undergoing 1130 cardiac operations for CHD at the Royal Brompton Hospital between 2002 and 2011. Early mortality was the primary outcome measure. Midterm to longer-term survival, cumulative incidence of reoperation, other interventions and/or new-onset arrhythmia were secondary outcome measures. Predictors of early/total mortality were identified. RESULTS: Age at surgery was 35±15 years, 53% male, 52.3% were in New York Heart Association (NYHA) class I, 37.2% in class II and 10.4% in class III/IV. Early mortality was 1.77% with independent predictors NYHA class ≥ III, tricuspid annular plane systolic excursion (TAPSE) <15 mm and female gender. Over a mean follow-up of 2.8±2.6 years, 46 patients died. Baseline predictors of total mortality were NYHA class ≥ III, TAPSE <15 mm and non-elective surgery. The number of sternotomies was not independently associated with neither early nor total mortality. At 10 years, probability of survival was 94%. NYHA class among survivors was significantly improved, compared with baseline. CONCLUSIONS: Contemporary cardiac surgery for ACHD performed at a single, tertiary reference centre with a multidisciplinary approach is associated with low mortality and improved functional status. Also, our findings emphasise the point that surgery should not be delayed because of reluctance to reoperate only.

Association of haemodynamic changes measured by serial central venous saturation during ultrafiltration for acutely decompensated heart failure with diuretic resistance and change in renal function.

BACKGROUND: Patients with acute decompensated heart failure with diuretic resistance (ADHF-DR) have a poor prognosis. The aim of this study was to assess in patients with ADHF-DR, whether haemodynamic changes during ultrafiltration (UF) are associated with changes in renal function (Δcreatinine) and whether Δcreatinine post UF is associated with mortality. METHODS: Seventeen patients with ADHF-DR underwent 20 treatments with UF. Serial bloods (4-6 hourly) from the onset of UF treatment were measured for renal function, electrolytes and central venous saturation (CVO2). Univariate and multivariate analysis were performed to assess the relationship between changes in markers of haemodynamics [heart rate (HR), systolic blood pressure (SBP), packed cell volume (PCV) and CVO2] and Δcreatinine. Patients were followed up and mortality recorded. Cox-regression survival analysis was performed to determine covariates associated with mortality. RESULTS: Renal function worsened after UF in 17 of the 20 UF treatments (baseline vs. post UF creatinine: 164±58 vs. 185±69µmol/l, P<0.01). ΔCVO2 was significantly associated with Δcreatinine [ß-coefficient of -1.3 95%CI (-1.8 to -0.7), P<0.001] and remained significantly associated with Δcreatinine after considering changes in SBP, HR and PCV [P<0.001]. Ten (59%) patients died at 1-year and 15(88%) by 2-years. Δcreatinine was independently associated with mortality (adjusted-hazard ratio 1.03 (1.01 to 1.07) per 1µmol/l increase in creatinine; P=0.02). CONCLUSIONS: Haemodynamic changes during UF as measured by the surrogate of cardiac output was associated with Δcreatinine. Worsening renal function at end of UF treatment occurred in the majority of patients and was associated with mortality.

Targeting innovation in antibiotic drug discovery and development: the need for a One Health – One Europe – One World Framework

Antimicrobial resistance is a global crisis that threatens public health and modern medicine. The discovery and development of novel antibiotic products are critical components in combating it. Many international, European Union and national initiatives address the scientific, regulatory and economic barriers to antibiotic innovation. This study identifies, reviews and critically assesses these initiatives, and provides policy recommendations for improving the global and European agendas for research and development of antibiotics.

Bicarbonate-dependent pH(i) regulation by chondrocytes within the superficial zone of bovine articular cartilage.

Control of chondrocyte pH (pH(i)) determines articular cartilage matrix metabolism. However, the transporters of chondrocytes in situ throughout cartilage zones are unclear, and we tested the hypothesis that chondocytes within the superficial zone (SZ) utilise a HCO(3) (-)-dependent system absent from other zones. Imaging of single BCECF-labelled cells was used to monitor the pH(i) of in situ chondrocytes within the cartilage zones, and also that of cells isolated from the SZ or full depth (FD) explants. Resting pH(i) and intrinsic buffering power (beta(i)) in HEPES-buffered saline was not different between SZ and DZ cells, however the pH(i) of SZ chondrocytes was lower in HCO(3) (-) saline. Ammonium pre-pulse was used to acid-load cells and pH(i) recovery by in situ or isolated SZ chondrocytes shown to be totally dependent on HCO(3) (-). pH(i) recovery rate was significantly (P < 0.05) greater for in situ cells, suggesting that isolation damaged the HCO(3) (-)-dependent system. Recovery of pH(i) by in situ cells was blocked by the anion transport inhibitor DIDS, and partially inhibited by EIPA probably non-specifically. Recovery of pH(i) by acidified MZ or DZ cells or those isolated from FD explants was not affected by HCO(3) (-) (P > 0.05). Na(+)-dependent HCO(3) (-)-(NBC) transporters were identified in SZ chondrocytes by fluorescence immunohistochemistry suggesting that this system might account for the HCO(3) (-)-dependent recovery of pH(i). Bovine articular cartilage chondrocytes possess a HCO(3) (-)-dependent transporter which plays a key role in pH(i) regulation in cells in the SZ, but not in chondrocytes within deeper cartilage zones.