Impact and Cost-Effectiveness of Point-Of-Care CD4 Testing on the HIV Epidemic in South Africa.

Rapid diagnostic tools have been shown to improve linkage of patients to care. In the context of infectious diseases, assessing the impact and cost-effectiveness of such tools at the population level, accounting for both direct and indirect effects, is key to informing adoption of these tools. Point-of-care (POC) CD4 testing has been shown to be highly effective in increasing the proportion of HIV positive patients who initiate ART. We assess the impact and cost-effectiveness of introducing POC CD4 testing at the population level in South Africa in a range of care contexts, using a dynamic compartmental model of HIV transmission, calibrated to the South African HIV epidemic. We performed a meta-analysis to quantify the differences between POC and laboratory CD4 testing on the proportion linking to care following CD4 testing. Cumulative infections averted and incremental cost-effectiveness ratios (ICERs) were estimated over one and three years. We estimated that POC CD4 testing introduced in the current South African care context can prevent 1.7% (95% CI: 0.4% - 4.3%) of new HIV infections over 1 year. In that context, POC CD4 testing was cost-effective 99.8% of the time after 1 year with a median estimated ICER of US$4,468/DALY averted. In healthcare contexts with expanded HIV testing and improved retention in care, POC CD4 testing only became cost-effective after 3 years. The results were similar when, in addition, ART was offered irrespective of CD4 count, and CD4 testing was used for clinical assessment. Our findings suggest that even if ART is expanded to all HIV positive individuals and HIV testing efforts are increased in the near future, POC CD4 testing is a cost-effective tool, even within a short time horizon. Our study also illustrates the importance of evaluating the potential impact of such diagnostic technologies at the population level, so that indirect benefits and costs can be incorporated into estimations of cost-effectiveness

Association between MAPT polymorphism but not APOE promoter and elite rugby athlete status

INTRODUCTION: Incidence and outcomes of concussions have been hypothesised to be genetically influenced. The APOE Promoter G219T (rs405509) polymorphism has been associated with differential promoter activity and unfavourable outcomes after traumatic brain injury. The TT genotype is associated with a 3-fold greater risk of multiple concussions. The TT genotype of MAPT (rs10445337) has also been associated with poorer outcomes after concussion. Rugby has one of the highest incidences of concussion in sport, so it was hypothesised that APOE Promoter TT and MAPT TT genotypes would be less prevalent in elite rugby athletes because those genotypes, previously associated with increased risk, would be less compatible with achieving elite athlete status. METHODS: Participants were from the RugbyGene project, comprising elite Caucasian male rugby athletes (n = 528; mean (standard deviation) height 1.85 (0.07) m, mass 101 (14) kg, age 29 (7) yr), including 420 rugby union (RU) athletes that for some analyses were divided into forwards and backs and 108 rugby league (RL) athletes. Non-athletes were 592 Caucasian men and women (57% male, height 1.72 (0.10) m, mass 74 (14) kg, age 31 (7) yr). PCR of genomic DNA was used to determine genotypes using TaqMan probes, then groups were compared using χ2 and odds ratio (OR) statistics. RESULTS: All genotype data were in Hardy-Weinberg equilibrium. For MAPT (rs10445337), the risk genotype (TT) was underrepresented in rugby athletes (60%) compared to non-athletes (66%), CT more common in rugby athletes (34%) than non-athletes (29%) and little difference in CC genotype frequencies (χ2 = 7.092, P = 0.029; TT genotype frequency OR = 0.80, 95% confidence intervals (CI) = 0.62-1.02). There were no differences in MAPT (rs10445337) genotype frequencies between RU forwards and backs. For APOE Promoter G219T (rs405509), there were no differences in genotype frequencies between all athletes (RU and RL) and non-athletes (27% TT genotype in players and non-athletes), nor between RU forwards and backs. CONCLUSION: The MAPT (rs10445337) TT genotype is 6% less common in elite rugby athletes than non-athletes. Therefore, carrying at least one rs10445337 C allele appears to increase the probability of sustained career success in the high-risk concussion environment of elite rugby, perhaps via a greater ability to recover from concussions.Peer reviewe

Association of MMP3 but not TIMP2 gene variants with elite rugby player status and rugby code

Introduction: Achilles tendon pathology and anterior cruciate ligament rupture are multifactorial conditions for which genetic risk factors have been identified. Single nucleotide polymorphisms (SNPs) within the MMP3 (rs591058, rs679620, rs650108) and TIMP2 (rs4789932) genes have previously been associated with tendon and ligament pathologies. Although not entirely clear, prior literature indicates the risk alleles for Achilles tendon pathology as T (rs591058), G (rs679620) and A (rs650108) for MMP3. However, prior evidence regarding TIMP2 is equivocal. MMP3 is considered an essential regulator of matrix degradation and remodelling within diseased and normal musculoskeletal soft tissues. TIMP2 maintains homeostasis in the extracellular matrix in part by inhibiting MMP function. Given the high incidence and severity of tendon and ligament injuries in elite rugby athletes, we hypothesised that the aforementioned SNPs would be associated with career success. Methods: Participants from the RugbyGene project were elite Caucasian male rugby athletes (n = 566; mean (standard deviation) height 1.85 (0.07) m, mass 101 (14) kg, age 29 (7) yr), including 420 rugby union (RU) athletes that for some analyses were divided into forwards and backs and 120 rugby league (RL) athletes. Non-athletes were 589 Caucasian men and women (n = 589, 57% male, height 1.72 (0.10) m, mass 74 (14) kg, age 31 (7) yr). PCR of genomic DNA was used to determine genotypes using TaqMan probes, then groups were compared using Χ2 and odds ratio (OR) statistics. Results: As hypothesized, the MMP3 rs591058 risk genotype (TT) was less frequent in rugby athletes (28%) compared to non-athletes (33%) (Χ2 = 7.265, P = 0.026; OR = 1.18, 95% confidence intervals (CI) = 0.86-1.63). No differences were found for MMP3 rs679620, rs650108 or TIMP2 rs4789932 between rugby athletes and non-athletes. When RL athletes were compared to non-athletes, the risk genotype (TT) of MMP3 rs591058 was underrepresented in RL athletes (19%) compared to non-athletes (33%). The MMP3 rs679620 ‘protective’ allele (C) was more frequent in RL athletes (55%) compared to non-athletes (48%) (OR = 1.3, 95% CI = 0.98-1.74). However, for MMP3 rs650108 the ‘risk’ allele (A) was overrepresented in RL athletes (32%) compared to non-athletes (26%). There were no genotype differences for any gene variant between RU athletes and non-athletes. The ‘risk’ allele (T) of the MMP3 rs679629 polymorphism and the ‘protective’ allele (G) of the MMP3 rs650108 polymorphism were less common in RL (45%, 68%, respectively) than RU athletes (54%, 76%, respectively). Conclusion: We provide evidence for elite rugby athletes possessing a protective genetic profile regarding tendon and ligament injury risk. Notably, a less frequent rs591058 TT genotype in athletes suggests a lower risk of injury could therefore enhance career success in rugby. Furthermore, RL players appear to have differing genetic characteristics compared to their RU counterparts, which might reflect some differences in physiological demands between codes.Peer reviewedFinal Published versio

Scaling up prevention and treatment towards the elimination of hepatitis C: a global mathematical model

Background The revolution in hepatitis C virus (HCV) treatment through the development of direct-acting antivirals (DAAs) has generated international interest in the global elimination of the disease as a public health threat. In 2017, this led WHO to establish elimination targets for 2030. We evaluated the impact of public health interventions on the global HCV epidemic and investigated whether WHO's elimination targets could be met. Methods We developed a dynamic transmission model of the global HCV epidemic, calibrated to 190 countries, which incorporates data on demography, people who inject drugs (PWID), current coverage of treatment and prevention programmes, natural history of the disease, HCV prevalence, and HCV-attributable mortality. We estimated the worldwide impact of scaling up interventions that reduce risk of transmission, improve access to treatment, and increase screening for HCV infection by considering six scenarios: no change made to existing levels of diagnosis or treatment; sequentially adding the following interventions: blood safety and infection control, PWID harm reduction, offering of DAAs at diagnosis, and outreach screening to increase the number diagnosed; and a scenario in which DAAs are not introduced (ie, treatment is only with pegylated interferon and oral ribavirin) to investigate the effect of DAA use. We explored the effect of varying the coverage or impact of these interventions in sensitivity analyses and also assessed the impact on the global epidemic of removing certain key countries from the package of interventions. Findings By 2030, interventions that reduce risk of transmission in the non-PWID population by 80% and increase coverage of harm reduction services to 40% of PWID could avert 14·1 million (95% credible interval 13·0–15·2) new infections. Offering DAAs at time of diagnosis in all countries could prevent 640 000 deaths (620 000–670 000) from cirrhosis and liver cancer. A comprehensive package of prevention, screening, and treatment interventions could avert 15·1 million (13·8–16·1) new infections and 1·5 million (1·4–1·6) cirrhosis and liver cancer deaths, corresponding to an 81% (78–82) reduction in incidence and a 61% (60–62) reduction in mortality compared with 2015 baseline. This reaches the WHO HCV incidence reduction target of 80% but is just short of the mortality reduction target of 65%, which could be reached by 2032. Reducing global burden depends upon success of prevention interventions, implemention of outreach screening, and progress made in key high-burden countries including China, India, and Pakistan. Interpretation Further improvements in blood safety and infection control, expansion or creation of PWID harm reduction services, and extensive screening for HCV with concomitant treatment for all are necessary to reduce the burden of HCV. These findings should inform the ongoing global action to eliminate the HCV epidemic

Denitrification and inference of nitrogen sources in the karstic Floridan Aquifer

Aquifer denitrification is among the most poorly constrained fluxes in global and regional nitrogen budgets. The few direct measurements of denitrification in groundwaters provide limited information about its spatial and temporal variability, particularly at the scale of whole aquifers. Uncertainty in estimates of denitrification may also lead to underestimates of its effect on isotopic signatures of inorganic N, and thereby confound the inference of N source from these data. In this study, our objectives are to quantify the magnitude and variability of denitrification in the Upper Floridan Aquifer (UFA) and evaluate its effect on N isotopic signatures at the regional scale. Using dual noble gas tracers (Ne, Ar) to generate physical predictions of N<sub>2</sub> gas concentrations for 112 observations from 61 UFA springs, we show that excess (i.e. denitrification-derived) N<sub>2</sub> is highly variable in space and inversely correlated with dissolved oxygen (O<sub>2</sub>). Negative relationships between O<sub>2</sub> and δ<sup>15</sup>N<sub>NO3</sub> across a larger dataset of 113 springs, well-constrained isotopic fractionation coefficients, and strong <sup>15</sup>N:<sup>18</sup>O covariation further support inferences of denitrification in this uniquely organic-matter-poor system. Despite relatively low average rates, denitrification accounted for 32 % of estimated aquifer N inputs across all sampled UFA springs. Back-calculations of source δ<sup>15</sup>N<sub>NO3</sub> based on denitrification progression suggest that isotopically-enriched nitrate (NO<sub>3</sub><sup>–</sup>) in many springs of the UFA reflects groundwater denitrification rather than urban- or animal-derived inputs

THE BALL ORIENTATIONS USED BY PLACE KICKERS AT THE 2019 RUGBY WORLD CUP AND THEIR ASSOCIATIONS WITH KICK SUCCESS

The outcomes of place kicks can have a large impact on Rugby Union match results. This study investigated the ball orientations used in place kicking and their potential implications for success. All 416 place kicks from the 2019 Rugby World Cup were grouped into one of three ball orientation categories, and predicted odds of success were calculated for each category using a binomial logistic regression which accounted for situational factors known to affect performance outcome. Kicks taken using a slanted orientation (n = 152) had the greatest odds of success (90.0%) when taken from the mean tournament distance (29.7 m), compared to a near vertical (n = 116) orientation (84.4%), and near horizontal (n = 148) orientation (86.8%). A further investigation into the impact characteristics associated with each ball orientation is required to better understand the relative merits of each

Effect of cap thickness on InAs/InP quantum dots grown by droplet epitaxy in metal–organic vapor phase epitaxy

InAs quantum dots (QDs) are grown on bare InP(001) via droplet epitaxy (DE) in metal–organic vapor phase epitaxy (MOVPE). Capping layer engineering, used to control QD size and shape, is explored for DE QDs in MOVPE. The method allows for the tuning of the QD emission over a broad range of wavelengths, ranging from the O- to the L-band. The effect of varying the InP capping layer is investigated optically by macro- and micro-photoluminescence (PL, µPL) and morphologically by transmission electron microscopy (TEM). A strong 500 nm blueshift of the QD emission wavelength is observed when the capping layer is reduced from 20 to 8 nm, which is reflected by a clear size reduction of the buried QDs