Quantification of Biopharmaceutically Relevant Nonionic Surfactant Excipients Using Benchtop qNMR.

Nonionic surfactant excipients (NISEs) are commonly added to biologics formulations to mitigate the effects of stress incurred by the active biotherapeutic during manufacturing, transport, and storage. During manufacturing, NISEs are added by dilution of a stock solution directly into a protein formulation, and their accurate addition is critical in maintaining the quality and integrity of the drug product and thus ensuring patient safety. This is especially true for the common NISEs, polysorbates 20 and 80 (PS20 and PS80, respectively) and poloxamer 188 (P188). With the increasing diversity of biologic modalities within modern pharmaceutical pipelines, there is thus a critical need to develop and deploy convenient and user-accessible analytical techniques that can rapidly and reliably quantify these NISEs under biopharmaceutically relevant conditions. We thus pursued 60 MHz benchtop quantitative NMR (qNMR) as a nondestructive and user-friendly analytical technique for the quantification of PS20, PS80, and P188 under such conditions. We demonstrated the ability of benchtop qNMR (1) to quantify simulated PS20, PS80, and P188 stock solutions representative of those used during the drug substance (DS) formulation step in biomanufacturing and (2) to quantify these NISEs at and below their target concentrations (≤0.025% w/v) directly in biologics formulations containing histidine, sucrose, and one of three biotherapeutic modalities (monoclonal antibody, antibody-drug conjugate, and Fc-fusion protein). Our results demonstrate that benchtop qNMR offers a fit-for-purpose, reliable, user-friendly, and green analytical route by which NISE of interest to the biopharmaceutical industry may be readily and reliably quantified. We conclude that benchtop qNMR has the potential to be applied to other excipient formulation components in the presence of various biological modalities as well as the potential for routine integration within analytical and QC laboratories across pharmaceutical development and manufacturing sites.

Regioconvergent Nucleophilic Substitutions with Morita-Baylis-Hillman Fluorides.

Lithium iodide enables regioconvergent C-F bond functionalization of isomeric Morita-Baylis-Hillman fluorides with carbon, sulfur, and nitrogen nucleophiles. The defluorinative carbon-carbon and carbon-heteroatom bond formations give multifunctional compounds in excellent yields and with good to high diastereoselectivities at room temperature. The possibility of catalytic enantioselective allylation is also discussed.

Beyond 10-Year Risk: A Cost-Effectiveness Analysis of Statins for the Primary Prevention of Cardiovascular Disease.

BACKGROUND: Cholesterol guidelines typically prioritize primary prevention statin therapy on the basis of 10-year risk of cardiovascular disease. The advent of generic pricing may justify expansion of statin eligibility. Moreover, 10-year risk may not be the optimal approach for statin prioritization. We estimated the cost-effectiveness of expanding preventive statin eligibility and evaluated novel approaches to prioritization from a Scottish health sector perspective. METHODS: A computer simulation model predicted long-term health and cost outcomes in Scottish adults ≥40 years of age. Epidemiologic analysis was completed using the Scottish Heart Health Extended Cohort, Scottish Morbidity Records, and National Records of Scotland. A simulation cohort was constructed with data from the Scottish Health Survey 2011 and contemporary population estimates. Treatment and cost inputs were derived from published literature and health service cost data. The main outcome measure was the lifetime incremental cost-effectiveness ratio, evaluated as cost (2020 GBP) per quality-adjusted life-year (QALY) gained. Three approaches to statin prioritization were analyzed: 10-year risk scoring using the ASSIGN score, age-stratified risk thresholds to increase treatment rates in younger individuals, and absolute risk reduction (ARR)-guided therapy to increase treatment rates in individuals with elevated cholesterol levels. For each approach, 2 policies were considered: treating the same number of individuals as those with an ASSIGN score ≥20% (age-stratified risk threshold 20, ARR 20) and treating the same number of individuals as those with an ASSIGN score ≥10% (age-stratified risk threshold 10, ARR 10). RESULTS: Compared with an ASSIGN score ≥20%, reducing the risk threshold for statin initiation to 10% expanded eligibility from 804 000 (32% of adults ≥40 years of age without CVD) to 1 445 500 individuals (58%). This policy would be cost-effective (incremental cost-effectiveness ratio, £12 300/QALY [95% CI, £7690/QALY-£26 500/QALY]). Incremental to an ASSIGN score ≥20%, ARR 20 produced ≈8800 QALYs and was cost-effective (£7050/QALY [95% CI, £4560/QALY-£10 700/QALY]). Incremental to an ASSIGN score ≥10%, ARR 10 produced ≈7950 QALYs and was cost-effective (£11 700/QALY [95% CI, £9250/QALY-£16 900/QALY]). Both age-stratified risk threshold strategies were dominated (ie, more expensive and less effective than alternative treatment strategies). CONCLUSIONS: Generic pricing has rendered preventive statin therapy cost-effective for many adults. ARR-guided therapy is more effective than 10-year risk scoring and is cost-effective.

Dynamic Covalent Optical Chirality Sensing with a Sterically Encumbered Aminoborane.

A sterically encumbered aminoborane sensor is introduced and used for quantitative stereochemical analysis of monoalcohols, diols and amino alcohols. The small-molecule probe exhibits a rigid ortho-substituted arene scaffold with a proximate boron binding site and a triarylamine circular dichroism (CD) reporter unit which proved to be crucial for the observed chiroptical signal induction. Coordination of the chiral target molecule produces strong Cotton effects and UV changes that are readily correlated to its absolute configuration, enantiomeric composition and concentration to achieve comprehensive stereochemical analysis within a 5 % absolute error margin. The sensing method was successfully applied in the chromatography-free analysis of less than one milligram of a crude asymmetric reaction mixture and the advantages of this chiroptical sensing approach, which is amenable to high-throughput experimentation equipment and automation, over traditional methods is discussed.

Inhibition of Ubiquitin-Specific Protease-13 Improves Behavioral Performance in Alpha-Synuclein Expressing Mice.

Ubiquitin-Specific Protease-13 (USP13) promotes protein de-ubiquitination. USP13 levels are upregulated in post-mortem Parkinson's disease, whereas USP13 knockdown via shRNA reduces alpha-synuclein levels in animal models. We studied the role of USP13 in knockout mice expressing lentiviral human alpha-synuclein and investigated the impact of a small molecule inhibitor of USP13, BK50118-C, on alpha-synuclein pathology and animal behavior. Alpha-synuclein was expressed unilaterally in substantia nigra (SN) of USP13 deficient mice that were treated with a daily intraperitoneal injection of 100 mg/kg BK50118-C or DMSO for four consecutive weeks, and behavioral and functional assays were performed. Wild-type USP13+/+ mice expressing lentiviral human alpha-synuclein showed motor and behavioral defects that were not seen in partially (USP13+/-) or completely (USP13-/-) deficient USP13 mice. BK50118-C displayed a wide and favorable therapeutic dose range in vivo. Treatment with BK50118-C significantly reduced ubiquitinated alpha-synuclein, increased dopamine levels, and improved motor and behavioral symptoms in wild-type (USP13+/+), but not USP13 deficient, mice. These data suggest that USP13 is critical to the neuropathology of alpha-synuclein, whereas a novel small molecule inhibitor of USP13 is a potential therapeutic agent of alpha-synucleinopathies.

Trial-Based Economic Evaluations of Supported Employment for Adults with Severe Mental Illness: A Systematic Review.

To identify, appraise, and summarize outcomes reported in trial-based economic evaluations of Individual Placement and Support programs for adults with severe mental illness. Six databases were searched, including Medline, PsycINFO, CINAHL, Cochrane, Scopus, and EconLit. Inclusion criteria were trial-based, full economic evaluations comparing Individual Placement and Support programs to traditional vocational rehabilitation programs for adults 18 years and older with severe mental illness. Study quality was appraised using the Consolidated Health Economic Evaluation Reporting Standards statement. Of the 476 articles identified in the database search, seven were included in the review. Studies conducted across Europe (n = 4) and Japan (n = 1) suggested that Individual Placement and Support may be a cost-effective alternative to traditional vocational rehabilitation programs. Two studies conducted in the United States demonstrated that Individual Placement and Support led to better vocational outcomes, but at neutral or higher costs than traditional vocational rehabilitation, depending on the benefit measure used. Trial-based economic evaluations of supported employment for adults with severe mental illness are limited and heterogeneous. The interpretation of economic outcomes warrants consideration of factors that may impact cost-effectiveness, such as geographical location. Future studies should evaluate whether the benefits of IPS outweigh additional costs for patients and other stakeholders.

Co-worker relationships and their impact on nurses in Irish public healthcare settings.

This article presents the findings of a secondary analysis of data arising from a quantitative study of 3769 nurses on co-worker relationships and their impact on nurses working in public healthcare settings in Ireland. The overall findings from this analysis suggest moderate to high levels of satisfaction with co-worker relationships, with an average scale mean of 77%. Statistically significant lower scale means were identified in respect of nurses whose basic nursing qualification was awarded in a country outside the EU, among students and among those working in the west of Ireland. Respondents intending to leave the healthcare workforce reported significantly lower scores (74%) on this index compared with those intending to stay (79%). Significant positive correlations between co-worker relationships and workplace engagement (0.233), job satisfaction (0.225), organisational commitment (0.221) and perception of managers (0.259) were identified. These findings have implications for the retention of nurses working in Irish public healthcare services.

Asymmetric synthesis with ynamides: unique reaction control, chemical diversity and applications.

Ynamides are among the most powerful building blocks in organic synthesis and have become invaluable starting materials for the construction of multifunctional compounds and challenging architectures that would be difficult to prepare otherwise. The rapidly growing popularity originates from the unique reactivity and ease of manipulation of the polarized ynamide triple bond, the advance of practical methods for making them, and the simplicity of storage and handling. These attractive features and the demonstration of numerous synthetic applications have spurred the development of intriguing asymmetric reaction strategies during the last decade. An impressive variety of chemo-, regio- and stereoselective carbon-carbon and carbon-heteroatom bond forming reactions with ynamides have been developed and now significantly enrich the toolbox of synthetic chemists. This review provides a comprehensive overview of asymmetric ynamide chemistry since 2010 with a focus on the general scope, current limitations, stereochemical reaction control and mechanistic aspects.

Burnout and its prevalence among public health nurses in Ireland.

This paper presents the findings from an analysis of survey data which was collected from public health nurses (N = 136) as part of a larger study with more than 4000 nurses and midwives in Ireland. The purpose of the study was to examine the prevalence of burnout using the Oldenburg Burnout Inventory and to compare relationships between burnout, demographic and work characteristics across this group of nurses. Younger PHNs were most likely to report feeling burnout (68%) compared with those aged 51 or over (47%) who reported the lowest levels. PHNs whose highest level of qualification was a primary degree were least likely to report feeling burnout (31%) compared with those who held a Masters / Doctoral degree (54.5%). PHNs who reported working on a fixed-term full-time contract were most likely to report feeling burnout (70%) compared with those who were on a permanent part-time contract (49%). Quantitative analysis, using both descriptive and inferential statistics, was carried out and the findings show that PHNs reported moderate levels of burnout. The findings also show that burnout among PHNs is strongly correlated with the physical demands placed on individuals during work, having constant time pressures, too much being expected of individuals, the work environment being too demanding and dissatisfaction with the physical conditions.

Optical Chirality Sensing with an Auxiliary-Free Earth-Abundant Cobalt Probe.

Broadly useful chiroptical enantiomeric excess (ee) sensing remains challenging and typically involves carefully designed molecular receptors or supramolecular assemblies. Herein, we report on the enantioselective sensing of 35 amino acids, amino phosphonic acids, hydroxy acids, amino alcohols, and diamines with an auxiliary-free cobalt probe. Chiroptical analysis of the enantiomeric composition and concentration of minute sample amounts was achieved with high accuracy by using earth-abundant cobalt salts and hydrogen peroxide as the oxidant. Despite the absence of an auxiliary ligand, the cobalt assay is applicable to aromatic and aliphatic compounds and yields strong CD signals at high wavelengths. This method obviates the general prerequisite for chromophoric metal ligands to generate chiroptical signals through ECCD (exciton-coupled circular dichroism) effects or through analyte-to-ligand chirality induction, and it offers operational simplicity, cost efficiency, waste reduction, and speed.

Long-term weight loss trajectories following participation in a randomised controlled trial of a weight management programme for men delivered through professional football clubs: a longitudinal cohort study and economic evaluation.

BACKGROUND: Obesity is a major public health concern requiring innovative interventions that support people to lose weight and keep it off long term. However, weight loss maintenance remains a challenge and is under-researched, particularly in men. The Football Fans in Training (FFIT) programme engages men in weight management through their interest in football, and encourages them to incorporate small, incremental physical activity and dietary changes into daily life to support long-term weight loss maintenance. In 2011/12, a randomised controlled trial (RCT) of FFIT demonstrated effectiveness and cost-effectiveness at 12 months. The current study aimed to investigate long-term maintenance of weight loss, behavioural outcomes and lifetime cost-effectiveness following FFIT. METHODS: A longitudinal cohort study comprised 3.5-year follow-up of the 747 FFIT RCT participants. Men aged 35-65 years, BMI ≥ 28 kg/m2 at RCT baseline who consented to long-term follow-up (n = 665) were invited to participate: those in the FFIT Follow Up Intervention group (FFIT-FU-I) undertook FFIT in 2011 during the RCT; the FFIT Follow Up Comparison group (FFIT-FU-C) undertook FFIT in 2012 under routine (non-research) conditions. The primary outcome was objectively-measured weight loss (from baseline) at 3.5 years. Secondary outcomes included changes in self-reported physical activity and diet at 3.5 years. Cost-effectiveness was estimated at 3.5 years and over participants' lifetime. RESULTS: Of 665 men invited, 488 (73%; 65% of the 747 RCT participants) attended 3.5-year measurements. The FFIT-FU-I group sustained a mean weight loss of 2.90 kg (95% CI 1.78, 4.02; p < 0.001) 3.5 years after starting FFIT; 32.2% (75/233) weighed ≥5% less than baseline. The FFIT-FU-C group had lost 2.71 kg (1.65, 3.77; p < 0.001) at the 3.5-year measurements (2.5 years after starting FFIT); 31.8% (81/255) weighed ≥5% less than baseline. There were significant sustained improvements in self-reported physical activity and diet in both groups. The estimated incremental cost-effectiveness of FFIT was £10,700-£15,300 per QALY gained at 3.5 years, and £1790-£2200 over participants' lifetime. CONCLUSIONS: Participation in FFIT under research and routine conditions leads to long-term weight loss and improvements in physical activity and diet. Investment in FFIT is likely to be cost-effective as part of obesity management strategies in countries where football is popular. TRIAL REGISTRATION: ISRCTN32677491 , 20 October 2011.

The Causal-Benefit Model to Prevent Cardiovascular Events.

Selecting individuals for preventive lipid-lowering therapy is presently governed by the 10-year risk model. Once a prespecified level of cardiovascular disease risk is equaled or exceeded, individuals become eligible for preventive lipid-lowering therapy. A key limitation of this model is that only a small minority of individuals below the age of 65 years are eligible for therapy. However, just under one-half of all cardiovascular disease events occur below this age. Additionally, in many, the disease that caused their events after 65 years of age developed and progressed before 65 years of age. The causal-benefit model of prevention identifies individuals based both on their risk and the estimated benefit from lowering atherogenic apoB lipoprotein levels. Adopting the causal-benefit model would increase the number of younger subjects eligible for preventive treatment, would increase the total number of cardiovascular disease events prevented at virtually the same number to treat, and would be cost-effective.

A cost-effectiveness analysis of a South African pregnancy support grant.

Poverty among expectant mothers often results in sub-optimal maternal nutrition and inadequate antenatal care, with negative consequences on child health outcomes. South Africa has a child support grant that is available from birth to those in need. This study aims to determine whether a pregnancy support grant, administered through the extension of the child support grant, would be cost-effective compared to the existing child support grant alone. A cost-utility analysis was performed using a decision-tree model to predict the incremental costs (ZAR) and disability-adjusted life years (DALYs) averted by the pregnancy support grant over a 2-year time horizon. An ingredients-based approach to costing was completed from a governmental perspective. The primary outcome was the incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses were performed. The intervention resulted in a cost saving of R13.8 billion ($930 million, 95% CI: ZAR3.91 billion - ZAR23.2 billion/ $1.57 billion - $264 million) and averted 59,000 DALYs (95% CI: -6,400-110,000), indicating that the intervention is highly cost-effective. The primary cost driver was low birthweight requiring neonatal intensive care, with a disaggregated incremental cost of R31,800 ($2,149) per pregnancy. Mortality contributed most significantly to the DALYs accrued in the comparator (0.68 DALYs). The intervention remained the dominant strategy in the sensitivity analyses. The pregnancy support grant is a highly cost-effective solution for supporting expecting mothers and ensuring healthy pregnancies. With its positive impact on child health outcomes, there is a clear imperative for government to implement this grant. By investing in this program, cost savings could be leveraged. The implementation of this grant should be given high priority in public health and social policies.

Extended cost-effectiveness analysis of interventions to improve uptake of diabetes services in South Africa.

The rising prevalence of diabetes in South Africa (SA), coupled with significant levels of unmet need for diagnosis and treatment, results in high rates of diabetes-associated complications. Income status is a determinant of utilization of diagnosis and treatment services, with transport costs and loss of wages being key barriers to care. A conditional cash transfer (CCT) programme, targeted to compensate for such costs, may improve service utilization. We applied extended cost-effectiveness analysis (ECEA) methods and used a Markov model to compare the costs, health benefits and financial risk protection (FRP) attributes of a CCT programme. A population was simulated, drawing from SA-specific data, which transitioned yearly through various health states, based on specific probabilities obtained from local data, over a 45-year time horizon. Costs and disability-adjusted life years (DALYs) were applied to each health state. Three CCT programme strategies were simulated and compared to a 'no programme' scenario: (1) covering diagnosis services only; (2) covering treatment services only; (3) covering both diagnosis and treatment services. Cost-effectiveness was reported as incremental net monetary benefit (INMB) using a cost-effectiveness threshold of USD3015 per DALY for SA, while FRP outcomes were reported as catastrophic health expenditure (CHE) cases averted. Distributions of the outcomes were reported by income quintile and sex. Covering both diagnosis and treatment services for the bottom two quintiles resulted in the greatest INMB (USD22 per person) and the greatest CHE cases averted. There were greater FRP benefits for women compared to men. A CCT programme covering diabetes diagnosis and treatment services was found to be cost-effective, when provided to the poorest 40% of the SA population. ECEA provides a useful platform for including equity considerations to inform priority setting and implementation policies in SA.

Hypertension in the South African public healthcare system: a cost-of-illness and burden of disease study.

OBJECTIVES: To quantify the health and economic burden of hypertension in the South African public healthcare system. SETTING: All inpatient, outpatient and rehabilitative care received in the national public healthcare system. PARTICIPANTS: Adults, aged ≥20 years, who receive care in the public healthcare system. OUTCOMES: Worksheet-based models synthesised data from multiple sources to estimate the burden of disease, direct healthcare costs, and societal costs associated with hypertension. Results were disaggregated by sex. RESULTS: Approximately 8.22 million (30.8%, 95% CI 29.5% to 32.1%) South African adults with no private health insurance have hypertension. Hypertension was estimated to cause 14 000 (95% CI 11 100 to 17 200) ischaemic heart disease events, 13 300 (95% CI 10 600 to 16 300) strokes and 6100 (95% CI 4970 to 7460) cases of chronic kidney disease annually. Rates of hypertension, hypertension-related stroke and hypertension-related chronic kidney disease were greater for women compared with men.The direct healthcare costs associated with hypertension were estimated to be ZAR 10.1 billion (95% CI 8.98 to 11.3 billion) or US$0.711 billion (95% CI 0.633 to 0.793 billion). Societal costs were estimated to be ZAR 29.4 billion (95% CI 26.0 to 33.2 billion) or US$2.08 billion (95% CI 1.83 to 2.34 billion). Direct healthcare costs were greater for women (ZAR 6.11 billion or US$0.431 billion) compared with men (ZAR 3.97 billion or US$0.280 billion). Conversely, societal costs were lower for women (ZAR 10.5 billion or US$0.743 billion) compared with men (ZAR 18.9 billion or US$1.33 billion). CONCLUSION: Hypertension exerts a heavy health and economic burden on South Africa. Establishing cost-effective best practice guidelines for hypertension treatment requires further research. Such research will be essential if South Africa is to make progress in its efforts to implement universal healthcare.

Estimating the healthcare cost of overweight and obesity in South Africa.

BACKGROUND: Overweight and obesity are major risk factors for noncommunicable diseases. This presents a major burden to health systems and to society in South Africa. Collectively, these conditions are overwhelming public healthcare. This is happening when the country has embarked on a journey to universal health coverage, hence the need to estimate the cost of overweight and obesity. OBJECTIVE: Our objective was to estimate the healthcare cost associated with treatment of weight-related conditions from the perspective of the South African public sector payer. METHODS: Using a bottom-up gross costing approach, this study draws data from multiple sources to estimate the direct healthcare cost of overweight and obesity in South Africa. Population Attributable Fractions (PAF) were calculated and multiplied by each disease's total treatment cost to apportion costs to overweight and obesity. Annual costs were estimated for 2020. RESULTS: The total cost of overweight and obesity is estimated to be ZAR33,194 million in 2020. This represents 15.38% of government health expenditure and is equivalent to 0.67% of GDP. Annual per person cost of overweight and obesity is ZAR2,769. The overweight and obesity cost is disaggregated as follows: cancers (ZAR352 million), cardiovascular diseases (ZAR8,874 million), diabetes (ZAR19,861 million), musculoskeletal disorders (ZAR3,353 million), respiratory diseases (ZAR360 million) and digestive diseases (ZAR395 million). Sensitivity analyses show that the total overweight and obesity cost is between ZAR30,369 million and ZAR36,207 million. CONCLUSION: This analysis has demonstrated that overweight and obesity impose a huge financial burden on the public health care system in South Africa. It suggests an urgent need for preventive, population-level interventions to reduce overweight and obesity rates. The reduction will lower the incidence, prevalence, and healthcare spending on noncommunicable diseases.

Cost-Effectiveness of Masked Hypertension Screening and Treatment in US Adults With Suspected Masked Hypertension: A Simulation Study.

BACKGROUND: Recent US blood pressure (BP) guidelines recommend using ambulatory BP monitoring (ABPM) or home BP monitoring (HBPM) to screen adults for masked hypertension. However, limited evidence exists of the expected long-term effects of screening for and treating masked hypertension. METHODS: We estimated the lifetime health and economic outcomes of screening for and treating masked hypertension using the Cardiovascular Disease (CVD) Policy Model, a validated microsimulation model. We simulated a cohort of 100,000 US adults aged ≥20 years with suspected masked hypertension (i.e., office BP 120-129/<80 mm Hg, not taking antihypertensive medications, without CVD history). We compared usual care only (i.e., no screening), usual care plus ABPM, and usual care plus HBPM. We projected total direct healthcare costs (2021 USD), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios. Future costs and QALYs were discounted 3% annually. Secondary outcomes included CVD events and serious adverse events. RESULTS: Relative to usual care, adding masked hypertension screening and treatment with ABPM and HBPM was projected to prevent 14.3 and 20.5 CVD events per 100,000 person-years, increase the proportion experiencing any treatment-related serious adverse events by 2.7 and 5.1 percentage points, and increase mean total costs by $1,076 and $1,046, respectively. Compared with usual care, adding ABPM was estimated to cost $85,164/QALY gained. HBPM resulted in lower QALYs than usual care due to increased treatment-related adverse events and pill-taking disutility. CONCLUSIONS: The results from our simulation study suggest screening with ABPM and treating masked hypertension is cost-effective in US adults with suspected masked hypertension.

Costs of seasonal influenza vaccination in South Africa.

BACKGROUND: Influenza accounts for a substantial number of deaths and hospitalisations annually in South Africa. To address this disease burden, the South African National Department of Health introduced a trivalent inactivated influenza vaccination programme in 2010. METHODS: We adapted and populated the WHO Seasonal Influenza Immunization Costing Tool (WHO SIICT) with country-specific data to estimate the cost of the influenza vaccination programme in South Africa. Data were obtained through key-informant interviews at different levels of the health system and through a review of existing secondary data sources. Costs were estimated from a public provider perspective and expressed in 2018 prices. We conducted scenario analyses to assess the impact of different levels of programme expansion and the use of quadrivalent vaccines on total programme costs. RESULTS: Total financial and economic costs were estimated at approximately USD 2.93 million and USD 7.91 million, respectively, while financial and economic cost per person immunised was estimated at USD 3.29 and USD 8.88, respectively. Expanding the programme by 5% and 10% increased economic cost per person immunised to USD 9.36 and USD 9.52 in the two scenarios, respectively. Finally, replacing trivalent inactivated influenza vaccine (TIV) with quadrivalent vaccine increased financial and economic costs to USD 4.89 and USD 10.48 per person immunised, respectively. CONCLUSION: We adapted the WHO SIICT and provide estimates of the total costs of the seasonal influenza vaccination programme in South Africa. These estimates provide a basis for planning future programme expansion and may serve as inputs for cost-effectiveness analyses of seasonal influenza vaccination programmes.

From Spreadsheets to Script: Experiences From Converting a Scottish Cardiovascular Disease Policy Model into R.

Given the advantages in transparency, reproducibility, adaptability and computational efficiency in R, there is a growing interest in converting existing spreadsheet-based models into an R script for model re-use and upskilling training among health economic modellers. The objective of this exercise was to convert the Scottish Cardiovascular Disease (CVD) Policy Model from Excel to R and discuss the lessons learnt throughout this process. The CVD model is a competing risk state transition cohort model. Four health economists, with varied experience of R, attempted to replicate an identical model structure in R based on the model in Excel and reproduce the intermediate and final results. Replications varied in their use of specialist health economics packages in addition to standard data management packages. Two versions of the CVD model were created in R along with a Shiny app. Version 1 was developed without health economics specialist packages and produced identical results to the Excel version. Version 2 used the heemod package and did not achieve the same results, possibly due to the non-standard elements of the model and limited time to adapt the functions. The R model requires less than half the computational time than the Excel model. Conversion of the spreadsheet models to script models is feasible for health economists. A step-by-step guide for the conversion process is provided and modellers' experience is discussed. Coding without specialist packages allows full flexibility, while specialist packages may add convenience if the model structure is suitable. Whichever approach is taken, transparency and replicability remain the key criteria in model programming. Model conversions must maintain standards in these areas regardless of the choice of software.

Novel Ubiquitin Specific Protease-13 Inhibitors Alleviate Neurodegenerative Pathology.

Ubiquitin Specific Protease-13 (USP13) promotes protein de-ubiquitination and is poorly understood in neurodegeneration. USP13 is upregulated in Alzheimer's disease (AD) and Parkinson's disease (PD), and USP13 knockdown via shRNA reduces neurotoxic proteins and increases proteasome activity in models of neurodegeneration. We synthesized novel analogues of spautin-1 which is a non-specific USP13 inhibitor but unable to penetrate the brain. Our synthesized small molecule compounds are able to enter the brain, more potently inhibit USP13, and significantly reduce alpha-synuclein levels in vivo and in vitro. USP13 inhibition in transgenic mutant alpha-synuclein (A53T) mice increased the ubiquitination of alpha-synuclein and reduced its protein levels. The data suggest that novel USP13 inhibitors improve neurodegenerative pathology via antagonism of de-ubiquitination, thus alleviating neurotoxic protein burden in neurodegenerative diseases.