Severe Hypertriglyceridaemia as a result of Familial Chylomicronaemia:

Lipoprotein lipase deficiency causes severe hypertriglyceridaemia due to chylomicronaemia, and leads to recurrent and potentially life-threatening pancreatitis. This disorder can only be managed by dietary fat restriction as drugs are ineffective. We review the experience with familial chylomicronaemia in patients who attended the lipid clinics at Groote Schuur Hospital and Red Cross Children's War Memorial Hospital in Cape Town. Criteria for inclusion were an initial plasma triglyceride concentration of >15 mmol/l and a typical type I Fredrickson hyperlipidaemia pattern on plasma lipoprotein electrophoresis. A total of 29 patients were seen over 25 years. The mean age of presentation was 10 years, but ranged from 0 to 43 years. The modes of presentation differed: pancreatitis (N=16), eruptive xanthomata (N=2), coincidental detection of hypertriglyceridaemia (N=2), screening relatives (N=7), and after death from pancreatitis (N=1). Plasma triglycerides responded rapidly and dramatically to dietary fat restriction, and some patients sustained good control of the hyperlipidaemia. The onset of pancreatitis was earlier in patients of Indian ancestry, suggesting a genotype/phenotype interaction within this disorder. Genetic work-up indicated founder effects in the Afrikaner and Indian patients. Lipaemic plasma should be taken seriously at all ages, and necessitates work-up at specialised clinics where the diagnosis of chylomicronaemia or type I hyperlipidaemia facilitates appropriate dietary management that can prevent pancreatitis. South African Medical Journal Vol. 98 (2) 2008: pp. 105-10

Severe hypertriglyceridaemia as a result of familial chylomicronaemia:The Cape Town experience

Lipoprotein lipase deficiency causes severe hypertriglyceridaemia due to chylomicronaemia, and leads to recurrent and potentially life-threatening pancreatitis. This disorder can only be managed by dietary fat restriction as drugs are ineffective. We review the experience with familial chylomicronaemia in patients who attended the lipid clinics at Groote Schuur Hospital and Red Cross Children's War Memorial Hospital in Cape Town. Criteria for inclusion were an initial plasma triglyceride concentration of >15 mmol/l and a typical type I Fredrickson hyperlipidaemia pattern on plasma lipoprotein electrophoresis. A total of 29 patients were seen over 25 years. The mean age of presentation was 10 years, but ranged from 0 to 43 years. The modes of presentation differed: pancreatitis (N=16), eruptive xanthomata (N=2), coincidental detection of hypertriglyceridaemia (N=2), screening relatives (N=7), and after death from pancreatitis (N=1). Plasma triglycerides responded rapidly and dramatically to dietary fat restriction, and some patients sustained good control of the hyperlipidaemia. The onset of pancreatitis was earlier in patients of Indian ancestry, suggesting a genotype/phenotype interaction within this disorder. Genetic work-up indicated founder effects in the Afrikaner and Indian patients. Lipaemic plasma should be taken seriously at all ages, and necessitates work-up at specialised clinics where the diagnosis of chylomicronaemia or type I hyperlipidaemia facilitates appropriate dietary management that can prevent pancreatitis

Identifying English practices that are high antibiotic prescribers accounting for comorbidities and other legitimate medical reasons for variation

Background: Seeing one’s practice as a high antibiotic prescriber compared to general practices with similar patient populations can be one of the best motivators for change. Current comparisons are based on age-sex weighting of the practice population for expected prescribing rates (STAR-PU). Here, we investigate whether there is a need to additionally account for further potentially legitimate medical reasons for higher antibiotic prescribing. Methods: Publicly available data from 7,376 general practices in England between April 2014 and March 2015 were used. We built two different negative binomial regression models to compare observed versus expected antibiotic dispensing levels per practice: one including comorbidities as covariates and another with the addition of smoking prevalence and deprivation. We compared the ranking of practices in terms of items prescribed per STAR-PU according to i) conventional STAR-PU methodology, ii) observed vs expected prescribing levels using the comorbidity model, and iii) observed vs expected prescribing levels using the full model. Findings: The median number of antibiotic items prescribed per practice per STAR-PU was 1.09 (25th -75th percentile, 0.92-1.25). 1,133 practices (76.8% of 1,476) were consistently identified as being in the top 20% of high antibiotic prescribers. However, some practices that would be classified as high prescribers using the current STAR-PU methodology would not be classified as high prescribers if comorbidity was accounted for (n=269, 18.2%) and if additionally smoking prevalence and deprivation were accounted for (n=312, 21.1%). Interpretation: Current age-sex weighted comparisons of antibiotic prescribing rates in England are fair for many, but not all practices. This new metric that accounts for legitimate medical reasons for higher antibiotic prescribing may have more credibility among general practitioners and, thus, more likely to be acted upon

Regulation of cellular senescence by extracellular matrix during chronic fibrotic diseases

The extracellular matrix (ECM) is a complex network of macromolecules surrounding cells providing structural support and stability to tissues. The understanding of the ECM and the diverse roles it plays in development, homoeostasis and injury have greatly advanced in the last three decades. The ECM is crucial for maintaining tissue homoeostasis but also many pathological conditions arise from aberrant matrix remodelling during ageing. Ageing is characterised as functional decline of tissue over time ultimately leading to tissue dysfunction, and is a risk factor in many diseases including cardiovascular disease, diabetes, cancer, dementia, glaucoma, chronic obstructive pulmonary disease (COPD) and fibrosis. ECM changes are recognised as a major driver of aberrant cell responses. Mesenchymal cells in aged tissue show signs of growth arrest and resistance to apoptosis, which are indicative of cellular senescence. It was recently postulated that cellular senescence contributes to the pathogenesis of chronic fibrotic diseases in the heart, kidney, liver and lung. Senescent cells negatively impact tissue regeneration while creating a pro-inflammatory environment as part of the senescence-associated secretory phenotype (SASP) favouring disease progression. In this review, we explore and summarise the current knowledge around how aberrant ECM potentially influences the senescent phenotype in chronic fibrotic diseases. Lastly, we will explore the possibility for interventions in the ECM-senescence regulatory pathways for therapeutic potential in chronic fibrotic diseases.</p

Potential Cost-Effectiveness of RSV Vaccination of Infants and Pregnant Women in Turkey:An Illustration Based on Bursa Data

BackgroundWorldwide, respiratory syncytial virus (RSV) is considered to be the most important viral cause of respiratory morbidity and mortality among infants and young children. Although no active vaccine is available on the market yet, there are several active vaccine development programs in various stages. To assess whether one of these vaccines might be a future asset for national immunization programs, modeling the costs and benefits of various vaccination strategies is needed. Objectives To evaluate the potential cost-effectiveness of RSV vaccination of infants and/or pregnant women in Turkey.MethodsA multi-cohort static Markov model with cycles of one month was used to compare the cost-effectiveness of vaccinated cohorts versus non-vaccinated cohorts. The 2014 Turkish birth cohort was divided by twelve to construct twelve monthly birth cohorts of equal size (111,459 new-borns). Model input was based on clinical data from a multicenter prospective study from Bursa, Turkey, combined with figures from the (inter) national literature and publicly available data from the Turkish Statistical Institute (TUIK). Incremental cost-effectiveness ratios (ICERs) were expressed in Turkish Lira (TL) per quality-adjusted life year (QALY) gained.ResultsVaccinating infants at 2 and 4 months of age would prevent 145,802 GP visits, 8,201 hospitalizations and 48 deaths during the first year of life, corresponding to a total gain of 1650 QALYs. The discounted ICER was estimated at 51,969 TL (26,220 US $in 2013) per QALY gained. Vaccinating both pregnant women and infants would prevent more cases, but was less attractive from a pure economic point of view with a discounted ICER of 61,653 TL (31,106 US$ in 2013) per QALY. Vaccinating only during pregnancy would result in fewer cases prevented than infant vaccination and a less favorable ICER.ConclusionRSV vaccination of infants and/or pregnant women has the potential to be cost-effective in Turkey. Although using relatively conservative assumptions, all evaluated strategies remained slightly below the threshold of 3 times the GDP per capita.</p

Аудит як процедура контролю за станом платіжної системи суб’єкта господарської діяльності

У статті розглядаються питання аудиту розрахункових операцій. Виділено різні види аудиторських процедур – аналітичні та альтернативні. Визначено порядок проведення аудиторської перевірки розрахунків.В статье рассматриваются вопросы аудита расчетных операций. Выделены различные виды аудиторских процедур – аналитические и альтернативные. Определен порядок проведения аудиторской проверки.In the article the issues of audit of payments are revealed. Various types of audit procedures – analytical and alternative are identified. The procedure for conducting the audit is stipulated

Quantifying the economic cost of antibiotic resistance and the impact of related interventions rapid methodological review, conceptual framework and recommendations for future studies

BACKGROUND: Antibiotic resistance (ABR) poses a major threat to health and economic wellbeing worldwide. Reducing ABR will require government interventions to incentivise antibiotic development, prudent antibiotic use, infection control and deployment of partial substitutes such as rapid diagnostics and vaccines. The scale of such interventions needs to be calibrated to accurate and comprehensive estimates of the economic cost of ABR. METHODS: A conceptual framework for estimating costs attributable to ABR was developed based on previous literature highlighting methodological shortcomings in the field and additional deductive epidemiological and economic reasoning. The framework was supplemented by a rapid methodological review. RESULTS: The review identified 110 articles quantifying ABR costs. Most were based in high-income countries only (91/110), set in hospitals (95/110), used a healthcare provider or payer perspective (97/110), and used matched cohort approaches to compare costs of patients with antibiotic-resistant infections and antibiotic-susceptible infections (or no infection) (87/110). Better use of methods to correct biases and confounding when making this comparison is needed. Findings also need to be extended beyond their limitations in (1) time (projecting present costs into the future), (2) perspective (from the healthcare sector to entire societies and economies), (3) scope (from individuals to communities and ecosystems), and (4) space (from single sites to countries and the world). Analyses of the impact of interventions need to be extended to examine the impact of the intervention on ABR, rather than considering ABR as an exogeneous factor. CONCLUSIONS: Quantifying the economic cost of resistance will require greater rigour and innovation in the use of existing methods to design studies that accurately collect relevant outcomes and further research into new techniques for capturing broader economic outcomes

Acute cigarette smoke-induced eQTL affects formyl peptide receptor expression and lung function

Background and objective Cigarette smoking is one of the most prevalent causes of preventable deaths worldwide, leading to chronic diseases, including chronic obstructive pulmonary disease (COPD). Cigarette smoke is known to induce significant transcriptional modifications throughout the respiratory tract. However, it is largely unknown how genetic profiles influence the smoking-related transcriptional changes and how changes in gene expression translate into altered alveolar epithelial repair responses. Methods We performed a candidate-based acute cigarette smoke-induced eQTL study, investigating the association between SNP and differential gene expression of FPR family members in bronchial epithelial cells isolated 24 h after smoking and after 48 h without smoking. The effects FPR1 on lung epithelial integrity and repair upon damage in the presence and absence of cigarette smoke were studied in CRISPR-Cas9-generated lung epithelial knockout cells. Results One significant (FDR 2-fold change in gene expression. The minor allele of rs3212855 was associated with significantly higher gene expression of FPR1, FPR2 and FPR3 upon smoking. Importantly, the minor allele of rs3212855 was also associated with lower lung function. Alveolar epithelial FPR1 knockout cells were protected against CSE-induced reduction in repair capacity upon wounding. Conclusion We identified a novel smoking-related inducible eQTL that is associated with a smoke-induced increase in the expression of FPR1, FPR2 and FPR3, and with lowered lung function. in vitro FPR1 down-regulation protects against smoke-induced reduction in lung epithelial repair

Symptoms and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Positivity in the General Population in the United Kingdom

BACKGROUND: “Classic” symptoms (cough, fever, loss of taste/smell) prompt severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) testing in the United Kingdom. Studies have assessed the ability of different symptoms to identify infection, but few have compared symptoms over time (reflecting variants) and by vaccination status. METHODS: Using the COVID-19 Infection Survey, sampling households across the United Kingdom, we compared symptoms in PCR-positives vs PCR-negatives, evaluating sensitivity of combinations of 12 symptoms (percentage symptomatic PCR-positives reporting specific symptoms) and tests per case (TPC) (PCR-positives or PCR-negatives reporting specific symptoms/ PCR-positives reporting specific symptoms). RESULTS: Between April 2020 and August 2021, 27 869 SARS-CoV-2 PCR-positive episodes occurred in 27 692 participants (median 42 years), of whom 13 427 (48%) self-reported symptoms (“symptomatic PCR-positives”). The comparator comprised 3 806 692 test-negative visits (457 215 participants); 130 612 (3%) self-reported symptoms (“symptomatic PCR-negatives”). Symptom reporting in PCR-positives varied by age, sex, and ethnicity, and over time, reflecting changes in prevalence of viral variants, incidental changes (eg, seasonal pathogens (with sore throat increasing in PCR-positives and PCR-negatives from April 2021), schools reopening) and vaccination rollout. After May 2021 when Delta emerged, headache and fever substantially increased in PCR-positives, but not PCR-negatives. Sensitivity of symptom-based detection increased from 74% using “classic” symptoms, to 81% adding fatigue/weakness, and 90% including all 8 additional symptoms. However, this increased TPC from 4.6 to 5.3 to 8.7. CONCLUSIONS: Expanded symptom combinations may provide modest benefits for sensitivity of PCR-based case detection, but this will vary between settings and over time, and increases tests/case. Large-scale changes to targeted PCR-testing approaches require careful evaluation given substantial resource and infrastructure implications