Airway granulation response to lung-implantable medical devices:a concise overview

Increasing numbers of endoscopically implantable devices are implanted in the airways, such as airway stents, one-way valves and coils, to treat both malignant and benign diseases. They significantly improve patient outcomes, but their long-term effectiveness and sustainability is hampered by the reaction of the formation of granulation tissue. Factors including procedural-related tissue injury; micro-organism presence; device-related factors, such as the material, design and sizing in relation to the airway; and patient-related factors, including genetic susceptibility, comorbidities and medication use, might all effect the severity of the tissue response and the subsequent degree of granulation tissue formation. However, research into the underlying mechanism and risk factors is scarce and therefore our knowledge is limited. Joint efforts from the scientific community, both pre-clinical and clinical, are needed to gain a deeper understanding and eventually improve the long-term treatment effectiveness of lung-implantable devices

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

Effect of Covid-19 Vaccination on Transmission of Alpha and Delta Variants

BACKGROUND: Before the emergence of the B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), vaccination reduced transmission of SARS-CoV-2 from vaccinated persons who became infected, potentially by reducing viral loads. Although vaccination still lowers the risk of infection, similar viral loads in vaccinated and unvaccinated persons who are infected with the delta variant call into question the degree to which vaccination prevents transmission. METHODS: We used contact-testing data from England to perform a retrospective observational cohort study involving adult contacts of SARS-CoV-2–infected adult index patients. We used multivariable Poisson regression to investigate associations between transmission and the vaccination status of index patients and contacts and to determine how these associations varied with the B.1.1.7 (alpha) and delta variants and time since the second vaccination. RESULTS: Among 146,243 tested contacts of 108,498 index patients, 54,667 (37%) had positive SARS-CoV-2 polymerase-chain-reaction (PCR) tests. In index patients who became infected with the alpha variant, two vaccinations with either BNT162b2 or ChAdOx1 nCoV-19 (also known as AZD1222), as compared with no vaccination, were independently associated with reduced PCR positivity in contacts (adjusted rate ratio with BNT162b2, 0.32; 95% confidence interval [CI], 0.21 to 0.48; and with ChAdOx1 nCoV-19, 0.48; 95% CI, 0.30 to 0.78). Vaccine-associated reductions in transmission of the delta variant were smaller than those with the alpha variant, and reductions in transmission of the delta variant after two BNT162b2 vaccinations were greater (adjusted rate ratio for the comparison with no vaccination, 0.50; 95% CI, 0.39 to 0.65) than after two ChAdOx1 nCoV-19 vaccinations (adjusted rate ratio, 0.76; 95% CI, 0.70 to 0.82). Variation in cycle-threshold (Ct) values (indicative of viral load) in index patients explained 7 to 23% of vaccine-associated reductions in transmission of the two variants. The reductions in transmission of the delta variant declined over time after the second vaccination, reaching levels that were similar to those in unvaccinated persons by 12 weeks in index patients who had received ChAdOx1 nCoV-19 and attenuating substantially in those who had received BNT162b2. Protection in contacts also declined in the 3-month period after the second vaccination. CONCLUSIONS: Vaccination was associated with a smaller reduction in transmission of the delta variant than of the alpha variant, and the effects of vaccination decreased over time. PCR Ct values at diagnosis of the index patient only partially explained decreased transmission. (Funded by the U.K. Government Department of Health and Social Care and others.

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

Preferences for Medical Consultations from Online Providers: Evidence from a Discrete Choice Experiment in the United Kingdom

Background: In the UK, consultations for prescription medicines are available via private providers such as online pharmacies. However, these providers may have lower thresholds for prescribing certain drugs. This is a particular concern for antibiotics, given the increasing burden of antimicrobial resistance. Public preferences for consultations with online providers are unknown, hence the impact of increased availability of online consultations on antibiotic use and population health is unclear. Objective: To conduct a discrete choice experiment survey to understand UK public preferences for seeking online consultations, and the factors that influence these preferences, in the context of having symptoms for which antibiotics may be appropriate. Methods: In a survey conducted between July and August 2018, general population respondents completed 16 questions in which they chose a primary care consultation via either their local medical centre or an online provider. Consultations were described in terms of five attributes, including cost and similarity to traditional ‘face-to-face’ appointments. Choices were modelled using regression analysis. Results: Respondents (n = 734) placed a high value on having a consultation via their local medical centre rather than an online provider, and a low value on consultations by phone or video. However, respondents characterised as ‘busy young professionals’ showed a lower strength of preference for traditional consultations, with a higher concern for convenience. Conclusion: Before COVID-19, the UK public had limited appetite for consultations with online providers, or for consultations that were not face-to-face. Nevertheless, prescriptions from online providers should be monitored going forward, particularly for antibiotics, and in key patient groups

Anchoring of proteins to lactic acid bacteria

The anchoring of proteins to the cell surface of lactic acid bacteria (LAB) using genetic techniques is an exciting and emerging research area that holds great promise for a wide variety of biotechnological applications. This paper reviews five different types of anchoring domains that have been explored for their efficiency in attaching hybrid proteins to the cell membrane or cell wall of LAB. The most exploited anchoring regions are those with the LPXTG box that bind the proteins in a covalent way to the cell wall. In recent years, two new modes of cell wall protein anchoring have been studied and these may provide new approaches in surface display. The important progress that is being made with cell surface display of chimaeric proteins in the areas of vaccine development and enzyme- or whole-cell immobilisation is highlighted.

Substrate stiffness engineered to replicate disease conditions influence senescence and fibrotic responses in primary lung fibroblasts

In fibrosis remodelling of ECM leads to changes in composition and stiffness. Such changes can have a major impact on cell functions including proliferation, secretory profile and differentiation. Several studies have reported that fibrosis is characterised by increased senescence and accumulating evidence suggests that changes to the ECM including altered composition and increased stiffness may contribute to premature cellular senescence. This study investigated if increased stiffness could modulate markers of senescence and/or fibrosis in primary human lung fibroblasts. Using hydrogels representing stiffnesses that fall within healthy and fibrotic ranges, we cultured primary fibroblasts from non-diseased lung tissue on top of these hydrogels for up to 7 days before assessing senescence and fibrosis markers. Fibroblasts cultured on stiffer (±15 kPa) hydrogels showed higher Yes-associated protein-1 (YAP) nuclear translocation compared to soft hydrogels. When looking at senescence-associated proteins we also found higher secretion of receptor activator of nuclear factor kappa-B ligand (RANKL) but no change in transforming growth factor-β1 (TGF-β1) or connective tissue growth factor (CTGF) expression and higher decorin protein deposition on stiffer matrices. With respect to genes associated with fibrosis, fibroblasts on stiffer hydrogels compared to soft had higher expression of smooth muscle alpha (α)-2 actin (ACTA2), collagen (COL) 1A1 and fibulin-1 (Fbln1) and higher Fbln1 protein deposition after 7 days. Our results show that exposure of lung fibroblasts to fibrotic stiffness activates genes and secreted factors that are part of fibrotic responses and part of the Senescence-associated secretory phenotype (SASP). This overlap may contribute to the creation of a feedback loop whereby fibroblasts create a perpetuating cycle reinforcing progression of a fibrotic response