Impact on the NHS and health of the UK's trade and cooperation relationship with the EU, and beyond.

The UK's relationship with the European Union (EU) is now embodied in two principal legal instruments: the EU-UK Trade and Cooperation Agreement, which formally entered into force on 1 May 2021; and the Withdrawal Agreement, with its Protocol on Ireland/Northern Ireland, which continues to apply. Using a 'building blocks' framework for analysis of national health systems derived from the World Health Organisation, this article examines the likely impacts in the UK of this legal settlement on the National Health Service (NHS), health and social care. Specifically, we determine the extent to which the trade, cooperation and regulatory aspects of those legal measures support positive impacts for the NHS and social care. We show that, as there is clear support for positive health and care outcomes in only one of the 17 NHS 'building blocks', unless mitigating action is taken, the likely outcomes will be detrimental. However, as the legal settlement gives the UK a great deal of regulatory freedom, especially in Great Britain, we argue that it is crucial to track the effects of proposed new health and social care-related policy choices in the months and years ahead.

Achieving higher performing primary care through patient registration: A review of twelve high-income countries.

BACKGROUND: Patient registration with a primary care providers supports continuity in the patient-provider relationship. This paper develops a framework for analysing the characteristics of patient registration across countries; applies this framework to a selection of countries; and identifies challenges and ongoing reform efforts. METHODS: 12 jurisdictions (Denmark, France, Germany, Ireland, Israel, Italy, Netherlands, Norway, Ontario [Canada], Sweden, Switzerland, United Kingdom) were selected for analysis. Information was collected by national researchers who reviewed relevant literature and policy documents to report on the establishment and evolution of patient registration, the requirements and benefits for patients, providers and payers, and its connection to primary care reforms. RESULTS: Patient registration emerged as part of major macro-level health reforms linked to the introduction of universal health coverage. Recent reforms introduced registration with the aim of improving quality through better coordination and efficiency through reductions in unnecessary referrals. Patient registration is mandatory only in three countries. Several countries achieve high levels of registration by using strong incentives for patients and physicians (capitation payments). CONCLUSION: Patient registration means different things in different countries and policy-makers and researchers need to take into consideration: the history and characteristics of the registration system; the use of incentives for patients and providers; and the potential for more explicit use of patient-provider agreements as a policy to achieve more timely, appropriate, continuous and integrated care.

sFasL-The Key to a Riddle: Immune Responses in Aging Lung and Disease.

By dint of the aging population and further deepened with the Covid-19 pandemic, lung disease has turned out to be a major cause of worldwide morbidity and mortality. The condition is exacerbated when the immune system further attacks the healthy, rather than the diseased, tissue within the lung. Governed by unremittingly proliferating mesenchymal cells and increased collagen deposition, if inflammation persists, as frequently occurs in aging lungs, the tissue develops tumors and/or turns into scars (fibrosis), with limited regenerative capacity and organ failure. Fas ligand (FasL, a ligand of the Fas cell death receptor) is a key factor in the regulation of these processes. FasL is primarily found in two forms: full length (membrane, or mFasL) and cleaved (soluble, or sFasL). We and others found that T-cells expressing the mFasL retain autoimmune surveillance that controls mesenchymal, as well as tumor cell accumulation following an inflammatory response. However, mesenchymal cells from fibrotic lungs, tumor cells, or cells from immune-privileged sites, resist FasL+ T-cell-induced cell death. The mechanisms involved are a counterattack of immune cells by FasL, by releasing a soluble form of FasL that competes with the membrane version, and inhibits their cell death, promoting cell survival. This review focuses on understanding the previously unrecognized role of FasL, and in particular its soluble form, sFasL, in the serum of aged subjects, and its association with the evolution of lung disease, paving the way to new methods of diagnosis and treatment.

Assessing the potential impact on health of the UK's future relationship agreement with the EU: analysis of the negotiating positions.

While policy attention is understandably diverted to COVID-19, the end of the UK's post-Brexit 'transition period' remains 31 December 2020. All forms of future EU-UK relationship are worse for health than EU membership, but analysis of the negotiating texts shows some forms are better than others. The likely outcomes involve major negative effects for NHS staffing, funding for health and social care, and capital financing for the NHS; and for UK global leadership and influence. We expect minor negative effects for cross border healthcare (except in Northern Ireland); research collaboration; and data sharing, such as the Early Warning and Response System for health threats. Despite political narratives, the legal texts show that the UK seeks de facto continuity in selected key areas for pharmaceuticals, medical devices, and equipment [including personal protective equipment (PPE)], especially clinical trials, pharmacovigilance, and batch-testing. The UK will be excluded from economies of scale of EU membership, e.g. joint procurement programmes as used recently for PPE. Above all, there is a major risk of reaching an agreement with significant adverse effects for health, without meaningful oversight by or input from the UK Parliament, or other health policy stakeholders.

Increased Regeneration Following Stress-Induced Lung Injury in Bleomycin-Treated Chimeric Mice with CD44 Knockout Mesenchymal Cells.

CD44, an adhesion-molecule promoting cell-migration, is shown here to increase in stress conditions following bleomycin-induced apoptosis in alveolar epithelial cells (AECs), a main target of lung injury. In vivo, it inhibits tissue regeneration and leads to fibrosis. We show that some AECs survive by the ataxia-telangiectasia mutated kinase/ATM pathway, and undergo a CD44-mediated epithelial-mesenchymal transdifferentiation (EMT) with migratory capacities in vitro, and in vivo. We assessed apoptosis vs. proliferation of AECs following bleomycin, ATM/P53 signaling pathway in AECs, and CD44 involvement in EMT, cell motility and tissue regeneration in vitro and in vivo. Expression of survival genes, CD44, and ATM/p53 pathway was elevated in AECs surviving bleomycin injury, as were the markers of EMT (downregulation of E-cadherin, upregulation of N-cadherin and vimentin, nuclear translocation of ß-catenin). Inhibition of CD44 decreased AECs transdifferentiation. Bleomycin-treated chimeric CD44KO-mice had decreased EMT markers, ATM, and mesenchymal cells (α-SMA+) accumulation in lung, increased surfactant-b, diminished lung mesenchymal cell motility, and increased lung tissue regenerative capacity following bleomycin injury, as indicated by lung collagen content and semiquantitave morphological index scoring. Thus, AECs surviving lung injury are plastic and undergo ATM-mediated, CD44-dependent transdifferentiation, preventing tissue regeneration and promoting fibrosis. Synthetic or natural compounds that downregulate CD44 may improve tissue regeneration following injury.

Overexpression of Telomerase Protects Human and Murine Lung Epithelial Cells from Fas- and Bleomycin-Induced Apoptosis via FLIP Upregulation.

High doses of bleomycin administered to patients with lymphomas and other tumors lead to significant lung toxicity in general, and to apoptosis of epithelial cells, in particular. Apoptosis of alveolar epithelium is an important step in the pathogenesis of bleomycin-induced pulmonary fibrosis. The Fas-FasL pathway is one of the main apoptotic pathways involved. Telomerase is a ribonucleoprotein RNA-dependent DNA polymerase complex consisting of an RNA template and a catalytic protein, telomerase reverse transcriptase (TERT). Telomerase also possess extra-telomeric roles, including modulation of transcription of anti-apoptotic genes, differentiation signals, and more. We hypothesized that telomerase overexpression affects Fas-induced epithelial cell apoptosis by an extra-telomeric role such as regulation of anti-apoptotic genes, specifically FLICE-like inhibitory protein (FLIP). Telomerase in mouse (MLE) and human (A549) lung epithelial cell lines was upregulated by transient transfection using cDNA hTERT expression vector. Telomerase activity was detected using a real-time PCR-based system. Bleomycin, and bleomycin-induced Fas-mediated apoptosis following treatment with anti-Fas activating mAb or control IgG, were assessed by Annexin V staining, FACS analysis, and confocal microscopy; caspase cleavage by Western blot; FLIP or Fas molecule detection by Western blot and flow cytometry. hTERT transfection of lung epithelial cells resulted in a 100% increase in their telomerase activity. Fas-induced lung epithelial cell apoptosis was significantly reduced in hTERT-transfected cells compared to controls in all experiments. Lung epithelial cells with increased telomerase activity had higher levels of FLIP expression but membrane Fas expression was unchanged. Upregulation of hTERT+ in human lung epithelial cells and subsequent downregulation of FLIP by shFLIP-RNA annulled hTERT-mediated resistance to apoptosis. Telomerase-mediated FLIP overexpression may be a novel mechanism to confer protection from apoptosis in bleomycin-exposed human lung epithelial cells.

Cutting edge: FasL(+) immune cells promote resolution of fibrosis.

Immune cells, particularly those expressing the ligand of the Fas-death receptor (FasL), e.g. cytotoxic T cells, induce apoptosis in 'undesirable' self- and non-self-cells, including lung fibroblasts, thus providing a means of immune surveillance. We aimed to validate this mechanism in resolution of lung fibrosis. In particular, we elucidated whether FasL(+) immune cells possess antifibrotic capabilities by induction of FasL-dependent myofibroblast apoptosis and whether antagonists of membrane (m) and soluble (s) FasL can inhibit these capabilities. Myofibroblast interaction with immune cells and its FasL-dependency, were investigated in vitro in coculture with T cells and in vivo, following transplantation into lungs of immune-deficient syngeneic Rag-/- as well as allogeneic SCID mice, and into lungs and air pouches of FasL-deficient (gld) mice, before and after reconstitution of the mice with wild-type (wt), FasL(+) immune cells. We found that myofibroblasts from lungs resolving fibrosis undergo FasL-dependent T cell-induced apoptosis in vitro and demonstrate susceptibility to in vivo immune surveillance in lungs of reconstituted, immune- and FasL-deficient, mice. However, immune-deficient Rag-/- and SCID mice, and gld-mice with FasL-deficiency, endure the accumulation of transplanted myofibroblasts in their lungs with subsequent development of fibrosis. Concomitantly, gld mice, in contrast to chimeric FasL-deficient mice with wt immune cells, accumulated transplanted myofibroblasts in the air pouch model. In humans we found that myofibroblasts from fibrotic lungs secrete sFasL and resist T cell-induced apoptosis, whereas normal lung myofibroblasts are susceptible to apoptosis but acquire resistance upon addition of anti-s/mFasL to the coculture. Immune surveillance, particularly functional FasL(+) immune cells, may represent an important extrinsic component in myofibroblast apoptosis and serve as a barrier to fibrosis. Factors interfering with Fas/FasL-immune cell-myofibroblast interaction such as sFasL secreted by fibrotic-lung myofibroblasts, may abrogate immune surveillance during fibrosis. Annulling these factors may pave a new direction to control human lung fibrosis.