Reforming disease definitions: a new primary care led, people-centred approach

Expanding disease definitions are causing more and more previously healthy people to be labelled as diseased, contributing to the problem of overdiagnosis and related overtreatment. Often the specialist guideline panels which expand definitions have close tis to industry and do not investigate the harms of defining more people as sick. Responding to growing calls to address these problems, an international group of leading researchers and clinicians is proposing a new way to set diagnostic thresholds and mark the boundaries of condition definitions, to try to tackle a key driver of overdiagnosis and overtreatment. The group proposes new evidence-informed principles, with new process and new people constituting new multi-disciplinary panels, free from financial conflicts of interest

An Observational study to assess Immediate hemodynamic outcomes in patients undergoing percutaneous Transvenous mitral commissurotomy in Our Institution

BACKGROUND AND OBJECTIVES: Several studies conducted on the prevalence of rheumatic heart disease reported a prevalence of 34.54/1000 in India. Furthermore, demands for adequate medical therapies are expanding with increasing use of Percutaneous transvenous mitral valvuloplasty. In comparison to the surgical mitral commissurotomy Percutaneous mitral valvotomy has shown better success rates, comparable restenosis rates, larger valve area and long term durability. The most widely used echocardiographic parameter for patient selection for PTMC, is the Wilkins score which we follow in our institute. Our study aims to analyse the immediate hemodynamic outcomes in patients undergoing Percutaneous mitral valvotomy in our institute selected by specific clinical and echo criteria. METHODS: In this following hospital based observational study, fifty patients who were admitted as inpatients for the above procedure in the department of cardiology, who met the inclusion and exclusion cirteria were followed up during intraoperative and postoperative period. Immediate functional outcome of the procedure in terms of hemodynamic improvement was assessed by measuring the percentage of improvement in mitral valve orifice area, Left atrial pressure and mitral valve peak gradient. RESULTS: Out of the 50 patients who were included in the study group 64% were in 21-40 age group, 78% were females, 52% have symptoms and NYHA II, 48% have symptoms in NYHA class III, 0% in NYHA class I & IV. All the patients had wilkins score of 8 or below. 84% Patients had no atrial fibrillation. Even though lower age group, female sex, no atrial fibrillation and lower NYHA class seemed to have better outcomes the association was not statistically significant. The association between wilkins score and outcome with regard to all three parameters was statistically significant. CONCLUSION: PTMC is the procedure of choice for the management of uncomplicated and pliable mitral stenosis. Even though Echocardiographic scores are not the only parameters determining the outcome of PTMC, they still have a significant role in patient selection for PTMC

A New Pharmacological Approach Based on Remdesivir Aerosolized Administration on SARS-CoV-2 Pulmonary Inflammation: A Possible and Rational Therapeutic Application

The new zoonotic coronavirus (SARS-CoV-2) responsible for coronavirus disease (COVID-19) is a new strain of coronavirus not previously seen in humans and which appears to come from bat species. It originated in Wuhan, Hubei Province, China, and spread rapidly throughout the world, causing over 5,569,679 global cases and 351,866 deaths in almost every country in the world, including Europe, particularly Italy. In general, based on existing data published to date, 80.9% of patients infected with the virus develop mild infection; 13.8% severe pneumonia; 4.7% respiratory failure, septic shock or multi-organ failure; 3% of these cases are fatal. Critical patients have been shown to develop acute respiratory distress syndrome (ARDS) and hospitalization in intensive care units. The average age of patients admitted to hospital is 57–79 years, with one third half with an un- derlying disease. Asymptomatic infections have also been described, but their frequency is not known. SARS- CoV-2 transmission is mainly airborne from one person to another via droplets. The data available so far seem to indicate that SARS-CoV-2 is capable of producing an excessive immune reaction in the host. The virus attacks type II pneumocytes in the lower bronchi through the binding of the Spike protein (S protein) to viral receptors, of which the angiotensin 2 conversion enzyme (ACE2) receptor is the most important. ACE2 receptor is widely expressed in numerous tissues, including the oropharynx and conjunctiva, but mostly distributed in ciliated bronchial epithelial cells and type II pneumocytes in the lower bronchi. The arrival of SARS-CoV-2 in the lungs causes severe primary interstitial viral pneumonia that can lead to the “cytokine storm syndrome”, a deadly uncontrolled systemic inflammatory response triggered by the activation of interleukin 6 (IL-6), whose effect is extensive lung tissue damage and disseminated intravascular coagulation (DIC), that are life-threatening for patients with COVID-19. In the absence of a therapy of proven efficacy, current management consists of off-label or compassionate use therapies based on antivirals, antiparasitic agents in both oral and parenteral formulation, anti-inflammatory drugs, oxygen therapy and heparin support and convalescent plasma. Like most respiratory viruses can function and replicate at low temperatures (i.e. 34–35 °C) and assuming viral thermolability of SARS- CoV-2, local instillation or aerosol of antiviral (i.e. remdesivir) in humid heat vaporization (40°–41 °C) in the first phase of infection (phenotype I, before admission), both in asymptomatic but nasopharyngeal swab positive patients, together with antiseptic-antiviral oral gargles and povidone-iodine eye drops for conjunctiva (0,8–5% conjunctival congestion), would attack the virus directly through the receptors to which it binds, significantly decreasing viral replication, risk of evolution to phenotypes IV and V, reducing hospitalization and therefore death

Heart failure with preserved ejection fraction in elderly. From pathophysiology to treatment: an unresolved problem.

Heart failure with preserved ejection fraction (HFpEF) has a significant impact on healthcare resources and while its occurrence in the elderly is increasing, its prognosis has not improved. Despite the prevalence of HFpEF, the understanding of its pathophysiology is still incomplete, and optimal treatment remains largely undefined. The net clinical benefit of medical treatment with ACE inhibitors, ARBs, MRAs and beta-blockers has led to the incorporation of these drugs into HF clinical practice guidelines. However, little or no progress has been done for patients with HFpEF and there are no convincing and validated therapies able to reduce mortality or morbidity. HFpEF is a heterogeneous clinical syndrome embracing varieties of phenotypes and could benefit from a phenotype-specific approach. In the era of precision medicine, targeted approaches have proved effective in various disciplinary medical settings and for this reason this modern approach should be encouraged also in cardiology. In elderly patients, multi-level strategies and interventions aimed at improving adherence to guidelines and tailoring therapy, could be the key to improving outcome, and to reducing costs related to HF-related re-admissions. In the present review we briefly discuss current information available regarding pathophysiology, outcome, treatment and safety of the most common drugs used in this "geriatric syndrome"

Comparative Effectiveness and Safety of Monoclonal Antibodies (Bevacizumab, Cetuximab, and Panitumumab) in Combination with Chemotherapy for Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis

Background: The last decade has seen the increasing use of biological medicines in combination with chemotherapy containing 5- Fluorouracil/oxaliplatin or irinotecan for the treatment of metastatic colorectal cancer (mCRC). These combinations have resulted in increased progression-free survival (PFS) in patients with mCRC; however, there are remaining concerns over the extent of their effect on overall survival (OS). Published studies to date suggest no major differences between the three currently available monoclonal antibodies (MoAbs); however, there are differences in costs. In addition, there is rising litigation in Brazil in order to access these medicines as they are currently not reimbursed. Objective: To compare the effectiveness and safety of three MoAbs (bevacizumab, cetuximab and panitumumab) associated with fluoropyrimidine-based chemotherapy regimens or compared to fluoropyrimidine-based chemotherapy alone in patients with mCRC through an updated systematic review and meta-analysis with concurrent or non concurrent observational cohort studies to guide the authorities and judiciary. Method: A systematic review and meta-analysis was performed based on cohort studies published in databases up to November 2017. Effectiveness measures include OS, PFS, post-progression survival (PPS), RECIST (Response Evaluation Criteria In Solid Tumors), response rate, metastasectomy and safety. The methodological quality of the studies was also evaluated. Results: 21 observational cohort studies were included. There were statistically significant and clinically relevant benefits in patients treated with bevacizumab versus no bevacizumab mainly around OS, PFS, PPS and the metastasectomy rate, but not for the disease control rates. However, there was an increase in treatment-related toxicities, and concerns with the heterogeneity of the studies. Conclusion: The results pointed to an advantage in favor of bevacizumab for OS, PFS, PPS, and metastasectomy. Although this advantage may be considered clinically modest, bevacizumab represents a hope for increased survival and a chance of metastasectomy for patients with mCRC. However, there are serious adverse events associated with its use, especially severe hypertension and gastrointestinal perforation that need to be considered

Women's experiences of living with a rare disease, lymphangioleiomyomatosis (LAM): A life history study

Women’s experiences of living with a rare disease, lymphangioleiomyomatosis (LAM): A life history study LAM is a rare, potentially life limiting, multisystem condition, affecting almost exclusively women and characterised by progressive cystic lung disease. This study aimed to understand the meaning of women’s experiences of living with LAM over time and how they were affected by the rarity of LAM. Life history methodology was used to fulfill the aim of the study. Interviews were conducted with 19 women living with LAM. Each participant's life story was analysed for turning points and themes using Rosenthal's (1993) biographic interpretive method. Following cross case analysis, a collective life history focused on the participants’ illness experiences was constructed. The participants revealed diagnosis, commencing oxygen therapy, respiratory failure, and receiving a transplant as turning points of significant life disruption. The rarity of LAM created feelings of isolation and uncertainty and a need for self-reliance and self-advocacy to access appropriate information, care and treatment. The participants developed resilience as they adapted to their illness in a period of transition. Resilience was a dynamic learning process of finding meaning and gaining knowledge and competence in illness self-management. It enabled them to experience wellness and constructively manage health-related and social changes over the course of living with LAM

Exercise Prescription for Chronic Disease Management

The beneficial role of exercise in chronic disease management is well recognized, but the challenge of effective exercise prescription within primary care persists. Initiatives requesting clinicians to prescribe specific exercises to their patients has left two underlying questions: 1) Who is the most appropriate clinician to prescribe exercise to meet the unique needs of individuals living with more than one disease; 2) How does this clinician ensure appropriate and safe exercise prescriptions are provided? Three studies were completed to begin addressing the aforementioned questions. A nationally distributed survey compared exercise curricula between physiotherapy, nursing, and medical programs, while a systematic literature review showed overlapping physiological and subjective markers that clinicians may use to define safe exercises for individuals living with multiple chronic diseases. Finally a novel approach and a preliminary tool are presented to help guide how exercise prescription could be implemented in primary care. Findings suggest that PTs should lead the exercise prescription movement in primary care with nurses and physicians as exercise advisors or facilitators. Evidence from this thesis supports improving access to PT in primary care. Also, exercise prescription in individuals with multiple chronic diseases from a body-systems perspective is proposed, rather than solely relying on the dominantly available single-disease exercise guidelines. Finally, a newly developed exercise prescription approach is presented, which takes into account the advisors role in exercise prescription, while a preliminary tool is proposed that considers physiological and personal profiles of individuals who have more than one chronic disease, to guide clinicians in developing tailored exercise prescriptions in the primary care context

An observational study of Donor Ex Vivo Lung Perfusion in UK lung transplantation: DEVELOP-UK

Background: Many patients awaiting lung transplantation die before a donor organ becomes available. Ex vivo lung perfusion (EVLP) allows initially unusable donor lungs to be assessed and reconditioned for clinical use. Objective: The objective of the Donor Ex Vivo Lung Perfusion in UK lung transplantation study was to evaluate the clinical effectiveness and cost-effectiveness of EVLP in increasing UK lung transplant activity. Design: A multicentre, unblinded, non-randomised, non-inferiority observational study to compare transplant outcomes between EVLP-assessed and standard donor lungs. Setting: Multicentre study involving all five UK officially designated NHS adult lung transplant centres. Participants: Patients aged ≥ 18 years with advanced lung disease accepted onto the lung transplant waiting list. Intervention: The study intervention was EVLP assessment of donor lungs before determining suitability for transplantation. Main outcome measures: The primary outcome measure was survival during the first 12 months following lung transplantation. Secondary outcome measures were patient-centred outcomes that are influenced by the effectiveness of lung transplantation and that contribute to the health-care costs. Results: Lungs from 53 donors unsuitable for standard transplant were assessed with EVLP, of which 18 (34%) were subsequently transplanted. A total of 184 participants received standard donor lungs. Owing to the early closure of the study, a non-inferiority analysis was not conducted. The Kaplan–Meier estimate of survival at 12 months was 0.67 [95% confidence interval (CI) 0.40 to 0.83] for the EVLP arm and 0.80 (95% CI 0.74 to 0.85) for the standard arm. The hazard ratio for overall 12-month survival in the EVLP arm relative to the standard arm was 1.96 (95% CI 0.83 to 4.67). Patients in the EVLP arm required ventilation for a longer period and stayed longer in an intensive therapy unit (ITU) than patients in the standard arm, but duration of overall hospital stay was similar in both groups. There was a higher rate of very early grade 3 primary graft dysfunction (PGD) in the EVLP arm, but rates of PGD did not differ between groups after 72 hours. The requirement for extracorporeal membrane oxygenation (ECMO) support was higher in the EVLP arm (7/18, 38.8%) than in the standard arm (6/184, 3.2%). There were no major differences in rates of chest radiograph abnormalities, infection, lung function or rejection by 12 months. The cost of EVLP transplants is approximately £35,000 higher than the cost of standard transplants, as a result of the cost of the EVLP procedure, and the increased ECMO use and ITU stay. Predictors of cost were quality of life on joining the waiting list, type of transplant and number of lungs transplanted. An exploratory model comparing a NHS lung transplant service that includes EVLP and standard lung transplants with one including only standard lung transplants resulted in an incremental cost-effectiveness ratio of £73,000. Interviews showed that patients had a good understanding of the need for, and the processes of, EVLP. If EVLP can increase the number of usable donor lungs and reduce waiting, it is likely to be acceptable to those waiting for lung transplantation. Study limitations include small numbers in the EVLP arm, limiting analysis to descriptive statistics and the EVLP protocol change during the study. Conclusions: Overall, one-third of donor lungs subjected to EVLP were deemed suitable for transplant. Estimated survival over 12 months was lower than in the standard group, but the data were also consistent with no difference in survival between groups. Patients receiving these additional transplants experience a higher rate of early graft injury and need for unplanned ECMO support, at increased cost. The small number of participants in the EVLP arm because of early study termination limits the robustness of these conclusions. The reason for the increased PGD rates, high ECMO requirement and possible differences in lung injury between EVLP protocols needs evaluation

The roles of tumour necrosis factor and its receptors in the injury, inflammation and resolution of acute lung injury

The acute respiratory distress syndrome (ARDS) remains a major cause of morbidity and mortality in the intensive care. Despite improvements in intensive care and advances in respiratory support, mortality remains high with no active treatments. Tumour necrosis factor (TNF) is a cytokine that has been implicated in ARDS for over 30 years but its precise roles remain elusive. It signals through two main receptors – the p55 TNF receptor and p75 TNF receptor. The first aspect of this thesis investigated the roles of TNF receptors (TNFR) in the early phase of acute acid-induced lung injury. Using genetically modified mice we discovered that alveolar oedema, as a result of acid aspiration, was specifically mediated through the p55-TNFR, whereas, the p75-TNFR promoted a protective effect. Alveolar oedema formation occurred through an effect independent to the downstream inflammatory events, but instead through the activation of TNF/p55-TNFR/caspase-8 death signalling specifically in the alveolar epithelium. Furthermore, this death-signalling axis led to a reduced alveolar epithelial fluid clearance rate. Epithelial dysfunction occurred prior to epithelial cell death and pharmacological blockade of caspase-8 rescued epithelial function with improvements in gas exchange, suggesting that the activation of caspase-8 per se induced this functional deficit in the alveolar epithelium. The second part of the thesis describes the development of a longer-term model of acid aspiration aimed at extending investigation into the later, arguably more clinically relevant, phases of lung injury (0-10 days). Mice showed respiratory physiology that reached clinical ARDS criteria with significant inflammation and epithelial/endothelial injury, which importantly, resolved facilitating investigation into reparative processes. This model was further characterised using novel flow cytometry protocols to examine the compartmental location of leukocytes during the various phases of ARDS. This model provides a translational platform to allow investigation into the injurious, inflammatory, and resolution mechanisms of ARDS.Open Acces