Strategies for anti-fibrotic therapies.

The fibrotic diseases encompass a wide spectrum of entities including such multisystemic diseases as systemic sclerosis, nephrogenic systemic fibrosis and sclerodermatous graft versus host disease, as well as organ-specific disorders such as pulmonary, liver, and kidney fibrosis. Collectively, given the wide variety of affected organs, the chronic nature of the fibrotic processes, and the large number of individuals suffering their devastating effects, these diseases pose one of the most serious health problems in current medicine and a serious economic burden to society. Despite these considerations there is currently no accepted effective treatment. However, remarkable progress has been achieved in the elucidation of their pathogenesis including the identification of the critical role of myofibroblasts and the determination of molecular mechanisms that result in the transcriptional activation of the genes responsible for the fibrotic process. Here we review the origin of the myofibroblast and discuss the crucial regulatory pathways involving multiple growth factors and cytokines that participate in the pathogenesis of the fibrotic process. Potentially effective therapeutic strategies based upon this new information are considered in detail and the major challenges that remain and their possible solutions are presented. It is expected that translational efforts devoted to convert this new knowledge into novel and effective anti-fibrotic drugs will be forthcoming in the near future. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease

A prospective observational study of mycophenolate mofetil treatment in progressive diffuse cutaneous systemic sclerosis of recent onset.

OBJECTIVE: A prospective observational study of mycophenolate mofetil (MMF) treatment in patients with diffuse progressive cutaneous systemic sclerosis (SSc) of recent onset. METHODS: Twenty-five previously untreated consecutive patients with recent-onset (\u3c 24 mo) diffuse progressive cutaneous SSc received MMF as the only disease-modifying therapy. Modified Rodnan skin score (mRSS) and affected body surface area (BSA) were compared from initiation of MMF to study end. Pulmonary function tests performed at the same institution before therapy and at study end were available in 15 patients. Histopathology and real-time PCR assessment of fibrosis-related gene expression were performed before and after treatment in skin biopsies from 3 patients. RESULTS: At 18.2 ± 8.73 months of MMF therapy (median 2000 mg/day) the mRSS decreased from 24.56 ± 8.62 to 14.52 ± 10.9 (p = 0.0004) and the affected BSA from 36% ± 16% to 14% ± 13.3% (p = 0.00001). Pulmonary function tests remained stable from initiation of MMF to the end of the study. Skin histopathology showed a remarkable reduction in accumulation of fibrotic tissue. Real-time PCR of skin biopsies demonstrated a marked decrease in expression of fibrosis-related genes. CONCLUSION: Patients with diffuse progressive cutaneous SSc of recent onset treated with MMF experienced marked improvement in skin involvement and stabilization of pulmonary function. Skin biopsies from 3 patients demonstrated histopathological improvement and decreased expression of fibrosis-related genes

Mechanism of NSF: New evidence challenging the prevailing theory

Nephrogenic systemic fibrosis (NSF) has been associated with the administration of gadolinium-based contrast agents in patients with severely impaired renal function (SIRF), endstage renal disease (ESRD), or acute renal failure (ARF). Since the vast majority of these patients do not get NSF, it is highly likely that patient factors play a role in its development. Although free or dechelated gadolinium is thought by some to be the only trigger of NSF, recent evidence suggests that chelated gadolinium may be important. Chelated gadolinium such as Omniscan (gadodiamide) and Magnevist (gadopentetate) can directly stimulate macrophages and monocytes in vitro to release profibrotic cytokines and growth factors capable of initiating and supporting the tissue fibrosis that is characteristic of NSF. In addition, an effect of chelated gadolinium on fibroblasts has also been demonstrated. Chelated gadolinium in the form of Omniscan, Magnevist, MultiHance, and ProHance increased proliferation of human dermal fibroblasts. Indeed, increased numbers of macrophages, together with activated fibroblasts and fibrocytes, are essential cells in the fibrotic process and are present in NSF skin. Accordingly, it is important that chelated gadolinium, in combination with patient cofactors, is considered in the etiology of NSF associated with enhanced scans

The Role of Radiotherapy In the Management of Massive Intrahepatic Cholangiocarcinoma

https://openworks.mdanderson.org/sumexp21/1005/thumbnail.jp

Systemic sclerosis disease modification clinical trials design: quo vadis?

The purpose of this manuscript is to discuss relevant aspects of clinical trials for Systemic Sclerosis (SSc) and to identify important considerations for the design of SSc disease modification clinical trials. Placebo randomized controlled trials with appropriate identification of SSc patients with diffuse progressive SSc skin involvement of recent onset, along with a rescue strategy for patients with worsening lung and skin involvement are suggested. If change in skin thickening is a major outcome of the study, the selection of patients with recent onset of disease and a predetermined degree of skin involvement are crucial requirements. The trial duration should be of at least 12 months. Sample size calculations should consider differences that exceed the Minimal Important Difference. Other relevant trial designs and potential threats to study validity are also discussed. Previous SSc-disease modifying trials have been beset by high dropout rates. Analyses on the subset of subjects completing the trial or applying the last observation- carried-forward approach can potentially lead to biased estimates and false conclusions. Strategies for retention of subjects should be included at the design stage and analyses to account for missing data should be performed

Additive friction stir processing and hybrid metal additive manufacturing of high melting point materials: A review

Ever since the beginning of 4th industrial revolution, metal additive manufacturing has revolutionized the paradigm of printing high melting point materials. In this context, this paper reviews experimental and computational aspects of friction stir processing and hybrid techniques applied for metal additive manufacturing of high melting point materials like steel, and titanium alloys. Initially, friction stir processing working principle has been discussed. Secondly, friction stir processing is compared with other severe plastic deformation techniques and summarized their advantages, disadvantages and applications in a tabular form. Then based on the state-of-the-art of literature, additive friction stir processing and hybrid metal additive manufacturing processes are discussed for high melting point materials and results have been presented with respect to their microstructural developments, mechanical behavior, etc. Finally, gaps are highlighted for high melting point materials that shows importance of selecting process parameters, tooling capacity, computational analysis, mathematical modelling, etc., and presented these as future scope of work

The perceived influence of sports betting marketing techniques on disordered gamblers in treatment

Research question: The proliferation of marketing stimuli to gamble on sports is a growing concern in many jurisdictions. However, little is known about the perceived influence of marketing among the most severe group of problem gamblers (i.e., those receiving treatment). This study aims to explore how problem sports bettors perceive gambling marketing is affecting them. Research methods: It examines the opinions of 43 sports bettors undergoing treatment for gambling disorder. Seven qualitative focus groups were carried out to understand their self-reported views on gambling marketing influence. Responses were analysed using a thematic analysis approach. Results and findings: The results showed three main marketing paths for impact: (i) mass-mediated marketing stimuli, (ii) personalised marketing, and (iii) stimuli inside betting shops. Price-related promotions (e.g., bonuses) were viewed as especially harmful. Also, the use of cognitive biases by bookmakers made it harder for sports bettors to stop gambling, and constantly facilitated their relapse. Implications: The paper provides evidence to substantiate regulatory action to restrict gambling promotions. In addition, it recommends gambling companies to develop responsible gambling measures to reduce the cognitive biases ingrained in their sports betting products

Do online gambling products require traditional therapy for gambling disorder to change? Evidence from focus group interviews with mental health professionals treating online gamblers

Online gambling has significantly altered the situational and structural characteristics of gambling products, to the extent that online gamblers might be substantially different from traditional offline gamblers. A growing body of literature has identified the evolving features of online gambling and the individuals who engage in it. However, beyond understanding the individual characteristics of this subgroup, relatively less effort has been made to examine whether existing cognitive-behavioural therapy (CBT) approaches are still entirely relevant for online problem gamblers, or whether changes are needed to adapt according to gambling mode of access. To understand what kind of challenges online gambling poses to mental health professionals dealing with disordered gamblers, four focus groups comprising 28 Spanish participants were carried out. All the treatment providers had ongoing experience with online gamblers undergoing treatment, and included clinical psychologists, mental health social workers, and a medical doctor. The data were examined using thematic analysis. The analysis identified five main themes that characterised online gamblers: (1) being of younger age, (2) lack of conflicts at home and at work/educational centre, rarely presenting violent or aggressive behaviour, (3) gambling disorder only being identified by overdue debt, (4) co-occurring conditions with technology-related abuse rather than other substance-related addictions, and (5) skill-based gambling. The study highlights mental health workers’ perceived insecurities about how to best treat online gamblers, and discusses the specific characteristics that CBT for gambling disorder might need to incorporate to adjust for this particular group of gamblers

Hospital Outcomes Among COVID-19 Hospitalizations With Myocarditis from the California State Inpatient Database

Many case reports have indicated that myocarditis could be a prognostic factor for predicting morbidity and mortality among patients with COVID-19. In this study, using a large database we examined the association between myocarditis among COVID-19 hospitalizations and in-hospital mortality and other adverse hospital outcomes. The present study was a retrospective analysis of data collected in the California State Inpatient Database during 2020. All hospitalizations for COVID-19 were included in the analysis and grouped into those with and without myocarditis. The outcomes were in-hospital mortality, cardiac arrest, cardiogenic shock, mechanical ventilation, and acute respiratory distress syndrome. Propensity score matching, followed by conditional logistic regression, was performed to find the association between myocarditis and outcomes. Among 164,417 COVID-19 hospitalizations, 578 (0.4%) were with myocarditis. After propensity score matching, the rate of in-hospital mortality was significantly higher among COVID-19 hospitalizations with myocarditis (30.0% vs 17.5%, p \u3c0.001). Survival analysis with log-rank test showed that 30-day survival rates were significantly lower among those with myocarditis (39.5% vs 46.3%, p \u3c0.001). Conditional logistic regression analysis showed that the odds of cardiac arrest (odds ratio [OR] 1.90, 95% confidence interval [CI] 1.16 to 3.14), cardiogenic shock (OR 4.13, 95% CI 2.14 to 7.99), mechanical ventilation (OR 3.30, 95% CI 2.47 to 4.41), and acute respiratory distress syndrome (OR 2.49, 95% CI 1.70 to 3.66) were significantly higher among those with myocarditis. Myocarditis was associated with greater rates of in-hospital mortality and adverse hospital outcomes among patients with COVID-19, and early suspicion is important for prompt diagnosis and management

Where, when and what? A time study of surgeons' work in urology.

INTRODUCTION: Staff time is a relevant resource in the delivery of health care interventions. Its measurement is a prerequisite for unit costing but usually complex. The aim of this study was to analyse the distribution of surgeons' work time among types and places of activities. A second aim was to use these data to calculate costs per unit of output. METHODS: A self-reporting work sampling study was carried out at a department of Urology. All of twelve surgeons involved in clinical care participated in a two-week analysis of their work time. RESULTS: A total of 2,485 data-points were collected, representing about 1,242 hours of work time. Surgeons spent the greater part of their work time in direct patient care, but substantial shares were required for documentation and organisation. Assistants were mainly required at the wards and consultants at the operating theatre and the outpatient unit. Staff costs of surgeons were 32 € and 29 € per patient day at the wards, respectively, 1.30 € per minute at the operating theatre and 32 € per visit at the outpatient unit. CONCLUSION: Results provided a basis for costing of health care interventions at the study site. However, future research should focus on the establishment of standardised terminology in order to increase transferability of results