Elective Open Suprarenal Aneurysm Repair in England from 2000 to 2010 an Observational Study of Hospital Episode Statistics

Background: Open surgery is widely used as a benchmark for the results of fenestrated endovascular repair of complex abdominal aortic aneurysms (AAA). However, the existing evidence stems from single-centre experiences, and may not be reproducible in wider practice. National outcomes provide valuable information regarding the safety of suprarenal aneurysm repair. Methods: Demographic and clinical data were extracted from English Hospital Episodes Statistics for patients undergoing elective suprarenal aneurysm repair from 1 April 2000 to 31 March 2010. Thirty-day mortality and five-year survival were analysed by logistic regression and Cox proportional hazards modeling. Results: 793 patients underwent surgery with 14% overall 30-day mortality, which did not improve over the study period. Independent predictors of 30-day mortality included age, renal disease and previous myocardial infarction. 5-year survival was independently reduced by age, renal disease, liver disease, chronic pulmonary disease, and known metastatic solid tumour. There was significant regional variation in both 30-day mortality and 5-year survival after risk-adjustment. Regional differences in outcome were eliminated in a sensitivity analysis for perioperative outcome, conducted by restricting analysis to survivors of the first 30 days after surgery. Conclusions: Elective suprarenal aneurysm repair was associated with considerable mortality and significant regional variation across England. These data provide a benchmark to assess the efficacy of complex endovascular repair of supra-renal aneurysms, though cautious interpretation is required due to the lack of information regarding aneurysm morphology. More detailed study is required, ideally through the mandatory submission of data to a national registry of suprarenal aneurysm repair

Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.

BackgroundT cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.MethodsPatients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.ResultsFourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.ConclusionThese findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity

Clinical course, costs and predictive factors for response to treatment in carpal tunnel syndrome: The PALMS study protocol

Background Carpal tunnel syndrome (CTS) is the most common neuropathy of the upper limb and a significant contributor to hand functional impairment and disability. Effective treatment options include conservative and surgical interventions, however it is not possible at present to predict the outcome of treatment. The primary aim of this study is to identify which baseline clinical factors predict a good outcome from conservative treatment (by injection) or surgery in patients diagnosed with carpal tunnel syndrome. Secondary aims are to describe the clinical course and progression of CTS, and to describe and predict the UK cost of CTS to the individual, National Health Service (NHS) and society over a two year period. Methods/Design In this prospective observational cohort study patients presenting with clinical signs and symptoms typical of CTS and in whom the diagnosis is confirmed by nerve conduction studies are invited to participate. Data on putative predictive factors are collected at baseline and follow-up through patient questionnaires and include standardised measures of symptom severity, hand function, psychological and physical health, comorbidity and quality of life. Resource use and cost over the 2 year period such as prescribed medications, NHS and private healthcare contacts are also collected through patient self-report at 6, 12, 18 and 24 months. The primary outcome used to classify treatment success or failures will be a 5-point global assessment of change. Secondary outcomes include changes in clinical symptoms, functioning, psychological health, quality of life and resource use. A multivariable model of factors which predict outcome and cost will be developed. Discussion This prospective cohort study will provide important data on the clinical course and UK costs of CTS over a two-year period and begin to identify predictive factors for treatment success from conservative and surgical interventions

A systematic review of frameworks for the interrelationships of mental health evidence and policy in low- and middle-income countries

Background: The interrelationships between research evidence and policy-making are complex. Different theoretical frameworks exist to explain general evidence–policy interactions. One largely unexplored element of these interrelationships is how evidence interrelates with, and influences, policy/political agenda-setting. This review aims to identify the elements and processes of theories, frameworks and models on interrelationships of research evidence and health policy-making, with a focus on actionability and agenda-setting in the context of mental health in low- and middle-income countries (LMICs). Methods: A systematic review of theories was conducted based on the BeHeMOTh search method, using a tested and refined search strategy. Nine electronic databases and other relevant sources were searched for peer-reviewed and grey literature. Two reviewers screened the abstracts, reviewed full-text articles, extracted data and performed quality assessments. Analysis was based on a thematic analysis. The included papers had to present an actionable theoretical framework/model on evidence and policy interrelationships, such as knowledge translation or evidence-based policy, specifically target the agenda-setting process, focus on mental health, be from LMICs and published in English. Results: From 236 publications included in the full text analysis, no studies fully complied with our inclusion criteria. Widening the focus by leaving out ‘agenda-setting’, we included ten studies, four of which had unique conceptual frameworks focusing on mental health and LMICs but not agenda-setting. The four analysed frameworks confirmed research gaps from LMICs and mental health, and a lack of focus on agenda-setting. Frameworks and models from other health and policy areas provide interesting conceptual approaches and lessons with regards to agenda-setting. Conclusion: Our systematic review identified frameworks on evidence and policy interrelations that differ in their elements and processes. No framework fulfilled all inclusion criteria. Four actionable frameworks are applicable to mental health and LMICs, but none specifically target agenda-setting. We have identified agenda-setting as a research theory gap in the context of mental health knowledge translation in LMICs. Frameworks from other health/policy areas could offer lessons on agenda-setting and new approaches for creating policy impact for mental health and to tackle the translational gap in LMICs

Rare site giant cell tumors: report of two cases on phalanges of the finger and review of literature

Giant cell tumor (GCT) of bone arising from a phalanx of a finger is extremely rare. We report two cases of GCT arising from a phalanx of a finger. One case presented with recurrence following the amputation of the left ring finger (performed elsewhere). He was treated successfully with ray amputation. The other case was treated primarily by intralesional curettage and autogenous bone graft. At their most recent follow-ups (80 and 24 months, respectively), both were recurrence free and had returned to their previous occupational and recreational activities

Pathophysiological classification of chronic rhinosinusitis

BACKGROUND: Recent consensus statements demonstrate the breadth of the chronic rhinosinusitis (CRS) differential diagnosis. However, the classification and mechanisms of different CRS phenotypes remains problematic. METHOD: Statistical patterns of subjective and objective findings were assessed by retrospective chart review. RESULTS: CRS patients were readily divided into those with (50/99) and without (49/99) polyposis. Aspirin sensitivity was limited to 17/50 polyp subjects. They had peripheral blood eosinophilia and small airways obstruction. Allergy skin tests were positive in 71% of the remaining polyp subjects. IgE was<10 IU/ml in 8/38 polyp and 20/45 nonpolyp subjects (p = 0.015, Fisher's Exact test). CT scans of the CRS without polyp group showed sinus mucosal thickening (probable glandular hypertrophy) in 28/49, and nasal osteomeatal disease in 21/49. Immunoglobulin isotype deficiencies were more prevalent in nonpolyp than polyp subjects (p < 0.05). CONCLUSION: CRS subjects were retrospectively classified in to 4 categories using the algorithm of (1) polyp vs. nonpolyp disease, (2) aspirin sensitivity in polyposis, and (3) sinus mucosal thickening vs. nasal osteomeatal disease (CT scan extent of disease) for nonpolypoid subjects. We propose that the pathogenic mechanisms responsible for polyposis, aspirin sensitivity, humoral immunodeficiency, glandular hypertrophy, eosinophilia and atopy are primary mechanisms underlying these CRS phenotypes. The influence of microbial disease and other factors remain to be examined in this framework. We predict that future clinical studies and treatment decisions will be more logical when these interactive disease mechanisms are used to stratify CRS patients

Mortality from HIV-associated meningitis in sub-Saharan Africa: a systematic review and meta-analysis.

INTRODUCTION: HIV-associated cryptococcal, TB and pneumococcal meningitis are the leading causes of adult meningitis in sub-Saharan Africa (SSA). We performed a systematic review and meta-analysis with the primary aim of estimating mortality from major causes of adult meningitis in routine care settings, and to contrast this with outcomes from clinical trial settings. METHODS: We searched PubMed, EMBASE and the Cochrane Library for published clinical trials (defined as randomized-controlled trials (RCTs) or investigator-managed prospective cohorts) and observational studies that evaluated outcomes of adult meningitis in SSA from 1 January 1990 through 15 September 2019. We performed random effects modelling to estimate pooled mortality, both in clinical trial and routine care settings. Outcomes were stratified as short-term (in-hospital or two weeks), medium-term (up to 10 weeks) and long-term (up to six months). RESULTS AND DISCUSSION: Seventy-nine studies met inclusion criteria. In routine care settings, pooled short-term mortality from cryptococcal meningitis was 44% (95% confidence interval (95% CI):39% to 49%, 40 studies), which did not differ between amphotericin (either alone or with fluconazole) and fluconazole-based induction regimens, and was twofold higher than pooled mortality in clinical trials using amphotericin based treatment (21% (95% CI:17% to 25%), 17 studies). Pooled short-term mortality of TB meningitis was 46% (95% CI: 33% to 59%, 11 studies, all routine care). For pneumococcal meningitis, pooled short-term mortality was 54% in routine care settings (95% CI:44% to 64%, nine studies), with similar mortality reported in two included randomized-controlled trials. Few studies evaluated long-term outcomes. CONCLUSIONS: Mortality rates from HIV-associated meningitis in SSA are very high under routine care conditions. Better strategies are needed to reduce mortality from HIV-associated meningitis in the region

Postural instability in an immersive Virtual Reality adapts with repetition and includes directional and gender specific effects

The ability to handle sensory conflicts and use the most appropriate sensory information is vital for successful recovery of human postural control after injury. The objective was to determine if virtual reality (VR) could provide a vehicle for sensory training, and determine the temporal and spatial nature of such adaptive changes. Twenty healthy subjects participated in the study (10 females). The subjects watched a 90-second VR simulation of railroad (rollercoaster) motion in mountainous terrain during five repeated simulations, while standing on a force platform that recorded their stability. The immediate response to watching the VR movie was an increased level of postural instability. Repeatedly watching the same VR movie significantly reduced both the anteroposterior (62%, p < 0.001) and lateral (47%, p = 0.001) energy used. However, females adapted more slowly to the VR stimuli as reflected by higher use of total (p = 0.007), low frequency (p = 0.027) and high frequency (p = 0.026) energy. Healthy subjects can significantly adapt to a multidirectional, provocative, visual environment after 4–5 repeated sessions of VR. Consequently, VR technology might be an effective tool for rehabilitation involving visual desensitisation. However, some females may require more training sessions to achieve effects with VR

Role of Caveolae in Cardiac Protection

Myocardial ischemia/reperfusion injury is a major cause of morbidity and mortality. The molecular signaling pathways involved in cardiac protection from myocardial ischemia/reperfusion injury are complex. An emerging idea in signal transduction suggests the existence of spatially organized complexes of signaling molecules in lipid-rich microdomains of the plasma membrane known as caveolae. Caveolins—proteins abundant in caveolae—provide a scaffold to organize, traffic, and regulate signaling molecules. Numerous signaling molecules involved in cardiac protection are known to exist within caveolae or interact directly with caveolins. Over the last 4 years, our laboratories have explored the hypothesis that caveolae are vitally important to cardiac protection from myocardial ischemia/reperfusion injury. We have provided evidence that (1) caveolae and the caveolin isoforms 1 and 3 are essential for cardiac protection from myocardial ischemia/reperfusion injury, (2) stimuli that produce preconditioning of cardiac myocytes, including brief periods of ischemia/reperfusion and exposure to volatile anesthetics, alter the number of membrane caveolae, and (3) cardiac myocyte-specific overexpression of caveolin-3 can produce innate cardiac protection from myocardial ischemia/reperfusion injury. The work demonstrates that caveolae and caveolins are critical elements of signaling pathways involved in cardiac protection and suggests that caveolins are unique targets for therapy in patients at risk of myocardial ischemia