Management of acute upper gastrointestinal bleeding:An update for the general physician

Acute upper gastrointestinal bleed (AUGIB) is one of the most common medical emergencies in the UK, with roughly one presentation every 6 min. Despite advances in therapeutics and endoscopy provision, mortality following AUGIB over the last two decades has remained high, with over 9,000 deaths annually in the UK; consequently, several national bodies have published UK-relevant guidelines. Despite this, the 2015 UK National Confidential Enquiry into Patient Outcome and Death in AUGIB highlighted variations in practice, raised concerns regarding suboptimal patient care and released a series of recommendations. This review paper incorporates the latest available evidence and UK-relevant guidelines to summarise the optimal pre-endoscopic, endoscopic, and post-endoscopic approach to and management of non-variceal and variceal AUGIB that will be of practical value to both general physicians and gastroenterologists

Testicular seminoma – unusual histology and staging with sub epithelial spread of seminoma along the vas deferans

BACKGROUND: The route of local and metastatic spread of testicular seminoma is well recognised and accepted. The spread is via lymphatics to the paraaortic nodes. CASE PRESENTATION: We present a case report of testicular seminoma in a 56 year old man with previously unreported histological findings. In this case seminoma tumour cells did not appear to have spread by the expected lymphatic route. There was no involvement of retro-peritoneal para-aortic lymph nodes. The tumour appeared to have spread directly along the vas deferans in the sub epithelial plane to the mesenteric lymph nodes. CONCLUSION: This type of seminoma tumour spread has not previously been described and it is not a recognised route for metastasis by seminoma tumour. In this case the macroscopic clinical appearance was of a stage I tumour with normal tumour markers. However, the pathological stage of the tumour was surprisingly increased to stage III on the basis of histology and CT radiological findings. We present the unusual histological findings. In view of this unusual histological finding we reinforce the need for accurate staging and for resection of the spermatic cord close to the deep inguinal ring. Accurate staging is crucial in planning the treatment and follow up of seminoma and determines the prognosis

Effects of gastroprotectant drugs for the prevention and treatment of peptic ulcer disease and its complications: a meta-analysis of randomised trials

Background: Gastroprotectant drugs are used for the prevention and treatment of peptic ulcer disease and might reduce its associated complications, but reliable estimates of the effects of gastroprotectants in different clinical settings are scarce. We aimed to examine the effects of proton-pump inhibitors (PPIs), prostaglandin analogues, and histamine-2 receptor antagonists (H2RAs) in different clinical circumstances by doing meta-analyses of tabular data from all relevant unconfounded randomised trials of gastroprotectant drugs. Background: Gastroprotectant drugs are used for the prevention and treatment of peptic ulcer disease and might reduce its associated complications, but reliable estimates of the effects of gastroprotectants in different clinical settings are scarce. We aimed to examine the effects of proton-pump inhibitors (PPIs), prostaglandin analogues, and histamine-2 receptor antagonists (H2RAs) in different clinical circumstances by doing meta-analyses of tabular data from all relevant unconfounded randomised trials of gastroprotectant drugs. Methods: We searched MEDLINE and Embase from Jan 1, 1950, to Dec 31, 2015, to identify unconfounded, randomised trials of a gastroprotectant drug (defined as a PPI, prostaglandin analogue, or H2RA) versus control, or versus another gastroprotectant. Two independent researchers reviewed the search results and extracted the prespecified outcomes and key characteristics for each trial. We did meta-analyses of the effects of gastroprotectant drugs on ulcer development, bleeding, and mortality overall, according to the class of gastroprotectant, and according to the individual drug within a gastroprotectant class. Findings: We identified comparisons of gastroprotectant versus control in 849 trials (142 485 participants): 580 prevention trials (110 626 participants), 233 healing trials (24 033 participants), and 36 trials for the treatment of acute upper gastrointestinal bleeding (7826 participants). Comparisons of one gastroprotectant drug versus another were available in 345 trials (64 905 participants), comprising 160 prevention trials (32 959 participants), 167 healing trials (28 306 participants), and 18 trials for treatment of acute upper gastrointestinal bleeding (3640 participants). The median number of patients in each trial was 78 (IQR 44·0–210·5) and the median duration was 1·4 months (0·9–2·8). In prevention trials, gastroprotectant drugs reduced development of endoscopic ulcers (odds ratio [OR] 0·27, 95% CI 0·25–0·29; p<0·0001), symptomatic ulcers (0·25, 0·22–0·29; p<0·0001), and upper gastrointestinal bleeding (0·40, 0·32–0·50; p<0·0001), but did not significantly reduce mortality (0·85, 0·69–1·04; p=0·11). Larger proportional reductions in upper gastrointestinal bleeding were observed for PPIs than for other gastroprotectant drugs (PPIs 0·21, 99% CI 0·12–0·36; prostaglandin analogues 0·63, 0·35–1·12; H2RAs 0·49, 0·30–0·80; phet=0·0005). Gastroprotectant drugs were effective in preventing bleeding irrespective of the use of non-steroidal anti-inflammatory drugs (phet=0·56). In healing trials, gastroprotectants increased endoscopic ulcer healing (3·49, 95% CI 3·28–3·72; p<0·0001), with PPIs more effective (5·22, 99% CI 4·00–6·80) than prostaglandin analogues (2·27, 1·91–2·70) and H2RAs (3·80, 3·44–4·20; phet<0·0001). In trials among patients with acute bleeding, gastroprotectants reduced further bleeding (OR 0·68, 95% CI 0·60–0·78; p<0·0001), blood transfusion (0·75, 0·65–0·88; p=0·0003), further endoscopic intervention (0·56, 0·45–0·70; p<0·0001), and surgery (0·72, 0·61–0·84; p<0·0001), but did not significantly reduce mortality (OR 0·90, 0·72–1·11; p=0·31). PPIs had larger protective effects than did H2RAs for further bleeding (phet=0·0107) and blood transfusion (phet=0·0130). Interpretation: Gastroprotectants, in particular PPIs, reduce the risk of peptic ulcer disease and its complications and promote healing of peptic ulcers in a wide range of clinical circumstances. However, this meta-analysis might have overestimated the benefits owing to small study bias

Survival from testicular cancer in England and Wales up to 2001

www.bjcancer.com For many years testicular cancer has been the prime example of the tumour that is chemocurable, even when metastatic. The disappointment in oncology is that these results have so far not been replicated in the more common solid tumours. Why this should be is not clear but germ-cell tumours retain sensitivity to chemotherapy in vitro and a number of mechanisms including reduced DNA repair capacity and proneness to apoptosis have been proposed (Mayer et al, 2003). Most patients with testicular cancer present after finding a lump in the testicle that may or may not be painful. A small proportion of patients present with symptoms of metastatic disease. With the exception of some patients with metastatic disease, initial treatment after first assessment is to remove the tumour by inguinal orchidectomy. Patients are staged by tumour marke

Clinical aspects of short-chain acyl-CoA dehydrogenase deficiency

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of mitochondrial fatty acid oxidation. SCADD is biochemically characterized by increased C4-carnitine in plasma and ethylmalonic acid in urine. The diagnosis of SCADD is confirmed by DNA analysis showing SCAD gene mutations and/or variants. SCAD gene variants are present in homozygous form in approximately 6% of the general population and considered to confer susceptibility to development of clinical disease. Clinically, SCADD generally appears to present early in life and to be most frequently associated with developmental delay, hypotonia, epilepsy, behavioral disorders, and hypoglycemia. However, these symptoms often ameliorate and even disappear spontaneously during follow-up and were found to be unrelated to the SCAD genotype. In addition, in some cases, symptoms initially attributed to SCADD could later be explained by other causes. Finally, SCADD relatives of SCADD patients as well as almost all SCADD individuals diagnosed by neonatal screening remained asymptomatic during follow-up. This potential lack of clinical consequences of SCADD has several implications. First, the diagnosis of SCADD should never preclude extension of the diagnostic workup for other potential causes of the observed symptoms. Second, patients and parents should be clearly informed about the potential lack of relevance of the disorder to avoid unfounded anxiety. Furthermore, to date, SCADD is not an optimal candidate for inclusion in newborn screening programs. More studies are needed to fully establish the relevance of SCADD and solve the question as to whether SCADD is involved in a multifactorial disease or represents a nondisease

Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling

Although concern remains about the athero-thrombotic risk posed by cyclo-oxygenase (COX)-2-selective inhibitors, recent data implicates rofecoxib, while celecoxib appears equivalent to NSAIDs naproxen and ibuprofen. We investigated the hypothesis that celecoxib activates AMP kinase (AMPK) signalling to enhance vascular endothelial protection. In human arterial and venous endothelial cells (EC), and in contrast to ibuprofen and naproxen, celecoxib induced the protective protein heme oxygenase-1 (HO-1). Celecoxib derivative 2,5-dimethyl-celecoxib (DMC) which lacks COX-2 inhibition also upregulated HO-1, implicating a COX-2-independent mechanism. Celecoxib activated AMPKα(Thr172) and CREB-1(Ser133) phosphorylation leading to Nrf2 nuclear translocation. Importantly, these responses were not reproduced by ibuprofen or naproxen, while AMPKα silencing abrogated celecoxib-mediated CREB and Nrf2 activation. Moreover, celecoxib induced H-ferritin via the same pathway, and increased HO-1 and H-ferritin in the aortic endothelium of mice fed celecoxib (1000 ppm) or control chow. Functionally, celecoxib inhibited TNF-α-induced NF-κB p65(Ser536) phosphorylation by activating AMPK. This attenuated VCAM-1 upregulation via induction of HO-1, a response reproduced by DMC but not ibuprofen or naproxen. Similarly, celecoxib prevented IL-1β-mediated induction of IL-6. Celecoxib enhances vascular protection via AMPK-CREB-Nrf2 signalling, a mechanism which may mitigate cardiovascular risk in patients prescribed celecoxib. Understanding NSAID heterogeneity and COX-2-independent signalling will ultimately lead to safer anti-inflammatory drugs

Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy

<p>Background: Statin therapy reduces the risk of occlusive vascular events, but uncertainty remains about potential effects on cancer. We sought to provide a detailed assessment of any effects on cancer of lowering LDL cholesterol (LDL-C) with a statin using individual patient records from 175,000 patients in 27 large-scale statin trials.</p> <p>Methods and Findings: Individual records of 134,537 participants in 22 randomised trials of statin versus control (median duration 4.8 years) and 39,612 participants in 5 trials of more intensive versus less intensive statin therapy (median duration 5.1 years) were obtained. Reducing LDL-C with a statin for about 5 years had no effect on newly diagnosed cancer or on death from such cancers in either the trials of statin versus control (cancer incidence: 3755 [1.4% per year [py]] versus 3738 [1.4% py], RR 1.00 [95% CI 0.96-1.05]; cancer mortality: 1365 [0.5% py] versus 1358 [0.5% py], RR 1.00 [95% CI 0.93–1.08]) or in the trials of more versus less statin (cancer incidence: 1466 [1.6% py] vs 1472 [1.6% py], RR 1.00 [95% CI 0.93–1.07]; cancer mortality: 447 [0.5% py] versus 481 [0.5% py], RR 0.93 [95% CI 0.82–1.06]). Moreover, there was no evidence of any effect of reducing LDL-C with statin therapy on cancer incidence or mortality at any of 23 individual categories of sites, with increasing years of treatment, for any individual statin, or in any given subgroup. In particular, among individuals with low baseline LDL-C (<2 mmol/L), there was no evidence that further LDL-C reduction (from about 1.7 to 1.3 mmol/L) increased cancer risk (381 [1.6% py] versus 408 [1.7% py]; RR 0.92 [99% CI 0.76–1.10]).</p> <p>Conclusions: In 27 randomised trials, a median of five years of statin therapy had no effect on the incidence of, or mortality from, any type of cancer (or the aggregate of all cancer).</p&gt

Frameworks for implementation, uptake and use of digital health interventions in ethnic minority populations: a scoping review using cardiometabolic disease as a case study

Background: Digital health interventions have become increasingly common across health care, both before and during the COVID-19 pandemic. Health inequalities, particularly with respect to ethnicity, may not be considered in frameworks that address the implementation of digital health interventions. We considered frameworks to include any models, theories, or taxonomies that describe or predict implementation, uptake, and use of digital health interventions. Objective: We aimed to assess how health inequalities are addressed in frameworks relevant to the implementation, uptake, and use of digital health interventions; health and ethnic inequalities; and interventions for cardiometabolic disease. Methods: SCOPUS, PubMed, EMBASE, Google Scholar, and gray literature were searched to identify papers on frameworks relevant to the implementation, uptake, and use of digital health interventions; ethnically or culturally diverse populations and health inequalities; and interventions for cardiometabolic disease. We assessed the extent to which frameworks address health inequalities, specifically ethnic inequalities; explored how they were addressed; and developed recommendations for good practice. Results: Of 58 relevant papers, 22 (38%) included frameworks that referred to health inequalities. Inequalities were conceptualized as society-level, system-level, intervention-level, and individual. Only 5 frameworks considered all levels. Three frameworks considered how digital health interventions might interact with or exacerbate existing health inequalities, and 3 considered the process of health technology implementation, uptake, and use and suggested opportunities to improve equity in digital health. When ethnicity was considered, it was often within the broader concepts of social determinants of health. Only 3 frameworks explicitly addressed ethnicity: one focused on culturally tailoring digital health interventions, and 2 were applied to management of cardiometabolic disease. Conclusions: Existing frameworks evaluate implementation, uptake, and use of digital health interventions, but to consider factors related to ethnicity, it is necessary to look across frameworks. We have developed a visual guide of the key constructs across the 4 potential levels of action for digital health inequalities, which can be used to support future research and inform digital health policies