Easily missed? Bladder cancer in women

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Safety, Tolerability, and Pharmacokinetics of ARC-520 Injection, an RNA Interference-Based Therapeutic for the Treatment of Chronic Hepatitis B Virus Infection, in Healthy Volunteers

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Unnatural amino acid analogues of membrane-active helical peptides with anti-mycobacterial activity and improved stability

Objectives The emergence of MDR-TB, coupled with shrinking antibiotic pipelines, has increased demands for new antimicrobials with novel mechanisms of action. Antimicrobial peptides have increasingly been explored as promising alternatives to antibiotics, but their inherent poor in vivo stability remains an impediment to their clinical utility. We therefore systematically evaluated unnatural amino acid-modified peptides to design analogues with enhanced anti-mycobacterial activities. Methods Anti-mycobacterial activities were evaluated in vitro and intracellularly against drug-susceptible and MDR isolates of Mycobacterium tuberculosis using MIC, killing efficacy and intracellular growth inhibition studies. Toxicity profiles were assessed against mammalian cells to verify cell selectivity. Anti-mycobacterial mechanisms were investigated using microfluidic live-cell imaging with time-lapse fluorescence microscopy and confocal laser-scanning microscopy. Results Unnatural amino acid incorporation was well tolerated without an appreciable effect on toxicity profiles and secondary conformations of the synthetic peptides. The modified peptides also withstood proteolytic digestion by trypsin. The all D-amino acid peptide, i(llkk)2i (II-D), displayed superior activity against all six mycobacterial strains tested, with a 4-fold increase in selectivity index as compared with the unmodified L-amino acid peptide in broth. II-D effectively reduced the intracellular bacterial burden of both drug-susceptible and MDR clinical isolates of M. tuberculosis after 4 days of treatment. Live-cell imaging studies demonstrated that II-D permeabilizes the mycobacterial membrane, while confocal microscopy revealed that II-D not only permeates the cell membrane, but also accumulates within the cytoplasm. Conclusions Unnatural amino acid modifications not only decreased the susceptibility of peptides to proteases, but also enhanced mycobacterial selectivity

Early detection of multiple myeloma in primary care using blood tests: a case-control study in primary care

This is the final version. Available on open access from Royal College of General Practitioners via the DOI in this recordBACKGROUND: Multiple myeloma is a haematological cancer characterised by numerous non-specific symptoms leading to diagnostic delay in a large proportion of patients. AIM: To identify which blood tests are useful in suggesting or excluding a diagnosis of myeloma. DESIGN AND SETTING: A matched case-control study set in UK primary care using routinely collected data from the Clinical Practice Research Datalink. METHOD: Symptom prevalence and blood tests were analysed up to 5 years before diagnosis in 2703 cases and 12 157 matched controls. Likelihood ratios (LR) were used to classify tests or their combinations as useful rule-in tests (LR+ = ≥5), or rule-out tests (LR- = ≤0.2). RESULTS: Raised plasma viscosity (PV) had an LR+ = 2.0, 95% confidence interval [CI] = 1.7 to 2.3; erythrocyte sedimentation rate (ESR) 1.9, 95% CI = 1.7 to 2.0; and C-reactive protein (CRP) 1.2, 95% CI = 1.1 to 1.4. A normal haemoglobin had an LR- = 0.42, 95% CI = 0.39 to 0.45; calcium LR- = 0.81, 95% CI = 0.78 to 0.83; and creatinine LR- = 0.80, 95% CI = 0.77 to 0.83. The test combination with the lowest LR- was all normal haemoglobin with calcium and PV, which had an LR- = 0.06, 95% CI = 0.02 to 0.18, though the LR- for normal haemoglobin and PV together was 0.12 (95% CI = 0.07 to 0.23). CONCLUSION: Plasma viscosity and ESR are better for both ruling in and ruling out the disease compared with C-reactive protein. A combination of a normal ESR or PV and normal haemoglobin is a simple rule-out approach for patients currently being tested in primary care.This manuscript presents work carried out as part of a DPhil scholarship awarded to Constantinos Koshiaris funded by the Primary Care Research Trust, the University of Oxford, and National Institute for Health Research (NIHR) Oxford CLAHRC. This article presents independent research funded by the NIHR

Chronic hepatitis caused by persistent parvovirus B19 infection

<p>Abstract</p> <p>Background</p> <p>Human infection with parvovirus B19 may lead to a diverse spectrum of clinical manifestations, including benign erythema infectiosum in children, transient aplastic crisis in patients with haemolytic anaemia, and congenital hydrops foetalis. These different diseases represent direct consequences of the ability of parvovirus B19 to target the erythroid cell lineage. However, accumulating evidence suggests that this virus can also infect other cell types resulting in diverse clinical manifestations, of which the pathogenesis remains to be fully elucidated. This has prompted important questions regarding the tropism of the virus and its possible involvement in a broad range of infectious and autoimmune medical conditions.</p> <p>Case Presentation</p> <p>Here, we present an unusual case of persistent parvovirus B19 infection as a cause of chronic hepatitis. This patient had persistent parvovirus B19 viraemia over a period of more than four years and displayed signs of chronic hepatitis evidenced by fluctuating elevated levels of ALAT and a liver biopsy demonstrating chronic hepatitis. Other known causes of hepatitis and liver damage were excluded. In addition, the patient was evaluated for immunodeficiency, since she had lymphopenia both prior to and following clearance of parvovirus B19 infection.</p> <p>Conclusions</p> <p>In this case report, we describe the current knowledge on the natural history and pathogenesis of parvovirus B19 infection, and discuss the existing evidence of parvovirus B19 as a cause of acute and chronic hepatitis. We suggest that parvovirus B19 was the direct cause of this patient's chronic hepatitis, and that she had an idiopathic lymphopenia, which may have predisposed her to persistent infection, rather than bone marrow depression secondary to infection. In addition, we propose that her liver involvement may have represented a viral reservoir. Finally, we suggest that clinicians should be aware of parvovirus B19 as an unusual aetiology of chronic hepatitis, when other causes have been ruled out.</p

Variation in 'fast-track' referrals for suspected cancer by patient characteristic and cancer diagnosis: evidence from 670 000 patients with cancers of 35 different sites.

BACKGROUND: In England, 'fast-track' (also known as 'two-week wait') general practitioner referrals for suspected cancer in symptomatic patients are used to shorten diagnostic intervals and are supported by clinical guidelines. However, the use of the fast-track pathway may vary for different patient groups. METHODS: We examined data from 669 220 patients with 35 cancers diagnosed in 2006-2010 following either fast-track or 'routine' primary-to-secondary care referrals using 'Routes to Diagnosis' data. We estimated the proportion of fast-track referrals by sociodemographic characteristic and cancer site and used logistic regression to estimate respective crude and adjusted odds ratios. We additionally explored whether sociodemographic associations varied by cancer. RESULTS: There were large variations in the odds of fast-track referral by cancer (P<0.001). Patients with testicular and breast cancer were most likely to have been diagnosed after a fast-track referral (adjusted odds ratios 2.73 and 2.35, respectively, using rectal cancer as reference); whereas patients with brain cancer and leukaemias least likely (adjusted odds ratios 0.05 and 0.09, respectively, for brain cancer and acute myeloid leukaemia). There were sex, age and deprivation differences in the odds of fast-track referral (P<0.013) that varied in their size and direction for patients with different cancers (P<0.001). For example, fast-track referrals were least likely in younger women with endometrial cancer and in older men with testicular cancer. CONCLUSIONS: Fast-track referrals are less likely for cancers characterised by nonspecific presenting symptoms and patients belonging to low cancer incidence demographic groups. Interventions beyond clinical guidelines for 'alarm' symptoms are needed to improve diagnostic timeliness

Estimating the workload associated with symptoms-based ovarian cancer screening in primary care: an audit of electronic medical records

BACKGROUND: Ovarian cancer is the most lethal gynaecological malignancy in the United Kingdom (UK). Studies have found that many women with ovarian cancer have symptoms for several months before diagnosis. Using a symptoms-based tool to diagnose ovarian cancer (OC) earlier is appealing, but may increase general practitioner (GP) workload because the symptoms are typically vague and non-specific. This study aimed to provide estimates of the GP workload associated with offering symptoms-based ovarian cancer screening. METHODS: A cross-sectional analysis of electronic records from four general practices in England, UK. We downloaded anonymous data on women aged 45–74 who consulted over one week to estimate the proportion who would be offered ‘screening’ according to the UK National Institute for Health and Care Excellence (NICE) guidelines and a symptoms index (Index 2) over one year. We used previous consultations (censoring women with no prior symptom at the date of their last recorded consultation) to estimate the proportion of women presenting with a new (not recorded in previous 12 months) NICE symptom each year. RESULTS: Data were obtained from 19,558 women. The proportion presenting over one week varied between practices (5%-14%), however, the proportion with an OC symptom was similar (17% overall). Over one year, an estimated 51.8% (95% CI 44.0%-59.7%) would present with an OC symptom, 26.6% (95% CI 19.3%-35.1%) with a NICE symptom and 20.3% (95% CI 13.7%-28.5%) with an Index 2 symptom. Each year, an estimated 11.9% (95% CI 5.0%-18.3%) of women would present with a new NICE symptom. CONCLUSION: One in two women aged 45–74 present to primary care at least once a year with an OC symptom, 11.9% with a new NICE symptom. This would be comparable to 2 to 8 yearly screening (depending on what symptoms triggered testing)

Psychological determinants of whole-body endurance performance

Background: No literature reviews have systematically identified and evaluated research on the psychological determinants of endurance performance, and sport psychology performance-enhancement guidelines for endurance sports are not founded on a systematic appraisal of endurance-specific research. Objective: A systematic literature review was conducted to identify practical psychological interventions that improve endurance performance and to identify additional psychological factors that affect endurance performance. Additional objectives were to evaluate the research practices of included studies, to suggest theoretical and applied implications, and to guide future research. Methods: Electronic databases, forward-citation searches, and manual searches of reference lists were used to locate relevant studies. Peer-reviewed studies were included when they chose an experimental or quasi-experimental research design, a psychological manipulation, endurance performance as the dependent variable, and athletes or physically-active, healthy adults as participants. Results: Consistent support was found for using imagery, self-talk, and goal setting to improve endurance performance, but it is unclear whether learning multiple psychological skills is more beneficial than learning one psychological skill. The results also demonstrated that mental fatigue undermines endurance performance, and verbal encouragement and head-to-head competition can have a beneficial effect. Interventions that influenced perception of effort consistently affected endurance performance. Conclusions: Psychological skills training could benefit an endurance athlete. Researchers are encouraged to compare different practical psychological interventions, to examine the effects of these interventions for athletes in competition, and to include a placebo control condition or an alternative control treatment. Researchers are also encouraged to explore additional psychological factors that could have a negative effect on endurance performance. Future research should include psychological mediating variables and moderating variables. Implications for theoretical explanations of endurance performance and evidence-based practice are described

Economic factors and suicide rates: associations over time in four countries

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