Serum OPG/TRAIL ratio predicts the presence of cardiovascular disease in people with type 2 diabetes mellitus.

AIMS: Cardiovascular disease (CVD) is the leading cause of mortality in type 2 diabetes mellitus (T2DM). Epidemiological studies suggest serum Osteoprotegrin (OPG)/Tumour-necrosis-factor-related-apoptosis-inducing- ligand (TRAIL) ratio may be a useful marker of cardiovascular risk. This study aimed to compare serum levels of TRAIL, OPG and OPG/TRAIL ratio in people with T2DM, with and without a history of CVD, and controls; and to determine which of these indices, if any, predict cardiovascular risk. METHODS: In this single centre observational study of 133 participants, people with T2DM, with and without a history of a cardiovascular event in the last 5 years, were recruited along with a control cohort without T2DM or CVD. Demographic information and anthropometric measurements were recorded. Blood samples were taken and OPG and TRAIL were measured using ELISA. RESULTS: People with T2DM and CVD had higher OPG/TRAIL ratios compared to controls or those with a new diagnosis of T2DM. After adjustment for potential confounding factors, OPG/TRAIL ratio was significantly associated with the presence of CVD in people with T2DM and an OPG/TRAIL ratio cut-off > 38.6 predicted the presence of CVD in this cohort with a sensitivity of 80% and specificity of 82%. CONCLUSION: This study suggests that OPG/TRAIL ratio may have a role as a biomarker of CVD in people with T2DM.

The leptin to adiponectin ratio (LAR) is reduced by sleeve gastrectomy in adults with severe obesity: a prospective cohort study.

Bariatric surgery is known to reduce leptin and increase adiponectin levels, but the influence of sleeve gastrectomy on the leptin: adiponectin ratio (LAR), a measure of insulin sensitivity and cardiovascular risk, has not previously been described. We sought to determine the influence of sleeve gastrectomy on LAR in adults with severe obesity.In a single centre prospective cohort study of adults undergoing laparoscopic sleeve gastrectomy over a four-month period in our unit, we measured LAR preoperatively and 12 months after surgery. Of 22 patients undergoing sleeve gastrectomy, 17 (12 females, 12 with type 2 diabetes) had follow-up LAR measured at 12.1 ± 1 months. Mean body weight decreased from 130.6 ± 30.8 kg to 97.6 ± 21.6 kg, body mass index (BMI) from 46.9 ± 7.8 to 35.3 ± 7.2 kg m-2 and excess body weight from 87.5 ± 31.3 to 41.3 ± 28.8% (all p < 0.001). The reduction in leptin from 40.7 ± 24.9 to 30.9 ± 30.5 ng/ml was not significant (p = 0.11), but adiponectin increased from 4.49 ± 1.6 to 8.93 ± 6.36 µg/ml (p = 0.005) and LAR decreased from 8.89 ± 4.8 to 5.26 ± 6.52 ng/µg (p = 0.001), equivalent to a 70.9% increase in insulin sensitivity. The correlation with the amount of weight lost was stronger for LAR than it was for leptin or adiponectin alone. In this single-centre, interventional prospective cohort, patients undergoing laparoscopic sleeve gastrectomy had a substantial reduction in their LAR after 12 months which was proportional to the amount of weight lost. This may indicate an improvement in insulin sensitivity and a reduction in cardiovascular risk.

Development of a Telehealth Intervention to Improve Access to Live Donor Kidney Transplantation.

BACKGROUND: Live donor kidney transplantation (LDKT) is underutilized by patients with end-stage kidney disease due to knowledge, communication, and logistical barriers. MATERIAL AND METHODS: The Talking About Live Kidney Donation Social Worker Intervention (TALK-SWI) is a previously validated intervention demonstrated to improve patients' access to and pursuit of LDKT through in-person delivery of education and social support. To help overcome logistical barriers to LDKT, we adapted TALK-SWI into a telehealth intervention employing digital (ie, tablet, smartphone) and telephone technologies. We studied the usability and acceptability of both the mobile device and telephone counseling portions of the intervention among people with kidney disease. For the digital portion, we assessed critical (ie, inability to complete a task) and non-critical (ie, ability to complete a task utilizing an alternative method) errors participants encountered when using the program and their preferences regarding digital materials. Simultaneously, we assessed participants' satisfaction with telephone-adapted counseling compared to the original, in-person counseling. RESULTS: The 15 participants testing the digital technology made 25 critical errors and 29 non-critical errors, while they easily completed 156 tasks (out of 210). A majority of participants (73%) preferred the tablet/smart phone education application over traditional materials, and most (80%) indicated they would be more likely to utilize the mobile platform over traditional materials. Participants testing the telephone-adapted (n = 45) and in-person (n = 125) social worker counseling all reported high satisfaction with the intervention. CONCLUSION: We successfully adapted a validated educational and behavioral intervention to improve access to LDKT into a usable and acceptable telehealth intervention.

Musculoskeletal Health, Kidney and Liver Function in Retired Jockeys.

The long-term implications of making-weight daily on musculoskeletal health and functioning of the kidney and liver remain unknown. This study aimed to investigate musculoskeletal health and kidney and liver function in a group of retired jockeys. 28 retired male jockeys (age 50-70 years) provided fasting blood samples for markers of bone metabolism and kidney and liver function. A dual-energy x-ray absorptiometry (DXA) scan was performed for the assessment of bone mineral density (BMD). Established reference ranges were used for interpretation of results. Comparisons were made between retired jockeys based on the professional racing licence held: Flat, National Hunt or Dual. Mean whole-body osteopenia was reported, with no differences between groups. Bone markers, micronutrients, electrolytes and associated hormones, and markers for kidney and liver function were within clinical normative ranges. No differences existed between groups. Results indicate the retired jockeys in this study do not demonstrate compromised bone health or kidney and liver function. However, the retired jockeys may not have undergone chronic weight cycling in the extreme manner evident in present-day jockeys, indicating the next generation of jockeys may face more of a problem. Jockeys should be tracked longitudinally throughout their racing career and beyond.

Evaluating PET-CT in routine surveillance and follow-up after treatment for cervical cancer: a cost-effectiveness analysis.

OBJECTIVE: To undertake a cost-effectiveness analysis that compares positron emission tomography - computed tomography (PET-CT) imaging plus standard practice with standard practice alone in the diagnosis of recurrent or persistent cervical cancer during routine surveillance and follow-up of women who have previously been diagnosed and treated. DESIGN: Model-based economic evaluation using data from a systematic review, supplemented with data from other sources, and taking a UK National Health Service (NHS) perspective. SETTING: Secondary Care in England. POPULATION: Women at least 3 months after the completion of treatment, with either recurrent or persistent cervical cancer. METHODS: A state transition (Markov) model was developed using TreeAge Pro 2011. The structure of the model was informed by the reviews of the trials and clinical input. In the model, two diagnostic strategies were examined. A one-way sensitivity analysis, probabilistic sensitivity analysis, and a value of information analysis were also carried out. MAIN OUTCOME MEASURES: Cost-effectiveness based on incremental cost per quality-adjusted life year (QALY). RESULTS: Adding PET-CT to the current treatment strategy of clinical examination and scanning [magnetic resonance imaging (MRI) and/or CT scan] during the routine surveillance and follow-up of women with recurrent or persistent cervical cancer is significantly more costly, with only a minimal increase in effectiveness. The incremental cost-effectiveness ratio (ICER) for the strategy of PET-CT as an adjunct to the standard treatment strategy that included clinical examination, MRI, and/or CT scan, compared with the usual treatment alone, was over £1 million per QALY. CONCLUSION: The results of the current analysis suggest that use of PET-CT in the diagnosis of recurrent or persistent cervical cancer is not cost-effective. Current guidelines recommending imaging using PET-CT as a diagnostic or surveillance tool need to be reconsidered in light of these results. This study did not specifically investigate the use of PET-CT in women with symptoms and radiological suspicion of recurrence where exenteration was considered. More research in that specific area is required.

Evaluating PET-CT in the detection and management of recurrent cervical cancer: systematic reviews of diagnostic accuracy and subjective elicitation.

BACKGROUND: Positron emission tomography-computed tomography (PET-CT) is recommended to triage women for exenterative surgery and surveillance after treatment for advanced cervical cancer. OBJECTIVE: To evaluate diagnostic accuracy of additional whole body PET-CT compared with CT/magnetic resonance imaging (MRI) alone in women with suspected recurrent/persistent cervical cancer and in asymptomatic women as surveillance. DESIGN: Systematic reviews. Subjective elicitation to supplement diagnostic information. SEARCH STRATEGY/SELECTION CRITERIA/DATA COLLECTION AND ANALYSIS: Searches of electronic databases were performed to June 2013. Studies in women with suspected recurrent/persistent cervical cancer and in asymptomatic women undergoing follow up with sufficient numeric data were included. We calculated sensitivity, specificity and corresponding 95% confidence intervals. Meta-analyses employed a bivariate model that included a random-effects term for between-study variations (CT studies) and univariate random effects meta-analyses (PET-CT studies) for sensitivity and specificity separately. SUBJECTIVE ELICITATION: Prevalence of recurrence and the accuracy of imaging elicited using the allocation of points technique. Coherence of elicited subjective probabilities with estimates in the literature examined. RESULTS: We identified 15 relevant studies; none directly compared additional PET-CT with MRI or CT separately. Most CT and MRI studies used older protocols and the majority did not distinguish between asymptomatic and symptomatic women. Meta-analysis of nine PET-CT studies in mostly symptomatic women showed sensitivity of 94.8 (95% CI 91.2-96.9), and specificity of 86.9% (95% CI 82.2-90.5). The summary estimate of the sensitivity of CT for detection of recurrence was 89.64% (95% CI 81.59-94.41) and specificity was 76% (95% CI 43.68-92.82). Meta-analysis for MRI test accuracy studies was not possible because of clinical heterogeneity. The sensitivity and specificity of MRI in pelvic recurrence varied between 82 and 100% and between 78 and 100%, respectively. Formal statistical comparisons of the accuracy of index tests were not possible. Subjective elicitation provided estimates comparable to the literature. Subjective estimates of the increase in accuracy from the addition of PET-CT were less than elicited increases required to justify the use in PET-CT for surveillance. CONCLUSION: Evidence to support additional PET-CT is scarce, of average quality and does not distinguish between application for surveillance and diagnosis. Guidelines recommending PET-CT in recurrent cervical cancer need to be reconsidered in the light of the existing evidence base.

Positron emission tomography/computerised tomography imaging in detecting and managing recurrent cervical cancer: systematic review of evidence, elicitation of subjective probabilities and economic modelling.

BACKGROUND: Cancer of the uterine cervix is a common cause of mortality in women. After initial treatment women may be symptom free, but the cancer may recur within a few years. It is uncertain whether it is more clinically effective to survey asymptomatic women for signs of recurrence or to await symptoms or signs before using imaging. OBJECTIVES: This project compared the diagnostic accuracy of imaging using positron emission tomography/computerised tomography (PET-CT) with that of imaging using CT or magnetic resonance imaging (MRI) alone and evaluated the cost-effectiveness of adding PET-CT as an adjunct to standard practice. DATA SOURCES: Standard systematic review methods were used to obtain and evaluate relevant test accuracy and effectiveness studies. Databases searched included MEDLINE, EMBASE, Science Citation Index and The Cochrane Library. All databases were searched from inception to May 2010. REVIEW METHODS: Study quality was assessed using appropriately modified Quality Assessment of Diagnostic Accuracy Studies (QUADAS) criteria. Included were any studies of PET-CT, MRI or CT compared with the reference standard of histopathological findings or clinical follow-up in symptomatic women suspected of having recurrent or persistent cervical cancer and in asymptomatic women a minimum of 3 months after completion of primary treatment. Subjective elicitation of expert opinion was used to supplement diagnostic information needed for the economic evaluation. The effectiveness of treatment with chemotherapy, radiotherapy, chemoradiotherapy, radical hysterectomy and pelvic exenteration was systematically reviewed. Meta-analysis was carried out in RevMan 5.1 (The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark) and Stata version 11 (StataCorp LP, College Station, Texas, USA). A Markov model was developed to compare the relative cost-effectiveness using TreeAge Pro software version 2011 (TreeAge Software Inc., Evanston, IL, USA). RESULTS: For the diagnostic review, a total of 7524 citations were identified, of which 12 test accuracy studies were included in the review: six studies evaluated PET-CT, two evaluated MRI, three evaluated CT and one evaluated both MRI and CT. All studies were small and the majority evaluated imaging in women in whom recurrence was suspected on the basis of symptoms. The PET-CT studies evaluated local and distant recurrence and most used methods similar to current practice, whereas five of the six CT and MRI studies evaluated local recurrence only and not all employed currently used methods. Meta-analysis of PET-CT studies gave a sensitivity of 92.2% [95% confidence interval (CI) 85.1% to 96.0%] and a specificity of 88.1% (95% CI 77.9% to 93.9%). MRI sensitivities and specificities varied between 82% and 100% and between 78% and 100%, respectively, and CT sensitivities and specificities varied between 78% and 93% and between 0% and 95%, respectively. One small study directly compared PET-CT with older imaging methods and showed more true-positives and fewer false-negatives with PET-CT. The subjective elicitation from 21 clinical experts gave test accuracy results for asymptomatic and symptomatic women and the results for symptomatic women were similar to those from the published literature. Their combined opinions also suggested that the mean elicited increase in accuracy from the addition of PET-CT to MRI and/or CT was less than the elicited minimum important difference in accuracy required to justify the routine addition of PET-CT for the investigation of women after completion of primary treatment. For the effectiveness review, a total of 24,943 citations were identified, of which 62 studies were included (chemotherapy, 19 randomised controlled trials; radiotherapy or chemoradiotherapy, 16 case series; radical hysterectomy and pelvic exenteration, 27 case series). None provided the effectiveness of cisplatin monotherapy, the most commonly used chemotherapeutic agent in the NHS, compared with supportive care in a background of other treatment such as radiotherapy in recurrent and persistent cervical cancer. The model results showed that adding PET-CT to the current treatment strategy of clinical examination, MRI and/or CT scan was significantly more costly with only a minimal increase in effectiveness, with incremental cost-effectiveness ratios for all models being > £1M per quality-adjusted life-year (QALY) and the additional cost per additional case of recurrence being in the region of £600,000. LIMITATIONS: There was considerable uncertainty in many of the parameters used because of a lack of good-quality evidence in recurrent or persistent cervical cancer. The evidence on diagnostic and therapeutic impact incorporated in the economic model was poor and there was little information on surveillance of asymptomatic women. CONCLUSIONS: Given the current evidence available, the addition of PET-CT to standard practice was not found to be cost-effective in the diagnosis of recurrent or persistent cervical cancer. However, although probabilistic sensitivity analysis showed that the main conclusion about cost-ineffectiveness of PET-CT was firm given the range of assumptions made, should more reliable information become available on accuracy, therapeutic impact and effectiveness, and the cost of PET-CT reduce, this conclusion may need revision. Current guidelines recommending imaging for diagnosis using expensive methods such as PET-CT need to be reconsidered in the light of the above. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Synchronous sigmoid and caecal cancers together with a primary renal cell carcinoma.

BACKGROUND: Multiple primary neoplasms, a common clinical entity, can be classified as synchronous or metachronous. Renal cell carcinoma, in particular, is associated with a high rate of multiple primary neoplasms. METHODS: We report a case of a 67-year-old Caucasian woman, who was admitted with history of bleeding per rectum. We conducted a literature review of metachronous and synchronous multiple primary neoplasms. RESULTS: Colonoscopy revealed a 3 cm tumour in the caecum and a small sigmoid tubulovillous polyp. Staging computed tomography showed a non-enhancing mass in the upper pole of the right kidney. Following a radical nephrectomy/right hemicolectomy, microscopy demonstrated a renal cell carcinoma. Follow-up colonoscopy visualised a mucosal irregularity at the site of the previous sigmoid polyp, with biopsies confirming invasive adenocarcinoma. Patient underwent a total colectomy with an ileo-rectal anastamosis. CONCLUSION: Multiple primary neoplasms are a well-recognised clinical entity. This report emphasises the need for a comprehensive evidence-based work-up in all cancer cases, especially when dealing with renal cell carcinoma, to look for coexisting metachronous/synchronous primary neoplasms.

Hypoglycaemia-induced myocardial infarction as a result of sulphonylurea misuse.

BACKGROUND: Recent large-scale randomized trials of intensive therapy in Type 2 diabetes have reported increased cardiovascular morbidity and mortality in patient populations who experience a high frequency of hypoglycaemic events. However, there are few descriptions of hypoglycaemia leading directly to a myocardial infarction (MI) in the medical literature to date. CASE REPORT: In this article we describe the case of a 76-year-old woman without diabetes who presented with symptoms, left bundle branch block and raised troponin, indicative of an MI. She was also noted to be hypoglycaemic with a plasma glucose level of 2.5 mmol/l. It was subsequently discovered that she had mistakenly been dispensed glibenclamide, a long-acting sulphonylurea, in the preceding weeks. Her cardiac symptoms resolved completely upon treatment of her hypoglycaemia and she had no significant coronary artery disease on angiography. CONCLUSION: This is the first case of sulphonylurea-induced MI in a patient without diabetes and illustrates the adverse effects of acute hypoglycaemia upon the cardiovascular system.

A systematic review of positron emission tomography (PET) and positron emission tomography/computed tomography (PET/CT) for the diagnosis of breast cancer recurrence.

BACKGROUND: Breast cancer (BC) accounts for one-third of all cases of cancer in women in the UK. Current strategies for the detection of BC recurrence include computed tomography (CT), magnetic resonance imaging (MRI) and bone scintigraphy. Positron emission tomography (PET) and, more recently, positron emission tomography/computed tomography (PET/CT) are technologies that have been shown to have increasing relevance in the detection and management of BC recurrence. OBJECTIVE: To review the accuracy of PET and PET/CT for the diagnosis of BC recurrence by assessing their value compared with current practice and compared with each other. DATA SOURCES: MEDLINE and EMBASE were searched from inception to May 2009. STUDY SELECTION: Studies were included if investigations used PET or PET/CT to diagnose BC recurrence in patients with a history of BC and if the reference standard used to define the true disease status was histological diagnosis and/or long-term clinical follow-up. Studies were excluded if a non-standard PET or PET/CT technology was used, investigations were conducted for screening or staging of primary breast cancer, there was an inadequate or undefined reference standard, or raw data for calculation of diagnostic accuracy were not available. STUDY APPRAISAL: Quality assessment and data extraction were performed independently by two reviewers. Direct and indirect comparisons were made between PET and PET/CT and between these technologies and methods of conventional imaging, and meta-analyses were carried out. Analysis was conducted separately on patient- and lesion-based data. Subgroup analysis was conducted to investigate variation in the accuracy of PET in certain populations or contexts and sensitivity analysis was conducted to examine the reliability of the primary outcome measures. RESULTS: Of the 28 studies included in the review, 25 presented patient-based data and 7 presented lesion-based data for PET and 5 presented patient-based data and 1 presented patient- and lesion-based data for PET/CT; 16 studies conducted direct comparisons with 12 comparing the accuracy of PET or PET/CT with conventional diagnostic tests and 4 with MRI. For patient-based data (direct comparison) PET had significantly higher sensitivity [89%, 95% confidence interval (CI) 83% to 93% vs 79%, 95% CI 72% to 85%, relative sensitivity 1.12, 95% CI 1.04 to 1.21, p = 0.005] and significantly higher specificity (93%, 95% CI 83% to 97% vs 83%, 95% CI 67% to 92%, relative specificity 1.12, 95% CI 1.01 to 1.24, p = 0.036) compared with conventional imaging tests (CITs)--test performance did not appear to vary according to the type of CIT tested. For patient-based data (direct comparison) PET/CT had significantly higher sensitivity compared with CT (95%, 95% CI 88% to 98% vs 80%, 95% CI 65% to 90%, relative sensitivity 1.19, 95% CI 1.03 to 1.37, p = 0.015), but the increase in specificity was not significant (89%, 95% CI 69% to 97% vs 77%, 95% CI 50% to 92%, relative specificity 1.15, 95% CI 0.95 to 1.41, p = 0.157). For patient-based data (direct comparison) PET/CT had significantly higher sensitivity compared with PET (96%, 95% CI 90% to 98% vs 85%, 95% CI 77% to 91%, relative sensitivity 1.11, 95% CI 1.03 to 1.18, p = 0.006), but the increase in specificity was not significant (89%, 95% CI 74% to 96% vs 82%, 95% CI 64% to 92%, relative specificity 1.08, 95% CI 0.94 to 1.20, p = 0.267). For patient-based data there were no significant differences in the sensitivity or specificity of PET when compared with MRI, and, in the one lesion based study, there was no significant differences in the sensitivity or specificity of PET/CT when compared with MRI. LIMITATIONS: Studies reviewed were generally small and retrospective and this may have limited the generalisability of findings. Subgroup analysis was conducted on the whole set of studies investigating PET and was not restricted to comparative studies. Conventional imaging studies that were not compared with PET or PET/CT were excluded from the review. CONCLUSIONS: Available evidence suggests that for the detection of BC recurrence PET, in addition to conventional imaging techniques, may generally offer improved diagnostic accuracy compared with current standard practice. However, uncertainty remains around its use as a replacement for, rather than an add-on to, existing imaging technologies. In addition, PET/CT appeared to show clear advantage over CT and PET alone for the diagnosis of BC recurrence. FUTURE WORK: Future research should include: prospective studies with patient populations clearly defined with regard to their clinical presentation; a study of diagnostic accuracy of PET/CT compared with conventional imaging techniques; a study of PET/CT compared with whole-body MRI; studies investigating the possibility of using PET/CT as a replacement for rather than an addition to CITs; and using modelling of the impact of PET/CT on patient outcomes to inform the possibility of conducting large-scale intervention trials.

"Dead in bed": a tragic complication of type 1 diabetes mellitus.

"Dead in bed" is a tragic description of a particular type of sudden death in type 1 diabetes mellitus (DM). Patients are typically found dead in the early morning, lying in an undisturbed bed, having been well the previous evening. The incidence of "dead in bed" syndrome is not known but studies suggest figures of between 4.7 and 27.3% of all unexplained deaths in type 1 DM. The pathogenesis is unclear but patients typically have a preceding history of recurrent severe hypoglycaemia. We describe two cases of "dead in bed" syndrome which occurred at our institution within a 12-month period.

Central pontine myelinolysis secondary to hypokalaemic nephrogenic diabetes insipidus.

Central pontine myelinolysis (CPM) has been described in alcoholic patients and in the aftermath of rapid correction of chronic hyponatraemia. We describe a case of CPM occurring secondary to nephrogenic diabetes insipidus (DI), which developed as a consequence of severe hypokalaemia. A 63-year-old man with alcohol dependence was admitted to hospital with severe pulmonary sepsis and type 1 respiratory failure. On admission, he had euvolaemic hyponatraemia of 127 mmol/L, consistent with a syndrome of inappropriate antidiuretic hormone secondary to his pneumonia. Following admission, his plasma potassium dropped from 3.2 to a nadir of 2.3 mmol/L. Mineralocorticoid excess, ectopic adrenocorticotrophic hormone production and other causes of hypokalaemia were excluded. The hypokalaemia provoked significant hypotonic polyuria and a slow rise in plasma sodium to 161 mmol/L over several days. Plasma glucose, calcium and creatinine were normal. The polyuria did not respond to desmopressin, and subsequent correction of his polyuria and hypernatraemia after normalization of plasma potassium confirmed the diagnosis of nephrogenic DI due to hypokalaemia. The patient remained obtunded, and the clinical suspicion of osmotic demyelination was confirmed on magnetic resonance imaging. The patient remained comatose and passed away 10 days later. This is the first reported case of nephrogenic DI resulting in the development of CPM, despite a relatively slow rise in plasma sodium of less than 12 mmol/L/24 h. Coexisting alcohol abuse, hypoxaemia and hypokalaemia may have contributed significantly to the development of CPM in this patient.

Evidence for HTR1A and LHPP as interacting genetic risk factors in major depression.

The HTR1A -1019C>G genotype was associated with major depression in the Utah population. Linkage analysis on Utah pedigrees with strong family histories of major depression including only cases with the HTR1A -1019G allele revealed a linkage peak on chromosome 10 (maximum HLOD=4.4). Sequencing of all known genes in the linkage region revealed disease-segregating single-nucleotide polymorphisms (SNPs) in LHPP. LHPP SNPs were also associated with major depression in both Utah and Ashkenazi populations. Consistent with the linkage evidence, LHPP associations depended on HTR1A genotype. Lhpp or a product of a collinear brain-specific transcript, therefore, may interact with Htr1a in the pathogenesis of major depression.

TB or not TB?: a case of isolated testicular TB with scrotal involvement.

Despite the genitourinary tract being the most common site affected by extrapulmonary TB, isolated testicular TB remains a rare clinical entity. In patients with co-morbidities such as hepatic impairment, treatment proves a challenge, as first-line hepatotoxic pharmaceuticals are contraindicated. Here, we report a case of isolated testicular TB with scrotal involvement, on a background of hepatic dysfunction.

Structural neuroimaging in psychosis: a systematic review and economic evaluation.

OBJECTIVES: To establish the clinical effectiveness and cost-effectiveness of structural neuroimaging [structural magnetic resonance imaging (MRI) or computed tomography (CT) scanning] for all patients with psychosis, particularly a first episode of psychosis, relative to the current UK practice of selective screening only where it is clinically indicated. DATA SOURCES: Major electronic databases were searched from inception to November 2006. REVIEW METHODS: A systematic review of studies reporting the additional diagnostic benefit of structural MRI, CT or combinations of these in patients with psychosis was conducted. The economic assessment consisted of a systematic review of economic evaluations and the development of a threshold analysis to predict the gain in quality-adjusted life-years (QALYs) required to make neuroimaging cost-effective at commonly accepted threshold levels (20,000 pounds and 30,000 pounds per QALY). Sensitivity analyses of several parameters including prevalence of psychosis were performed. RESULTS: The systematic review included 24 studies of a diagnostic before-after type of design evaluating the clinical benefit of CT, structural MRI or combinations in treatment-naive, first-episode or unspecified psychotic patients, including one in schizophrenia patients resistant to treatment. Also included was a review of published case reports of misidentification syndromes. Almost all evidence was in patients aged less than 65 years. In most studies, structural neuroimaging identified very little that would influence patient management that was not suspected based on a medical history and/or physical examination and there were more incidental findings. In the four MRI studies, approximately 5% of patients had findings that would influence clinical management, whereas in the CT studies, approximately 0.5% of patients had these findings. The review of misidentification syndromes found that 25% of CT scans affected clinical management, but this may have been a selected and therefore unrepresentative sample. A threshold analysis with a 1-year time horizon was undertaken. This combined the incremental cost of routine scanning with a threshold cost per QALY value of 20,000 pounds and 30,000 pounds to predict the QoL gain required to meet these threshold values. Routine scanning versus selective scanning appears to produce different results for MRI and CT. With MRI scanning the incremental cost is positive, ranging from 37 pounds to 150 pounds; however, when scanning routinely using CT, the result is cost saving, ranging from 7 pounds to 108 pounds with the assumption of a 1% prevalence rate of tumours/cysts or other organic causes amenable to treatment. This means that for the intervention to be viewed as cost-effective, the QALY gain necessary for MRI scanning is 0.002-0.007 and with CT scanning the QALY loss that can be tolerated is between 0.0003 and 0.0054 using a 20,000 pounds threshold value. These estimates were subjected to sensitivity analysis. With a 3-month time delay, MRI remains cost-incurring with a small gain in QoL required for the intervention to be cost-effective; routine scanning with CT remains cost-saving. When the sensitivity of CT is varied to 50%, routine scanning is both cost-incurring or cost-saving depending on the scenario. Finally, the results have been shown to be sensitive to the assumed prevalence rate of brain tumours in a psychotic population. CONCLUSIONS: The evidence to date suggests that if screening with structural neuroimaging was implemented in all patients presenting with psychotic symptoms, little would be found to affect clinical management in addition to that suspected by a full clinical history and neurological examination. From an economic perspective, the outcome is not clear. The strategy of neuroimaging for all is either cost-incurring or cost-saving (dependent upon whether MRI or CT is used) if the prevalence of organic causes is around 1%. However, these values are nested within a number of assumptions, and so have to be interpreted with caution. The main research priorities are to monitor the current use of structural neuroimaging in psychosis in the NHS to identify clinical triggers to its current use and subsequent outcomes; to undertake well-conducted diagnostic before-and-after studies on representative populations to determine the clinical utility of structural neuroimaging in this patient group, and to determine whether the most appropriate structural imaging modality in psychosis should be CT or MRI.

Practical problems and resource implications with the use of warfarin for venous thromboembolism in patients with cancer.

BACKGROUND: Oral anticoagulants present multiple practical problems for patients undergoing chemotherapy. To assess the practice implications of anticoagulation therapy, a review was carried out. METHODS: A review of all patients with cancer treated with warfarin for venous thromboembolism (VTE) over a 1-year-period was carried out. Adverse events and therapeutic efficacy were assessed and the extra volume of work involved in monitoring was quantified. RESULTS: Fifty-five patients with cancer and VTE were treated with warfarin from 07/04 to 06/05. Twenty-one invasive interventions required disruption of anticoagulation. There were eight admissions for haemorrhage. Nine patients died while on warfarin. A total of 1,379 coagulation tests were performed. There were 382 extra dayward visits attributable to warfarin monitoring. On treatment, 13 patients (24%) were changed from warfarin therapy to low molecular weight heparin (LMWH). CONCLUSIONS: This study identifies and quantifies the extra resource utilization with warfarin therapy in patients undergoing chemotherapy.

Variants in Apaf-1 segregating with major depression promote apoptosome function.

APAF1, encoding the protein apoptosis protease activating factor 1 (Apaf-1), has recently been established as a chromosome 12 gene conferring predisposition to major depression in humans. The molecular phenotypes of Apaf-1 variants were determined by in vitro reconstruction of the apoptosome complex in which Apaf-1 activates caspase 9 and thus initiates a cascade of proteolytic events leading to apoptotic destruction of the cell. Cellular phenotypes were measured using a yeast heterologous expression assay in which human Apaf-1 and other proteins necessary to constitute a functional apoptotic pathway were overexpressed. Apaf-1 variants encoded by APAF1 alleles that segregate with major depression in families linked to chromosome 12 shared a common gain-of-function phenotype in both assay systems. In contrast, other Apaf-1 variants showed neutral or loss-of-function phenotypes. The depression-associated alleles thus have a common phenotype that is distinct from that of non-associated variants. This result suggests an etiologic role for enhanced apoptosis in major depression.

The effectiveness and cost-effectiveness of parent training/education programmes for the treatment of conduct disorder, including oppositional defiant disorder, in children.

OBJECTIVES: To assess the clinical and cost-effectiveness of parent training programmes for the treatment of children with conduct disorder (CD) up to the age of 18 years. DATA SOURCES: Electronic databases. REVIEW METHODS: For the effectiveness review, relevant studies were identified and evaluated. A quantitative synthesis of behavioural outcomes across trials was also undertaken using two approaches: vote counting and meta-analysis. The economic analysis consisted of reviewing previous economic/cost evaluations of parent training/education programmes and the economic information within sponsor's submissions; carrying out a detailed exploration of costs of parent training/education programmes; and a de novo modelling assessment of the cost-effectiveness of parent training/education programmes. The potential budget impact to the health service of implementing such programmes was also considered. RESULTS: Many of the 37 randomised controlled trials that met the review inclusion and exclusion criteria were assessed as being of poor methodological quality. Studies were clinically heterogeneous in terms of the population, type of parent training/education programme and content, setting, delivery, length and child behaviour outcomes used. Both vote counting and meta-analysis revealed a consistent trend across all studies towards short-term effectiveness (up to 4 months) of parent training/education programmes (compared with control) as measured by a change in child behaviour. Pooled estimates showed a statistically significant improvement on the Eyberg Child Behaviour Inventory frequency and intensity scales, the Dyadic Parent-Child Interaction Coding System and the Child Behaviour Checklist. No studies reported a statistically significant result favouring control over parent training/education programmes. There were few statistically significant differences between different parent training/education programmes, although there was a trend towards more intensive interventions (e.g. longer contact hours, additional child involvement) being more effective. The cost of treating CD is high, with costs incurred by many agencies. A recent study suggested that by age 28, costs for individuals with CD were around 10 times higher than for those with no problems, with a mean cost of 70,019 pounds sterling. Criminality incurs the greatest cost, followed by educational provision, foster and residential care and state benefits. Only a small proportion of these costs fall on health services. Using a 'bottom-up' costing approach, the costs per family of providing parent training/education programmes range from 629 pounds sterling to 3839 pounds sterling depending on the type and style of delivery. Using the conservative assumption that there are no cost savings from treatment, a total lifetime quality of life gain of 0.1 would give a cost per quality-adjusted life-year of between 38,393 pounds sterling and 6288 pounds sterling depending on the type of programme delivery and setting. CONCLUSIONS: Parent training/education programmes appear to be an effective and potentially cost-effective therapy for children with CD. However, the relative effectiveness and cost-effectiveness of different models (such as therapy intensity and setting) require further investigation. Further research is required on the impact of parent training/education programmes on the quality of life of children with CD and their parents/carers, as well as on longer term child outcomes.

Identification and assessment of ongoing trials in health technology assessment reviews.

OBJECTIVES: To assess the importance of ongoing trials in health technology assessment reviews (HTARs) for the National Institute for Clinical Excellence and to provide practical recommendations for identifying ongoing trials and assessing their possible impact. DATA SOURCES: Electronic databases. REVIEW METHODS: Ongoing trials (or trials in progress) were defined as any trials that have started but where the results are not yet available or only interim results are available for HTARs. This methodological review included: (1) an assessment of ongoing trials in HTARs completed by the end of August 2002, (2) a survey and assessment of trial registers and other sources of ongoing trials and (3) a summary and assessment of available methods for assessing the possible impacts of ongoing trials. RESULTS: The identification of ongoing trials is a common phenomenon in reviews of health technology assessment. Twenty-three of the 32 HTARs identified one or more ongoing trials and in eight of these the information on identified ongoing trials was not considered in the evidence synthesis and research recommendations. All but one HTAR that considered the potential impact of ongoing trials adopted a narrative approach. Trial registers and grey literature are important sources of information on ongoing trials. All 32 HTARs explicitly or implicitly searched for unpublished studies, and/or ongoing trials and/or grey literature and trial registers. The assessment of six commonly used trial registers suggested that most registers provided sufficient information for reviewers to decide the relevance of identified ongoing trials. However, it is sometimes extremely difficult to know whether ongoing trials identified from different sources (registers) are the same trials or belong to the same multicentre trials. The ISRCTN (the International Standard Randomised Controlled Trial Number) is the most reliable system but it has not been widely adopted. The qualitative assessment of ongoing trials compared major features of completed and ongoing trials, providing information about the possible impact of ongoing trials in terms of relevance, validity, reliability and generalisability. Quantitative methods to assess the impact of ongoing trials include cumulative meta-analysis related methods, fail-safe N, Bayesian data monitoring, and Bayesian interim predictions. The most useful method may be the Bayesian predictive probability, which estimates predictive probabilities for any possible values of treatment effect. A case study indicated that the appropriate use of quantitative methods would strengthen findings from narrative assessment of possible impact of ongoing trials. CONCLUSIONS: Identification of ongoing trials is common in HTARs. Searching for ongoing trials in effectiveness reviews should be more thorough and explicit. Conversely, primary researchers, in particular those working with in multicentre trials, should label ongoing trials more clearly, preferably by ISRCTN. Qualitative assessment of identified ongoing trials is crucial and informative. Available quantitative methods could be used to strengthen findings from narrative assessment, although further research and more empirical examples are required. Information from ongoing trials may contribute to syntheses of results, conclusions and recommendations for future research. Future research is suggested into the identification and assessment of ongoing trials in other systematic reviews of effectiveness of health care interventions; existing and new methods for incorporating information on ongoing trials; comparing estimated impacts with the actual results of ongoing trials; and to incorporate findings from the assessment of ongoing trials into decision models.

The effectiveness of routine dental checks: a systematic review of the evidence base.

AIMS: To systematically review the effectiveness of routine dental checks of different recall frequencies in adults and children. METHODS: Search methods included electronic bibliographic databases up to March 2001, relevant internet sites, citation checking and contact with experts and professional dental bodies. INCLUSION CRITERIA: (1) STUDY DESIGN: any; (2) POPULATION: deciduous, mixed and permanent dentition; (3) INTERVENTION: 'Routine dental check': 'clinical examination, advice, charting (including monitoring of periodontal status) and report' as defined in the NHS Executive General Dental Service Statement of Dental Remuneration; (4) Comparator: no routine dental check or routine dental check(s) of different recall frequency; (5) PRIMARY OUTCOMES: caries, periodontal disease, quality of life, oral cancer. RESULTS: Twenty eight studies were identified for the review. Studies were poorly reported and clinically heterogenous which restricted comparison between studies and limited generalisability to the UK situation. There was no consistency across multiple studies in the direction of effect of different dental check frequencies on measures of caries in deciduous mixed or permanent dentition, periodontal disease or oral cancer in permanent dentition. No studies were identified linking empirical measures of quality of life associated with oral health and dental check frequency. CONCLUSIONS: There is no existing high quality evidence to support or refute the practice of encouraging six-monthly dental checks in adults and children.