Effectiveness and safety of dolutegravir two-drug regimens in virologically suppressed people living with HIV: a systematic literature review and meta-analysis of real-world evidence.

OBJECTIVES: Dolutegravir (DTG) is widely recommended within three-drug regimens. However, similar efficacy and tolerability have also been achieved with DTG within two-drug regimens in clinical trials. This study evaluated the real-world effectiveness and discontinuations in people living with HIV-1 (PLHIV) switching to DTG with lamivudine (3TC) or rilpivirine (RPV). METHODS: This was a one-arm meta-analysis utilizing data from a systematic literature review. Data from real-world evidence studies of DTG + RPV and DTG + 3TC were extracted, pooled and analysed. The primary outcome was the proportion of patients with viral failure (VF; ≥ 50 copies/mL in two consecutive measurements and/or ≥ 1000 copies/mL in a single measurement) at week 48 (W48) and week 96 (W96). Other outcomes included virological suppression (VS; < 50 copies/mL) and discontinuations (W48 and W96). Estimates were calculated for VF, VS as per snapshot (VSS) and on treatment analysis (VSOT), and discontinuations. RESULTS: Pooled mean estimates of VF for DTG + 3TC and DTG + RPV were 0.8% [95% confidence interval (CI): 0.4-1.3] and 0.6% (95% CI: 0.0-1.6), respectively, at W48. VSS rate at W48 was 85.0% (95% CI: 82.3-87.5) for DTG + 3TC regimen and 92.4% (95% CI: 85.0-97.7) in the DTG + RPV regimen. The DTG + 3TC and DTG + RPV regimens led to discontinuations in 13.6% (95% CI: 11.1-16.2) and 7.2% (95% CI: 2.1-14.4) of patients, respectively, at W48. Similar results were observed at W96. CONCLUSIONS: Treatment with DTG + 3TC or DTG + RPV in clinical practice provides a low rate of VF and a high rate of VS when initiated in virologically suppressed PLHIV with diverse backgrounds.

Polypharmacy and potential drug-drug interactions for people with HIV in the UK from the Climate-HIV database.

OBJECTIVES: People with HIV (PWHIV) are likely to need therapies for comorbidities as they age. We assessed risk of drug-drug interactions (DDIs) in PWHIV. METHODS: The Climate-HIV electronic recording system was used to cross-sectionally analyse records from PWHIV aged ≥ 18 years attending four UK HIV units with a current antiretroviral (ARV) prescription in February 2018. Antiretroviral and non-ARV medications were categorized by clinical significance of DDIs (University of Liverpool DDI tool). Potential DDIs were predicted using treatment guidelines for commonly recorded comorbidities. RESULTS: Among 4630 PWHIV (44% female), 41% were ≥ 50 years old. The average number of non-ARV comedications increased from < 1 for patients aged ≤ 24 years to > 5 for patients aged ≥ 75 years; 65% were taking one or more non-ARV comedications. The median (interquartile range) number of non-ARVs was 1 (0-2) and 2 (1-5) for those aged < 50 and ≥ 50 years, respectively. Common comorbidities/concurrent health conditions occurred more frequently in patients aged ≥ 50 years vs. < 50 (53% vs. 34%). Boosted protease inhibitors were associated with the highest proportion of contraindicated comedications; dolutegravir and raltegravir had the fewest. For non-ARVs, sildenafil and quetiapine were most likely to result in DDIs. Guideline-recommended treatments for hepatitis C, hepatitis B, and tuberculosis had the highest proportions of contraindications when combined with ARV regimens, while treatments for hepatitis C, malignancy, and mental health conditions had the highest proportion of combinations potentially causing DDIs requiring dose monitoring or adjustment. CONCLUSIONS: Non-ARV use by PWHIV is high and increases with age. Treatment decisions for ageing PWHIV should consider guideline recommendations for comorbidities.

Uva-ursi extract and ibuprofen as alternative treatments for uncomplicated urinary tract infection in women (ATAFUTI): a factorial randomized trial.

OBJECTIVES: The aim was to investigate if offering symptomatic therapy (Uva-ursi or ibuprofen) alongside a delayed prescription would relieve symptoms and reduce the consumption of antibiotics for adult women presenting with acute uncomplicated urinary tract infection (UTI). METHODS: A 2 × 2 factorial placebo controlled randomized trial in primary care. The participants were 382 women aged 18-70 years with symptoms of dysuria, urgency, or frequency of urination and suspected by a clinician to have a lower UTI. The interventions were Uva-ursi extract and/or ibuprofen advice. All women were provided with a delayed or 'back-up' prescription for antibiotics. Missing data were imputed using multiple imputation methods (ISRCTN registry: ISRCTN43397016). RESULTS: An ITT analysis of mean score for frequency symptoms assessed on Days 2-4 found no evidence of a difference between Uva-ursi vs. placebo -0.06 (95% CI -0.33 to 0.21; p 0.661), nor ibuprofen vs. no ibuprofen advice -0.01 (95% CI -0.27 to 0.26; p 0.951). There was no evidence of a reduction in antibiotic consumption with Uva-ursi (39.9% vs. placebo 47.4%; logistic regression odds ratio (OR) 0.59 (95% CI 0.22-1.58; p 0.293) but there was a significant reduction for ibuprofen advice (34.9% vs. no advice 51.0%; OR 0.27 (95% CI 0.10 to 0.72; p 0.009). There were no safety concerns and no episodes of upper tract infection were recorded. CONCLUSIONS: We found no evidence of an effect of either intervention on the severity of frequency symptoms. There is evidence that advice to take ibuprofen will reduce antibiotic consumption without increasing complications. For every seven women given this advice, one less will use antibiotics.

Haplotype inference using a Bayesian Hidden Markov model.

Knowledge of haplotypes is useful for understanding block structure in the genome and disease risk associations. Direct measurement of haplotypes in the absence of family data is presently impractical, and hence, several methods have been developed for reconstructing haplotypes from population data. We have developed a new population-based method using a Bayesian Hidden Markov model for the source of the ancestral haplotype segments. In our Bayesian model, a higher order Markov model is used as the prior for ancestral haplotypes, to account for linkage disequilibrium. Our model includes parameters for the genotyping error rate, the mutation rate, and the recombination rate at each position. Computation is done by Markov Chain Monte Carlo using the forward-backward algorithm to efficiently sum over all possible state sequences of the Hidden Markov model. We have used the model to reconstruct the haplotypes of 129 children at a region on chromosome 5 in the data set of Daly et al. [2001] (for which true haplotypes are obtained based on parental genotypes) and of 30 children at selected regions in the CEU and YRI data of the HAPMAP project. The results are quite close to the family-based reconstructions and comparable with the state-of-the-art PHASE program. Our haplotype reconstruction method does not require division of the markers into small blocks of loci. The recombination rates inferred from our model can help to predict haplotype block boundaries, and estimate recombination hotspots.

Difference detection in LC-MS data for protein biomarker discovery.

MOTIVATION: There is a pressing need for improved proteomic screening methods allowing for earlier diagnosis of disease, systematic monitoring of physiological responses and the uncovering of fundamental mechanisms of drug action. The combined platform of LC-MS (Liquid-Chromatography-Mass-Spectrometry) has shown promise in moving toward a solution in these areas. In this paper we present a technique for discovering differences in protein signal between two classes of samples of LC-MS serum proteomic data without use of tandem mass spectrometry, gels or labeling. This method works on data from a lower-precision MS instrument, the type routinely used by and available to the community at large today. We test our technique on a controlled (spike-in) but realistic (serum biomarker discovery) experiment which is therefore verifiable. We also develop a new method for helping to assess the difficulty of a given spike-in problem. Lastly, we show that the problem of class prediction, sometimes mistaken as a solution to biomarker discovery, is actually a much simpler problem. RESULTS: Using precision-recall curves with experimentally extracted ground truth, we show that (1) our technique has good performance using seven replicates from each class, (2) performance degrades with decreasing number of replicates, (3) the signal that we are teasing out is not trivially available (i.e. the differences are not so large that the task is easy). Lastly, we easily obtain perfect classification results for data in which the problem of extracting differences does not produce absolutely perfect results. This emphasizes the different nature of the two problems and also their relative difficulties. AVAILABILITY: Our data are publicly available as a benchmark for further studies of this nature at http://www.cs.toronto.edu/~jenn/LCMS

Gene function classification using Bayesian models with hierarchy-based priors.

BACKGROUND: We investigate whether annotation of gene function can be improved using a classification scheme that is aware that functional classes are organized in a hierarchy. The classifiers look at phylogenic descriptors, sequence based attributes, and predicted secondary structure. We discuss three Bayesian models and compare their performance in terms of predictive accuracy. These models are the ordinary multinomial logit (MNL) model, a hierarchical model based on a set of nested MNL models, and an MNL model with a prior that introduces correlations between the parameters for classes that are nearby in the hierarchy. We also provide a new scheme for combining different sources of information. We use these models to predict the functional class of Open Reading Frames (ORFs) from the E. coli genome. RESULTS: The results from all three models show substantial improvement over previous methods, which were based on the C5 decision tree algorithm. The MNL model using a prior based on the hierarchy outperforms both the non-hierarchical MNL model and the nested MNL model. In contrast to previous attempts at combining the three sources of information in this dataset, our new approach to combining data sources produces a higher accuracy rate than applying our models to each data source alone. CONCLUSION: Together, these results show that gene function can be predicted with higher accuracy than previously achieved, using Bayesian models that incorporate suitable prior information.

Data feedback efforts in quality improvement: lessons learned from US hospitals.

BACKGROUND: Data feedback is a fundamental component of quality improvement efforts, but previous studies provide mixed results on its effectiveness. This study illustrates the diversity of hospital based efforts at data feedback and highlights successful strategies and common pitfalls in designing and implementing data feedback to support performance improvement. METHODS: Open ended interviews with 45 clinical and administrative staff in eight US hospitals in 2000 concerning their perceptions about the effectiveness of data feedback in supporting performance improvement efforts were analysed. The hospitals were chosen to represent a range of sizes, geographical regions, and beta blocker improvement rates over a 3 year period. Data were organized and analyzed in NUD-IST 4 using the constant comparative method of qualitative data analysis. RESULTS: Although the data feedback efforts at the hospitals were diverse, the interviews suggested that seven key themes may be important: (1) data must be perceived by physicians as valid to motivate change; (2) it takes time to develop the credibility of data within a hospital; (3) the source and timeliness of data are critical to perceived validity; (4) benchmarking improves the meaningfulness of data feedback; (5) physician leaders can enhance the effectiveness of data feedback; (6) data feedback that profiles an individual physician's practices can be effective but may be perceived as punitive; (7) data feedback must persist to sustain improved performance. Embedded in several themes was the view that the effectiveness of data feedback depends not only on the quality and timeliness of the data, but also on the organizational context in which such efforts are implemented. CONCLUSIONS: Data feedback is a complex and textured concept. Data feedback strategies that might be most effective are suggested, as well as potential pitfalls in using data to promote performance improvement.

Management of skeletal metastases.

Bone is a frequent site of tumour metastasis and is the third most common site of metastatic carcinoma. With advances in the use of immunotherapy, hormonal manipulation, chemotherapy and radiation for the palliation of patients with metastatic bone disease, significant improvements in survival, wellbeing and overall quality of life have been achieved.

Prevalence and quality of warfarin use for patients with atrial fibrillation in the long-term care setting.

BACKGROUND: Evidence-based clinical practice guidelines recommend the use of warfarin sodium for stroke prevention in most patients with atrial fibrillation (AF) who do not have risk factors for hemorrhagic complications, irrespective of age. METHODS: The medical records of all residents of a convenience sample of long-term care facilities in Connecticut (n = 21) were reviewed. The percentages of all patients with AF (AF patients) and ideal candidates for warfarin therapy (ie, AF patients with no risk factors for hemorrhage) who received warfarin were determined; for patients receiving warfarin, the percentage of days spent in the therapeutic range of international normalized ratio (INR) values (2.0-3.0) was also assessed. The relationship between receipt of warfarin and the presence of stroke and bleeding risk factors was assessed in multivariate models. RESULTS: Atrial fibrillation was present in 429 (17%) of the 2587 long-term care residents. Overall, 42% of AF patients were receiving warfarin. However, only 44 (53%) of 83 ideal candidates were receiving this therapy. In residents who received warfarin therapy, the therapeutic range of INR values was maintained only 51% of the time. The odds of receiving warfarin in the study sample decreased with increasing number of risk factors for bleeding and increased (nonsignificant trend) with increasing number of stroke risk factors present. CONCLUSIONS: Atrial fibrillation is very common among residents of long-term care facilities. Even among apparently ideal candidates, warfarin therapy is underused for stroke prevention in patients with AF. Prescribing decisions and monitoring related to warfarin therapy in the long-term care setting warrant improvement.

Sex differences in cardiac catheterization: the role of physician gender.

CONTEXT: Many studies indicate that women are less likely than men to undergo cardiac procedures after an acute myocardial infarction (AMI), raising concerns of sexual bias in clinical care. However, no data exist regarding the relationship between patient sex, physician sex, and use of cardiac procedures. OBJECTIVE: To determine whether sex differences in cardiac catheterization after AMI were greater when patients were treated by male attending physicians compared with female attending physicians. DESIGN, SETTING, AND PATIENTS: Analysis of data from the Cooperative Cardiovascular Project, a retrospective medical record review. A total of 104 >231 Medicare fee-for-service beneficiaries who were hospitalized in US acute care hospitals for an AMI between January 1994 and February 1995. MAIN OUTCOME MEASURE: Use of cardiac catheterization within 60 days of admission, compared between the 4 groups of patient sex-physician sex combinations. RESULTS: Women underwent fewer cardiac catheterizations than men when treated by either male physicians (38.6% vs 50.8%; P =.001) or female physicians (34.8% vs 45.8%; P =.001). Sex differences in procedure use were not greater when a patient and physician were of different sexes (P for interaction =.85). After potential confounders in multivariable analysis were accounted for, women were less likely to undergo cardiac catheterization (risk ratio, 0.90 [95% confidence interval (CI), 0.88-0.92]), regardless of the treating physician's sex. Patients treated by male physicians were more likely to undergo cardiac catheterization (risk ratio, 1.06 [95%CI, 1.02-1.10]) than those treated by female physicians, regardless of patient sex. CONCLUSIONS: Women who have had an AMI undergo a cardiac catheterization less often than men, whether treated by a male or female physician. These results suggest that factors other than sexual bias by male physicians toward women account for sex differences in cardiac procedure use.

Case of interstitial 12q deletion in association with Wilms tumor.

A 14-month-old boy presenting with Wilms tumor (WT) was found to have a small de novo deletion of the long arm of chromosome 12 (12q11-12q13.11). Microsatellite analysis of this region from constitutional DNA showed that the paternal allele was absent between the markers D12S331 and D12S1713 (inclusive). In the WT there was no evidence of loss of the maternal chromosome. Constitutional chromosome abnormalities can often point to the presence of genes that are important in disease, and the deletion of chromosome 12 in this patient may indicate a gene involved in WT. To determine whether a WT predisposition locus exists at 12q we examined the region in two familial Wilms tumor (FWT) pedigrees unlinked to the known FWT genes on chromosomes 17q (FWT1), 19q (FWT2), and 11p (WT1). In both families WT did not segregate with chromosome 12q markers located within the deletion boundaries.

The Connecticut Cardiovascular Consortium: a unique, state-wide research collaboration to advance clinical outcomes in patients with heart disease.

The establishment of "best clinical practices" founded upon evidence-based medicine has become an increasingly important priority. Frequently, management guidelines are derived from published research data and disseminated among practitioners to help optimize patient care. The ultimate clinical impact of these guidelines in the "real world," however, is often clouded by an incomplete assessment of patient outcomes throughout the continuum of health-care delivery models. In order to address this gap in clinical outcome assessment, we propose to establish the Connecticut Cardiovascular Consortium. The Consortium will consist of a collaborative partnership among all 31 Connecticut hospitals working in concert with Connecticut Office of Health Care Access (OHCA). The primary objective of the Consortium will be to assess, compare, and optimize clinical outcomes among Connecticut residents with cardiovascular disease. As an initial goal for the Consortium, we further propose to undertake a prospective, observational study of Connecticut residents who present with ST Segment Elevation Acute Myocardial Infarction (STEMI). Recent advances in pharmacologic and mechanical reperfusion for STEMI have resulted in a need to define the optimal use of these therapies in the community at large. The primary purpose of this study will be to determine the relative merits of different treatment patterns for STEMI with regard to the use of fibrinolytic therapy and percutaneous coronary intervention (PCI). Particular emphasis will be placed on assessing the relative benefits of urgent mechanical revascularization performed at the state's seven tertiary facilities with PCI capability compared to all other treatment modalities. Successful completion of this unique collaborative endeavor is expected to have significant impact on improved patient care and on current health-care policy for medical resource allocation. Moreover, continued collaboration of health-care providers within the Connecticut Cardiovascular Consortium infrastructure should serve as a useful mechanism for ongoing improvements in evidence-based cardiovascular medicine and clinical research in the state of Connecticut.

Re-transfusion of autologous blood from wound drains: the means for reducing transfusion requirements in total knee arthroplasty.

The requirements for homologous blood transfusion in patients undergoing total knee replacements under tourniquet, before and after the introduction of autologous transfusion of blood collected from wound drains, are compared. In a control population of 93 patients undergoing total knee replacement, 67 required homologous transfusions of two units or more. In 160 patients who were re-transfused with blood from wound drains, only 30 required additional homologous transfusions. Re-transfusion of filtered drained blood reduces the need for homologous bank blood. This avoids the risks associated with donated blood and affords significant cost savings.

The association between white blood cell count and acute myocardial infarction mortality in patients > or =65 years of age: findings from the cooperative cardiovascular project.

OBJECTIVES: The purpose of the study was to examine the association between white blood cell (WBC) count on admission and 30-day mortality in patients with acute myocardial infarction (AMI). BACKGROUND: Elevations in WBC count have been associated with the development of AMI and with long-term mortality in patients with coronary artery disease. However, the relationship between WBC count and prognosis following AMI is less clear. METHODS: Using the Cooperative Cardiovascular Project database, we evaluated 153,213 patients > or = 65 years of age admitted with AMI. RESULTS: An increasing WBC count is associated with a significantly higher risk of in-hospital events, in-hospital mortality and 30-day mortality. Relative to those patients in the lowest quintile, patients in the highest quintile were three times more likely to die at 30 days (10.3% vs. 32.3%; p < 0.001). After adjustment for confounding factors, WBC count was found to be a strong independent predictor of 30-day mortality (odds ratio = 2.37; 95% confidence interval 2.25 to 2.49, p = 0.0001 for the highest quintile of WBC count). CONCLUSIONS: White blood cell count within 24 h of admission for an AMI is a strong and independent predictor of in-hospital and 30-day mortality as well as in-hospital clinical events. Although the mechanism of the association remains speculative, the results of this study have important clinical implications for risk-stratifying patients with AMI.

Blood transfusion in elderly patients with acute myocardial infarction.

BACKGROUND: Anemia may have adverse effects in patients with coronary artery disease. However, the benefit of blood transfusion in elderly patients with acute myocardial infarction and various degrees of anemia is uncertain. METHODS: We conducted a retrospective study of data on 78,974 Medicare beneficiaries 65 years old or older who were hospitalized with acute myocardial infarction. Patients were categorized according to the hematocrit on admission (5.0 to 24.0 percent, 24.1 to 27.0 percent, 27.1 to 30.0 percent, 30.1 to 33.0 percent, 33.1 to 36.0 percent, 36.1 to 39.0 percent, or 39.1 to 48.0 percent), and data were evaluated to determine whether there was an association between the use of transfusion and 30-day mortality. RESULTS: Patients with lower hematocrit values on admission had higher 30-day mortality rates. Blood transfusion was associated with a reduction in 30-day mortality among patients whose hematocrit on admission fell into the categories ranging from 5.0 to 24.0 percent (adjusted odds ratio, 0.22; 95 percent confidence interval, 0.11 to 0.45) to 30.1 to 33.0 percent (adjusted odds ratio, 0.69; 95 percent confidence interval, 0.53 to 0.89). It was not associated with a reduction in 30-day mortality among those whose hematocrit values fell in the higher ranges. In one of seven subgroup analyses (among patients who survived at least two days), transfusion was not associated with a reduction in mortality for patients with hematocrit values of 30.1 percent or higher. CONCLUSIONS: Blood transfusion is associated with a lower short-term mortality rate among elderly patients with acute myocardial infarction if the hematocrit on admission is 30.0 percent or lower and may be effective in patients with a hematocrit as high as 33.0 percent on admission.