Federated electronic health records research technology to support clinical trial protocol optimization: Evidence from EHR4CR and the InSite platform.

OBJECTIVE: To determine if inclusion/exclusion (I/E) criteria of clinical trial protocols can be represented as structured queries and executed using a secure federated research platform (InSite) on hospital electronic health records (EHR) systems, to estimate the number of potentially eligible patients. METHODS: Twenty-three clinical trial protocols completed during 2011-2017 across diverse disease areas were analyzed to construct queries that were executed with InSite using EHR records from 24 European hospitals containing records of >14 million patients. The number of patients matching I/E criteria of each protocol was estimated. RESULTS: All protocols could be formalized to some extent into a medical coding system (e.g. ICD-10CM, ATC, LOINC, SNOMED) and mapped to local hospital coding systems. The median number of I/E criteria of protocols tested was 29 (range: 14-47). A median of 55% (range 38-89%) of I/E criteria in each protocol could be transformed into a computable format. The median number of eligible patients identified was 26 per hospital site (range: 1-134). CONCLUSION: Clinical trial I/E eligibility criteria can be structured computationally and executed as queries on EHR systems to estimate the patient recruitment pool at each site. The results further suggest that an increase in structured coded information in EHRs would increase the number of I/E criteria that could be evaluated. Additional work is needed on broader deployment of federated platforms such as InSite.

Short-course Combivir after single-dose nevirapine reduces but does not eliminate the emergence of nevirapine resistance in women.

BACKGROUND: In the Treatment Options Preservation Study (TOPS) trial, 4 or 7 days of Combivir (CBV; zidovudine/lamivudine) with maternal single-dose nevirapine (sdNVP) significantly reduced the emergence of NVP resistance as determined by virus population genotyping. To detect NVP resistance with greater sensitivity, we analysed TOPS samples by allele-specific real-time PCR (ASP). METHODS: In a random subset of women from each arm of the trial, plasma samples from before and 6 weeks after sdNVP were analysed using ASP at codons 103, 181, 184 and 190. RESULTS: Samples were analysed from 27 women in the sdNVP arm and 24 each in the CBV 4-day (sdNVP/CBV4) and 7-day (sdNVP/CBV7) arms. ASP detected NVP-resistant variants in week 6 samples from 70% of women in the sdNVP arm, 29% in the sdNVP/CBV4 arm and 33% in sdNVP/CBV7 arm (P<0.01 for sdNVP/CBV4 or sdNVP/CBV7 versus sdNVP; P=1.0 for sdNVP/CBV4 versus sdNVP/CBV7). Lamivudine resistance was detected by ASP in only 1 of 51 women who received CBV. CONCLUSIONS: Short-course CBV significantly reduced but did not eliminate the emergence of NVP resistance after sdNVP. NVP-resistant variants were detected in about one-third of women despite CBV treatment, but the duration of persistence and clinical impact of these variants in response to antiretroviral therapy is uncertain.

Optimization of allele-specific PCR using patient-specific HIV consensus sequences for primer design.

Allele-specific PCR based on subtype consensus sequences is a powerful technique for detecting low frequency drug resistant mutants in HIV-1 infected patients. However, this approach can be limited by genetic variation in the region complementary to the primers, leading to variability in allele detection. The goals of this study were to quantify this effect and then to improve assay performance.

Efficacy of short-course AZT plus 3TC to reduce nevirapine resistance in the prevention of mother-to-child HIV transmission: a randomized clinical trial.

BACKGROUND: Single-dose nevirapine (sdNVP)-which prevents mother-to-child transmission of HIV-selects non-nucleoside reverse-transcriptase inhibitor (NNRTI) resistance mutations in the majority of women and HIV-infected infants receiving it. This open-label, randomised trial examined the efficacy of short-course zidovudine (AZT) and lamivudine (3TC) with sdNVP in reducing NNRTI resistance in mothers, and as a secondary objective, in infants, in a setting where sdNVP was standard-of-care. METHODS AND FINDINGS: sdNVP alone, administered at the onset of labour and to the infant, was compared to sdNVP with AZT plus 3TC, given as combivir (CBV) for 4 (NVP/CBV4) or 7 (NVP/CBV7) days, initiated simultaneously with sdNVP in labour; their newborns received the same regimens. Women were randomised 1ratio1ratio1. HIV-1 resistance was assessed by population sequencing at: baseline, 2, and 6 wk after birth. An unplanned interim analysis resulted in early stopping of the sdNVP arm. 406 pregnant women were randomised and took study medication (sdNVP 74, NVP/CBV4 164, and NVP/CBV7 168). HIV-1 resistance mutations emerged in 59.2%, 11.7%, and 7.3% of women in the sdNVP, NVP/CBV4, and NVP/CBV7 arms by 6 wk postpartum; differences between NVP-only and both NVP/CBV arms were significant (p<0.0001), but the difference between NVP/CBV4 and NVP/CBV7 was not (p = 0.27). Estimated efficacy comparing combined CBV arms with sdNVP was 85.6%. Similar resistance reductions were seen in infants who were HIV-infected by their 6-wk visit. CONCLUSIONS: A short course of AZT plus 3TC, supplementing maternal and infant sdNVP, reduces emergent NNRTI resistance mutations in both mothers and their infants. However, this trial was not powered to detect small differences between the CBV arms. TRIAL REGISTRATION: www.ClinicalTrials.govNCT 00144183.

Increased oxidants and reduced antioxidants in irradiated parenteral nutrition solutions may contribute to the inflammatory response.

BACKGROUND/OBJECTIVES: To measure reactive oxidant production and the decline in antioxidant potential in commercially available, irradiated parenteral nutrition (PN) solutions and the effect that these have on oxidant production in patients in the intensive care unit. SUBJECTS AND METHODS: Vitamin E and malondialdehyde in irradiated and nonirradiated commercially available, PN solutions were measured. The PBN (alpha-phenyl-n-test-butylnitrone (PBN) spin trap was used to measure free radicals and TEMPOL (2,2,6,6-tetramethyl-4-hydroxy-piperidine-oxyl) was used to assess antioxidant capacity. The irradiated PN was administered (as per unit protocol) to 10 patients with gut failure and plasma and urinary isoprostanes and interleukin-6 (IL-6) were measured 1 hour preadministration, at the time of, and 1 and 2 hours postadministration of PN. RESULTS: Irradiation reduced vitamin E significantly (P < .0025). Malondialdehyde products were present in both samples, but more so in irradiated samples (P < .0001), as were free radicals measured by PBN spin trapping. Irradiated samples had a higher scavenging capacity of TEMPOL free radical due to depletion of antioxidants in irradiated samples. Urinary isoprostanes increased at time 2 by 6.3 units relative to time 0 and by 5.23 units relative to time 1(Friedman ANOVA: P < .01413). CONCLUSIONS: Lipid hydroperoxides are formed in PN solutions and increase further following irradiation. This is associated with a significant reduction in vitamin E and antioxidant potential. The increase in urinary isoprostanes indicates a potentially proinflammatory effect of irradiated PN.

A longitudinal study of rheumatoid arthritis in South Africans.

Little is known about the functional outcome of rheumatoid arthritis (RA) in Africans treated with disease-modifying antirheumatic drugs (DMARDs). We describe our experience with 182 RA patients seen at a tertiary hospital in South Africa. During the median follow-up period of 3.3 years, the proportion of patients with severe functional disability (American College of Rheumatology [ACR] functional classes [FCs] 3 and 4) declined significantly from 48.9% at presentation to 30.8% at last visit (P =.0006). There was a significant fall in the median Westergren erythrocyte sedimentation rate (ESR) (46-28 mm/hour, P <.00001) and C-reactive protein (CRP) (19-15.5 mg/L, P =.006) over this period. Logistic regression analysis showed that the factors that negatively affected functional outcome at last visit were severe functional disability at presentation (odds ratio [OR] = 4.1, P =.0004), delay in referral for specialist care > 2 years (OR = 3.1, P =.02), and ESR at last visit > 28 mm/hour (OR = 3.2, P =.002). DMARDs and oral corticosteroids were prescribed in 93.1% of patients at presentation and 60.4% of patients at last visit. Life-table analysis showed that the survival time with methotrexate (MTX) use was significantly longer compared with the other DMARDs (P =.0002). A total of only 37 surgical procedures were performed on 21 patients. This retrospective study shows that despite the late presentation and severe disease, patients do improve on DMARD therapy in the medium term. The study highlights the need for prospective studies to assess the efficacy and safety of DMARDs, particularly in early disease, in the developing countries where biologics are unlikely to be affordable in the foreseeable future.

The addition of pentoxifylline to conventional therapy improves outcome in patients with peripartum cardiomyopathy.

We have reported previously that despite treatment with angiotensin-converting enzyme inhibitors and beta blockers, the outcome of patients with peripartum cardiomyopathy (PPC) remains unfavorable. Similar to other etiologies of left ventricular dysfunction, we found elevated levels of tumor necrosis factor-alpha (TNF-alpha) in this group of patients. In the present study we sought to evaluate the effects of pentoxifylline, a drug known to inhibit the production of TNF-alpha, on clinical status, left ventricular function, and circulating plasma levels of TNF-alpha, in patients with PPC. We followed prospectively 59 consecutive women with PPC. The first 29 patients (group 1) were treated with diuretics, digoxin, enalapril and carvedilol. The next 30 consecutive patients (group 2) received pentoxifylline 400 mg TID in addition to the previous therapy. Clinical evaluation, echocardiograms and TNF-alpha determinations were performed at baseline and after 6 months of treatment. Patients in the pentoxifylline group were older and had a higher E/A ratio. Nine patients died (eight in group 1, P = 0.009 between groups). A combined end-point of poor outcome defined as either death, failure to improve the left ventricular ejection fraction >10 absolute points or functional class III or IV at latest follow-up, occurred in 52% of patients in group 1 and 27% of patients in group 2 (P = 0.03). Treatment with pentoxifylline (P = 0.04) was the only independent predictor of outcome. In conclusion, the results of this study suggest that the addition of pentoxifylline to conventional treatment, improves outcome in patients with peripartum cardiomyopathy.

Percutaneous embolotherapy for life-threatening hemoptysis.

STUDY OBJECTIVES: The management of life-threatening hemoptysis frequently poses a therapeutic dilemma because such patients are often poor surgical risks. Less often, patients refuse surgical intervention. The value of percutaneous embolotherapy, a useful alternative in these situations, was assessed. DESIGN, SETTING, PATIENTS, INTERVENTIONS: Sixteen consecutive patients who underwent percutaneous embolotherapy for life-threatening hemoptysis in a tertiary-care hospital were evaluated retrospectively. The bronchial arteries, as well as other intrathoracic arteries, were evaluated and selectively embolized if they were considered to supply the pathologic area from which the hemoptysis arose. RESULTS: The most common cause for hemoptysis was posttuberculous bronchiectasis (n = 12) with or without mycetomas. Ten patients required blood transfusions before embolotherapy. Pleural disease was noted on the chest radiograph in 13 patients and was generally associated with the presence of nonbronchial systemic collateral vessels. In three patients, arteries other than the bronchial arteries were the only source of hemoptysis. Percutaneous embolotherapy was successful in controlling the hemoptysis in all patients. The only complication documented was a transient paraparesis in one patient. Six patients did not return for follow-up. Of the remaining 10 patients, 3 patients had minor episodes of hemoptysis that were treated conservatively with success. One patient had significant recurrent hemoptysis that was managed with radiotherapy. One patient subsequently underwent a lobectomy. CONCLUSION: Percutaneous embolotherapy is a useful therapeutic modality in the management of life-threatening hemoptysis. The contribution of nonbronchial systemic collateral vessels, particularly where there is evidence of coexistent pleural disease, should always be suspected. In experienced hands, this is a safe and potentially life-saving procedure.