Recurrent stroke risk and cerebral microbleed burden in ischemic stroke and TIA: A meta-analysis.

OBJECTIVE: To determine associations between cerebral microbleed (CMB) burden with recurrent ischemic stroke (IS) and intracerebral hemorrhage (ICH) risk after IS or TIA. METHODS: We identified prospective studies of patients with IS or TIA that investigated CMBs and stroke (ICH and IS) risk during ≥3 months follow-up. Authors provided aggregate summary-level data on stroke outcomes, with CMBs categorized according to burden (single, 2-4, and ≥5 CMBs) and distribution. We calculated absolute event rates and pooled risk ratios (RR) using random-effects meta-analysis. RESULTS: We included 5,068 patients from 15 studies. There were 115/1,284 (9.6%) recurrent IS events in patients with CMBs vs 212/3,781 (5.6%) in patients without CMBs (pooled RR 1.8 for CMBs vs no CMBs; 95% confidence interval [CI] 1.4-2.5). There were 49/1,142 (4.3%) ICH events in those with CMBs vs 17/2,912 (0.58%) in those without CMBs (pooled RR 6.3 for CMBs vs no CMBs; 95% CI 3.5-11.4). Increasing CMB burden increased the risk of IS (pooled RR [95% CI] 1.8 [1.0-3.1], 2.4 [1.3-4.4], and 2.7 [1.5-4.9] for 1 CMB, 2-4 CMBs, and ≥5 CMBs, respectively) and ICH (pooled RR [95% CI] 4.6 [1.9-10.7], 5.6 [2.4-13.3], and 14.1 [6.9-29.0] for 1 CMB, 2-4 CMBs, and ≥5 CMBs, respectively). CONCLUSIONS: CMBs are associated with increased stroke risk after IS or TIA. With increasing CMB burden (compared to no CMBs), the risk of ICH increases more steeply than that of IS. However, IS absolute event rates remain higher than ICH absolute event rates in all CMB burden categories.

Parkin disease: a clinicopathologic entity?

IMPORTANCE: Mutations in the gene encoding parkin (PARK2) are the most common cause of autosomal recessive juvenile-onset and young-onset parkinsonism. The few available detailed neuropathologic reports suggest that homozygous and compound heterozygous parkin mutations are characterized by severe substantia nigra pars compacta neuronal loss. OBJECTIVE: To investigate whether parkin-linked parkinsonism is a different clinicopathologic entity to Parkinson disease (PD). DESIGN, SETTING, AND PARTICIPANTS: We describe the clinical, genetic, and neuropathologic findings of 5 unrelated cases of parkin disease and compare them with 5 pathologically confirmed PD cases and 4 control subjects. The PD control cases and normal control subjects were matched first for age at death then disease duration (PD only) for comparison. RESULTS: Presenting signs in the parkin disease cases were hand or leg tremor often combined with dystonia. Mean age at onset was 34 years; all cases were compound heterozygous for mutations of parkin. Freezing of gait, postural deformity, and motor fluctuations were common late features. No patients had any evidence of cognitive impairment or dementia. Neuronal counts in the substantia nigra pars compacta revealed that neuronal loss in the parkin cases was as severe as that seen in PD, but relative preservation of the dorsal tier was seen in comparison with PD (P = .04). Mild neuronal loss was identified in the locus coeruleus and dorsal motor nucleus of the vagus, but not in the nucleus basalis of Meynert, raphe nucleus, or other brain regions. Sparse Lewy bodies were identified in 2 cases (brainstem and cortex). CONCLUSIONS AND RELEVANCE: These findings support the notion that parkin disease is characterized by a more restricted morphologic abnormality than is found in PD, with predominantly ventral nigral degeneration and absent or rare Lewy bodies.

Predictors of having a resistance test following confirmed virological failure of combination antiretroviral therapy: data from EuroSIDA.

BACKGROUND: Guidelines suggest that patients on continuous antiretroviral therapy for >4 months with current viral load (VL)>1,000 copies/ml should be tested for resistance. There are limited data showing the frequency of resistance testing in routine clinical practice following these recommendations. METHODS: In EuroSIDA, virological failure (VF) was defined as confirmed VL>1,000 copies/ml after ≥ 4 months continuous use of any antiretroviral in a ≥ 3-drug regimen started during or after 2002. We assessed whether a resistance test was performed around VF (from 4 months before to 1 year after VF) and used logistic regression analysis to assess factors associated with having a resistance test. RESULTS: A total of 1,090 patients experienced VF a median 8.1 months (range 4 months to 6.3 years) after starting their regimen. There were 395 (36.2%; 95% CI 33.4-39.1) patients with a resistance test around the time of VF. Predictors of having a resistance test following VF include availability of a resistance test earlier than 4 months before VF (OR 2.20, 95% CI 1.77-2.75 for yes versus no; P<0.0001), region (OR 0.29, 95% CI 0.14-0.62 for Eastern Europe versus Northern Europe and OR 0.64, 95% CI 0.48-0.85 for Southern Europe versus Northern Europe; global P=0.0006) and current calendar year (OR 0.45, 95% CI 0.30-0.68 for ≥ 2007 versus 2004; global P=0.003). CONCLUSIONS: This analysis suggests a delay in genotypic testing after VF that seems longer than expected given current treatment guidelines. This delay is highly variable across Europe.

Factors associated with the development of cytomegalovirus infection following solid organ transplantation.

BACKGROUND: Infection with cytomegalovirus (CMV) remains a potentially serious complication in transplant patients. In this study we explored the risk factors for CMV infection in the 12 months following a solid organ transplantation (n = 242) in patients monitored for CMV infection from 2004 to 2007. METHODS: CMV infection was defined as 2 consecutive quantifiable CMV-polymerase chain reaction (PCR) values or 1 measurement of >3000 copies/ml. Data describing pre- and post-transplantation variables were extracted from electronic health records. Time to CMV infection was investigated using Cox proportional hazards analysis. RESULTS: Overall, 31% (75/242) of solid organ transplant patients developed CMV infection: 4/8 (50.0%) heart, 15/43 (34.9%) liver, 30/89 (33.7%) lung and 26/102 (25.5%) kidney transplant patients. The risk of CMV infection according to donor (D)/recipient (R) CMV serostatus (positive + or negative-) was highest for D+/R-(adjusted hazard ratio 2.6, 95% confidence interval 1.6-4.2) vs D+/R+, and was reduced for D-/R+(adjusted hazard ratio 0.2, 95% confidence interval 0.2-0.8) vs D+/R+. CONCLUSION: Positive donor CMV-serostatus is a major risk factor for CMV-infection in CMV-na ve recipients, but also in recipients with positive CMV-serostatus. Conversely, if donor is CMV serostatus is negative, the risk of CMV infection is low, irrespective of recipients CMV-serostatus. These findings suggest poorer immune function towards donor-induced strains of CMV versus recipient own latent strains.

Low-frequency K103N strengthens the impact of transmitted drug resistance on virologic responses to first-line efavirenz or nevirapine-based highly active antiretroviral therapy.

BACKGROUND: There are conflicting data on the impact of low-frequency transmitted drug-resistant mutants on responses to first-line highly active antiretroviral therapy (HAART). METHODS: Patients started nevirapine or efavirenz with two or more nucleoside/nucleotide reverse transcriptase inhibitors in 1998-2007 without a prior resistance test at a median 1.0 (interquartile range, 0.0-3.4) year after diagnosis and with a median 218 (interquartile range, 131-296) CD4 cells/mm3, and had at least 24 weeks of follow up. Pre-HAART plasma samples were tested retrospectively by bulk genotyping and sensitive real-time polymerase chain reaction targeting reverse transcriptase K65R, K103N, Y181C, M184V, and G190A (interpretative cutoff 0.3%-0.9%). RESULTS: Among 93 patients, seven of 18 who experienced virologic failure and zero of 75 who maintained virologic suppression showed pre-HAART resistance, including three with high-frequency mutations detectable by bulk genotyping (two K103N, one G190A) and four with low-frequency K103N detectable only by polymerase chain reaction. Detection of either bulk (P = 0.006) or low-frequency (P = 0.001) resistance was significantly associated with the odds of virologic failure; combining the two markedly increased the strength of the association (P < 0.0001). At failure, the pre-HAART mutations were detected by bulk genotyping in five of seven patients alongside additional reverse transcriptase mutations. CONCLUSIONS: Low-frequency K103N mutants were as prevalent as bulk-detectable variants before starting HAART. Both high- and low-frequency mutants were significantly associated with virologic failure.

The ability of four genotypic interpretation systems to predict virological response to ritonavir-boosted protease inhibitors.

BACKGROUND: : Limited information exists on the prognostic value of genotypic interpretation systems (GISs) for ritonavir-boosted protease inhibitors (PI/rs). We compared PI/r resistance levels ascribed by four GIS and examined their abilities to predict HIV-RNA reductions after starting a PI/r-based regimen (baseline). METHODS: : Data on viraemic (HIV-RNA > 500 copies/ml) patients starting a PI/r with a baseline resistance test were combined from an observational cohort study (EuroSIDA) and three randomized trials (MaxCmin1; MaxCmin2 and COLATE). The GIS surveyed were ANRS, DMC, REGA and Stanford. Factors associated with HIV-RNA change were identified through censored regression analysis. RESULTS: : We included 744 patients, of whom 67% were PI experienced. At baseline 12-28% (depending on the GIS) patients had a virus with predicted resistance/intermediate resistance to the PI/r initiated. Concordance between GISs on ascribed PI/r resistance levels was moderate: kappa values ranged from 0.01 to 1.00, with the lowest kappas seen for amprenavir. The median (interquartile range) baseline HIV-RNA was 4.4 (3.5-5.1) log10 and was reduced by 2.2 (2.1-2.3) log10 12 (9-13) weeks after baseline. GIS consistently showed greater HIV-RNA reductions as the ascribed level of sensitivity to the PI/r increased. Conversely, the number of other active drugs in the rest of the regimen, according to each GIS did not predict HIV-RNA reductions consistently. CONCLUSION: : Despite large variations in how GIS classify HIV susceptibility to PI/r, all GIS predicted HIV-RNA reductions of a similar magnitude. The ascribed level of susceptibility to other drugs in the regimen did not predict HIV-RNA decline.