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1.  Cortical superficial siderosis and intracerebral hemorrhage risk in cerebral amyloid angiopathy 
Neurology  2013;81(19):1666-1673.
Objective:
To investigate whether cortical superficial siderosis (cSS) on MRI, especially if disseminated (involving more than 3 sulci), increases the risk of future symptomatic lobar intracerebral hemorrhage (ICH) in cerebral amyloid angiopathy (CAA).
Methods:
European multicenter cohort study of 118 patients with CAA (104 with baseline symptomatic lobar ICH) diagnosed according to the Boston criteria. We obtained baseline clinical, MRI, and follow-up data on symptomatic lobar ICH. Using Kaplan-Meier and Cox regression analyses, we investigated cSS and ICH risk, adjusting for known confounders.
Results:
During a median follow-up time of 24 months (interquartile range 9–44 months), 23 of 118 patients (19.5%, 95% confidence interval [CI]: 12.8%–27.8%) experienced symptomatic lobar ICH. Any cSS and disseminated cSS were predictors of time until first or recurrent ICH (log-rank test: p = 0.0045 and p = 0.0009, respectively). ICH risk at 4 years was 25% (95% CI: 7.6%–28.3%) for patients without siderosis; 28.9% (95% CI: 7.7%–76.7%) for patients with focal siderosis; and 74% (95% CI: 44.1%–95.7%) for patients with disseminated cSS (log-rank test: p = 0.0031). In Cox regression models, any cSS and disseminated cSS were both independently associated with increased lobar ICH risk, after adjusting for ≥2 microbleeds and age (hazard ratio: 2.53; 95% CI: 1.05–6.15; p = 0.040 and hazard ratio: 3.16; 95% CI: 1.35–7.43; p = 0.008, respectively). These results remained consistent in sensitivity analyses including only patients with symptomatic lobar ICH at baseline.
Conclusions:
Our findings indicate that cSS, particularly if disseminated, is associated with an increased risk of symptomatic lobar ICH in CAA. cSS may help stratify future bleeding risk in CAA, with implications for prognosis and treatment.
doi:10.1212/01.wnl.0000435298.80023.7a
PMCID: PMC3812101  PMID: 24107862
2.  Parkin Disease: A Clinicopathologic Entity? 
JAMA neurology  2013;70(5):571-579.
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.
doi:10.1001/jamaneurol.2013.172
PMCID: PMC4202385  PMID: 23459986
3.  The Relationship between Therapeutic Alliance and Service User Satisfaction in Mental Health Inpatient Wards and Crisis House Alternatives: A Cross-Sectional Study 
PLoS ONE  2014;9(7):e100153.
Background
Poor service user experiences are often reported on mental health inpatient wards. Crisis houses are an alternative, but evidence is limited. This paper investigates therapeutic alliances in acute wards and crisis houses, exploring how far stronger therapeutic alliance may underlie greater client satisfaction in crisis houses.
Methods and Findings
Mixed methods were used. In the quantitative component, 108 crisis house and 247 acute ward service users responded to measures of satisfaction, therapeutic relationships, informal peer support, recovery and negative events experienced during the admission. Linear regressions were conducted to estimate the association between service setting and measures, and to model the factors associated with satisfaction. Qualitative interviews exploring therapeutic alliances were conducted with service users and staff in each setting and analysed thematically.
Results
We found that therapeutic alliances, service user satisfaction and informal peer support were greater in crisis houses than on acute wards, whilst self-rated recovery and numbers of negative events were lower. Adjusted multivariable analyses suggest that therapeutic relationships, informal peer support and negative experiences related to staff may be important factors in accounting for greater satisfaction in crisis houses. Qualitative results suggest factors that influence therapeutic alliances include service user perceptions of basic human qualities such as kindness and empathy in staff and, at service level, the extent of loss of liberty and autonomy.
Conclusions and Implications
We found that service users experience better therapeutic relationships and higher satisfaction in crisis houses compared to acute wards, although we cannot exclude the possibility that differences in service user characteristics contribute to this. This finding provides some support for the expansion of crisis house provision. Further research is needed to investigate why acute ward service users experience a lack of compassion and humanity from ward staff and how this could be changed.
doi:10.1371/journal.pone.0100153
PMCID: PMC4091866  PMID: 25010773
4.  Precise determination of time to reach viral load set point after acute HIV-1 infection 
Objective
HIV viral load set point has long been used as a prognostic marker of disease progression and more recently as an end-point parameter in HIV vaccine clinical trials. The definition of set point, however, is variable. Moreover, the earliest time at which the set point is reached after the onset of infection has never been clearly defined.
Methods
In this study, we obtained sequential plasma viral load data from 60 acutely HIV-infected Chinese patients among a cohort of men who have sex with men (MSM), mathematically determined viral load set point levels, and estimated time to attain set point after infection. We also compared the results derived from our models and that obtained from an empirical method.
Results
With novel uncomplicated mathematic model, we discovered that setpoint may vary from 21 to 119 days dependent on the patients' initial viral load trajectory. The viral load set points were 4.28 ± 0.86 and 4.25 ± 0.87 log10 copies/ml (P = 0.08), respectively, as determined by our model and an empirical method, suggesting an excellent agreement between the old and new methods.
Conclusion
We provide a novel method to estimate viral load set point at the very early stage of HIV infection. Application of this model can accuratly and reliably determine set point, thus providing a new tool for physicians to better monitor early intervention strategies in acutely infected patients, and scientists to rationally design preventative vaccine studies.
doi:10.1097/QAI.0b013e31827146e0
PMCID: PMC3705732  PMID: 23143525
HIV-1; viral load; set point; acute infection; seroconversion
5.  Sensitive Assessment of the Virologic Outcomes of Stopping and Restarting Non-Nucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy 
PLoS ONE  2013;8(7):e69266.
Background
Non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutants have been shown to emerge after interruption of suppressive NNRTI-based antiretroviral therapy (ART) using routine testing. The aim of this study was to quantify the risk of resistance by sensitive testing and correlate the detection of resistance with NNRTI concentrations after treatment interruption and virologic responses after treatment resumption.
Methods
Resistance-associated mutations (RAMs) and NNRTI concentrations were studied in plasma from 132 patients who interrupted suppressive ART within SMART. RAMs were detected by Sanger sequencing, allele-specific PCR, and ultra-deep sequencing. NNRTI concentrations were measured by sensitive high-performance liquid chromatography.
Results
Four weeks after NNRTI interruption, 19/31 (61.3%) and 34/39 (87.2%) patients showed measurable nevirapine (>0.25 ng/ml) or efavirenz (>5 ng/ml) concentrations, respectively. Median eight weeks after interruption, 22/131 (16.8%) patients showed ≥1 NNRTI-RAM, including eight patients with NNRTI-RAMs detected only by sensitive testing. The adjusted odds ratio (OR) of NNRTI-RAM detection was 7.62 (95% confidence interval [CI] 1.52, 38.30; p = 0.01) with nevirapine or efavirenz concentrations above vs. below the median measured in the study population. Staggered interruption, whereby nucleos(t)ide reverse transcriptase inhibitors (NRTIs) were continued for median nine days after NNRTI interruption, did not prevent NNRTI-RAMs, but increased detection of NRTI-RAMs (OR 4.25; 95% CI 1.02, 17.77; p = 0.03). After restarting NNRTI-based ART (n = 90), virologic suppression rates <400 copies/ml were 8/13 (61.5%) with NNRTI-RAMs, 7/11 (63.6%) with NRTI-RAMs only, and 51/59 (86.4%) without RAMs. The ORs of re-suppression were 0.18 (95% CI 0.03, 0.89) and 0.17 (95% CI 0.03, 1.15) for patients with NNRTI-RAMs or NRTI-RAMs only respectively vs. those without RAMs (p = 0.04).
Conclusions
Detection of resistant mutants in the rebound viremia after interruption of efavirenz- or nevirapine-based ART affects outcomes once these drugs are restarted. Further studies are needed to determine RAM persistence in untreated patients and impact on newer NNRTIs.
doi:10.1371/journal.pone.0069266
PMCID: PMC3715458  PMID: 23874928
6.  Atypical face shape and genomic structural variants in epilepsy 
Brain  2012;135(10):3101-3114.
Many pathogenic structural variants of the human genome are known to cause facial dysmorphism. During the past decade, pathogenic structural variants have also been found to be an important class of genetic risk factor for epilepsy. In other fields, face shape has been assessed objectively using 3D stereophotogrammetry and dense surface models. We hypothesized that computer-based analysis of 3D face images would detect subtle facial abnormality in people with epilepsy who carry pathogenic structural variants as determined by chromosome microarray. In 118 children and adults attending three European epilepsy clinics, we used an objective measure called Face Shape Difference to show that those with pathogenic structural variants have a significantly more atypical face shape than those without such variants. This is true when analysing the whole face, or the periorbital region or the perinasal region alone. We then tested the predictive accuracy of our measure in a second group of 63 patients. Using a minimum threshold to detect face shape abnormalities with pathogenic structural variants, we found high sensitivity (4/5, 80% for whole face; 3/5, 60% for periorbital and perinasal regions) and specificity (45/58, 78% for whole face and perinasal regions; 40/58, 69% for periorbital region). We show that the results do not seem to be affected by facial injury, facial expression, intellectual disability, drug history or demographic differences. Finally, we use bioinformatics tools to explore relationships between facial shape and gene expression within the developing forebrain. Stereophotogrammetry and dense surface models are powerful, objective, non-contact methods of detecting relevant face shape abnormalities. We demonstrate that they are useful in identifying atypical face shape in adults or children with structural variants, and they may give insights into the molecular genetics of facial development.
doi:10.1093/brain/aws232
PMCID: PMC3470710  PMID: 22975390
epilepsy; dysmorphism; structural variants; genomics; dense surface models
7.  Activation and Coagulation Biomarkers are Independent Predictors for the Development of Opportunistic Disease in Patients with HIV Infection 
The Journal of infectious diseases  2009;200(6):973-983.
Background
Activation and coagulation biomarkers were measured within the SMART trial. Their associations with opportunistic disease (OD) in HIV-positive patients were examined.
Methods
Inflammatory (high-sensitivity C-reactive protein [hsCRP], interleukin-6 [IL-6], amyloid-A, and amyloid-P) and coagulation (D-dimer and prothrombin-fragment 1+2) markers were determined. Conditional logistic regression analyses were used to assess associations between these biomarkers and risk of OD.
Results
The 91 patients who developed an OD were matched to 182 controls. Patients with hsCRP≥5 μg/mL at baseline had a 3.5 (95%CI: 1.5-8.1) higher odds of OD versus those with hsCRP<1 μg/ml, Ptrend=0.003, and patients with IL-6≥3 pg/mL at baseline had a 2.4 (95%CI: 1.0-5.4) higher odds of OD versus those with IL-6<1.5 pg/mL, Ptrend=0.02. No other baseline biomarkers predicted development of an OD. Latest hsCRP (OR: 7.6 (95%CI: 2.0-28.5) for those with hsCRP≥5 μg/mL versus hsCRP<1 μg/mL, Ptrend=0.002), latest amyloid-A (OR: 3.8 (95%CI: 1.1-13.4) for those with amyloid-A ≥6 mg/L versus amyloid-A <2 mg/L, Ptrend=0.03) and latest IL-6 (OR 2.4 (95%CI: 0.7-8.8) for those with IL-6≥3 pg/mL versus IL-6<1.5 pg/mL, Ptrend=0.04) were also associated with developing an OD.
Conclusions
Higher IL-6 and hsCRP independently predicted development of OD. These biomarkers could provide additional prognostic information for predicting risk of OD.
doi:10.1086/605447
PMCID: PMC2892757  PMID: 19678756
HIV-infection; opportunistic disease; IL-6; hsCRP; inflammation; coagulation; biomarkers
8.  Comparative Evaluation of the ExaVir Load Version 3 Reverse Transcriptase Assay for Measurement of Human Immunodeficiency Virus Type 1 Plasma Load ▿  
Journal of Clinical Microbiology  2009;47(10):3266-3270.
In resource-limited settings, the virological monitoring of antiretroviral therapy is limited by high cost and the lack of infrastructure. The Cavidi ExaVir Load assay employs a simple and inexpensive enzyme-linked immunosorbent assay format to measure human immunodeficiency virus (HIV) reverse transcriptase activity, which correlates with plasma RNA load. The version 3 assay has been described as having improved precision and sensitivity. There are limited data on its performance relative to those of current real-time assays. Our objective was to compare HIV type 1 (HIV-1) RNA load measurement in plasma by ExaVir Load version 3 (designated ExaVir), Abbott M2000sp/M2000rt RealTime HIV-1 assay (designated RealTime), and Roche COBAS Ampliprep/COBAS TaqMan HIV-1 version 1 assay (designated TaqMan). Plasma from 119 patients (34 with subtype B infection, 85 with non-subtype B infection [A-H, CRF01, CRF02, CRF06, CRF12, CRF14, and complex]; 48 subjects were treatment experienced, 71 were naive) and serial dilutions of the second international standard (IS) were tested. Assay relationship and agreement were determined by linear regression, correlation analysis, and the Bland-Altman method. The ExaVir assay quantified 77/83 (92.8%) samples with viral loads of >2.3 log10 copies/ml by the molecular assays. Results were linearly associated and strongly correlated with RealTime and TaqMan measurements (R of 0.94 and 0.92, respectively) for both subtype B (R of 0.97 and 0.95, respectively) and non-subtype B (R of 0.93 and 0.91, respectively) samples. Mean differences were 0.28 and 0.18 log10 copies/ml in favor of the two molecular assays; 7/119 (5.9%) and 5/119 (4.2%) samples were outside the 95% level of agreement. ExaVir underquantified the IS by a mean of 0.2 (range, 0.0 to 0.5) log10 copies/ml. The ExaVir assay showed excellent concordance with real-time molecular assays, offering a suitable option for virological monitoring in settings with limited infrastructure.
doi:10.1128/JCM.00715-09
PMCID: PMC2756939  PMID: 19656978
9.  Viral re-suppression and detection of drug resistance following interruption of a suppressive NNRTI-based regimen 
AIDS (London, England)  2008;22(17):2279-2289.
Background
Interruption of an NNRTI-regimen is often necessary, but must be performed with caution because NNRTIs have a low genetic barrier to resistance. Limited data exist to guide clinical practice on the best interruption strategy to use.
Methods
Patients in the drug-conservation arm of SMART who interrupted a fully suppressive NNRTI-regimen were evaluated. From 2003, SMART recommended interruption of an NNRTI by: a staggered-interruption, where the NNRTI was stopped before the NRTIs; or by replacing the NNRTI with another drug before interruption. Simultaneous-interruption of all ARVs was discouraged. Re-suppression rates four-to-eight months after re-initiating NNRTI-therapy were assessed, as was the detection of drug-resistance mutations within two months of the treatment interruption in a subset (N=141).
Results
Overall, 601/688 (87.4%) patients who re-started an NNRTI achieved viral re-suppression. The adjusted odds ratio (95% CI) for achieving re-suppression was 1.94 (1.02-3.69) for patients with a staggered-interruption and 3.64 (1.37-9.64) for those with a switched-interruption compared to patients with a simultaneous-interruption. At least one NNRTI-mutation was detected in the virus of 16.4% patients with simultaneous-interruption, 12.5% patients with staggered-interruption and 4.2% patients with switched-interruption. Fewer patients with detectable mutations (i.e. 69.2%) achieved HIV-RNA≤400 copies/mL compared to those in whom no mutations were detected (i.e. 86.7%), p=0.05.
Conclusions
In patients who interrupt a suppressive NNRTI-regimen, the choice of interruption-strategy may influence re-suppression rates when re-starting a similar regimen. NNRTI drug-resistance mutations were observed in a relatively high proportion of patients. These data provide additional support for a staggered- or switched-interruption strategy for NNRTI drugs.
doi:10.1097/QAD.0b013e328311d16f
PMCID: PMC2745911  PMID: 18981767
NNRTI-based therapy; treatment interruption strategies; viral re-suppression; genotypic resistance emergence
11.  Cerebral microbleeds and the risk of intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: systematic review and meta-analysis 
Background
Intracerebral haemorrhage (ICH) remains the most devastating yet unpredictable complication of intravenous thrombolysis for acute ischaemic stroke. We performed a systematic review and meta-analysis, to assess whether the presence of cerebral microbleeds (CMBs) on prethrombolysis MRI scans is associated with an increased risk of ICH.
Methods
We searched PubMed for studies assessing ICH risk in patients with acute ischaemic stroke treated with thrombolysis, in relation to the presence of pre-treatment CMBs.
Results
We identified five studies including 790 patients and pooled data in a meta-analysis. The CMB (+) versus CMB (−) groups were not significantly different in age, gender or stroke severity. The overall prevalence of CMBs was 135/790 (17.1%). Amongst patients with CMBs, 10/135 (7.4%) experienced a symptomatic ICH after thrombolysis, compared to 29/655 (4.4%) patients without CMBs. The pooled relative risk of ICH was 1.90 (95% CI 0.92 to 3.93; p=0.082).
Conclusions
The available evidence does not demonstrate a statistically significant increased risk of symptomatic ICH after thrombolysis for ischaemic stroke in patients with CMBs. However, in view of the methodological limitations of the studies included, the clinical relevance of any potential hazard associated with CMBs remains uncertain. Further studies are warranted to evaluate whether the risk of ICH might outweigh the benefit of thrombolysis, especially in patients with multiple lobar CMBs suggestive of cerebral amyloid angiopathy.
doi:10.1136/jnnp-2012-303379
PMCID: PMC3905626  PMID: 23024352
Stroke; Cerebrovascular Disease; Amyloid; Meta-Analysis; MRI
12.  Enlarged perivascular spaces as a marker of underlying arteriopathy in intracerebral haemorrhage: a multicentre MRI cohort study 
Background and purpose
Small vessel disease (mainly hypertensive arteriopathy and cerebral amyloid angiopathy (CAA)) is an important cause of spontaneous intracerebral haemorrhage (ICH), a devastating and still poorly understood stroke type. Enlarged perivascular spaces (EPVS) are a promising neuroimaging marker of small vessel disease. Based on the underlying arteriopathy distributions, we hypothesised that severe centrum semiovale EPVS are more common in lobar ICH attributed to CAA than other ICH. We evaluated EPVS prevalence, severity and distribution, and their clinical–radiological associations.
Methods
Retrospective multicentre cohort study of 121 ICH patients. Clinical information was obtained using standardised forms. Basal ganglia and centrum semiovale EPVS on T2-weighted MRI (graded 0–4 (>40 EPVS)), white-matter changes, cerebral microbleeds (CMBs) and lacunes were rated using validated scales.
Results
Patients with probable or possible CAA (n=76) had a higher prevalence of severe (>40) centrum semiovale EPVS compared with other ICH patients (35.5% vs 17.8%; p=0.041). In logistic regression age (OR: 1.43; 95% CI 1.01 to 2.02; p=0.045), deep CMBs (OR: 3.27; 95% CI 1.27 to 8.45; p=0.014) and mean white-matter changes score (OR: 1.29; 95% CI 1.17 to 1.43; p<0.0001) were independently associated with increased basal ganglia EPVS severity; only age was associated with increased centrum semiovale EPVS severity (OR: 1.50; 95% CI 1.08 to 2.10; p=0.017).
Conclusions
EPVS are common in ICH. Different mechanisms may account for EPVS according to their anatomical distribution. Severe centrum semiovale EPVS may be secondary to, and indicative of, CAA with value as a new neuroimaging marker. By contrast, basal ganglia EPVS severity is associated with markers of hypertensive arteriopathy.
doi:10.1136/jnnp-2012-304434
PMCID: PMC3905629  PMID: 23412074
Amyloid; Cerebrovascular Disease; Clinical Neurology; MRI
13.  MRI-visible perivascular spaces: relationship to cognition and small vessel disease MRI markers in ischaemic stroke and TIA 
Background
MRI-visible perivascular spaces (PVS) are potential neuroimaging markers of cerebral small vessel disease, but their functional significance and mechanisms remain uncertain. We investigated the association between PVS and cognitive impairment, and other MRI markers of small vessel disease, in a patient cohort of ischaemic stroke/transient ischaemic attack (TIA) referrals.
Methods
Data were collected from a prospective observational database. Standardised detailed neuropsychological testing was performed. A validated visual rating scale on T2-weighted MRI was used to categorise PVS severity; validated scales were used to assess white matter hyperintensities (WMH), cerebral microbleeds (CMB) and lacunes.
Results
We included 246 patients (45.1% female, mean age 62 years). No significant association between PVS severity grade in any brain region and impairment in any cognitive domain was identified. In multivariable analysis, WMH and hypertension (but not age) were independently associated with basal ganglia PVS severity (OR: 1.27; p<0.0001 and OR: 4.89; p=0.013, respectively). Increasing PVS severity in the basal ganglia was associated with lacunar stroke subtype (p<0.0001). Age and hypertension (but not WMH or lacunar stroke subtype) were independently associated with centrum semiovale PVS severity (OR: 1.19; p=0.013 and OR: 3.71; p=0.007, respectively).
Conclusions
PVS do not have an independent association with cognitive impairment in patients with ischaemic stroke or TIA. The associations with clinical-radiological factors are consistent with the hypothesis that PVS reflect cerebral small vessel disease; the different associations for basal ganglia and centrum semiovale PVS might indicate different underlying small vessel arteriopathies according to PVS anatomical distribution, but this requires further study.
doi:10.1136/jnnp-2013-305815
PMCID: PMC3995332  PMID: 24249785
Stroke; MRI; Image Analysis

Results 1-13 (13)