Holly Wilhalme

Postischemic hyperperfusion on arterial spin labeled perfusion MRI is linked to hemorrhagic transformation in stroke

The purpose of this study was to investigate the relationship between hyperperfusion and hemorrhagic transformation (HT) in acute ischemic stroke (AIS). Pseudo-continuous arterial spin labeling (ASL) with background suppressed 3D GRASE was performed during routine clinical magnetic resonance imaging (MRI) on AIS patients at various time points. Arterial spin labeling cerebral blood flow (CBF) maps were visually inspected for the presence of hyperperfusion. Hemorrhagic transformation was followed during hospitalization and was graded on gradient recalled echo (GRE) scans into hemorrhagic infarction (HI) and parenchymal hematoma (PH). A total of 361 ASL scans were collected from 221 consecutive patients with middle cerebral artery stroke from May 2010 to September 2013. Hyperperfusion was more frequently detected posttreatment (odds ratio (OR)=4.8, 95% confidence interval (CI) 2.5 to 8.9, P<0.001) and with high National Institutes of Health Stroke Scale (NIHSS) scores at admission (P<0.001). There was a significant association between having hyperperfusion at any time point and HT (OR=3.5, 95% CI 2.0 to 6.3, P<0.001). There was a positive relationship between the grade of HT and time—hyperperfusion with the Spearmans rank correlation of 0.44 (P=0.003). Arterial spin labeling hyperperfusion may provide an imaging marker of HT, which may guide the management of AIS patients post tissue-type plasminogen activator (tPA) and/or endovascular treatments. Late hyperperfusion should be given more attention to prevent high-grade HT.

RNAi-mediated CCR5 knockdown provides HIV-1 resistance to memory T cells in humanized BLT mice

Transplantation of hematopoietic stem/progenitor cells (HSPC) modified with a lentiviral vector bearing a potent nontoxic short hairpin RNA (sh1005) directed to the HIV coreceptor CCR5 is capable of continuously producing CCR5 downregulated CD4+ T lymphocytes. Here, we characterized HIV-1 resistance of the sh1005-modified CD4+ T lymphocytes in vivo in humanized bone marrow/liver/thymus (hu BLT) mice. The sh1005-modified CD4+ T lymphocytes were positively selected in CCR5-tropic HIV-1–challenged mice. The sh1005-modified memory CD4+ T lymphocytes (the primary target of CCR5-tropic HIV-1) expressing sh1005 were maintained in lymphoid tissues in CCR5-tropic HIV-1–challenged mice. Frequencies of HIV-1 p24 expressing cells were significantly reduced in the sh1005-modified splenocytes by ex vivo cell stimulation confirming that CCR5 downregulated sh1005 modified cells are protected from viral infection. These results demonstrate that stable CCR5 downregulation through genetic modification of human HSPC by lentivirally delivered sh1005 is highly effective in providing HIV-1 resistance. Our results provide in vivo evidence in a relevant small animal model that sh1005 is a potent early-step anti-HIV reagent that has potential as a novel anti-HIV-1 HSPC gene therapeutic reagent for human applications.

Heat Death Associations with the built environment, social vulnerability and their interactions with rising temperature

In an extreme heat event, people can go to air-conditioned public facilities if residential air-conditioning is not available. Residences that heat slowly may also mitigate health effects, particularly in neighborhoods with social vulnerability. We explored the contributions of social vulnerability and these infrastructures to heat mortality in Maricopa County and whether these relationships are sensitive to temperature. Using Poisson regression modeling with heat-related mortality as the outcome, we assessed the interaction of increasing temperature with social vulnerability, access to publicly available air conditioned space, home air conditioning and the thermal properties of residences. As temperatures increase, mortality from heat-related illness increases less in census tracts with more publicly accessible cooled spaces. Mortality from all internal causes of death did not have this association. Building thermal protection was not associated with mortality. Social vulnerability was still associated with mortality after adjusting for the infrastructure variables. To reduce heat-related mortality, the use of public cooled spaces might be expanded to target the most vulnerable.

Efficacy of Mycophenolate Mofetil and Oral Cyclophosphamide on Skin Thickness: Post Hoc Analyses From Two Randomized Placebo‐Controlled Trials

To assess the efficacy of mycophenolate mofetil (MMF) and cyclophosphamide (CYC) on modified Rodnan skin score (MRSS) in participants enrolled in the Scleroderma Lung Study (SLS) I and II.

Associations of the Top 20 Alzheimer Disease Risk Variants With Brain Amyloidosis

Importance Late-onset Alzheimer disease (AD) is highly heritable. Genome-wide association studies have identified more than 20 AD risk genes. The precise mechanism through which many of these genes are associated with AD remains unknown. Objective To investigate the association of the top 20 AD risk variants with brain amyloidosis. Design, Setting, and Participants This study analyzed the genetic and florbetapir F 18 data from 322 cognitively normal control individuals, 496 individuals with mild cognitive impairment, and 159 individuals with AD dementia who had genome-wide association studies and 18F-florbetapir positron emission tomographic data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a prospective, observational, multisite tertiary center clinical and biomarker study. This ongoing study began in 2005. Main Outcomes and Measures The study tested the association of AD risk allele carrier status (exposure) with florbetapir mean standard uptake value ratio (outcome) using stepwise multivariable linear regression while controlling for age, sex, and apolipoprotein E &egr;4 genotype. The study also reports on an exploratory 3-dimensional stepwise regression model using an unbiased voxelwise approach in Statistical Parametric Mapping 8 with cluster and significance thresholds at 50 voxels and uncorrected P < .01. Results This study included 977 participants (mean [SD] age, 74 [7.5] years; 535 [54.8%] male and 442 [45.2%] female) from the ADNI-1, ADNI-2, and ADNI–Grand Opportunity. The adenosine triphosphate–binding cassette subfamily A member 7 (ABCA7) gene had the strongest association with amyloid deposition (&khgr;2 = 8.38, false discovery rate–corrected P < .001), after apolioprotein E &egr;4. Significant associations were found between ABCA7 in the asymptomatic and early symptomatic disease stages, suggesting an association with rapid amyloid accumulation. The fermitin family homolog 2 (FERMT2) gene had a stage-dependent association with brain amyloidosis (FERMT2 × diagnosis &khgr;2 = 3.53, false discovery rate–corrected P = .05), which was most pronounced in the mild cognitive impairment stage. Conclusions and Relevance This study found an association of several AD risk variants with brain amyloidosis. The data also suggest that AD genes might differentially regulate AD pathologic findings across the disease stages.

Reliability and Minimal Clinically Important Differences of FVC. Results from the Scleroderma Lung Studies (SLS-I and SLS-II)

Rationale: FVC percent predicted (FVC%) is the primary outcome measure in clinical trials of systemic sclerosis interstitial lung disease. For interpretation of change in the FVC% over time, it is important to define whether these changes are clinically meaningful. Objectives:: To assess the reliability and the minimal clinically important differences (MCID) for FVC% in the Scleroderma Lung Study I and II (SLS‐I and ‐II). Methods: Using data from SLS‐I and ‐II (N = 300), we evaluated the test‐retest reliability for FVC% (screening vs. baseline) using intraclass correlation. MCID estimates at 12 months were calculated in the pooled cohort (SLS‐I and ‐II) using two anchors: Transition Dyspnea Index (≥change of 1.5 units for improvement and worsening, respectively) and the Medical Outcomes Short Form‐36 Health Transition question (“Compared with one year ago, how would you rate your health in general now”?), where “somewhat better” or “somewhat worse” were defined as the MCID estimates. We next assessed the association of MCID estimates for improvement and worsening of FVC% with patient‐reported outcomes (PROs) and computer‐assisted quantitation of extent of fibrosis (QLF) and of total interstitial lung disease (QILD) on high‐resolution computed tomography. Students t test was used to compare the mean difference in outcomes between the MCID improvement/worsening and the “no change” group. Measurements and Main Results: Reliability of FVC%, assessed at a mean of 34 days, intraclass correlation was 0.93 for the pooled cohort. The MCID estimates for the pooled cohort at 12 months for FVC% improvement ranged from 3.0% to 5.3% and for worsening from −3.0% to −3.3%. FVC% improvement by greater than or equal to MCID was associated with either statistically significant or numerical improvements in some PROs, QILD, and QLF, whereas FVC% worsening greater than or equal to MCID was associated with statistically significant or numerical worsening of PROs, QILD, and QLF. Conclusions: FVC% has acceptable test‐retest reliability, and we have provided the MCID estimates for FVC% in systemic sclerosis interstitial lung disease‐based changes at 12 months from baseline in two clinical trials. Clinical trial registered with www.clinicaltrials.gov (NCT00004563 for SLS‐I and NCT00883129 for SLS‐II).

The effect of the top 20 Alzheimer disease risk genes on gray-matter density and FDG PET brain metabolism

We analyzed the effects of the top 20 Alzheimer disease (AD) risk genes on gray‐matter density (GMD) and metabolism.

A comparison of theoretical and statistically derived indices for predicting cognitive decline

Both theoretical and statistically derived approaches have been used in research settings for predicting cognitive decline.

Isotretinoin Therapy: A Retrospective Cohort Analysis of Completion Rates and Factors Associated with Non-Adherence

CAT, Clinical activities tool; CI, confidence interval; IQR, interquartile range; OBME, outcomes-based medical education. *Adjused for beginning-of-clerkship student self-assessment survey scores. yMean scores are calculated from a 1-10epoint scale, from strongly disagree to strongly agree, with 5 being neutral. zAgreeing indicates a score

Mortality and Morbidity during Extreme Heat Events and Prevalence of Outdoor Work: An Analysis of Community-Level Data from Los Angeles County, California

6. xAverage evaluation score is the mean of 6 individual clerkship evaluations. jjP value of .271 from Wilcoxon rank-sum test. J AM ACAD DERMATOL VOLUME 79, NUMBER 3 Research Letters 571