The Influence of HLA on HIV-Associated Neurocognitive Impairment in Anhui, China

HLA-DR*04 was identified as a predictor of HIV-Associated neurocognitive disorder (HAND), low CD4 T-cell responses to HIV, and low plasma HIV RNA levels in a U.S. cohort. We hypothesized that low CD4 T-cell activation leads to poor immune control of HIV in the CNS, predisposing to HAND, but also provided fewer target (activated CD4 T-cells) for HIV replication. To assess the consistency of these HLA Class II associations in a new cohort and extend analysis to HLA Class I, HLA types, neurocognitive, and virologic status were examined in a cohort of former plasma donors in China.178 HIV infected individuals in Anhui China, were HLA typed and underwent neurocognitive evaluations (using locally standardized norms), neuromedical, treatment and virologic assessments at baseline and at 12 months.HLA DR*04 was associated with a higher rate of baseline neurocognitive impairment (p = 0.04), neurocognitive decline (p = 0.04), and lower levels of HIV RNA in plasma (p = 0.05). HLA Class I alleles (B*27,57,58,A*03,33) that specify a CD8 T-cell response to conserved HIV sequences were neuroprotective, associated with less impairment at baseline (p = 0.037), at month 012 (p = 0.013) and less neurocognitive decline (p = 0.023) in the interval. Consistent with the theory that effective CD8 T-cell responses require CD4 T-cell support, the HLA DR*04 allele reduced the neuroprotective effect of the Class I alleles. The presence of HLA-DR*04 and the Alzheimer associated allele ApoE4 in the same individual had a synergistic negative effect on cognition (p = 0.003).Despite major background differences between U.S. and Anhui China cohorts, HLA DR*04 predicted neurocognitive impairment and lower plasma HIV RNA levels in both populations. HLA Class I alleles associated with CD8 T-cell control of HIV were associated with protection from HAND, but protection was reduced in the presence of HLA-DR*04

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

COVID-19 instructional approaches (in-person, online, hybrid), school start times, and sleep in over 5,000 U.S. adolescents

Study objectives: To examine associations among instructional approaches, school start times, and sleep during the COVID-19 pandemic in a large, nationwide sample of U.S. adolescents. Methods: Cross-sectional, anonymous self-report survey study of a community-dwelling sample of adolescents (grades 6-12), recruited through social media outlets in October/November 2020. Participants reported on instructional approach (in-person, online/synchronous, online/asynchronous) for each weekday (past week), school start times (in-person or online/synchronous days), and bedtimes (BT) and wake times (WT) for each identified school type and weekends/no school days. Sleep opportunity was calculated as BT-to-WT interval. Night-to-night sleep variability was calculated with mean square successive differences. Results: Respondents included 5,245 racially and geographically diverse students (~50% female). BT and WT were earliest for in-person instruction; followed by online/synchronous days. Sleep opportunity was longer on individual nights students did not have scheduled instruction (>1.5 h longer for online/asynchronous than in-person). More students obtained sufficient sleep with later school start times. However, even with the same start times, more students with online/synchronous instruction obtained sufficient sleep than in-person instruction. Significantly greater night-to-night variability in sleep-wake patterns was observed for students with in-person hybrid schedules versus students with online/synchronous + asynchronous schedules. Conclusions: These findings provide important insights regarding the association between instructional approach and school start times on the timing, amount, and variability of sleep in U.S. adolescents. Given the public health consequences of short and variable sleep in adolescents, results may be useful for education and health policy decision-making for post-pandemic secondary schools

Are Increased Tumor Aneuploidy and Heightened Cell Proliferation Along With Heterogeneity Associated With Patient Outcome for Carcinomas of the Uterine Cervix? A Combined Analysis of Subjects Treated in RTOG 9001 and a Single-Institution Trial

To look for possible associations between measurements of DNA index (DI), S-phase fraction (SPF), and tumor heterogeneity (TH) using flow cytometry and overall survival for patients with invasive cervical carcinoma treated with definitive irradiation. A total of 57 patients with International Federation of Obstetrics and Gynecology Stages IB 2 through IVB cervical carcinomas treated with definitive radiotherapy with or without concurrent chemotherapy were enrolled into this registry study that involved flow cytometric analysis of fresh tissue from each cervical cancer obtained by pretreatment biopsy. These specimens were evaluated for DNA aneuploidy (DI ≤1.5 vs. >1.5), SPF (≤15% vs. >15%), and TH (uniploid vs. multiploid). In these analyses 27 of the patients were treated in Radiation Therapy Oncology Group protocol 9001, and an additional 30 were offered chemoradiation at a single institution. Forty-one patients had DI ≤1.5 and 16 DI >1.5. Twenty-nine patients had SPF ≤15%, 26 >15%, and 2 had no determinable SPF. Forty-three patients had uniploid and 14 multiploid tumors. The 4-year estimated overall survival rate for the entire study cohort was 62% (95% confidence interval 48%–74%). With a median follow-up of 3.7 years, there were no observable associations by univariate analysis for DI, SPF, or TH concerning patient survival. There were no statistically significant associations among DI, SPF, or TH and patient outcome. Additional studies are indicated to identify tumor biomarkers that could predict patients at risk for disseminated disease

Mental comorbidity and multiple sclerosis: validating administrative data to support population-based surveillance

Background: While mental comorbidity is considered common in multiple sclerosis (MS), its impact is poorly defined; methods are needed to support studies of mental comorbidity. We validated and applied administrative case definitions for any mental comorbidities in MS. Methods: Using administrative health data we identified persons with MS and a matched general population cohort. Administrative case definitions for any mental comorbidity, any mood disorder, depression, anxiety, bipolar disorder and schizophrenia were developed and validated against medical records using a a kappa statistic (k). Using these definitions we estimated the prevalence of these comorbidities in the study populations. Results: Compared to medical records, administrative definitions showed moderate agreement for any mental comorbidity, mood disorders and depression (all k ≥ 0.49), fair agreement for anxiety (k = 0.23) and bipolar disorder (k = 0.30), and near perfect agreement for schizophrenia (k = 1.0). The age-standardized prevalence of all mental comorbidities was higher in the MS than in the general populations: depression (31.7% vs. 20.5%), anxiety (35.6% vs. 29.6%), and bipolar disorder (5.83% vs. 3.45%), except for schizophrenia (0.93% vs. 0.93%). Conclusions: Administrative data are a valid means of surveillance of mental comorbidity in MS. The prevalence of mental comorbidities, except schizophrenia, is increased in MS compared to the general population.Medicine, Department ofMedicine, Faculty ofNeurology, Division ofNon UBCReviewedFacult

Individuals who are DR*04+ and have detectable HIV RNA have a greater risk of neurocognitive decline.

<p>Values (other than sample N) in tables represent averages of the indicated variables. BL is baseline score and 012 is twelve-month evaluation point. “Decline” is significant neurocognitive decline between BL and 012 (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032303#s2" target="_blank">methods</a>). Percent ART is percentage of group on at least 2 anti-retroviral medications. CD4 values are absolute cells/microliter. HRNA log is log value of HIV RNA copies/ml with a lower limit of detection of 50 copies. All statistical tests are two tailed, values <.05 are underlined. A p value with an asterisk denotes Fisher’s Exact Test and others were derived using Wilcoxen non-parametric test.</p

HLA DR*04 and ApoE4 have a synergistically negative effect on cognition.

<p>Values (other than sample N) in tables represent averages of the indicated variables. BL is baseline score and 012 is twelve month evaluation point. Edu is years of education. GDS is ‘global deficit score’ and neurocognitive impairment is defined as ≥0.5. Percent ART is percentage of group on at least 2 anti-retroviral medications. CD4 and CD8 value are absolute cells/microliter. HRNA log is log value of HIV RNA copies/ml with a lower limit of detection of 50 copies. All statistical tests are two tailed and values <.05 are underlined. A p value with an asterisk denotes Fisher’s Exact Test and others were derived using Wilcoxen non-parametric test.</p

Individuals with HLA DR*04 tend to be more impaired but also have lower HIV RNA.

<p>Values (other than sample N) in tables represent averages of the indicated variables. BL is baseline score and 012 is twelve month evaluation point. GDS is ‘global deficit score’ and neurocognitive impairment is defined as ≥0.5. GDS values were square root transformed. Percent ART is percentage of group on at least 2 anti-retroviral medications. CD4 and CD8 value are absolute cells/microliter. HRNA log is log value of HIV RNA copies/ml with a lower limit of detection of 50 copies. All statistical tests are two tailed, values <.05 are underlined and an asterisk denotes Fisher Exact Test.</p

HLA Class I alleles that specifiy recognition of conserved HIV sequences protect from neurocognitive impairment and decline.

<p>Values (other than sample N) in tables represent averages of the indicated variables. BL is baseline score and 012 is twelve month evaluation point. “Decline” is significant neurocognitive decline between BL and 012 (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032303#s2" target="_blank">methods</a>). GDS is ‘global deficit score’ and neurocognitive impairment is defined as ≥0.5. Percent ART is percentage of group on at least 2 anti-retroviral medications. CD4 and CD8 value are absolute cells/microliter. HRNA log is log value of HIV RNA copies/ml with a lower limit of detection of 50 copies. All statistical tests are two tailed, values <.05 are underlined. A p value with an asterisk denotes Fisher’s Exact Test and others were derived using Wilcoxen non-parametric test.</p