Unique pattern of COVID-19 infection in the State of Hawai'i.

This is a brief report on an unusual observation regarding COVID-19 cases. The State of Hawaii is one of the most remote of the Pacific islands and the population is approximately 1.4 million. The racial and ethnic diversity is very high. For example, white Caucasians comprise ∼25%, Asians including Japanese, Chinese, and other Asians account for ∼30%, Hawaiians for 20%, and Pacific Islanders mostly from Micronesia and Samoa comprise ∼4%. We discovered that the COVID-19 rate in the latter group was up to 10 times that in all of the other groups combined and they accounted for almost 30% of cases. Moreover, we are unaware of COVID-19 transmission from Pacific Islanders to islanders with other ethnicities. Thus, there is an epidemic within the epidemic in Hawai'i.

Behavioural clusters and predictors of performance during recovery from stroke.

We examined the patterns and variability of recovery post-stroke in multiple behavioral domains. A large cohort of first time stroke patients with heterogeneous lesions was studied prospectively and longitudinally at 1-2 weeks, 3 months and one year post-injury with structural MRI to measure lesion anatomy and in-depth neuropsychological assessment. Impairment was described at all timepoints by a few clusters of correlated deficits. The time course and magnitude of recovery was similar across domains, with change scores largely proportional to the initial deficit and most recovery occurring within the first three months. Damage to specific white matter tracts produced poorer recovery over several domains: attention and superior longitudinal fasciculus II/III, language and posterior arcuate fasciculus, motor and corticospinal tract. Finally, after accounting for the severity of the initial deficit, language and visual memory recovery/outcome was worse with lower education, while the occurrence of multiple deficits negatively impacted attention recovery.

Genetics of ancestry-specific risk for relapse in acute lymphoblastic leukemia.

The causes of individual relapses in children with acute lymphoblastic leukemia (ALL) remain incompletely understood. We evaluated the contribution of germline genetic factors to relapse in 2225 children treated on Children's Oncology Group trial AALL0232. We identified 302 germline single-nucleotide polymorphisms (SNPs) associated with relapse after adjusting for treatment and ancestry and 715 additional SNPs associated with relapse in an ancestry-specific manner. We tested for replication of these relapse-associated SNPs in external data sets of antileukemic drug pharmacokinetics and pharmacodynamics and an independent clinical cohort. 224 SNPs were associated with rapid drug clearance or drug resistance, and 32 were replicated in the independent cohort. The adverse risk associated with black and Hispanic ancestries was attenuated by addition of the 4 SNPs most strongly associated with relapse in these populations (for blacks: model without SNPs hazard ratio (HR)=2.32, P=2.27 × 10-4, model with SNPs HR=1.07, P=0.79; for Hispanics: model without SNPs HR=1.7, P=8.23 × 10-5, model with SNPs HR=1.31, P=0.065). Relapse SNPs associated with asparaginase resistance or allergy were overrepresented among SNPs associated with relapse in the more asparaginase intensive treatment arm (20/54 in Capizzi-methorexate arm vs 8/54 in high-dose methotrexate arm, P=0.015). Inherited genetic variation contributes to race-specific and treatment-specific relapse risk.

Genome-Wide Study Links PNPLA3 Variant With Elevated Hepatic Transaminase After Acute Lymphoblastic Leukemia Therapy.

Remission induction therapy for acute lymphoblastic leukemia (ALL) includes medications that may cause hepatotoxicity, including asparaginase. We used a genome-wide association study to identify loci associated with elevated alanine transaminase (ALT) levels after induction therapy in children with ALL enrolled on St. Jude Children's Research Hospital (SJCRH) protocols. Germline DNA was genotyped using arrays and exome sequencing. Adjusting for age, body mass index, ancestry, asparaginase preparation, and dosage, the PNPLA3 rs738409 (C>G) I148M variant, previously associated with fatty liver disease risk, had the strongest genetic association with ALT (P = 2.5 × 10-8 ). The PNPLA3 rs738409 variant explained 3.8% of the variability in ALT, and partly explained race-related differences in ALT. The PNPLA3 rs738409 association was replicated in an independent cohort of 2,285 patients treated on Children's Oncology Group protocol AALL0232 (P = 0.024). This is an example of a pharmacogenetic variant overlapping with a disease risk variant.

The clinical pharmacogenetics implementation consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update.

Simvastatin is among the most commonly used prescription medications for cholesterol reduction. A single coding single-nucleotide polymorphism, rs4149056T>C, in SLCO1B1 increases systemic exposure to simvastatin and the risk of muscle toxicity. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for simvastatin based on SLCO1B1 genotype. This article is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and simvastatin-induced myopathy.

Exploitation of interspecific diversity for monocot crop improvement.

In many cultivated crop species there is limited genetic variation available for the development of new higher yielding varieties adapted to climate change and sustainable farming practises. The distant relatives of crop species provide a vast and largely untapped reservoir of genetic variation for a wide range of agronomically important traits that can be exploited by breeders for crop improvement. In this paper, in what we believe to be the largest introgression programme undertaken in the monocots, we describe the transfer of the entire genome of Festuca pratensis into Lolium perenne in overlapping chromosome segments. The L. perenne/F. pratensis introgressions were identified and characterised via 131 simple sequence repeats and 1612 SNPs anchored to the rice genome. Comparative analyses were undertaken to determine the syntenic relationship between L. perenne/F. pratensis and rice, wheat, barley, sorghum and Brachypodium distachyon. Analyses comparing recombination frequency and gene distribution indicated that a large proportion of the genes within the genome are located in the proximal regions of chromosomes which undergo low/very low frequencies of recombination. Thus, it is proposed that past breeding efforts to produce improved varieties have centred on the subset of genes located in the distal regions of chromosomes where recombination is highest. The use of alien introgression for crop improvement is important for meeting the challenges of global food supply and the monocots such as the forage grasses and cereals, together with recent technological advances in molecular biology, can help meet these challenges.

Concordance of DMET plus genotyping results with those of orthogonal genotyping methods.

There are several hurdles to the clinical implementation of pharmacogenetics. One approach is to employ pre-prescription genotyping, involving interrogation of multiple pharmacogenetic variants using a high-throughput platform. We compared the performance of the Drug Metabolizing Enzymes and Transporters (DMET) Plus array (1,931 variants in 225 genes) with that of orthogonal genotyping methods in 220 pediatric patients. A total of 1,692 variants had call rates >98% and were in Hardy-Weinberg equilibrium. Of these, 259 were genotyped by at least one independent method, and a total of 19,942 single-nucleotide polymorphism (SNP)-patient sample pairs were evaluated. The concordance rate was 99.9%, with only 28 genotype discordances observed. For the genes deemed most likely to be clinically relevant (TPMT, CYP2D6, CYP2C19, CYP2C9, VKORC1, DPYD, UGT1A1, and SLCO1B1), a total of 3,799 SNP-patient sample pairs were evaluable and had a concordance rate of 99.96%. We conclude that the DMET Plus array performs well with primary patient samples, with the results in good concordance with those of several lower-throughput genotyping methods.

The clinical pharmacogenomics implementation consortium: CPIC guideline for SLCO1B1 and simvastatin-induced myopathy.

Cholesterol reduction from statin therapy has been one of the greatest public health successes in modern medicine. Simvastatin is among the most commonly used prescription medications. A non-synonymous coding single-nucleotide polymorphism (SNP), rs4149056, in SLCO1B1 markedly increases systemic exposure to simvastatin and the risk of muscle toxicity. This guideline explores the relationship between rs4149056 (c.521T>C, p.V174A) and clinical outcome for all statins. The strength of the evidence is high for myopathy with simvastatin. We limit our recommendations accordingly.

Functional characterization of liver enhancers that regulate drug-associated transporters.

Little is known about how genetic variations in enhancers influence drug response. In this study, we investigated whether nucleotide variations in enhancers that regulate drug transporters can alter their expression levels. Using comparative genomics and liver-specific transcription factor binding site (TFBS) analyses, we identified evolutionary conserved regions (ECRs) surrounding nine liver membrane transporters that interact with commonly used pharmaceuticals. The top 50 ECRs were screened for enhancer activity in vivo, of which five--located around ABCB11, SLC10A1, SLCO1B1, SLCO1A2, and SLC47A1--exhibited significant enhancer activity. Common variants identified in a large ethnically diverse cohort (n = 272) were assayed for differential enhancer activity, and three variants were found to have significant effects on reporter activity as compared with the reference allele. In addition, one variant was associated with reduced SLCO1A2 mRNA expression levels in human liver tissues, and another was associated with increased methotrexate (MTX) clearance in patients. This work provides a general model for the rapid characterization of liver enhancers and identifies associations between enhancer variants and drug response.

Lesions of the dorsomedial striatum disrupt prepulse inhibition.

Prepulse inhibition (PPI) of startle is an experimentally tractable measure of sensorimotor gating that can be readily evaluated in mice, rats, monkeys, and humans. PPI is the inhibitory effect of a low-intensity stimulus, the prepulse, on the startle response to a subsequent high-intensity stimulus. PPI has garnered great interest as a marker of clinically relevant information processing abnormalities, because it is impaired in such neuropsychiatric conditions as schizophrenia, Tourette syndrome, and obsessive compulsive disorder (OCD). Pathology of the basal ganglia has been described in all three of these disorders, and it is therefore of great interest to determine the role of the basal ganglia in PPI. Previous work in rats described a PPI deficit after excitotoxic ventral striatal lesions and a more subtle attenuation after caudodorsal lesion, but no effect of other large lateral dorsal lesions. However, previous studies have not specifically investigated the role of the dorsomedial striatum in PPI. We investigated this issue using excitotoxic lesions in mice. We describe a marked reduction in PPI, at a variety of prepulse intensities, after bilateral lesions of dorsomedial striatum. There was no effect of lesion on baseline startle or habituation. In contrast, comparably sized lesions of the central dorsal striatum had no effect on PPI. These results reveal a role for the dorsomedial striatum in prepulse inhibition, which may have relevance for the abnormalities observed in this region in such disorders as Tourette syndrome and OCD.

A phase II dose finding study of darbepoetin alpha and filgrastim for the management of anaemia and neutropenia in chronic hepatitis C treatment.

Dose reductions of pegylated interferon alpha and ribavirin may be avoided by using growth factors. This phase II clinical trial assesses the dose, efficacy and safety of darbepoetin alpha and filgrastim for treatment of anaemia and neutropenia associated with combination therapy for hepatitis C virus (HCV). Chronic hepatitis C patients (n = 101) received pegylated interferon alpha-2b (1.5 mug/kg once weekly) and ribavirin (800-1400 mg once daily). Patients with anaemia [haemoglobin (Hb) /= 0.75 x 10(9)/L and <10 x 10(9)/L. During antiviral therapy, 52% of patients required darbepoetin alpha, filgrastim or both. Hb at the time of darbepoetin alpha initiation was 10.2 +/- 0.4 g/dL. After 81 days of darbepoetin alpha, Hb increased by 1.9 +/- 1.0 g/dL to 12.1 +/- 1.1 g/dL (P < 0.0001). Filgrastim resulted in a significant increase in ANC [0.75 +/- 0.16 x 109/L to 8.28 +/- 5.67 x 10(9)/L (P < 0.0001)]. In treatment-naïve patients, 48% achieved sustained virological response (SVR), whereas 27% of patients previously treated with a course of pegylated interferon alpha achieved SVR. Low viral load, nongenotype 1 and treatment with growth factors were independently associated with SVR. Mild and severe anaemia were associated with quality of life impairments. Darbepoetin alpha resulted in an improvement in the Vitality domain of Short Form-36. No significant adverse events were related to growth factors. During anti-HCV therapy, filgrastim improved neutropenia and darbepoetin alpha improved both anaemia and quality of life. Future randomized clinical trials are needed to establish the impact of growth factors in improving sustained virological response.

Effects of cross-sex hormones on cerebral activation during language and mental rotation: An fMRI study in transsexuals.

Androgens and estrogens affect the performance on certain cognitive tests, particularly those measuring verbal fluency and mental rotation. Their effects on cognition have frequently been attributed to changes in cerebral lateralization. This study tested the impact of a reversal of the sex steroid milieu on cerebral activation and lateralization during verbal and spatial tasks in transsexuals. fMRI scans were obtained from 6 female-to-male and 8 male-to-female transsexuals at baseline and after cross-sex steroid treatment. Activation was measured during language and mental rotation tasks. Language activation increased after sex steroid treatment in both groups (F(1,12) =3.7, p=0.08), and total language activity was correlated to post-treatment estradiol levels (rho=0.54, p=0.05). Lateralization was not affected by the reversal of sex steroid milieus (F(1,12)=1.47, p=0.25). Activation during mental rotation did not increase during treatment (F(1,12)=0.54, p=0.34), but post-treatment testosterone levels correlated to total activation during mental rotation (rho=0.64, p=0.01). Findings suggest that sex steroids may influence cerebral activation, but lateralization remains stable.

Injury prevention practices as depicted in G and PG rated movies: the sequel.

OBJECTIVE: To determine whether the depiction of injury prevention practices in children's movies released during 1998-2002 is different from an earlier study, which found that characters were infrequently depicted practicing recommended safety behaviors. METHODS: The top 25 G (general audience) and PG (parental guidance suggested) rated movies per year from 1998-2002 comprised the study sample. Movies or scenes not set in the present day, animated, documentary, or not in English were excluded; fantasy scenes were also excluded. Injury prevention practices of motor vehicle occupants, pedestrians, bicyclists, and boaters were recorded for characters with speaking roles. RESULTS: Compared with the first study, the proportion of scenes with characters wearing safety belts increased (27% v 35%, p<0.01), the proportion of scenes with characters wearing personal flotation devices decreased (17% v 0%, p<0.05), and no improvement was noted in pedestrian behavior or use of bicycle helmets. CONCLUSIONS: Despite a modest increase in safety belt usage, appropriate injury prevention practices are still infrequently shown in top grossing G and PG rated movies. The authors recommend that the entertainment industry incorporate safe practices into children's movies. Parents should call attention to the depiction of unsafe behaviors in movies and educate children to follow recommended safety practices.

In situ evaluation of sodium hexametaphosphate-containing dentifrices.

The purpose of this investigator-blinded, five-treatment, crossover human intraoral study was to evaluate the effects of two experimental dentifrice formulations containing either stannous fluoride (SnF(2)) or sodium fluoride (NaF) packaged with sodium hexametaphosphate in a dual-phase delivery system on demineralization-remineralization using an in situ model system. The experimental dentifrice formulations' ability to alter demineralization-remineralization was compared to a series of three controls: SnF(2)-positive control, NaF-positive control and no-fluoride placebo-negative control. The single-section crown model, developed at the University of Iowa, was used to assess the fluoride efficacy of two experimental products versus the placebo containing no fluoride and positive controls. The results of the current in situ study suggest a clinical level of anticaries activity for the experimental SnF(2) and NaF dentifrice formulations that was as good as either of the positive controls, when evaluated using polarized light microscopy. This supports the conclusion that the use of the sodium hexametaphosphate ingredient does not interfere with the normal fluoride activity of these toothpastes. In addition, the experimental SnF(2) product was numerically better than both the NaF and placebo controls at preventing demineralization of sound root surfaces.

Exercise in sickle cell anemia: effect on inflammatory and vasoactive mediators.

The aim of this study was to determine the response of inflammatory and vasoactive mediators to 3 consecutive days of exercise in African-American women with and without sickle cell anemia (SCA). Circulating inflammatory mediators [C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha)] were measured before, and vasoactive mediators [endothelin-1 (ET-1), nitric oxide metabolites (NOx)] before and after each exercise bout in ten subjects with SCA and ten controls. Exercise did not affect ET-1, IL-6 or CRP concentrations (p >.05). TNFalpha was higher in SCA than controls (p < or = .0005) at all times; however, the response pattern was similar for the groups: no change from day 1 to day 2, but a decrease from day 2 to day 3 (p < or = .05). NOx increased significantly after exercise (p < or = .0001) but returned to baseline by 24 h afterward. On the 3rd day, NOx increased after exercise in SCA but not in the controls (p < or = .05). In conclusion, exercise did not cause a harmful inflammatory response in these individuals with SCA. However, NOx increased after exercise on all 3 days in SCA but appeared attenuated after 2 days in controls.

Preferential repair by squamous epithelium of thermal induced injury to the proximal stomach in patients undergoing ablation of Barrett's esophagus.

BACKGROUND: The presence of extensions of squamous epithelium into the proximal stomach in patients undergoing routine upper endoscopy has recently been described. The factors that may favor development of squamous epithelium within the proximal stomach remain unknown. METHODS: Patients with Barrett's esophagus who agreed to undergo ablation of Barrett's epithelium by using multipolar electrocoagulation were included. Patients were treated with a high dose of a proton pump inhibitor. The columnar-appearing mucosa was systematically treated. Occasionally, thermal injury was inadvertently induced in the proximal stomach. On endoscopy performed 4 to 6 weeks after treatment, the presence of squamous epithelium extending into the proximal stomach was documented. The use of Lugol's stain assisted in confirming the squamous nature of the abnormal tissue, which was confirmed histologically by cytokeratin immunohistochemistry. RESULTS: The 12 patients included in the study had a mean length of Barrett's epithelium of 3.8 +/- 0.7 cm. Patients were treated with omeprazole, mean dose 66 +/- 6.0 mg, and had a mean percent total time that the pH was less than 4 of 1.9 +/- 0.8. The mean length and width of gastric squamous extensions were 1.7 +/- 0.2 cm and 0.8 +/- 0.1 cm, respectively. None of the squamous extensions into the stomach were documented before mucosal ablation. The extensions stained positively for cytokeratin 13 and negatively for cytokeratin 8, thereby confirming their squamous nature. CONCLUSIONS: Thermal injury to the proximal stomach in patients undergoing ablation of Barrett's epithelium and profound acid suppression results in repair by squamous epithelium. Recognition of this lesion is essential because it may lead to confusion as to the location of the esophagogastric junction in subsequent endoscopic evaluations.

Body composition in women with sickle cell disease.

INTRODUCTION: Adults with sickle cell disease (SCD) have increased morbidity and low perceived health status, similar to patients with other chronic conditions. These patients may be sedentary due to exercise intolerance, physical incapacity due to sickle cell-related complications or medical conservatism. Obesity is an indicator of low health status and overall well-being in the general population, and we hypothesize that adults with SCD will have a high total body fat (%BF). The purpose of this study was to assess body composition in women with SCD using dual-energy X-ray absorptiometry (DXA). METHODS: Baseline medical examination, laboratory assessments, and seven-day activity recall to estimate energy expenditure (EE) were obtained for 22 women with SCD. BMI was calculated and whole body DXA was performed [fat mass (FM), fat-free soft tissue (FFST), and bone mineral content (BMC)]. Descriptive statistics were obtained and associations between body composition indices, total hemoglobin (Hb), treatment with hydroxyurea (HU), and EE were determined. RESULTS: Patient age was 30.5+/-9.3 years and total Hb was 8.85+/-1.92 g/dL (mean+/-SD). Mean body mass index (BMI) (22.6 kg/m2) was in the 'acceptable' range, while DXA measurement of mean % fat (32.6%) indicated obesity. Fat-free mass (FFM) was 40.0+/-5.62 and bone mineral density (BMD) was 1.13+/-0.14 g/cm2 (mean+/-SD). There were no correlations between body composition indices and total Hb, HU, or EE. CONCLUSIONS: This is the first report of high levels of adiposity, low FFM, and low BMD in normal weight women with SCD. The findings were not affected by total Hb, EE, HU. Further studies are needed to better define body composition, body composition determinants, and their impact on overall health status in adults with SCD.

Aplanatic corrector designs for the extremely large telescope.

The next century is knocking on our door, bringing with it the possibility of telescopes even bigger than the 8-10-m-class instruments that have proliferated over the past decade. The fixed spherical reflector is the most economical and pragmatic way to construct an extremely large primary mirror (30-50 m in diameter). Although spherical mirrors have virtues such as manufacturability and identically figured segments, they also create great amounts of spherical aberration and coma. Here we show that there are several catoptric (all-reflecting) corrector designs that enable a fast telescope based on a spherical primary mirror.