Increased donor inhibitory KIR are associated with reduced GVHD and improved survival following HLA-matched unrelated donor HCT in paediatric acute leukaemia.

Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer cell-mediated effects after haematopoietic stem cell transplantation (HCT). Previous work has shown that accounting for known KIR-KIRL interactions may identify donors with optimal NK cell-mediated alloreactivity in the adult transplant setting. Paediatric acute leukaemia patients were retrospectively analysed, and KIR-KIRL combinations and maximal inhibitory KIR ligand (IM-KIR) scores were determined. Clinical outcomes were examined using a series of graphs depicting clinical events and endpoints. The graph methodology demonstrated that prognostic variables significant in the occurrence of specific clinical endpoints remained significant for relevant downstream events. KIR-KIRL combinations were significantly predictive for reduced grade 3-4 aGVHD likelihood, in patients transplanted with increased inhibitory KIR gene content and IM-KIR = 5 scores. Improvements were also observed in associated outcomes for both ALL and AML patients, including relapse-free survival, GRFS and overall survival. This study demonstrates that NK cell KIR HLA interactions may be relevant to the paediatric acute leukaemia transplant setting. Reduction in aGVHD suggests KIR effects may extend beyond NK cells. Moving forward clinical trials utilizing donors with a higher iKIR should be considered for URD HCT in paediatric recipients with acute leukaemia to optimize clinical outcomes.

Sunscreen compound benzophenone-3 and its relationship with white blood cell counts.

BACKGROUND: Evidence from animal models suggests a role for the organic ultraviolet filter benzophenone-3's (BP-3) on white blood cells (WBCs). However, BP-3's effect on WBCs in humans is unknown. MATERIALS AND METHODS: We used National Health and Nutrition Examination Survey data from 2003 to 2016. We included participants >6 years with data on urinary BP-3, urinary creatinine, and WBC count. Quintiles of urinary creatinine-normalized BP-3 (CnBP-3) levels were used in linear regression models adjusting for age, gender, race, body mass index (BMI), smoking status, education level, family income to poverty threshold ratio, survey cycle, and season. RESULTS: Of the 16 959 participants, 8564 (50.5%) were females, 6602 (38.9%) were White, and 3870 (22.8%) were Black. The mean (standard deviation) age was 37.6 (22.7) years, BMI was 26.8 (7.40) kg/m2, WBC count was 7.22 (2.53) × 109/L, neutrophil count was 4.15 (1.86) × 109/L, and lymphocyte count was 2.25 (1.33) × 109/L and median (interquartile range) of CnBP-3 was 12.1 (44.9) µg/gm. The highest quintile of CnBP-3 was associated with significantly lower WBC and neutrophil counts compared to the lowest quintile of CnBP-3 (Δ quintiles = -137 × 106/L, 95% CI: -249 to -24, p = 0.02 and = -177 × 106/L, 95% CI: -323 to -30, p = 0.02, respectively). In contrast, we did not observe a difference in lymphocyte count between the lowest and highest quintiles of CnBP-3 in unadjusted or adjusted analyses. CONCLUSION: We found an inverse relationship between BP-3 levels and WBC and neutrophil counts, and not with lymphocyte count. Further research is needed to confirm our findings.

Sex-specific relationship between blood selenium levels and platelet count in a large cohort representative of the United States population.

While several small studies have found that selenium deficiency is associated with low platelet counts, they lack generalizability. We used data from the National Health and Nutrition Examination Surveys collected over a 12-year period. We examined the relationship between selenium quartiles and platelet count using survey-weighted linear regression models adjusting for age, sex, race, household income to poverty threshold income, highest education attainment, smoking status, red blood cell folate, and body mass index. Of the 21,764 participants, 51% were females, 23% African Americans, and 25% were >65 years of age. Mean (SD) platelet count was 243(64) 109/L and selenium was 183(32) µg/L. Women had significantly higher platelet count but lower selenium levels than men (258 vs. 227 109/L and 181 vs. 185 µg/L respectively; both P < 0.0001). In adjusted analysis, participants in the highest selenium quartile had 8.0x109/L higher platelet count as compared to those in the lowest selenium quartile (95%CI = 4.1 to 11.9; P < 0.0001). Gender modified the relationship between the two; although there was no difference in women, platelet count was higher in the highest than the lowest selenium quartile in men (interaction p-value = 0.001). These findings highlight the importance of selenium and gender in platelet biology which needs to be explored.

Several small studies have found an association between selenium deficiency and low platelet counts but a large study is needed. We examined this association using data from the National Health and Nutrition Examination Surveys while adjusting for age, sex, race, household income to poverty threshold income, highest education attainment, smoking status, red blood cell folate, and body mass index. In this cohort of 21,764 participants, we found that participants in the highest selenium quartile had significantly higher platelet count than those in the lowest quartile and that this relationship between selenium and platelet count differs by gender. Our findings highlight the importance of both selenium and gender in platelet biology which needs further exploration.

Killer Immunoglobulin-Like Receptor-Ligand Interactions Predict Clinical Outcomes following Unrelated Donor Transplantations.

Killer immunoglobulin-like receptor (KIR) and KIR ligand (KIRL) interactions play an important role in natural killer (NK) cell-mediated graft-versus-leukemia effect following hematopoietic cell transplantation (HCT). However, there is considerable heterogeneity in the KIR gene and KIRL content in individuals, making it difficult to estimate the full clinical impact of NK cell reconstitution following HCT. Here we present a novel adaptive mathematical model designed to quantify these interactions to better assess the influence of NK cell-mediated alloreactivity on transplant outcomes. Ninety-eight HLA- matched unrelated donor (URD) HCT recipients were studied retrospectively. The KIR-KIRL interactions were quantified using a system of matrix equations. Unit values were ascribed to each KIR-KIRL interaction, and the directionality of interactions was denoted by either a positive (activating) or negative (inhibition) symbol; these interactions were then summed. The absolute values of both the missing KIRL and inhibitory KIR-KIRL interactions were significantly associated with overall survival and relapse. These score components were initially used to develop a weighted score (w-KIR score) and subsequently a simplified, nonweighted KIR-KIRL interaction score (IM-KIR score). Increased w-KIR score and IM-KIR score were predictive of all-cause mortality and relapse (w-KIR score: hazard ratio [HR], .37 [P = .001] and .44 [P = .044], respectively; IM-KIR score: HR, .5 [P = .049] and .44 [P = .002], respectively). IM-KIR score was also associated with NK cell reconstitution post-HCT. KIR-KIRL interactions as reflected by the w-KIR and IM-KIR scores influence both relapse risk and survival in recipients of HLA-matched URD HCT with hematologic malignancies.

Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis.

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.

Use of Telehealth Expedites Evaluation and Listing of Patients Referred for Liver Transplantation.

BACKGROUND & AIMS: Liver transplantation is the only treatment that increases survival times of patients with decompensated cirrhosis. Patients who live farther away from a transplant center are disadvantaged. Health care delivery via telehealth is an effective way to manage patients with decompensated cirrhosis remotely. We investigated the effects of telehealth on the liver transplant evaluation process. METHODS: We performed a retrospective study of 465 patients who underwent evaluation for liver transplantation at the Richmond Veterans Affairs Medical Center from 2005 through 2017. Of these, 232 patients were evaluated via telehealth, and 233 via in-person evaluation. Using regression models, we evaluated the differential effects of telehealth vs usual care on placement on the liver transplant waitlist. We also investigated the effects of telehealth on time from referral to initial evaluation by a transplant hepatologist, liver transplantation, and mortality. RESULTS: Patients in the telehealth group were evaluated significantly faster than patients evaluated in person, without or with adjustment for potential confounders (21.7 vs 79.5 d; P < .01). Telehealth also was associated with a significantly shorter time on the liver transplant waitlist (138.8 vs 249 d; P < .01). After propensity-matched analysis, telehealth was associated with a reduction in the time from referral to evaluation (hazard ratio, 0.15; 95% CI, 0.09-0.21; P < .01) and listing (hazard ratio, 0.26; 95% CI, 0.12-0.40; P < .01), but not to transplantation. In the intent-to-treat analysis of all referred patients, we found no significant difference in pretransplant mortality between patients evaluated via telehealth vs in-person. There was statistically significant interaction between model for end-stage liver disease (MELD)-Na scores and time to evaluation (P = .009) and placement on the transplant waitlist (P = .002), with telehealth offering greater benefits to patients with low MELD-Na scores. CONCLUSIONS: Use of telehealth is associated with a substantial reduction in time from referral to initial evaluation by a hepatologist and placement on the liver transplant waitlist, especially for patients with low MELD scores, with no changes in time to transplantation or pretransplant mortality. More studies are needed, particularly outside of the Veterans Administration Health System, to confirm that telehealth is a safe and effective way to expand access for patients undergoing evaluation for liver transplantation.

Non-lactate strong ion difference and cardiovascular, cancer and all-cause mortality.

Objectives: Non-lactate strong ion difference (SID) has been shown to be associated with predictors of mortality in intensive care unit. However, the existence of any association between non-lactate SID (nlSID) and all cause, cardiovascular and cancer mortality has not been explored before in community dwelling US adults. Methods: In a nationally representative cross-sectional survey of the US non-institutionalized population, all adult participants (≥20 years of age) using National Health and Nutrition Examination Survey data (1999-2010) combined with National Death Index for mortality status through December 2011. Cox proportional hazard models were built to estimate the hazard ratios for cardiovascular, cancer, and all-cause mortality for each unit increase in non-lactate SID. The models were adjusted for demographic and confounder variables. Results: In the study population the mean (SD) age was 49.6 (18.4) years. Of the study population, 31,475 (91.5%) were alive and 2,893 (8.4%) died during the mean (SD) follow-up period of 5.5 (3.5) years. In univariate regression model using nlSID as continuous variable, we found 2% (unadjusted hazard ratio, HR=1.02; 95% CI, 1.004-1.05) increase in all-cause but not in cardiovascular and cancer mortality (HR=1.03; 95% CI, 0.99-1.08, HR=1.01; 95% CI, 0.97-1.06). After adjusting for potential confounders, we found 7% (adjusted HR=1.07; 95% CI, 1.04-1.10), 5% (HR=1.05; 95% CI, 1.00-1.11) and 7% (HR=1.07; 95% CI, 1.02-1.12) increase in all-cause, cardiovascular, and cancer mortality. Conclusions: A high nlSID is associated with an increase in cardiovascular, cancer and all-cause mortality and may be a prognostic indicator of mortality in general adult population. These findings may provide a point of reference for further studies.

Platelet-lymphocyte ratio (PLR) and all-cause mortality in general population: insights from national health and nutrition education survey.

Platelet lymphocyte ratio (PLR) is a novel marker of inflammation that has gained popularity, especially in prognostication of cardiac diseases and malignant conditions. Several studies have examined the relationship between PLR and disease-specific mortality but none has examined this relationship with all-cause mortality in general population. Therefore, we examined the relationship between PLR and all-cause mortality using data from the National Health and Nutrition Examination Survey (NHANES) from the year 1999 to 2010. The role of PLR in predicting all-cause mortality was evaluated using Cox proportional hazards model adjusting for age, race, gender, smoking history, diabetes, hypertension, serum cholesterol, estimated glomerular filtration rate, serum c-reactive protein, and body mass index. Differential effect of age was examined using difference of differences analysis. Of the 27321 individuals, 2581 died during 171223 person-year follow-up. Mean PLR was significantly higher in participants who died than those who were living at the end of follow-up (145.7 vs. 133.0, respectively, p < 0.001). Individuals in the fourth quartile of PLR were at significantly higher risk of mortality than those in the first quartile (HR = 1.26, 95% CI: 1.08-1.47, p = 0.004 and adjusted HR = 1.33, HR, 95% CI: 1.15-1.54, p < 0.001, respectively). When examining the differential effect of age, association between PLR and mortality was seen in the elderly but not in the middle age or younger participants. Elevated PLR is associated with increased all-cause mortality, especially in the elderly. Further studies examining the mechanism through which PLR may increase mortality are needed.

A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration.

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

The effect of sleep duration on exhaled nitric oxide levels in U.S. adults.

PURPOSE: Poor sleep quality and duration are associated with systemic endothelial dysfunction. However, an association between poor sleep and pulmonary endothelial dysfunction has not been elucidated. We sought to determine if there is a relationship between sleep duration and fractional exhaled nitric oxide (FeNO) concentrations as a surrogate for pulmonary endothelial function. METHODS: We used three National Health and Nutrition Examination Survey (NHANES) cycles (2007-2012). Linear regression models were built with and without adjustment for age, sex, race, BMI, asthma/bronchitis, CRP, smoking, folate, renal function, respiratory infections, and steroid use. To examine a non-linear relationship, we introduced a spline, with single knot at mean sleep duration (7 h). RESULTS: Of 13,173 participants (50.8% male, 44.2% Caucasian), 78% slept 6-8 hours (h). FeNO was significantly higher in the group sleeping 6-8 h (17.3 ± 14.9 ppb) than in the other two groups (16.0 ± 13.0 ppb, 15.9 ± 12.7 ppb for <6 and >8 h respectively; P < 0.001). In unadjusted linear regression, FeNO increased by 1.1 ppb for each hour increase in sleep up to 7 h (P < 0.001). Increased sleep duration beyond 7 h saw a 0.96 ppb decrease in FeNO (P < 0.001). After adjustment for confounders, FeNO increased by 1.09 ppb for each hour of sleep up to 7 h (P = 0.001) and decreased by 0.71 ppb for each hour after (P = 0.02). CONCLUSION: Sleeping less or more than 7 h is associated with pulmonary endothelial dysfunction as measured by FeNO. Further study is needed to evaluate mechanism(s) of this association and validity of FeNO as a marker of endothelial function.

Hospital Discharge Disposition of Stroke Patients in Tennessee.

OBJECTIVES: Early determination of hospital discharge disposition status at an acute admission is extremely important for stroke management and the eventual outcomes of patients with stroke. We investigated the hospital discharge disposition of patients with stroke residing in Tennessee and developed a predictive tool for clinical adoption. Our investigational aims were to evaluate the association of selected patient characteristics with hospital discharge disposition status and predict such status at the time of an acute stroke admission. METHODS: We analyzed 127,581 records of patients with stroke hospitalized between 2010 and 2014. Logistic regression was used to generate odds ratios with 95% confidence intervals to examine the factor outcome association. An easy-to-use clinical predictive tool was built by using integer-based risk scores derived from coefficients of multivariable logistic regression. RESULTS: Among the 127,581 records of patients with stroke, 86,114 (67.5%) indicated home discharge and 41,467 (32.5%) corresponded to facility discharge. All considered patient characteristics had significant correlations with hospital discharge disposition status. Patients were at greater odds of being discharged to another facility if they were women; older; black; patients with a subarachnoid or intracerebral hemorrhage; those with the comorbidities of diabetes mellitus, heart disease, hypertension, chronic kidney disease, arrhythmia, or depression; those transferred from another hospital; or patients with Medicare as the primary payer. A predictive tool had a discriminatory capability with area under the curve estimates of 0.737 and 0.724 for derivation and validation cohorts, respectively. CONCLUSIONS: Our investigation revealed that the hospital discharge disposition pattern of patients with stroke in Tennessee was associated with the key patient characteristics of selected demographics, clinical indicators, and insurance status. These analyses resulted in the development of an easy-to-use predictive tool for early determination of hospital discharge disposition status.

Trans-ethnic meta-analysis of white blood cell phenotypes.

White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.

The Effect of Serum Vitamin D on Serum ALT Levels in Healthy Individuals.

BACKGROUND: Several studies have examined the relationship between vitamin D (VD) and liver disease but none have explored this relationship in adults with normal liver enzymes. Our aim was to explore an independent association of VD with alanine aminotransferase (ALT) in a large sample of the US adults with liver enzymes in normal range (≤39 U/L). METHODS: We used the continuous National Health and Nutrition Examination Survey from 2001 to 2006. We excluded individuals with serum ALT>39 U/L. We built linear regression models to estimate unadjusted and adjusted (age, sex, race, diabetes, hypertension, alcohol use, smoking, and body mass index) effect sizes, taking into account the complex probability survey design. RESULTS: Of the 12,155 participants, 6635 (54.6%) were women, mean±SD age was 49.9±19.4 years, VD was 21.9±9.2 ng/mL, and ALT was 20.9±6.9 U/L. In unadjusted analysis, VD was significantly associated with serum ALT (0.02 U/L/ng/mL of VD, P=0.007). After adjustment for confounders, VD remained statistically significantly associated with serum ALT levels (0.04 U/L, P<0.001). Similarly, individuals in the highest quartile of VD had significantly higher serum levels of ALT than those in the lowest quartile (unadjusted difference=0.98 U/L, P<0.001; adjusted difference=1.21 U/L, P<0.001). CONCLUSIONS: We found a positive association between VD and ALT after excluding individuals with suspected active liver injury (ALT>39 U/L). The underlying mechanisms for this association are not known and needs further study.

Genome-wide association analysis of red blood cell traits in African Americans: the COGENT Network.

Laboratory red blood cell (RBC) measurements are clinically important, heritable and differ among ethnic groups. To identify genetic variants that contribute to RBC phenotypes in African Americans (AAs), we conducted a genome-wide association study in up to ~16 500 AAs. The alpha-globin locus on chromosome 16pter [lead SNP rs13335629 in ITFG3 gene; P < 1E-13 for hemoglobin (Hgb), RBC count, mean corpuscular volume (MCV), MCH and MCHC] and the G6PD locus on Xq28 [lead SNP rs1050828; P < 1E - 13 for Hgb, hematocrit (Hct), MCV, RBC count and red cell distribution width (RDW)] were each associated with multiple RBC traits. At the alpha-globin region, both the common African 3.7 kb deletion and common single nucleotide polymorphisms (SNPs) appear to contribute independently to RBC phenotypes among AAs. In the 2p21 region, we identified a novel variant of PRKCE distinctly associated with Hct in AAs. In a genome-wide admixture mapping scan, local European ancestry at the 6p22 region containing HFE and LRRC16A was associated with higher Hgb. LRRC16A has been previously associated with the platelet count and mean platelet volume in AAs, but not with Hgb. Finally, we extended to AAs the findings of association of erythrocyte traits with several loci previously reported in Europeans and/or Asians, including CD164 and HBS1L-MYB. In summary, this large-scale genome-wide analysis in AAs has extended the importance of several RBC-associated genetic loci to AAs and identified allelic heterogeneity and pleiotropy at several previously known genetic loci associated with blood cell traits in AAs.

Comparison of breast cancer risk in women with and without systemic lupus erythematosus in a Medicare population.

Studies have suggested a decreased breast cancer risk in women with systemic lupus erythematosus. However, these studies enrolled younger patients identified primarily from lupus clinics. We compared the 5-year incidence of breast cancer among women with and without a diagnosis of SLE in a large population-based study of Medicare beneficiaries. We used a 20 % sample to create a cohort of 3,670,138 women from 2006 Medicare claims data with and without SLE at baseline. The study had 80 % power to detect whether the 5-year breast cancer incidence in the SLE cohort was 13 % higher or lower than the non-SLE cohort. Of the 18,423 women with SLE, 21 % were African American and 53 % were ≥65 years. The absolute age-adjusted risk for breast cancer in women with SLE was 2.23 (95 % CI 1.94-2.55) and 2.14 (95 % CI 1.96-2.34) in controls per 100 women. The overall absolute age and race adjusted incidence rate was 1.04 (95 % CI 0.90-1.21). Among women with SLE from "Others" (Hispanic, Native American, and/or Asian), the age-adjusted risk for breast cancer was 2.44 per 100 women (95 % CI 1.07-2.18), and age-adjusted incidence rate was 1.52 (95 % CI 1.07-2.18). In contrast to prior clinic-based studies, this population-based cohort study showed that the risk of breast cancer in women with SLE was not lower than in women without SLE. Women with SLE should follow routine breast cancer screening recommendations for their age group to avoid delay in diagnosis, because the presence of SLE may affect selection of early breast cancer therapies.

Genome-wide association study of platelet aggregation in African Americans.

BACKGROUND: We have previously shown that platelet aggregation has higher heritability in African Americans than European Americans. However, a genome-wide association study (GWAS) of platelet aggregation in African Americans has not been reported. We measured platelet aggregation in response to arachidonic acid, ADP, collagen, or epinephrine by optical aggregometry. The discovery cohort was 825 African Americans from the GeneSTAR study. Two replication cohorts were used: 119 African Americans from the Platelet Genes and Physiology Study and 1221 European Americans from GeneSTAR. Genotyping was conducted with Illumina 1 M arrays. For each cohort, age- and sex-adjusted linear mixed models were used to test for association between each SNP and each phenotype under an additive model. RESULTS: Six SNPs were significantly associated with platelet aggregation (P<5×10(-8)) in the discovery sample. Of these, three SNPs in three different loci were confirmed: 1) rs12041331, in PEAR1 (platelet endothelial aggregation receptor 1), replicated in both African and European Americans for collagen- and epinephrine-induced aggregation, and in European Americans for ADP-induced aggregation; 2) rs11202221, in BMPR1A (bone morphogenetic protein receptor type1A), replicated in African Americans for ADP-induced aggregation; and 3) rs6566765 replicated in European Americans for ADP-induced aggregation. The rs11202221 and rs6566765 associations with agonist-induced platelet aggregation are novel. CONCLUSIONS: In this first GWAS of agonist-induced platelet aggregation in African Americans, we discovered and replicated, novel associations of two variants with ADP-induced aggregation, and confirmed the association of a PEAR1 variant with multi-agonist-induced aggregation. Further study of these genes may provide novel insights into platelet biology.

A meta-analysis and genome-wide association study of platelet count and mean platelet volume in african americans.

Several genetic variants associated with platelet count and mean platelet volume (MPV) were recently reported in people of European ancestry. In this meta-analysis of 7 genome-wide association studies (GWAS) enrolling African Americans, our aim was to identify novel genetic variants associated with platelet count and MPV. For all cohorts, GWAS analysis was performed using additive models after adjusting for age, sex, and population stratification. For both platelet phenotypes, meta-analyses were conducted using inverse-variance weighted fixed-effect models. Platelet aggregation assays in whole blood were performed in the participants of the GeneSTAR cohort. Genetic variants in ten independent regions were associated with platelet count (N = 16,388) with p<5×10(-8) of which 5 have not been associated with platelet count in previous GWAS. The novel genetic variants associated with platelet count were in the following regions (the most significant SNP, closest gene, and p-value): 6p22 (rs12526480, LRRC16A, p = 9.1×10(-9)), 7q11 (rs13236689, CD36, p = 2.8×10(-9)), 10q21 (rs7896518, JMJD1C, p = 2.3×10(-12)), 11q13 (rs477895, BAD, p = 4.9×10(-8)), and 20q13 (rs151361, SLMO2, p = 9.4×10(-9)). Three of these loci (10q21, 11q13, and 20q13) were replicated in European Americans (N = 14,909) and one (11q13) in Hispanic Americans (N = 3,462). For MPV (N = 4,531), genetic variants in 3 regions were significant at p<5×10(-8), two of which were also associated with platelet count. Previously reported regions that were also significant in this study were 6p21, 6q23, 7q22, 12q24, and 19p13 for platelet count and 7q22, 17q11, and 19p13 for MPV. The most significant SNP in 1 region was also associated with ADP-induced maximal platelet aggregation in whole blood (12q24). Thus through a meta-analysis of GWAS enrolling African Americans, we have identified 5 novel regions associated with platelet count of which 3 were replicated in other ethnic groups. In addition, we also found one region associated with platelet aggregation that may play a potential role in atherothrombosis.

Effect of Time Interval Between Tumescent Local Anesthesia Infiltration and Start of Surgery on Operative Field Visibility in Hand Surgery Without Tourniquet.

PURPOSE: To determine the optimal time interval between tumescent local anesthesia infiltration and the start of hand surgery without a tourniquet for improved operative field visibility. METHODS: Patients aged 16 to 60 years who needed contracture release and tendon repair in the hand were enrolled from the outpatient clinic. Patients were randomized to 10-, 15-, or 25-minute intervals between tumescent anesthetic solution infiltration (0.18% lidocaine and 1:221,000 epinephrine) and the start of surgery. The end point of tumescence anesthetic infiltration was pale and firm skin. The surgical team was blinded to the time of anesthetic infiltration. At the completion of the procedure, the surgeon and the first assistant rated the operative field visibility as excellent, fair, or poor. We used logistic regression models without and with adjustment for confounding variables. RESULTS: Of the 75 patients enrolled in the study, 59 (79%) were males, 7 were randomized to 10-minute time intervals (further randomization was stopped after interim analysis found consistently poor operative field visibility), and 34 were randomized to the each of the 15- and 25-minute groups. Patients who were randomized to the 25-minute delay group had 29 times higher odds of having an excellent operative visual field than those randomized to the 15-minute delay group. After adjusting for age, sex, amount of tumescent solution infiltration, and duration of operation, the odds ratio remained highly significant. CONCLUSIONS: We found that an interval of 25 minutes provides vastly superior operative field visibility; 10-minute delay had the poorest results. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic I.

Association of platelet distribution width with all-cause and cause-specific mortality in US adults.

BACKGROUND: Platelet distribution width (PDW) indicates heterogeneity in circulating platelet sizes. Studies reporting PDW association with mortality were limited by small sample sizes. Therefore, we examined the relationship between PDW and all-cause and cause-specific mortality in a large representative cohort. METHODS: The NHANES III data were linked to mortality files to examine the association between PDW and mortality. We excluded participants <18 years old and had a history of myocardial infarction. Since the hazards violated the proportionality assumption, we used piece-wise spline with 5-year time intervals in Cox models without and with adjustment for age, gender, race, smoking history, diabetes mellitus, hypertension, eGFR and total cholesterol. RESULTS: Of 15,688 participants, 53.2% were females, 36.2% had a history of hypertension, and 6368(40.6%) died during follow-up (range 0 to 31 years). The mean (SD) age of the participants was 47(20) years, platelet count was 275.0(71.7) 109/L, and PDW 16.5(0.5). In multivariable analyses, PDW was associated with all-cause mortality at 0-5 years (HR = 1.44; 95%CI = 1.21, 1.72; P < 0.001) and at 5-10 years (HR = 1.23; 95%CI =1.03, 1.46; P = 0.02). Similarly, PDW association was significant for the first 0-5 years in cardiovascular mortality (HR = 1.58, 95%CI = 1.10, 2.25; P = 0.013) and for cancer mortality (HR = 1.48 (1.15, 95%CI = 1.15, 1.91, P = 0.003). For other-cause mortality, PDW remained significantly associated for 0-5 years (HR = 1.35, 95%CI =1.05, 1.74; P = 0.02) and for 5-10 years (HR = 1.38, 95%CI = 1.05, 1.83; P = 0.023). CONCLUSIONS: PDW is an independent, but time-dependent, predictor of all-cause, cardiovascular, cancer and other-cause mortality up to 5 years. The mechanisms underlying this association need further study.