Clinical and genetic analysis of MAPT, GRN, and C9orf72 genes in Korean patients with frontotemporal dementia

The hexanucleotide repeat expansion (GGGGCC) in chromosome 9 open-reading frame 72 (C9orf72) and mutations in the microtubule-associated protein tau (MAPT) and progranulin (GRN) genes are known to be associated with the main causes of familial or sporadic amyotrophic lateral sclerosis and frontotemporal dementia (FTD) in Western populations. These genetic abnormalities have rarely been studied in Asian FTD populations. We investigated the frequencies of mutations in MAPT and GRN and the C9orf72 abnormal expansion in 75 Korean FTD patients. Two novel missense variants of unknown significance in the MAPT and GRN were detected in each gene. However, neither abnormal C9orf72 expansion nor pathogenic MAPT or GRN mutation was found. Our findings indicate that MAPT, GRN, and C9orf72 mutations are rare causes of FTD in Korean patients.     

Genomic diagnostics within a medically underserved population: efficacy and implications

PurposeWe integrated whole-exome sequencing (WES) and chromosomal microarray analysis (CMA) into a clinical workflow to serve an endogamous, uninsured, agrarian community.MethodsSeventy-nine probands (newborn to 49.8 years) who presented between 1998 and 2015 remained undiagnosed after biochemical and molecular investigations. We generated WES data for probands and family members and vetted variants through rephenotyping, segregation analyses, and population studies.ResultsThe most common presentation was neurological disease (64%). Seven (9%) probands were diagnosed by CMA. Family WES data were informative for 37 (51%) of the 72 remaining individuals, yielding a specific genetic diagnosis (n = 32) or revealing a novel molecular etiology (n = 5). For five (7%) additional subjects, negative WES decreased the likelihood of genetic disease. Compared to trio analysis, “family” WES (average seven exomes per proband) reduced filtered candidate variants from 22 ± 6 to 5 ± 3 per proband. Nineteen (51%) alleles were de novo and 17 (46%) inherited; the latter added to a population-based diagnostic panel. We found actionable secondary variants in 21 (4.2%) of 502 subjects, all of whom opted to be informed.ConclusionCMA and family-based WES streamline and economize diagnosis of rare genetic disorders, accelerate novel gene discovery, and create new opportunities for community-based screening and prevention in underserved populations.     

Low frequency of Fabry disease in patients with common heart disease

PurposeTo test the hypothesis that undiagnosed patients with Fabry disease exist among patients affected by common heart disease.MethodsGlobotriaosylceramide in random whole urine using tandem mass spectroscopy, α-galactosidase A activity in dried blood spots, and next-generation sequencing of pooled or individual genomic DNA samples supplemented by Sanger sequencing.ResultsWe tested 2,256 consecutive patients: 852 women (median age 65 years (19–95)) and 1,404 men (median age 65 years (21–92)). The primary diagnoses were coronary artery disease (n = 994), arrhythmia (n = 607), cardiomyopathy (n = 138), and valvular disease (n = 568). Urinary globotriaosylceramide was elevated in 15% of patients and 15 males had low α-galactosidase A activity. GLA variants found included R118C (n = 2), D83N, and D313Y (n = 7); IVS6-22 C>T, IVS4-16 A>G, IVS2+990C>A, 5′UTR-10 C>T (n = 4), IVS1-581 C>T, IVS1-1238 G>A, 5′UTR-30 G>A, IVS2+590C>T, IVS0-12 G>A, IVS4+68A>G, IVS0-10 C>T, IVS2-81–77delCAGCC, IVS2-77delC. Although the pathogenicity of several of these missense mutations and complex intronic haplotypes has been controversial, none of the patients screened in this study were diagnosed definitively with Fabry disease.ConclusionThis population of patients with common heart disease did not contain a substantial number of patients with undiagnosed Fabry disease. GLA gene sequencing is superior to urinary globotriaosylceramide or α-galactosidase A activity in the screening for Fabry disease.     

The impact of medical informatics on patient satisfaction: A USA-based literature review

PurposePatient satisfaction is increasingly recognized as an important component of quality. The expansion of health information technologies (HIT) might have an impact on patient satisfaction – either positively or negatively. We conducted a literature review to explore the impact of these technologies on patient satisfaction.MethodsThe database of PubMed was searched from inception through May 2010, using the MeSH terms “Medical Informatics” and “Patient Satisfaction”. We included all original interventional studies regardless of their study design that were published in English and were evaluating HIT impact on patient satisfaction. Studies were categorized by technology type according to the American Medical Informatics Association framework and by study design. The major outcome of interest was the HIT impact on patient satisfaction.ResultsOf 1293 citations reviewed, 56 studies met our inclusion criteria. Design of these studies included mostly randomized controlled trials (RCTs) (n = 20, 36%), cross-sectional surveys (n = 17, 30%), and a pre and post studies (n = 14, 25%). Overall, 54% (n = 30) of the studies demonstrated a positive effect of HIT on patient satisfaction, 34% (n = 19) failed to show any effect, 11% (n = 6) had inconclusive results, and 2% (n = 1) revealed a negative effect. Of the 20 RCTs, 40% (n = 8) showed a positive effect of HIT on patient satisfaction, 50% (n = 10) failed to show any effect, and 10% (2) had inconclusive results.ConclusionsAnalysis suggested that while there is some evidence that HIT improves patient satisfaction, studies in this literature review, and in particularly RCTs, were not consistent in their findings. Although HIT may be a promising tool to improve patient satisfaction, more well-designed research studies are needed in order to get a better understanding of this domain and accordingly find new opportunities to improve quality of care.     

RET somatic mutations are underrecognized in Hirschsprung disease

PurposeWe aimed to determine the frequency of RET mosaicism in Hirschsprung disease (HSCR), test whether it has been underestimated, and to assess its contribution to HSCR risk.MethodsTargeted exome sequencing (n = 83) and RET single-gene screening (n = 69) were performed. Amplicon-based deep sequencing was applied on multiple tissue samples. TA cloning and sequencing were conducted for validation.ResultsWe identified eight de novo mutations in 152 patients (5.2%), of which six were pathogenic mosaic mutations. Two of these patients were somatic mosaics, with mutations detected in blood, colon, and saliva (mutant allele frequency: 35–44%). In addition, germ-line mosaicism was identified in four clinically unaffected subjects, each with an affected child, in multiple tissues (mutant allele frequency: 1–28%).ConclusionSomatic mutations of the RET gene are underrecognized in HSCR. Molecular investigation of the parents of patients with seemingly sporadic mutations is essential to determine recurrence risk in these families.     

HIV-1 viral load and phenotypic antiretroviral drug resistance assays based on reverse transcriptase activity in comparison to amplification based HIV-1 RNA and genotypic assays

BackgroundAmplification based HIV-1 viral load and genotypic resistance assays are expensive, technologically complex and may be difficult to implement in resource limited settings. Inexpensive, simpler assays are urgently needed.ObjectivesTo determine the suitability of the ExaVir? Load and ExaVir? Drug assays for use in patient monitoring.Study designSpecimens from 108 adults were used to compare ExaVir? Load HIV-1 RT to Amplicor HIV-1 Monitor^® HIV-1 RNA, and ExaVir? Drug phenotype to HIV GenoSure? genotype.ResultsHIV-1 RT and HIV-1 RNA levels were comparable (Pearson correlation coefficient 0.83). Most (94%) had detectable results in both assays. The mean difference (HIV-1 RT minus HIV-1 RNA) was ?0.21 log₁₀ cps/mL equiv. Relationship between HIV-1 RT and HIV-1 RNA was not affected by RT mutations, CD4 cell count, or efavirenz (EFV) or nevirapine (NVP) use. Phenotypes were generally consistent with genotype findings for EFV, but not for NVP. Most patients (93.9%) with phenotypic EFV resistance had at least one EFV mutation, while 78.0% of patients with phenotypic NVP resistance had at least one NVP mutation. Eleven of 49 samples tested for EFV susceptibility were found resistant (n = 2) or with reduced susceptibility (n = 9) despite the absence of genotypic resistance. Eleven of 45 samples tested for NVP susceptibility were found resistant (n = 9) or with reduced susceptibility (n = 2) with no evidence of genotypic mutations.ConclusionsThe ExaVir? Load assay performed well and may be an alternative to amplification based techniques for HIV-1 RNA quantification. The ExaVir? Drug assay for phenotypic resistance testing requires further evaluation, especially for NVP.     

Review with novel markers facilitates precise categorization of 41 cases of diagnostically challenging, “undifferentiated small round cell tumors”. A clinicopathologic,immunophenotypic and molecular analysis

BackgroundDespite extensive immunohistochemical (IHC) and molecular studies combined with morphologic findings, a group of round/ovoid cell tumors histologically similar to Ewing sarcomas (ES) but lacking EWSR1-rearrangements may remain unclassifiable.DesignWe retrospectively analyzed 41 Ewing-like tumors (formalin-fixed, paraffin-embedded) previously determined as negative or non-informative for EWSR1-rearrangements by FISH and/or RT-PCR. A new histopathology revision and additional IHC and molecular analyses were carried out in order to investigate whether additional IHC and/or molecular testing in combination with the morphological findings may help in reaching a definitive diagnosis.ResultsAlmost all the tumors (n = 40) involved soft tissue and/or bone and half the patients died of disease. In the archival cases all diagnoses were Ewing sarcoma (ES), Ewing-like sarcoma (ELS), myoepithelial tumor and undifferentiated sarcoma (US). In the new review all the tumors were re-classified as, ES (n = 16), Ewing-like tumor with EWSR1 rearrangement and amplification and possible EWSR1-NFATC2 gene fusion (n = 1), CIC-rearranged sarcomas or undifferentiated sarcoma, most consistent with CIC-rearranged sarcoma (n = 7), sarcoma with BCOR-alteration or undifferentiated sarcoma, consistent with BCOR-associated sarcoma (n = 3), neuroblastoma (n = 2), unclassifiable neoplasm with neuroblastic differentiation (n = 1), malignant rhabdoid tumor (n = 2), lymphoblastic lymphoma (n = 1), clear cell sarcoma of the gastrointestinal tract (n = 1), small cell carcinoma (n = 1), sclerosing rhabdomyosarcoma (n = 1), desmoplastic small round cell tumor (n = 1), malignant peripheral sheath nerve tumor (n = 1), poorly-differentiated synovial sarcoma (n = 1), Possible gastrointestinal stromal tumor/GIST with predominant round cells (n = 1) and possible SMARCA4-deficient-sarcoma (n = 1). NKX2.2, ETV4 and BCOR immunoreactivity was observed in all ES, CIC-rearranged sarcomas and sarcomas with BCOR alteration, respectively. CIC-rearrangement by FISH was observed in many of the CIC-rearranged sarcomas.ConclusionOur analysis of 41 Ewing-like tumors confirms that there may be a significant pathological and IHC overlap among Ewing-like tumors, with prognostic and therapeutic impacts. Additional IHC (NKX2.2, ETV4 and BCOR) and molecular studies including FUS, CIC or BCOR analysis may support the final diagnosis when FISH or RT-PCR fail to detect EWSR1-rearrangements. Any molecular findings should always be interpreted in relation to the specific clinical and pathological context.     

Multispectral characterization of tissues encountered during laparoscopic colorectal surgery

AimsThis study investigated the feasibility of automated differentiation between essential tissue types encountered during laparoscopic colorectal surgery using spectral analysis.MethodsWide band (440–1830 nm) spectra were collected using an optical fiber probe and spectrometer from freshly explanted, ex vivo, human colonic specimens. These data were normalized at 810 nm (an isobestic wavelength for hemoglobin and oxy-hemoglobin) and mathematically analyzed using total principal component regression (TPCR).Results929 spectra were collected from specimens of 19 patients, distinguishing 5 tissue types: mesenteric fat (MF, n = 269), blood vessels (BV, n = 377), colonic tissue (CT, n = 213), ureter (UR, n = 10) and tumorous tissue in colon (TT, n = 60). For each individual tissue type the distinctive ability was determined against all other tissue types pooled as a group. Paired probability density function (PDF) of “tissue” (centered around label 1) versus “all other pooled tissues” (centered around label 0) and the cumulative distribution function (CDF) at label crossover value 0.5 was determined for each tissue type (MF: CDF = 0.99 [SD = 0.19]; BV: CDF = 0.95 [SD = 0.29]; CT: CDF = 0.98 [SD = 0.22]; UR: CDF = 0.99 [SD = 0.09]; TT: CDF = 0.99 [SD = 0.18]).ConclusionAutomated spectral differentiation of blood vessel, ureter, mesenteric adipose tissue, colonic tissue and tumorous tissue in colon, is feasible in freshly explanted human colonic specimens. These results may be exploited for further steps toward multi- or hyperspectrally enhanced in vivo (laparoscopic) surgical imaging.     

A brief dyadic group based psychoeducation program improves relapse rates in recently remitted bipolar disorder: A pilot randomised controlled trial

BackgroundVarious adjunctive psychotherapies assist in decreasing relapse and improving outcomes for people with bipolar disorder (BD). Psychoeducation programs involving patient-only or caregiver-only groups have demonstrated some efficacy. We tested in recently remitted BD if a combined group based psychoeducation program involving patient–companion dyads decreased relapse.Method58 recently remitted BD out-patients were randomised to receive either treatment as usual (TAU, n = 31) or 12 × 90 minute psychoeducation sessions delivered weekly in a group program to the patient and companion (SIMSEP, n = 27). After 12 weeks SIMSEP patients reverted to TAU and all patients were followed until week 60 or relapse. The primary outcome measure was relapse requiring hospital or intensive community intervention.Results45 patients completed the study. 29 patients remained well at week 60 (SIMSEP n = 17, TAU n = 12), whilst 16 had relapsed (SIMSEP n = 3, TAU n = 13). The SIMSEP group were less likely to relapse (Fisher's exact test p = 0.013; OR = 0.16; 95% CI 0.04–0.70) and had an 11 week longer time to relapse compared to the TAU group (chi-square (1) = 8.48, p < 0.01). At study completion SIMSEP compared to TAU patients had lower Young Mania Rating Scale scores (Mann–Whitney U = 255, p < 0.01).LimitationsThe study was limited by a small sample size.ConclusionA brief group psychoeducation program with recently remitted BD patients and their companions resulted in a decreased relapse rate, longer time to relapse, decreased manic symptoms and improved medication adherence suggesting utility in the adjunctive psychotherapeutic treatment of BD.     

Tumor detection rates in screening of individuals with SDHx-related hereditary paraganglioma–pheochromocytoma syndrome

PurposeMinimal data exist regarding the efficacy of screening protocols for individuals with SDHx germline pathogenic variants with hereditary paraganglioma–pheochromocytoma syndrome. This study aimed to evaluate the SDHx-related tumor detection rate in individuals undergoing clinical screening protocols.MethodsA multicenter retrospective longitudinal observational study was conducted. Individuals with germline SDHx pathogenic variants underwent clinical whole-body imaging and biochemical testing.ResultsTwo hundred sixty-three individuals with SDHx germline pathogenic variants completed 491 imaging screens. Individuals with SDHB germline pathogenic variants were most common (n = 188/263, 72%), followed by SDHD (n = 35/263, 13%) and SDHC (n = 28/263, 11%). SDHx-related tumors were found in 17% (n = 45/263) of the cohort. Most SDHx-related tumors were identified on baseline imaging screen (n = 39/46, 85%). Individuals with SDHD pathogenic variants had the highest tumor detection rate (n = 14/35, 40%). Of imaging screens identifying SDHx-related paraganglioma/pheochromocytoma, 29% (n = 12/41) had negative biochemical testing. Secondary actionable findings were identified in 15% (n = 75/491) of imaging screens.ConclusionCurrent SDHx screening protocols are effective at identifying SDHx-related tumors. Tumor detection rates vary by SDHx gene and screening has the potential to uncover actionable secondary findings. Imaging is an essential part of the screening process as biochemical testing alone does not detect all disease.     

The variability of hepatitis B envelope is associated with HBs antigen persistence in either chronic or acute HBV genotype A infection

BackgroundMore than 240 million people are chronically infected by hepatitis B virus (HBV) worldwide. Envelope proteins play a crucial role in viral cellular entry and immune recognition. The loss of HBs antigen (HBsAg) correlated with a good clinical prognosis is rarely achieved with or without treatment (3–16%).ObjectivesHBV envelope variability was investigated according to HBsAg persistence.Study designThe cohort consisted of 15 HBV genotype A-infected patients divided into “resolvers”, with HBsAg clearance, and “non-resolvers”, with HBsAg persistence and in subgroups: acute (n = 5, AHBV) or chronic infection (n = 4, CHBV) and HBV/HIV coinfection (n = 6, CHBV/HIV). HBV S and preS sequences were studied by direct and ultra-deep sequencing. Amino acid sequences were analyzed with bioinformatics for predicted antigenicity.ResultsIn S gene, the complexity was lower in AHBV than in chronic-infected patients (p = 0.046). Major mutations, detected using direct sequencing, were more frequent in AHBV developing chronicity (p = 0.01) than in AHBV resolvers. In the Major Hydrophilic Region, more frequent mutations were observed in non-resolvers versus resolvers (p = 0.047) and non-resolvers tended to have more haplotypes with a reduced predicted antigenicity (p = 0.07). Most of the mutations in preS/S region were found rather in epitopic than in non-epitopic areas (p = 0.025). Interestingly, the mutation sY161F found in 3/8 non-resolvers was associated with a decrease in predicted antigenicity (28%; AnTheProt).ConclusionsHBsAg persistence was correlated with mutations and deletions in areas playing a key role in immune recognition. These data suggest that variability in HBV envelope could favor immune escape in various clinical settings of HBV genotype A-infected patients.     

Social networks for improving healthy weight loss behaviors for overweight and obese adults: A randomized clinical trial of the social pounds off digitally (Social POD) mobile app

ObjectiveTo test the efficacy of a weight loss mobile app based on recommender systems and developed by experts in health promotion and computer science to target social support and self-monitoring of diet, physical activity (PA), and weight (Social POD app), compared to a commercially available diet and PA tracking app (standard).Materials and methodsOverweight adults [N = 51] were recruited and randomly assigned to either the experimental group [n = 26; theory-based podcasts (TBP) + Social POD app] or the comparison group (n = 25; TBP + standard app). The Social POD app issued notifications to encourage users to self-monitor and send theory-based messages to support users who had not self-monitored in the previous 48 h. Independent samples t-test were used to examine group differences in kilograms lost and change in BMI. Analysis of covariance was used to analyze secondary outcomes while controlling for baseline values.ResultsParticipant attrition was 12% (n = 3 experimental and n = 3 comparison). Experimental group participants lost significantly more weight (−5.3 kg, CI: −7.5, −3.0) than comparison group (−2.23 kg, CI: −3.6, −1.0; d = 0.8, r = 0.4, p = 0.02) and had a greater reduction in BMI (p = 0.02). While there were significant differences in positive outcome expectations between groups (p = 0.04) other secondary outcomes (e.g., caloric intake and social support) were not significant.DiscussionUse of the Social POD app resulted in significantly greater weight loss than use of a commercially available tracking app. This mobile health intervention has the potential to be widely disseminated to reduce the risk of chronic disease associated with overweight and obesity.     

Caspase-cleaved fragments of cytokeratin-18 as a marker of inflammatory activity in chronic hepatitis B virus infection

BackgroundThe differential diagnosis between inactive carrier and active hepatitis is important in patients with chronic hepatitis B (CHB) virus infection. Serum cytokeratin (CK)-18 fragments (M30-antigen) are proposed as biomarkers of apoptosis.ObjectivesWe investigated whether serum M30-antigen levels might help to characterize the various phases of CHB and predict the state of significant inflammation in patients with CHB.Study designA total of 339 CHB patients who underwent liver biopsy, were included. Serum M30-antigen levels were compared between inactive carriers (n = 21), patients with HBeAg-negative hepatitis (n = 95), HBeAg-positive hepatitis (n = 141) and liver cirrhosis (n = 82).ResultsSerum M30-antigen levels were correlated significantly not only with AST (r = 0.544, p < 0.001) and ALT (r = 0.315, p < 0.001) and but also inflammatory grading score on liver biopsy (r = 0.240, p < 0.001). Serum M30-antigen level in HBeAg-negative CHB was significantly higher than that of inactive HBV carrier (399.78 U/L vs 148.90 U/L, p < 0.001). Multivariate analysis showed that AST (p < 0.001), albumin (p = 0.009) and M30-antigen (p = 0.020) were the independent predictors of significant inflammation. Combined serum M30-antigen level (>344 U/L) and AST (>78 IU/L) measurement provided the most accurate identification of significant inflammation, showing 38.2% sensitivity, 96.1% specificity, 91.0% positive predictive value and 56.1% negative predictive value.ConclusionsSerum M30-antigen can be a predictive marker for distinguishing between inactive carrier and HBeAg-negative CHB. Serum M30 levels are associated with the presence of significant inflammation, especially in patients with normal or minimally elevated ALT in CHB patients.     

The Ghana vasectomy initiative: Facilitating client–provider communication on no-scalpel vasectomy

ObjectiveIn 2003–2004 and 2007–2008, an initiative was implemented to improve client and provider knowledge and acceptance of no-scalpel vasectomy (NSV) in Ghana.MethodsAt eight facilities, physicians were trained in NSV and staff received training in the provision of “male-friendly” services. Health promotion activities provided NSV information to prospective clients. Client–provider communication was assessed via a mystery client study (n = 6). Knowledge and acceptance of NSV among potential clients were assessed with baseline and follow-up surveys (each n = 200) in 2003–2004 and three follow-up panel surveys in 2008 (each n = 240).ResultsTrained health staff exhibited improved attitudes and knowledge regarding NSV. Mystery clients reported receiving accurate, nonjudgmental NSV counseling. Awareness of NSV among panel respondents doubled from 31% to 59% in 2003–2004 and remained high (44%) in 2008. The proportion of men who would consider NSV increased from 10% to 19% in 2007–2008. NSV procedures increased three-fold from 2003 (n = 26) to 2004 (n = 83) and 2007 (n = 18) to 2008 (n = 53).ConclusionProvider training in client-centered services, coupled with targeted health promotion, improved client and provider knowledge and acceptance of NSV in an African context.Practice implicationsComplementary, sustained provider training and health promotion are needed to maintain NSV service quality and acceptance.     

A genomics approach to male infertility

PurposeMale infertility remains poorly understood at the molecular level. We aimed in this study to investigate the yield of a “genomics first” approach to male infertility.MethodsPatients with severe oligospermia and nonobstructive azoospermia were investigated using exome sequencing (ES) in parallel with the standard practice of chromosomal analysis.ResultsIn 285 patients, 10.5% (n = 30) had evidence of chromosomal aberrations while nearly a quarter (n = 69; 24.2%) had a potential monogenic form of male infertility. The latter ranged from variants in genes previously reported to cause male infertility with or without other phenotypes in humans (24 patients; 8.4%) to those in novel candidate genes reported in this study (37 patients; 12.9%). The 33 candidate genes have biological links to male germ cell development including compatible mouse knockouts, and a few (TERB1 [CCDC79], PIWIL2, MAGEE2, and ZSWIM7) were found to be independently mutated in unrelated patients in our cohort. We also found that male infertility can be the sole or major phenotypic expression of a number of genes that are known to cause multisystemic manifestations in humans (n = 9 patients; 3.1%).ConclusionThe standard approach to male infertility overlooks the significant contribution of monogenic causes to this important clinical entity.     

Analiza ekspresji genów odpowiedzialnych za rozwój przewlekłej małopłytkowości immunologicznej u dzieci

BackgroundA complex multifactorial dysregulation of immune system, including cytokines and autoantibodies production, and also proteins modification underlay the primary mechanism of immune thrombocytopenia (ITP). Specific genetic profile of ITP patients is presumed, especially those with a long and complex natural history of the disease.Aim of the studyGene expression analysis of VNN1 and PPARγ in children with immune thrombocytopenia.Materials and methodsCandidate genes were identified with microarray cDNA procedure. For the validation of VNN1 and PPARγ expression changes we used qRT-PCR performed comparatively in samples of newly diagnosed ITP (ndITP, n = 16), chronic ITP (cITP, n = 8) and patients without thrombocytopenia (n = 5).ResultsWe analyzed the data of patients, followed for at least 12 months after ITP diagnosis. No significant differences of VNN1 expression profile were found in between groups (p > 0.05). Lower signatures of mean PPARγ normalized expression values were noticed in chronic ITP patients in contrast to newly diagnosed ITP subjects (p = 0.009). Differences between VNN1/PPARγ ratio values found in ndITP group comparing to subjects with progression to cITP were close to statistical significance (p = 0.054).ConclusionsAnalysis of the VNN1 and PPARγ expression profiles utility in children diagnosed with ITP requires further investigation.     

Genetic associations of killer immunoglobulin like receptors and class I human leukocyte antigens on childhood acute lymphoblastic leukemia among north Indians

BackgroundMolecular interactions between KIRs and their cognate HLA class-I ligands, play a central role in the regulation of natural killer (NK) cell responses in malignancies. We aimed to determine the role of KIR genes and their HLA ligands in genetic predisposition of childhood acute lymphoblastic leukemia (ALL).MethodsGenotyping of 16 KIR genes, along with HLA class-I groups C1/C2 and Bw4 super-type ligands, was carried-out in 137 childhood ALL cases and 274 healthy controls.ResultsWe observed an increased incidence of activating KIRs namely; 2DS2 (OR = 2.23, p = <0.001), 2DS3 (OR = 1.74, p = 0.011), 3DS1 (OR = 2.22, p = <0.001), 2DS5 (OR = 2.10, p = 0.001), 2DS1 (OR = 4.42, p = <0.001) and 2DS4 (OR = 2.88, p = <0.001) genes in childhood ALL cases compared to controls. Frequency of BB genotype that possess 2–6 activating KIR genes was predominant in cases compared to controls (OR = 2.55, p = <0.001). KIR-receptor/HLA-ligand combinations analysis revealed a moderate risk of almost 2-fold for activating KIR-ligand combinations namely; KIR2DS1-HLAC2, KIR2DS2-HLAC1 and KIR3DS1-HLABw4 in childhood ALL cases.ConclusionOur data suggests the role for KIR genes and their HLA ligands in aetiology of childhood ALL.     

The landscape of pharmacogenetic testing in a US managed care population

PurposeLittle is known about how many insured patients receive pharmacogenetic testing. We describe trends of single-gene pharmacogenetic testing in a US managed care population, and demographic and clinical characteristics of patients who received a test.MethodsWe leveraged a random sample of nearly 11 million patients from a data set of paid medical and pharmacy claims to identify patients with at least one claim indicating receipt of at least one of these single-gene pharmacogenetic tests: CYP2C19, CYP2D6, CYP2C9, VKORC1, UGT1A1, and HLA class 1 typing.ResultsFrom 1 January 2013 to 30 September 2017, 5712 patients received at least one pharmacogenetic test (55% female; mean age = 43 years). The median number of tests per patient was 3 (mean = 2.7, max = 12); 54% were processed through Managed Medicare/Medicaid, while 45% were processed through commercial insurance. The total number of pharmacogenetic tests received more than doubled from 2013 (n = 1955) to 2015 (n = 4192), then decreased slightly in 2016 (n = 3946). The most common test was CYP2C19 (n = 4719), and “long-term (current) use of other medications” was the most common diagnosis.ConclusionPharmacogenetic testing through patients’ insurance was low, but more than doubled from 2013 to 2016. This study highlights the need to better understand utilization patterns and insurance coverage for pharmacogenetic tests.     

Static autoregulation in humans: a review and reanalysis

IntroductionCerebral autoregulation (CA) is a theoretical construct characterized by the relationship between mean arterial pressure (MAP) and cerebral blood flow (CBF). We performed a comprehensive literature search to provide an up-to-date review on the static relationship between MAP and CBF.MethodsThe results are based on 40 studies (49 individual experimental protocols) in healthy subjects between 18 and 65 years. Exclusion criteria were: a ΔMAP <5%, hypoxia/hyperoxia or hypo/hypercapnia, and unstable levels (<2 min stages). The partial pressure of arterial CO₂ (PaCO₂) was measured in a subset of the included studies (n = 28); therefore, CBF was also adjusted to account for small changes in PaCO₂.ResultsThe linear regression coefficient between MAP and CBF (or velocity) of 0.82 ± 0.77%ΔCBF/%ΔMAP during decreases in MAP (n = 23 experiments) was significantly different than the relationship of 0.21 ± 0.47%ΔCBF/%ΔMAP during increases (n = 26 experiments; p < 0.001). After correction for increases/decreases in PaCO₂, the slopes were not significantly different: 0.64 ± 1.16%ΔCBF/%ΔMAP (n = 16) and 0.39 ± 0.30%ΔCBF/%ΔMAP (n = 12) for increased vs. decreased MAP changes, respectively (p = 0.60).ConclusionThe autoregulatory ability of the cerebral circulation appears to be more active in buffering increases in MAP as compared to reductions in MAP. However, the statistical finding of hysteresis is lost following an attempt to correct for PaCO₂.