IgG4-related disease and B-cell malignancy due to an IKZF1 gain-of-function variant.

BACKGROUND: Monoallelic loss-of-function IKZF1 (IKAROS) variants cause B-cell deficiency or combined immunodeficiency, whereas monoallelic gain-of-function (GOF) IKZF1 variants have recently been reported to cause hypergammaglobulinemia, abnormal plasma cell differentiation, autoimmune and allergic manifestations, and infections. OBJECTIVE: We studied 7 relatives with autoimmune/inflammatory and lymphoproliferative manifestations to identify the immunologic disturbances and the genetic cause of their disease. METHODS: We analyzed biopsy results and performed whole-exome sequencing and immunologic studies. RESULTS: Disease onset occurred at a mean age of 25.2 years (range, 10-64, years). Six patients suffered from autoimmune/inflammatory diseases, 4 had confirmed IG4-related disease (IgG4-RD), and 5 developed B-cell malignancies: lymphoma in 4 and multiple myeloma in the remaining patient. Patients without immunosuppression were not particularly prone to infectious diseases. Three patients suffered from life-threatening coronavirus disease 2019 pneumonia, of whom 1 had autoantibodies neutralizing IFN-α. The recently described IKZF1 GOF p.R183H variant was found in the 5 affected relatives tested and in a 6-year-old asymptomatic girl. Immunologic analysis revealed hypergammaglobulinemia and high frequencies of certain lymphocyte subsets (exhausted B cells, effector memory CD4 T cells, effector memory CD4 T cells that have regained surface expression of CD45RA and CD28-CD57+ CD4+ and CD8+ T cells, TH2, and Tfh2 cells) attesting to immune dysregulation. Partial clinical responses to rituximab and corticosteroids were observed, and treatment with lenalidomide, which promotes IKAROS degradation, was initiated in 3 patients. CONCLUSIONS: Heterozygosity for GOF IKZF1 variants underlies autoimmunity/inflammatory diseases, IgG4-RD, and B-cell malignancies, the onset of which may occur in adulthood. Clinical and immunologic data are similar to those for patients with unexplained IgG4-RD. Patients may therefore benefit from treatments inhibiting pathways displaying IKAROS-mediated overactivity.

Novel genes and sex differences in COVID-19 severity.

Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10-22 and P = 8.1 × 10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10-8) and ARHGAP33 (P = 1.3 × 10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

Prediction of photoperiodic regulators from quantitative gene circuit models.

Photoperiod sensors allow physiological adaptation to the changing seasons. The prevalent hypothesis is that day length perception is mediated through coupling of an endogenous rhythm with an external light signal. Sufficient molecular data are available to test this quantitatively in plants, though not yet in mammals. In Arabidopsis, the clock-regulated genes CONSTANS (CO) and FLAVIN, KELCH, F-BOX (FKF1) and their light-sensitive proteins are thought to form an external coincidence sensor. Here, we model the integration of light and timing information by CO, its target gene FLOWERING LOCUS T (FT), and the circadian clock. Among other predictions, our models show that FKF1 activates FT. We demonstrate experimentally that this effect is independent of the known activation of CO by FKF1, thus we locate a major, novel controller of photoperiodism. External coincidence is part of a complex photoperiod sensor: modeling makes this complexity explicit and may thus contribute to crop improvement.

PCSK6 and Survival in Idiopathic Pulmonary Fibrosis.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. A better understanding of the molecular drivers of IPF progression is needed. Objectives: To identify and validate molecular determinants of IPF survival. Methods: A staged genome-wide association study was performed using paired genomic and survival data. Stage I cases were drawn from centers across the United States and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplantation-free survival (TFS). Stage I variants with nominal significance (P < 5 × 10-5) were advanced for stage II testing and meta-analyzed to identify those reaching genome-wide significance (P < 5 × 10-8). Downstream analyses were performed for genes and proteins associated with variants reaching genome-wide significance. Measurements and Main Results: After quality controls, 1,481 stage I cases and 397 stage II cases were included in the analysis. After filtering, 9,075,629 variants were tested in stage I, with 158 meeting advancement criteria. Four variants associated with TFS with consistent effect direction were identified in stage II, including one in an intron of PCSK6 (proprotein convertase subtilisin/kexin type 6) reaching genome-wide significance (hazard ratio, 4.11 [95% confidence interval, 2.54-6.67]; P = 9.45 × 10-9). PCSK6 protein was highly expressed in IPF lung parenchyma. PCSK6 lung staining intensity, peripheral blood gene expression, and plasma concentration were associated with reduced TFS. Conclusions: We identified four novel variants associated with IPF survival, including one in PCSK6 that reached genome-wide significance. Downstream analyses suggested that PCSK6 protein plays a potentially important role in IPF progression.

TM2D genes regulate Notch signaling and neuronal function in Drosophila.

TM2 domain containing (TM2D) proteins are conserved in metazoans and encoded by three separate genes in each model organism species that has been sequenced. Rare variants in TM2D3 are associated with Alzheimer's disease (AD) and its fly ortholog almondex is required for embryonic Notch signaling. However, the functions of this gene family remain elusive. We knocked-out all three TM2D genes (almondex, CG11103/amaretto, CG10795/biscotti) in Drosophila and found that they share the same maternal-effect neurogenic defect. Triple null animals are not phenotypically worse than single nulls, suggesting these genes function together. Overexpression of the most conserved region of the TM2D proteins acts as a potent inhibitor of Notch signaling at the γ-secretase cleavage step. Lastly, Almondex is detected in the brain and its loss causes shortened lifespan accompanied by progressive motor and electrophysiological defects. The functional links between all three TM2D genes are likely to be evolutionarily conserved, suggesting that this entire gene family may be involved in AD.

Parental bias in expression and interaction of genes in the equine placenta.

Most autosomal genes in the placenta show a biallelic expression pattern. However, some genes exhibit allele-specific transcription depending on the parental origin of the chromosomes on which the copy of the gene resides. Parentally expressed genes are involved in the reciprocal interaction between maternal and paternal genes, coordinating the allocation of resources between fetus and mother. One of the main challenges of studying parental-specific allelic expression (allele-specific expression [ASE]) in the placenta is the maternal cellular remnant at the fetomaternal interface. Horses (Equus caballus) have an epitheliochorial placenta in which both the endometrial epithelium and the epithelium of the chorionic villi are juxtaposed with minimal extension into the uterine mucosa, yet there is no information available on the allelic gene expression of equine chorioallantois (CA). In the current study, we present a dataset of 1,336 genes showing ASE in the equine CA (https://pouya-dini.github.io/equine-gene-db/) along with a workflow for analyzing ASE genes. We further identified 254 potentially imprinted genes among the parentally expressed genes in the equine CA and evaluated the expression pattern of these genes throughout gestation. Our gene ontology analysis implies that maternally expressed genes tend to decrease the length of gestation, while paternally expressed genes extend the length of gestation. This study provides fundamental information regarding parental gene expression during equine pregnancy, a species with a negligible amount of maternal cellular remnant in its placenta. This information will provide the basis for a better understanding of the role of parental gene expression in the placenta during gestation.

Admixture mapping analysis reveals differential genetic ancestry associated with Chagas disease susceptibility in the Colombian population.

Chagas disease is an infection caused by the parasite Trypanosoma cruzi, endemic in Latino America. Leveraging the three-way admixture between Native American (AMR), European (EUR) and African (AFR) populations in Latin Americans, we aimed to better understand the genetic basis of Chagas disease by performing an admixture mapping study in a Colombian population. A two-stage study was conducted, and subjects were classified as seropositive and seronegative for T. cruzi. In stage 1, global and local ancestries were estimated using reference data from the 1000 Genomes Project (1KGP), and local ancestry associations were performed by logistic regression models. The AMR ancestry showed a protective association with Chagas disease within the major histocompatibility complex region [Odds ratio (OR) = 0.74, 95% confidence interval (CI) = 0.66-0.83, lowest P-value = 4.53 × 10-8]. The fine mapping assessment on imputed genotypes combining data from stage 1 and 2 from an independent Colombian cohort, revealed nominally associated variants in high linkage disequilibrium with the top signal (rs2032134, OR = 0.93, 95% CI = 0.90-0.97, P-value = 3.54 × 10-4) in the previously associated locus. To assess ancestry-specific adaptive signals, a selective sweep scan in an AMR reference population from 1KGP together with an in silico functional analysis highlighted the Tripartite Motif family and the human leukocyte antigen genes, with crucial role in the immune response against pathogens. Furthermore, these analyses emphasized the macrophages, neutrophils and eosinophils, as key players in the defense against T. cruzi. This first admixture mapping study in Chagas disease provided novel insights underlying the host immune response in the pathogenesis of this neglected disease.

Location of Treatment Among Infants Requiring Complex Surgical Care.

INTRODUCTION: Rural children have worse health outcomes compared to urban children. One mechanism for this finding may be decreased access to specialized care at children's hospitals. The objective of this study was to evaluate the hospital types where complex surgical care in infants is performed nationally. METHODS: This study examined infants (<1 y old) in the Kids' Inpatient Database from 2009 to 2019 who underwent surgery for one of the following conditions: esophageal atresia, gastroschisis, omphalocele, Hirschsprung disease, anorectal malformation, pyloric stenosis, small bowel atresia, congenital diaphragmatic hernia, and necrotizing enterocolitis. The relationship between patient residence (rural versus urban) and location of surgical care (children's hospital versus other) was compared in relation to other covariates using multivariable logistic regression models. RESULTS: Among 29,185 infants undergoing these operations, 16.0% lived in a rural area. Rural infants were more frequently White (64.8% versus 43.4% P < 0.001), from the lowest two income quartiles (86.5% versus 52.0%, P < 0.001), and from the South or Midwest regions (P < 0.001). Surgical care was predominantly (94.1%) provided at urban teaching hospitals but frequently not at children's hospitals, especially among rural infants. After adjusting for other covariates, rural infants were significantly less likely to undergo care at a children's hospital for both 2009 (adjusted odds ratio 0.66, P < 0.001) and 2012-2019 (adjusted odds ratio 0.78, P < 0.001). CONCLUSIONS: A sizable portion of complex surgical care in infants is performed outside children's hospitals, especially among those from rural areas. Further work is necessary to ensure adequate access to children's hospitals for rural children.

Impaired lung function in multiple sclerosis: a single-center observational study in 371 persons.

INTRODUCTION: Abnormal lung function in people with multiple sclerosis (PwMS) could be considered as the result of muscle weakness or MS-specific structural central nervous system (CNS) abnormalities as a precipitant factor for the worsening of motor impairment or cognitive symptoms. METHODS: This is a cross-sectional observational study in PwMS. Forced spirometry was conducted, and normative metrics of forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and the relation FEV1/FVC were calculated. Qualitative and quantitative brain magnetic resonance imaging (MRI) examinations were carried out. RESULTS: A total of 371 PwMS were included in the study. Of those, 196 (53%) had RRMS, 92 (25%) SPMS, and 83 (22%) PPMS. Low FVC and FEV1 was present in 16 (8%), 16 (19%), and 23 (25%) of the patients in the RRMS, PPMS, and SPMS, respectively. PwMS with T2-FLAIR lesions involving the corpus callosum (CC) had a significantly higher frequency of abnormally low FVC and FEV1 (OR 3.62; 95% CI 1.33-9.83; p = 0.012) than patients without lesions in that region. This association remained significant in the RRMS group (OR 10.1; 95% CI 1.3-67.8; p 0.031) when the model excluded PPMS and SPMS. According to our study, for every increase of 1 z score of FVC, we observed an increase of 0.25 cm3 of hippocampal volume (ß 0.25; 95% CI 0.03-0.47; p 0.023) and 0.43 cm3 of left hippocampus volume (ß 0.43; 95% CI 0.16-0.71; p 0.002). CONCLUSIONS: We observed an incremental prevalence of abnormally low pulmonary function tests that parallels a sequence from more early relapsing courses to long-standing progressive courses (RRMS to PPMS or SPMS).

Dynamics of the Equine Placental DNA Methylome and Transcriptome from Mid- to Late Gestation.

The placenta is a temporary organ that is essential for the survival of the fetus, with a lifelong effect on the health of both the offspring and the dam. The functions of the placenta are controlled by its dynamic gene expression during gestation. In this study, we aimed to investigate the equine placental DNA methylome as one of the fundamental mechanisms that controls the gene expression dynamic. Chorioallantois samples from four (4M), six (6M), and ten (10M) months of gestation were used to map the methylation pattern of the placenta. Globally, methylation levels increased toward the end of gestation. We identified 921 differentially methylated regions (DMRs) between 4M and 6M, 1225 DMRs between 4M and 10M, and 1026 DMRs between 6M and 10M. A total of 817 genes carried DMRs comparing 4M and 6M, 978 comparing 4M and 10M, and 804 comparing 6M and 10M. We compared the transcriptomes between the samples and found 1381 differentially expressed genes (DEGs) when comparing 4M and 6M, 1428 DEGs between 4M and 10M, and 741 DEGs between 6M and 10M. Finally, we overlapped the DEGs and genes carrying DMRs (DMRs-DEGs). Genes exhibiting (a) higher expression, low methylation and (b) low expression, high methylation at different time points were identified. The majority of these DMRs-DEGs were located in introns (48.4%), promoters (25.8%), and exons (17.7%) and were involved in changes in the extracellular matrix; regulation of epithelial cell migration; vascularization; and regulation of minerals, glucose, and metabolites, among other factors. Overall, this is the first report highlighting the dynamics in the equine placenta methylome during normal pregnancy. The findings presented serve as a foundation for future studies on the impact of abnormal methylation on the outcomes of equine pregnancies.

Evaluation of a whole-exome sequencing pipeline and benchmarking of causal germline variant prioritizers.

Most causal variants of Mendelian diseases are exonic. Whole-exome sequencing (WES) has become the diagnostic gold standard, but causative variant prioritization constitutes a bottleneck. Here we assessed an in-house sample-to-sequence pipeline and benchmarked free prioritization tools for germline causal variants from WES data. WES of 61 unselected patients with a known genetic disease cause was obtained. Variant prioritizations were performed by diverse tools and recorded to obtain a diagnostic yield when the causal variant was present in the first, fifth, and 10th top rankings. A fraction of causal variants was not captured by WES (8.2%) or did not pass the quality control criteria (13.1%). Most of the applications inspected were unavailable or had technical limitations, leaving nine tools for complete evaluation. Exomiser performed best in the top first rankings, while LIRICAL led in the top fifth rankings. Based on the more conservative top 10th rankings, Xrare had the highest diagnostic yield, followed by a three-way tie among Exomiser, LIRICAL, and PhenIX, then followed by AMELIE, TAPES, Phen-Gen,  AIVar, and VarNote-PAT. Xrare, Exomiser, LIRICAL, and PhenIX are the most efficient options for variant prioritization in real patient WES data.

Evaluation of CRISPR gene-editing tools in zebrafish.

BACKGROUND: Zebrafish have practical features that make them a useful model for higher-throughput tests of gene function using CRISPR/Cas9 editing to create 'knockout' models. In particular, the use of G0 mosaic mutants has potential to increase throughput of functional studies significantly but may suffer from transient effects of introducing Cas9 via microinjection. Further, a large number of computational and empirical tools exist to design CRISPR assays but often produce varied predictions across methods leaving uncertainty in choosing an optimal approach for zebrafish studies. METHODS: To systematically assess accuracy of tool predictions of on- and off-target gene editing, we subjected zebrafish embryos to CRISPR/Cas9 with 50 different guide RNAs (gRNAs) targeting 14 genes. We also investigate potential confounders of G0-based CRISPR screens by assaying control embryos for spurious mutations and altered gene expression. RESULTS: We compared our experimental in vivo editing efficiencies in mosaic G0 embryos with those predicted by eight commonly used gRNA design tools and found large discrepancies between methods. Assessing off-target mutations (predicted in silico and in vitro) found that the majority of tested loci had low in vivo frequencies (< 1%). To characterize if commonly used 'mock' CRISPR controls (larvae injected with Cas9 enzyme or mRNA with no gRNA) exhibited spurious molecular features that might exacerbate studies of G0 mosaic CRISPR knockout fish, we generated an RNA-seq dataset of various control larvae at 5 days post fertilization. While we found no evidence of spontaneous somatic mutations of injected larvae, we did identify several hundred differentially-expressed genes with high variability between injection types. Network analyses of shared differentially-expressed genes in the 'mock' injected larvae implicated a number of key regulators of common metabolic pathways, and gene-ontology analysis revealed connections with response to wounding and cytoskeleton organization, highlighting a potentially lasting effect from the microinjection process that requires further investigation. CONCLUSION: Overall, our results provide a valuable resource for the zebrafish community for the design and execution of CRISPR/Cas9 experiments.

A genome-wide association study of survival in patients with sepsis.

BACKGROUND: Sepsis is a severe systemic inflammatory response to infections that is accompanied by organ dysfunction and has a high mortality rate in adult intensive care units. Most genetic studies have identified gene variants associated with development and outcomes of sepsis focusing on biological candidates. We conducted the first genome-wide association study (GWAS) of 28-day survival in adult patients with sepsis. METHODS: This study was conducted in two stages. The first stage was performed on 687 European sepsis patients from the GEN-SEP network and 7.5 million imputed variants. Association testing was conducted with Cox regression models, adjusting by sex, age, and the main principal components of genetic variation. A second stage focusing on the prioritized genetic variants was performed on 2,063 ICU sepsis patients (1362 European Americans and 701 African-Americans) from the MESSI study. A meta-analysis of results from the two stages was conducted and significance was established at p < 5.0 × 10-8. Whole-blood transcriptomic, functional annotations, and sensitivity analyses were evaluated on the identified genes and variants. FINDINGS: We identified three independent low-frequency variants associated with reduced 28-day sepsis survival, including a missense variant in SAMD9 (hazard ratio [95% confidence interval] = 1.64 [1.37-6.78], p = 4.92 × 10-8). SAMD9 encodes a possible mediator of the inflammatory response to tissue injury. INTERPRETATION: We performed the first GWAS of 28-day sepsis survival and identified novel variants associated with reduced survival. Larger sample size studies are needed to better assess the genetic effects in sepsis survival and to validate the findings.

Correlation of Anti-Tissue Transglutaminase Antibodies With the Mucosal Changes and IgA Status of Children With Celiac Disease.

OBJECTIVES: The objective of this study was to assess the association between serological markers and changes of the intestinal mucosa in children with celiac disease (CD). METHODS: Clinical data from CD patients under 15 years old were collected from the participating centers in an on-line multicenter nationwide observational Spanish registry called REPAC-2 (2011-2017). Correlation between anti-tissue transglutaminase antibodies (t-TGA) levels and other variables, including mucosal damage and clinical findings (symptoms, age, and gender), was assessed. RESULTS: A total of 2955 of 4838 patients had t-TGA and a small bowel biopsy (SBB) performed for CD diagnosis. A total of 1931 (66.2%) patients with normal IgA values had a Marsh 3b-c lesion and 1892 (64.9%) had t-TGA Immunoglobulin A (IgA) ≥ 10 times upper limit of normal (ULN). There is a statistically significant association between t-TGA IgA levels and the degree of mucosal damage ( P < 0.001), the higher the t-TGA IgA levels the more severe the mucosal damage. Those patients who reported symptoms had more severe mucosal damage ( P = 0.001). On the contrary, there was a negative association between age and changes of the intestinal mucosa ( P < 0.001). No association was found with gender. Regarding the IgA-deficient patients, 47.4% (18 cases) had t-TGA Immunoglobulin A (IgA) ≥ 10 times ULN and a Marsh 3b-c lesion was observed in 68.4% (26 patients). No statistical relation was found between t-TGA IgG levels and the changes of the intestinal mucosa, neither a relation with age, gender, or symptoms. CONCLUSIONS: There is a positive correlation between t-TGA IgA levels and the severity of changes of the intestinal mucosa. Such correlation was not found in IgA-deficient patients who had positive t-TGA IgG serology. The results in this group of patients support the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition recommendations about the need of performing a SBB in IgA-deficient individuals despite high t-TGA IgG levels.

Transactive Response DNA-Binding Protein (TARDBP/TDP-43) Regulates Cell Permissivity to HIV-1 Infection by Acting on HDAC6.

The transactive response DNA-binding protein (TARDBP/TDP-43) influences the processing of diverse transcripts, including that of histone deacetylase 6 (HDAC6). Here, we assessed TDP-43 activity in terms of regulating CD4+ T-cell permissivity to HIV-1 infection. We observed that overexpression of wt-TDP-43 increased both mRNA and protein levels of HDAC6, resulting in impaired HIV-1 infection independently of the viral envelope glycoprotein complex (Env) tropism. Consistently, using an HIV-1 Env-mediated cell-to-cell fusion model, the overexpression of TDP-43 levels negatively affected viral Env fusion capacity. Silencing of endogenous TDP-43 significantly decreased HDAC6 levels and increased the fusogenic and infection activities of the HIV-1 Env. Using pseudovirus bearing primary viral Envs from HIV-1 individuals, overexpression of wt-TDP-43 strongly reduced the infection activity of Envs from viremic non-progressors (VNP) and rapid progressors (RP) patients down to the levels of the inefficient HIV-1 Envs observed in long-term non-progressor elite controllers (LTNP-EC). On the contrary, silencing endogenous TDP-43 significantly favored the infectivity of primary Envs from VNP and RP individuals, and notably increased the infection of those from LTNP-EC. Taken together, our results indicate that TDP-43 shapes cell permissivity to HIV-1 infection, affecting viral Env fusion and infection capacities by altering the HDAC6 levels and associated tubulin-deacetylase anti-HIV-1 activity.

Description of the 'pronation manoeuvre' for the diagnosis of developmental hip dysplasia.

Introduction: Without a prompt diagnosis, developmental dysplasia of the hip (DDH) in infants can lead to severe sequelae. Current screening strategies emphasize the use of Ortolani and Barlow physical examination manoeuvres, yet they exhibit low sensitivity. The purpose of this study is to evaluate the performance of a new physical examination tool (the pronation manoeuvre) as a screening tool for DDH. Methods: To evaluate the new manoeuvre, a cross-sectional and analytic study was performed with a nonprobabilistic sampling method. Patients with either a positive Ortolani or Barlow manoeuver were evaluated with the new manoeuvre and hip ultrasound. Controls were infants with negative Ortolani, Barlow and pronation manoeuvres and also had ultrasound performed. Results: DDH was confirmed in 83 of 130 cases (64%) and 2 of 130 controls (2%). The new pronation manoeuvre had a sensitivity of 76% and a specificity of 94% as compared to the Ortolani and Barlow manoeuvres (sensitivity 31 to 32%, specificity 93 to 100%) (P<0.05). Conclusion: This new physical examination manoeuvre could serve as another clinical tool for the initial screening of DDH in newborns. Its promising results against traditional screening procedures might potentially impact diagnosis and prognosis for patients with DDH.

Overutilization and Underutilization of Thyroid Function Tests are Major Causes of Diagnostic Errors in Pregnant Women.

BACKGROUND: The failure to order the correct diagnostic test at the right time is one of the major contributing factors of diagnostic error. Excessive testing can lead to added economic burden and addressing underutilization is precarious as clinicians often fail to order the tests that would improve diagnosis, prognosis, and management. METHODS: A retrospective analysis of errors in test orders of thyroid function testing (TFT) in 321 pregnant women suspected of clinical and subclinical thyroid disorders was performed. Test selection was evaluated, and determinations were made about the extent of overutilization and underutilization of TFTs in reviewing each individual patient case by a Doctorate in Clinical Laboratory Science (DCLS) scholar. RESULTS: About 77% (247 cases) of the cases were found to have errors associated with test ordering for TFT. Of the cases reviewed, 18% cases were associated with overutilization, 53% of the cases were associated with underutilization, and 7% were associated with both (overutilization and underutilization). The annual cost burden because of ordering unnecessary tests was estimated to be approximately $13,000. The cost burden from errors resulting from not ordering a test would be of much greater magnitude but was difficult to estimate because underutilization has a ripple effect and may cause prolonged hospital stays, unnecessary medical bills, and delayed/ missed diagnosis leading to poor outcomes for patients. CONCLUSIONS: This study evaluated whether proper utilization of TFT were made at maternal health clinic locations of a large academic medical center in pregnant women to diagnose thyroid disorder and reported the issue of wastage of resources in the clinical laboratory. The study findings show significant errors in ordering of TFT for pregnant women in more than 75% of the cases that was based on evidence-based review of patient cases.

Contextual influences on Latino men's sexual and substance use behaviors following immigration to the Midwestern United States.

Objectives: Latinos in the United States experience a disproportionate number of HIV and other sexually transmitted infections (STIs) and higher use of alcohol and illegal drugs, which has been attributed to increases in risk behaviors following immigration. Whereas substantial research documents these behavioral changes, little is known about how immigrants increase their risk or why some immigrants increase their risk and other immigrants do not. This study explored how the social and normative context affects sexual and substance use behaviors among Latino immigrant men in a midsized Midwestern city of the United States.Methods: We interviewed 64 Latino immigrant men recruited from community sites in Milwaukee, Wisconsin (mean age = 32.6 years). Participants reported the social and normative contexts preceding and following immigration, including social networks and support, perceptions of the law, and familiar and peer normative influences.Results: Immigrants attributed changes in their sexual and substance use behaviors to their immigration goals, social support, peer and familial normative influences, and restrictions related to their immigrant status. Immigration for economic and personal advancement was generally protective from behaviors that would interfere with those goals as were extended familial networks that could provide support, resources, and normative control. The need to stay under the radar of authorities, the proportion of Latinos in the community, the social and normative changes associated with immigrants' age, and the higher perceptions of risk for HIV in the United States compared with their home countries also influenced immigrants' sexual and substance use behaviors.Conclusions: Changes in risk behavior after immigration to the United States reflect a combination of social and normative factors and personal goals. Interventions and policies aiming to prevent HIV and substance use among Latino immigrants should understand the contextual conditions that decrease or increase their risk behaviors in the United States.

Features, State and Context of Narcissism in Drug Misuse.

Both clinical and street-based encounters with people who misuse drugs have led the authors to examine the relationship between misuse of drugs and narcissism. Widely accepted criteria for diagnosing Substance Use Disorder (SUD) suggest parallels between narcissistic traits (e.g. invulnerability to consequences and lack of empathy for others) and the characteristics of drug abusers. Because narcissism as a concept has a long and somewhat confusing history, we first reviewed its origins in the psychoanalytic tradition of psychiatry and its exegesis into current clinical concepts in order to arrive at a set of attributes that may be useful when applied to problems of drug abuse. This process required extensive review of the literature on narcissism and its interactions with the literature on drug abuse. This process led to an understanding that positive self-concept may exemplify a variety of socially beneficial narcissism, but that at the other end of narcissism's continuum of traits may be found exploitative and non-empathetic traits. Furthermore, the negative traits of narcissism, as they may arise in adolescence along with drug use, can support an individual's ongoing dependence on drugs, especially if narcissism and drug use persist into adulthood. Our investigation of narcissism and drug use revealed, through in-depth interviewing, that some drug users employ drugs and alcohol to feed their self-concepts of superiority over other people. Our findings suggest that treatment for drug abuse cannot proceed assuming that drug users have low self-concepts. Rather, their continued use of drugs may emanate from a narcissistic sense of superiority.

Admixture mapping of asthma in southwestern Europeans with North African ancestry influences.

The prevalence of asthma symptoms in Canary Islanders, a southwestern European population from Spain, is almost three times higher than the country average. Because the genetic risks identified so far explain <5% of asthma heritability, here we aimed to discover new asthma loci by completing the first admixture mapping study in Canary Islanders leveraging their distinctive genetic makeup, where significant northwest African influences coexist in the European genetic diversity landscape. A 2-stage study was conducted in 1,491 unrelated individuals self-declaring having a Canary Islands origin for the 4 grandparents. Local ancestry estimates were obtained for the shared positions with reference data from putative ancestral populations from Europe, North Africa, and sub-Saharan Africa. Case-control deviations in local ancestry were tested for each ancestry separately using logistic regressions adjusted for principal components, followed by fine-mapping analyses based on imputed genotypes and analyses of the likely deleterious exonic variants. The admixture mapping analysis of asthma detected that local North African ancestry in a locus spanning 365 kb of chromosome 16q23.3 was associated with asthma risk at study-wide significance [lowest P = 1.12 × 10-4; odds ratio (OR) = 2.05; 95% confidence interval (CI) = 1.41-3.00]. Fine-mapping studies identified a variant associated with asthma, and results were replicated in independent samples (rs3852738, OR = 1.34; 95% CI = 1.13-1.59, P = 7.58 × 10-4). Whole exome sequencing data from a subset of individuals revealed an enrichment of likely deleterious variants among asthma cases in 16q23.3, particularly in the phospholipase Cγ2 (PLCG2) gene (P = 3.67 × 10-4). By completing the first mapping study of asthma in admixed populations from Europe, our results revealed a new plausible asthma locus.