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In December 2020, the Centers for Disease Control and Prevention updated its treatment guidelines for gonococcal infection and, for the first time, recommended universal test-of-cure for all individuals treated for pharyngeal gonorrhea. After the release of these guidelines, data are lacking on rates of return for the test-of-cure, particularly in populations other than men who have sex with men.We analyzed the demographic characteristics, clinical characteristics, rate of return for the recommended test-of-cure, and percent positivity for Neisseria gonorrhoeae on repeat pharyngeal specimens at a local public health department in Durham, NC.Of 101 individuals treated for pharyngeal gonorrhea between March 2021 and April 2022, 54.5% were men, 71.2% Black or African American, and 58.4% between the ages of 20 and 29 years. Most identified as either women who have sex with men (38.6%), men who have sex with men (24.8%), or men who have sex with women (22.8%). Of these individuals, 41 (40.6%) returned for a test-of-cure, with LGBTQ+ individuals more likely to return than men who have sex with women and women who have sex with men. Of those who returned for the test-of-cure, 4.9% of pharyngeal samples were equivocal and 2.4% positive for N. gonorrhoeae by nucleic acid amplification testing, likely reflecting false-positive tests.Despite recommendations to perform a test-of-cure 7 to 14 days after treatment of pharyngeal gonorrhea, rates of return continue to be low. Alternative strategies should be investigated to increase test-of-cure rates.

This study assessed the prevalence of prenatal smoking, factors associated with prenatal smoking, and its association with birth outcomes in a sample of pregnant women in Egypt. Pregnant women were recruited during their last trimester from antenatal clinics in Cairo from June 2015 to May 2016. Participants completed an interviewer-administered survey that assessed tobacco use and attitudes, and exhaled carbon monoxide (CO) was measured. Gestational age at delivery and offspring birth weight were collected via a postnatal phone interview. Two hundred pregnant women ages 16–37 years participated. More than a quarter (29.0%) of women reported smoking (cigarettes, hookah, or both) during their current pregnancy, and hookah was more popular than cigarettes. Most women who smoked prior to their current pregnancy either maintained their current smoking habits (46.6%) or switched from dual to hookah-only smoking (46.6%). Current smokers during pregnancy had a higher mean (±SD) exhaled CO level (2.97 ± 1.45 vs. 0.25 ± 0.60 ppm, p < 0.001) and had babies with a lower mean birth weight (2583 ± 300 vs. 2991 ± 478 g, p < 0.001) than non-smokers. Smokers during pregnancy had greater odds of premature birth and/or low birth weight babies compared to non-smokers. Dual cigarette-hookah smokers had the highest risk. Additional focused programs are required to prevent women of childbearing age from initiating tobacco use and empower women to stop tobacco use during the preconception and gestational periods.

When a novel coronavirus disease (COVID-19) made major headlines in 2020, it further exposed an existing public health crisis related to inequities within our communities and health care delivery system. Throughout the COVID-19 pandemic, populations of color had higher infection and mortality rates, and even experienced greater disease severity compared to whites. Populations of color often bear the brunt of COVID-19 and other health inequities, due to the multifaceted relationship between systemic racism and the social determinants of health. As this relationship continues to perpetuate health inequities, the local health department is an agency that has the jurisdiction and responsibility to prevent disease and protect the health of the communities they serve. When equity is integrated into a health department’s operational infrastructure as a disease prevention strategy, it can elevate the agency’s response to public health emergencies. Collecting, reporting, and tracking demographic data that is necessary to identify inequities becomes a priority to facilitate a more robust public health response. The purpose of this paper is to present strategies of how a local health department operationalized equity in various stages of COVID-19 response and apply these methods to future public health emergencies to better serve vulnerable communities.

Background: We examined the association of adult lung transplant candidates’ self-reported affect with transplant-related outcomes, evaluating whether a positive (vs negative) frame of mind might be protective. Method: Consenting waitlisted candidates from 6 centers completed the questionnaires including the Positive and Negative Affect Schedule annually and posttransplant. Univariate logistic regression analysis was performed to determine the association of baseline affect with outcomes of death or delisting. Models were subsequently adjusted for age, marital status, and education. Results: Questionnaires were completed by 169 candidates (77.9% participation). Mean positive affect, negative affect, and positive-to-negative affect ratio (positivity ratio) were similar to expected norms. The scores of the questionnaire did not change significantly over time. Fifteen (8.9%) waitlisted participants died. Candidates who died while waiting had lower positivity ratios compared to those who survived (1.82 vs 2.45; P = .02). A more negative affect was associated with increased death on the waiting list (adjusted odds ratio [OR] 1.10; P = .021). Conversely, a higher positivity ratio was associated with decreased death while waiting (adjusted OR: 0.45; P = .027). Conclusion: Negative affect may represent a novel risk factor for death on the waitlist. Enhancing positive affect may represent a useful target for psychological optimization in lung transplant candidates.

Dystroglycan, an extracellular matrix receptor, has essential functions in various tissues. Loss of α‐dystroglycan‐laminin interaction due to defective glycosylation of α‐dystroglycan underlies a group of congenital muscular dystrophies often associated with brain malformations, referred to as dystroglycanopathies. The lack of isogenic human dystroglycanopathy cell models has limited our ability to test potential drugs in a human‐ and neural‐specific context. Here, we generated induced pluripotent stem cells (iPSCs) from a severe dystroglycanopathy patient with homozygous FKRP (fukutin‐related protein gene) mutation. We showed that CRISPR/Cas9‐mediated gene correction of FKRP restored glycosylation of α‐dystroglycan in iPSC‐derived cortical neurons, whereas targeted gene mutation of FKRP in wild‐type cells disrupted this glycosylation. In parallel, we screened 31,954 small molecule compounds using a mouse myoblast line for increased glycosylation of α‐dystroglycan. Using human FKRP‐iPSC‐derived neural cells for hit validation, we demonstrated that compound 4‐(4‐bromophenyl)‐6‐ethylsulfanyl‐2‐oxo‐3,4‐dihydro‐1H‐pyridine‐5‐carbonitrile (4BPPNit) significantly augmented glycosylation of α‐dystroglycan, in part through upregulation of LARGE1 glycosyltransferase gene expression. Together, isogenic human iPSC‐derived cells represent a valuable platform for facilitating dystroglycanopathy drug discovery and therapeutic development.

[Image: see text] In humans, C–X–C chemokine receptor type 4 (CXCR4) is a protein that is encoded by the CXCR4 gene and binds the ligand CXCL12 (also known as SDF-1). The CXCR4–CXCL12 interaction in cancer elicits biological activities that result in tumor progression and has accordingly been the subject of significant investigation for detection and treatment of the disease. Peptidic antagonists have been labeled with a variety of radioisotopes for the detection of CXCR4, but the methodology utilizing small molecules has predominantly used radiometals. We report here the development of a (18)F-radiolabeled cyclam-based small molecule radioprobe, [(18)F]MCFB, for imaging CXCR4 expression. The IC(50) value of [(19)F]MCFB for CXCR4 was similar to that of AMD3465 (111.3 and 89.8 nM, respectively). In vitro binding assays show that the tracer depicted a differential CXCR4 expression, which was blocked in the presence of AMD3465, demonstrating the specificity of [(18)F]MCFB. Positron emission tomography (PET) imaging studies showed a distinct uptake of the radioprobe in lymphoma and breast cancer xenografts. High liver and kidney uptakes were seen with [(18)F]MCFB, leading us to further examine the basis of its pharmacokinetics in relation to the tracer’s cationic nature and thus the role of organic cation transporters (OCTs). Substrate competition following the intravenous injection of metformin led to a marked decrease in the urinary excretion of [(18)F]MCFB, with moderate changes observed in other organs, including the liver. Our results suggest involvement of OCTs in the renal elimination of the tracer. In conclusion, the (18)F-radiolabeled monocyclam, [(18)F]MCFB, has potential to detect tumor CXCR4 in nonhepatic tissues.

Ample research has shown that intensive applied behavior analysis (ABA) treatment produces robust outcomes for individuals with autism spectrum disorder (ASD); however, little is known about the relationship between treatment intensity and treatment outcomes. The current study was designed to evaluate this relationship. Participants included 726 children, ages 1.5 to 12 years old, receiving community-based behavioral intervention services. Results indicated a strong relationship between treatment intensity and mastery of learning objectives, where higher treatment intensity predicted greater progress. Specifically, 35% of the variance in mastery of learning objectives was accounted for by treatment hours using standard linear regression, and 60% of variance was accounted for using artificial neural networks. These results add to the existing support for higher intensity treatment for children with ASD.

The delta isoform of phosphoinositide 3-kinase (PI3Kδ) regulates various lymphocyte functions. Considering the key pro-inflammatory role of IL-17A and IL-17F cytokines in psoriasis and spondyloarthritis (SpA), we investigated the potential of PI3Kδ blockade to suppress IL-17A, IL-17F and associated pro-inflammatory cytokines that could synergize with IL-17A and IL-17F. Using in vitro studies with primary human cells and ex vivo studies with inflamed target tissues, we assessed if seletalisib, a selective PI3Kδ inhibitor, suppresses cytokine production by T cells and innate-like lymphocytes, and if seletalisib modulates the inflammatory responses in stromal cell populations in psoriasis (human dermal fibroblasts (HDF)) and SpA (fibroblast-like synoviocytes (FLS)). In vitro, seletalisib inhibited the production of pro-inflammatory cytokines, including IL-17A and IL-17F, from peripheral blood mononuclear cells (PBMCs), T helper 17 (Th17) cells as well as γδ-T cells and mucosal-associated invariant T cells. This inhibition resulted in decreased inflammatory activation of HDF in co-culture systems. Seletalisib was also efficacious in inhibiting SpA PBMCs and synovial fluid mononuclear cells (SFMCs) from producing pro-inflammatory cytokines. Furthermore, supernatant derived from cultured seletalisib-treated Th17 cells showed reduced potency for activating inflammatory responses from cultured SpA FLS and decreased their osteogenic differentiation capacity. Finally, analysis of inflamed SpA synovial tissue biopsies revealed activation of the PI3K-Akt-mTOR pathway. We observed that ex vivo seletalisib treatment of inflamed synovial tissue reduced IL-17A and IL-17F expression. Collectively, inhibition of PI3Kδ reduces the production of pro-inflammatory cytokines from IL-17-producing adaptive and innate-like lymphocytes and thereby inhibits downstream inflammatory and tissue remodeling responses. PI3Kδ-targeting may therefore represent a novel therapeutic avenue for the treatment of IL-17-mediated chronic inflammatory diseases such as psoriasis and SpA.

© 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.

Background and objective Autism spectrum disorder (ASD) is a heterogeneous disorder. Research has explored potential ASD subgroups with preliminary evidence supporting the existence of behaviorally and genetically distinct subgroups; however, research has yet to leverage machine learning to identify phenotypes on a scale large enough to robustly examine treatment response across such subgroups. The purpose of the present study was to apply Gaussian Mixture Models and Hierarchical Clustering to identify behavioral phenotypes of ASD and examine treatment response across the learned phenotypes. Materials and methods The present study included a sample of children with ASD (N = 2400), the largest of its kind to date. Unsupervised machine learning was applied to model ASD subgroups as well as their taxonomic relationships. Retrospective treatment data were available for a portion of the sample (n = 1034). Treatment response was examined within each subgroup via regression. Results The application of a Gaussian Mixture Model revealed 16 subgroups. Further examination of the subgroups through Hierarchical Agglomerative Clustering suggested 2 overlying behavioral phenotypes with unique deficit profiles each composed of subgroups that differed in severity of those deficits. Furthermore, differentiated response to treatment was found across subtypes, with a substantially higher amount of variance accounted for due to the homogenization effect of the clustering. Discussion The high amount of variance explained by the regression models indicates that clustering provides a basis for homogenization, and thus an opportunity to tailor treatment based on cluster memberships. These findings have significant implications on prognosis and targeted treatment of ASD, and pave the way for personalized intervention based on unsupervised machine learning.

Received August 23, 2013; revised October 7, 2013; accepted October 8, 2013. From University of Texas Health Science Center at San Antonio, San Antonio, TX; Audie L. Murphy Memorial Veterans Administration Center, San Antonio, TX. Send correspondence and reprint requests to Thomas M. Brown, M.D., Audie L. Murphy Memorial Veterans Administration Center, 7400 Merton Minter Boulevard, San Antonio, TX 78229; e-mail: thomas.brown5@va.gov, drthomasmbrown@yahoo.com Published by Elsevier Inc. on behalf of The Academy of Psychosomatic Medicine. Introduction

Dystroglycanopathies are a clinically and genetically diverse group of recessively inherited conditions ranging from the most severe of the congenital muscular dystrophies, Walker-Warburg syndrome, to mild forms of adult-onset limb-girdle muscular dystrophy. Their hallmark is a reduction in the functional glycosylation of α-dystroglycan, which can be detected in muscle biopsies. An important part of this glycosylation is a unique O-mannosylation, essential for the interaction of α-dystroglycan with extracellular matrix proteins such as laminin-α2. Mutations in eight genes coding for proteins in the glycosylation pathway are responsible for ∼50% of dystroglycanopathy cases. Despite multiple efforts using traditional positional cloning, the causative genes for unsolved dystroglycanopathy cases have escaped discovery for several years. In a recent collaborative study, we discovered that loss-of-function recessive mutations in a novel gene, called isoprenoid synthase domain containing (ISPD), are a relatively common cause of Walker-Warburg syndrome. In this article, we report the involvement of the ISPD gene in milder dystroglycanopathy phenotypes ranging from congenital muscular dystrophy to limb-girdle muscular dystrophy and identified allelic ISPD variants in nine cases belonging to seven families. In two ambulant cases, there was evidence of structural brain involvement, whereas in seven, the clinical manifestation was restricted to a dystrophic skeletal muscle phenotype. Although the function of ISPD in mammals is not yet known, mutations in this gene clearly lead to a reduction in the functional glycosylation of α-dystroglycan, which not only causes the severe Walker-Warburg syndrome but is also a common cause of the milder forms of dystroglycanopathy.

Four models of resident education in obstetric triage with midwifery faculty consultants are presented. Common trends in the structure and function of these models are reviewed. The four models represent diverse settings where midwives serve as clinical teachers primarily for first-year obstetric residents and residents from other subspecialties. Each model supports a growing number of midwives working in the triage setting, functioning as both teacher and consultant for new residents. This expanded midwifery teaching role extends beyond labor assessment to include a wide range of common obstetric and gynecologic conditions in the triage setting. Additional advantages include the ability of the midwife to bill for triage services and to provide a safety net to decrease medical errors which, in a busy triage unit, occur most often during patient transfers.

Ectopic pregnancy and ovarian torsion are 2 of the most common causes of acute abdominal pain in early pregnancy. The following article will discuss the physiology and pathophysiology, evaluation, diagnosis, clinical management options, and nursing considerations for ovarian torsion and ectopic pregnancy. Both conditions require timely diagnosis to prevent mortality and minimize morbidity, and both may require surgical management.

Background Cognitive function is reported to improve after the initiation of combination antiretroviral therapy (cART). Data on the evolution of such changes are limited. We assessed the dynamics of changes in cognitive parameters, in HIV-positive subjects initiating cART. Methods Cognitive function in seven domains was evaluated for HIV-infected patients without clinically significant cognitive impairment prior to the initiation of cART, and 24 and 48 weeks after. Cognitive scores were transformed using standardised z-scores according to the pooled baseline standard deviation. Global, speed, and accuracy composite z-scores were calculated with changes calculated using a paired t test. Results In 14 subjects, change in global cognitive z-scores from baseline was by 0.08 at week 24 (p = 0.59) and 0.15 at week 48 (p = 0.43). Change in composite speed and accuracy z-scores from baseline at weeks 24/48 were 0.07/0.05 (p = 0.45/0.82) and 0.13/0.23 (p = 0.47/0.45), respectively. In two of the cognitive domains assessing speed (learning and monitoring time), a continued improvement from baseline to weeks 24 and 48 was observed (changes of 0.06–0.08 and 0.10–0.19, respectively), whereas in two domains (detection and identification) an initial improvement at week 24 (changes of −0.10 and 0.04 from baseline, respectively) was followed by a deterioration in score at week 48 (changes of −0.12 and −0.08 from baseline, respectively). None of these changes were statistically significant. Conclusions A trend for improvement in cognitive function was observed in naïve HIV-positive patients starting cART. The dynamics of this improvement differed both between cognitive domains and the time-points assessed.

Molecular imaging is an ideal platform for non-invasive detection and assessment of cancer. In recent years, the targeted imaging of CXCR4, a chemokine receptor that has been associated with tumour metastasis, has become an area of intensive research. In our pursuit of a CXCR4-specific radiotracer, we designed and synthesised a novel derivative of the CXCR4 peptidic antagonist TN14003, CCIC16, which is amenable to radiolabelling by chelation with a range of PET and SPECT radiometals, such as (68)Ga, (64)Cu and (111)In as well as (18)F (Al(18)F). Potent in vitro binding affinity and inhibition of signalling-dependent cell migration by unlabelled CCIC16 were confirmed by a threefold uptake in CXCR4-over-expressing cells compared to their isogenic counterparts. Furthermore, in vivo experiments demonstrated the favourable pharmacokinetic properties of the (68)Ga-labelled tracer (68)Ga-CCIC16, along with its CXCR4-specific accumulation in tissues with desirable contrast (tumour-to-muscle ratio: 9.5). The specificity of our tracer was confirmed by blocking experiments. Taking into account the attractive intrinsic PET imaging properties of (68)Ga, the comprehensive preclinical evaluation presented here suggests that (68)Ga-CCIC16 is a promising PET tracer for the specific imaging of CXCR4-expressing tumours.

Huisgen cycloaddition is attractive to label peptide because of its rapidity and bioorthogonality. However, for larger tracers, the physico-chemical differences between the precursor and the tracer are usually insufficient to allow their separation by HPLC, reducing the specific activity. This is of importance for peptidic tracers because the combination of their high-affinity receptor with low specific activity results in the precursor saturating the receptors, causing non-specific tracer binding. Here, we report a fast, one-pot, general strategy to circumvent this issue, yielding a tracer of improved specific activity. It consists in adding a lipophilic azide after the labeling step to scavenge unreacted precursor into a more lipophilic species that does not co-elute with the tracer. We applied this strategy to a new fluorinated cyclopentapeptidic CXCR4 antagonist for the PET imaging of cancer, CCIC15, for which we managed to reduce the apparent peptide concentration by a factor of 34 in 10 min. This tracer was radiolabeled by click chemistry with 2-[(18) F]fluoroethylazide, yielding the tracer in 18 ± 6% (n = 5) end-of-synthesis radiochemical yields (EOS-RCY) in 1.5 h from [(18) F]fluoride with a specific activity of 19.4 GBq µmol(-1) . Preliminary biological evaluation of the probe confirmed potency and specificity for CXCR4; further biological evaluation is underway.

Purpose: To examine the psychosocial issues related to growing up with a physical disability. Methods: Adolescents with physical disabilities aged 11–16 years were compared with a Canadian national sample of adolescents using the Health Behaviours in School-Aged Children (HBSC), a World Health Organization Cross-National Study survey. Results: Adolescents with physical disabilities reported good self-esteem, strong family relationships, and as many close friends as adolescents in the national sample. However, adolescents with physical disabilities participated in fewer social activities and had less intimate relationships with their friends. They had more positive attitudes toward school, teachers, and their fellow classmates than the national sample, but fewer had plans for postsecondary education. The majority of adolescents with physical disabilities reported that they had not received information on parenthood, birth control, and sexually transmitted diseases. Conclusions: There are a number of critical areas of risk for adolescents with physical disabilities to which health promotion efforts should be directed. These include lower levels of peer integration, heightened adult orientation, low educational aspirations, and poor knowledge of sexuality.

Mutations in several known or putative glycosyltransferases cause glycosylation defects in alpha-dystroglycan (alpha-DG), an integral component of the dystrophin glycoprotein complex. The hypoglycosylation reduces the ability of alpha-DG to bind laminin and other extracellular matrix ligands and is responsible for the pathogenesis of an inherited subset of muscular dystrophies known as the dystroglycanopathies. By exome and Sanger sequencing we identified two individuals affected by a dystroglycanopathy with mutations in beta-1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2). B3GALNT2 transfers N-acetyl galactosamine (GalNAc) in a beta-1,3 linkage to N-acetyl glucosamine (GlcNAc). A subsequent study of a separate cohort of individuals identified recessive mutations in four additional cases that were all affected by dystroglycanopathy with structural brain involvement. We show that functional dystroglycan glycosylation was reduced in the fibroblasts and muscle (when available) of these individuals via flow cytometry, immunoblotting, and immunocytochemistry. B3GALNT2 localized to the endoplasmic reticulum, and this localization was perturbed by some of the missense mutations identified. Moreover, knockdown of b3galnt2 in zebrafish recapitulated the human congenital muscular dystrophy phenotype with reduced motility, brain abnormalities, and disordered muscle fibers with evidence of damage to both the myosepta and the sarcolemma. Functional dystroglycan glycosylation was also reduced in the b3galnt2 knockdown zebralish embryos. Together these results demonstrate a role for B3GALNT2 in the glycosylation of alpha-DG and show that B3GALNT2 mutations can cause dystroglycanopathy with muscle and brain involvement.

The study purpose was to describe multiunit landlord attitudes and behaviors toward smoke-free policies.This was a descriptive, cross-sectional survey of multiunit landlords in Douglas County (N=392).A 25-item survey was developed and pilot tested. It was administered by telephone (n=143) and mail (n=249) to multiunit landlords.Combined response rate was 30.1% (81/143 telephone, 37/249 mail) representing 24,080 units on 974 properties with 34,399 tenants. Most respondents (73.7%) allowed smoking. Reasons for not implementing smoke-free policies were potential enforcement problems (57.0%), tenant objections (43.0%), loss of market share (39.5%). Respondents without smoke-free policies expected vacancy (53.6%) and turnover (50.0%) rates to increase, which was significantly different (p.0001) than respondents with smoke-free policies where only 10.7% reported increased vacancy and only 3.7% reported increased turnover.Expected adverse impacts of smoke-free policies do not reflect real experiences of smoke-free policy implementation. Public health advocates can use these study findings to develop community-based education and social marketing messages directed at voluntary smoke-free policy changes. Respondents without smoke-free policies expressed interest at the end of the survey in learning how to implement smoke-free policies indicating a readiness for change.

SUMMARY The relationship of education to risk factors at baseline and to long-term mortality from coronary heart disease (CHD), cardiovascular diseases (CVD), and all causes was analyzed for three cohorts of middle-aged employed white men in Chicago: 8047 from the Chicago Heart Association Detection Project in Industry (CHA) (entry 1967-1973), 1250 from the Peoples Gas Company Study (PG) (entry 1958-1959) and 1730 from the Western Electric Study (WE) (entry 1957-1958). Each man was classified into one of four groups: not a high school graduate, high school graduate, some college but not a graduate, or college graduate. For all three cohorts, a graded, inverse association was observed at baseline between education and blood pressure, which was statistically significant for CHA and WE men and independent of age and relative weight. For all three cohorts, a significant, graded, inverse association was also recorded between education and cigarette use at entry. For serum cholesterol, no clear pattern was observed for the education groups in any of the three cohorts. CHA men showed a graded, inverse relationship between education and relative weight. This cohort was the only one of three showing a significant, graded inverse association between education and prevalence of ECG abnormalities at entry. For this CHA cohort, 5-year follow-up data showed a statistically significant, graded, inverse relationship between education and ageadjusted mortality rates from CHD, CVD and all causes. With adjustment for entry age, diastolic pressure, cigarettes, serum cholesterol, relative weight and ECG abnormalities, this inverse relationship remainedreduced in degree, but still statistically significant for CVD mortality. Similarly, for the pooled PG-WE cohort of 2980 with 20-21 years of follow-up, education and the three mortality end points were inversely related but not graded, with statistical significance for all three end points in the univariate analyses. The results of these studies indicate inverse relationships between education and lifestyle-related risk factors at baseline and between education and long-term risk of CHD, CVD and all-causes mortality. The inverse relationship between education and mortality is accounted for in part by the established major biomedical risk factors.

Two methodological problems in characterizing an individual's plasma glucose level are examined in this study. First, how large is the intra-individual variation of an individual's 1-hr post-load glucose level and for this estimated intra-individual variation what are the probabilities of misclassifying individuals based on a one-time measurement only of glucose level? Second, do different tests—i.e. fasting, 1-hr, 2-hr post-load, GTT—yield consistent ranking for the same individual? The first of these was explored with data on subsamples from the Chicago Peoples Gas Company (PG) study and the Chicago Heart Association Detection Project in Industry (CHA) study; the second, with data from the Chicago Coronary Prevention Evaluation Program (CPEP). For both the PG and CHA studies, the estimated ratios of the intra- to inter-individual variances were generally higher for post-load plasma glucose than blood pressure, heart rate, weight and serum uric acid. The conditional probabilities of misclassifying individuals into quintiles or deciles based on one measurement of 1-hr post-load glucose were also estimated from these data. These estimated probabilities indicate that the possible attenuation due to intraindividual variation cannot abolish a strong association; however, it may create some problem if the relationship is not very strong. Furthermore, both rank correlation and quintile classification analyses show that fasting, 1-hr and 2-hr plasma glucose level characterize individuals differently. Thus it is possible that the inconsistent results of previous studies, all using a one-time measure of plasma glucose, are partially due to the large intra-individual variation of this variable, and the use of methods that are not highly consistent in their classification of individuals.

Item does not contain fulltext Congenital muscular dystrophies with hypoglycosylation of alpha-dystroglycan (alpha-DG) are a heterogeneous group of disorders often associated with brain and eye defects in addition to muscular dystrophy. Causative variants in 14 genes thought to be involved in the glycosylation of alpha-DG have been identified thus far. Allelic mutations in these genes might also cause milder limb-girdle muscular dystrophy phenotypes. Using a combination of exome and Sanger sequencing in eight unrelated individuals, we present evidence that mutations in guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) can result in muscular dystrophy variants with hypoglycosylated alpha-DG. GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-1-phosphate. GDP-mannose is required for O-mannosylation of proteins, including alpha-DG, and it is the substrate of cytosolic mannosyltransferases. We found reduced alpha-DG glycosylation in the muscle biopsies of affected individuals and in available fibroblasts. Overexpression of wild-type GMPPB in fibroblasts from an affected individual partially restored glycosylation of alpha-DG. Whereas wild-type GMPPB localized to the cytoplasm, five of the identified missense mutations caused formation of aggregates in the cytoplasm or near membrane protrusions. Additionally, knockdown of the GMPPB ortholog in zebrafish caused structural muscle defects with decreased motility, eye abnormalities, and reduced glycosylation of alpha-DG. Together, these data indicate that GMPPB mutations are responsible for congenital and limb-girdle muscular dystrophies with hypoglycosylation of alpha-DG.

Studies of possible association between asymptomatic hyperglycemia and coronary disease were conducted among middle-aged employed men in Chicago. In one cohort, frequency of ECG abnormalities at baseline was examined among men at different glucose levels. In univariate analysis, those at the highest glucose levels had higher rates of ECG evidence of CHD, but this association did not remain when such factors as age, blood pressure, weight, cholesterol and cigarettes were taken into account in multivariate analysis. Among the studies, long-term follow-up to mortality (10, 13 and 15 yr) showed inconsistent findings on association of hyperglycemia and subsequent death. In one cohort (Gas Company men followed for 10 yr after a 1-hr post-load glucose determination) a positive glucose-mortality association was found in both univariate and multivariate analysis. But in the two remaining cohorts (Gas Company 13 yr after casual glucose determination and Western Electric 15 yr after 2-hr post-load determination), no such association was found. While differences in method and sample size as well as other limitations may have contributed to the differences observed, the inconsistency of the findings do not permit a conclusion that asymptomatic hyperglycemia is a positive coronary risk factor.

A population-based survey of 134 white men, recruited from the Chicago People's Gas Company labor force, was carried out to examine the association between sodium-lithium (Na-Li) countertransport and hypertension. Of the 134 participants in this industry-sponsored periodic health examination, 64 were normotensive and 70 were either taking antihypertensive medications or had a systolic pressure greater than or equal to 140 or a diastolic pressure greater than or equal to 90 mm Hg. The hypertensives were older and more overweight. Countertransport was significantly higher in hypertensives than in normotensives. Among the three subgroups of hypertensives--untreated, borderline (140/90 to 160/95 mm Hg), untreated definite (over 160/95 mm Hg), and treated--an increase in countertransport was consistently observed, significant for the latter two groups. The relationship between countertransport and hypertension was independent of overweight, with countertransport being significantly related to both blood pressure and overweight. Altered ion transport may play an important role in the etiology and/or pathophysiology of hypertension.