Associations between maternal depression and mother and infant oxytocin receptor gene (OXTR_rs53576) polymorphisms

Polymorphisms in the oxytocin receptor gene, OXTR_rs53576, have been linked to differences in maternal sensitivity and depressive symptoms. Although some studies suggest the A allele confers risk for mood disorders, individuals homozygous for the G allele may exhibit greater sensitivity to both positive and negative social experiences, including in the mother–infant dyad. Given the bi-directional nature of mother–infant influences on maternal mood, we tested the association between both mothers’ and infants’ OXTR_rs53576 genotype and maternal depression, as assessed through a self-report inventory. Although Beck Depression Inventory (BDI-II) scores were significantly higher for GG in comparison to AG/AA mothers, and for mothers of GG in comparison to AG/AA infants, an ANCOVA revealed that after sociodemographic risk factors had been controlled, infants’, but not mothers’, OXTR genotype predicted maternal depression scores, with no significant interaction between the two. The effect of infant OXTR on maternal depression was not explained by maternal reports of difficult infant temperament. We propose that GG infants have an enhanced capacity for processing both positive and negative socially meaningful contextual information, first amplifying and then differentially perpetuating negative affectivity in mothers who exhibit depressive characteristics.     

Analysis of structure and gene expression in developing kidneys of male and female rats exposed to low protein diets in utero

A maternal low protein (LP) diet in rodents often results in low nephron endowment and renal pathophysiology in adult life, with outcomes often differing between male and female offspring. Precisely how a maternal LP diet results in low nephron endowment is unknown. We conducted morphological and molecular studies of branching morphogenesis and nephrogenesis to identify mechanisms and timepoints that might give rise to low nephron endowment. Sprague–Dawley rats were fed a normal protein (19.4% protein, NP) or LP (9% protein) diet for 3 weeks prior to mating and throughout gestation. Embryonic day 14.25 (E14.25) kidneys from males and females were either cultured for 2 days after which branching morphogenesis was quantified, or frozen for gene expression analysis. Real-time PCR was used to quantify expression of key nephrogenesis and branching morphogenesis genes at E14.25 and 17.25. At E17.25, nephron number was determined in fixed tissue. There was no effect of either maternal diet or sex on branching morphogenesis. Nephron number at E17.25 was 14% lower in male and female LP offspring than in NP controls. At E14.25 expression levels of genes involved in branching morphogenesis (Gfrα1, Bmp4, Gdnf) and nephrogenesis (Hnf4a, Pax2, Wnt4) were similar in the dietary groups, but significant differences between sexes were identified. At E17.25, expression of Gfrα1, Gdnf, Bmp4, Pax2 and Six2 was lower in LP offspring than NP offspring, in both male and female offspring. These findings provide new insights into how a LP diet leads to low nephron endowment and renal sexual dimorphism.     

Cerebellar ataxia with normal intellect associated with a homozygous truncating variant in CA8

Biallelic pathogenic variants in CA8 cause cerebellar ataxia, mental retardation and dysequilibrium syndrome 3 (CAMRQ3), a rare form of hereditary ataxia characterised by cerebellar hypoplasia/atrophy, variable intellectual disability and often quadrupedal gait. The few cases reported in the medical literature are all caused by pathogenic homozygous or compound heterozygous missense variants in CA8. We report a 9 year-old boy with marked gross motor delay, ataxia and progressive cerebellar atrophy with limited bipedal gait, but without intellectual disability. Singleton whole exome sequencing was performed. A novel homozygous truncating variant in CA8 (c.232C>T) with a predicted premature termination codon at position 78 (p.Arg78*) was identified. Both parents and the proband's healthy sister are heterozygous for the variant. This variant is likely pathogenic and the cause of the condition in this child. Functional evidence in the form of a spontaneous mouse model involving homozygous intragenic deletion of the mouse analogue of CA8 with nonsense-mediated decay and similar clinical features to the proband support pathogenicity. Identification of this truncating variant broadens the genotypic and phenotypic spectrum of CA8-related cerebellar ataxia.     

Discordant and heterogeneous clinically relevant genomic alterations in circulating tumor cells vs plasma DNA from men with metastatic castration resistant prostate cancer

Circulating tumor cell (CTC) and cell‐free (cf) DNA‐based genomic alterations are increasingly being used for clinical decision‐making in oncology. However, the concordance and discordance between paired CTC and cfDNA genomic profiles remain largely unknown. We performed comparative genomic hybridization (CGH) on CTCs and cfDNA, and low‐pass whole genome sequencing (lpWGS) on cfDNA to characterize genomic alterations (CNA) and tumor content in two independent prospective studies of 93 men with mCRPC treated with enzalutamide/abiraterone, or radium‐223. Comprehensive analysis of 69 patient CTCs and 72 cfDNA samples from 93 men with mCRPC, including 64 paired samples, identified common concordant gains in FOXA1, AR, and MYC, and losses in BRCA1, PTEN, and RB1 between CTCs and cfDNA. Concordant PTEN loss and discordant BRCA2 gain were associated with significantly worse outcomes in Epic AR‐V7 negative men with mCRPC treated with abiraterone/enzalutamide. We identified and externally validated CTC‐specific genomic alternations that were discordant in paired cfDNA, even in samples with high tumor content. These CTC/cfDNA‐discordant regions included key genomic regulators of lineage plasticity, osteomimicry, and cellular differentiation, including MYCN gain in CTCs (31%) that was rarely detected in cfDNA. CTC MYCN gain was associated with poor clinical outcomes in AR‐V7 negative men and small cell transformation. In conclusion, we demonstrated concordance of multiple genomic alterations across CTC and cfDNA platforms; however, some genomic alterations displayed substantial discordance between CTC DNA and cfDNA despite the use of identical copy number analysis methods, suggesting tumor heterogeneity and divergent evolution associated with poor clinical outcomes.     

Infected pancreatic fluid collections: percutaneous catheter drainage

Thirty-eight infected pancreatic fluid collections in 23 patients with acute or chronic pancreatitis were drained percutaneously following initial diagnosis with computed tomography and fine-needle aspiration. Fifteen (65.2%) patients were cured completely without surgery. Eight (34.8%) patients required some type of surgery despite successful treatment of the fluid collection, and in two (6.5%) the collection recurred after catheter removal. Complications occurred in three (13%) patients, but only one complication (4%), empyema, was a direct result of catheter drainage. Catheter drainage time averaged 29 days for 16 patients with isolated collections and 96 days and 104 days for patients with collections with pancreatic duct fistulas (nine patients) or gastrointestinal fistulas (14 patients), respectively. This study confirms that infected pancreatic fluid collections can be safely and effectively treated with percutaneous catheter techniques in most patients.     

Unique sleep‐stage transitions determined by obstructive sleep apnea severity,age and gender

In obstructive sleep apnea, patients’ sleep is fragmented leading to excessive daytime sleepiness and co‐morbidities like arterial hypertension. However, traditional metrics are not always directly correlated with daytime sleepiness, and the association between traditional sleep quality metrics like sleep duration and arterial hypertension is still ambiguous. In a development cohort, we analysed hypnograms from mild (n = 209), moderate (n = 222) and severe (n = 272) obstructive sleep apnea patients as well as healthy controls (n = 105) from the European Sleep Apnea Database. We assessed sleep by the analysis of two‐step transitions depending on obstructive sleep apnea severity and anthropometric factors. Two‐step transition patterns were examined for an association to arterial hypertension or daytime sleepiness. We also tested cumulative distributions of wake as well as sleep‐states for power‐laws (exponent α) and exponential distributions (decay time τ) in dependency on obstructive sleep apnea severity and potential confounders. Independent of obstructive sleep apnea severity and potential confounders, wake‐state durations followed a power‐law distribution, while sleep‐state durations were characterized by an exponential distribution. Sleep‐stage transitions are influenced by obstructive sleep apnea severity, age and gender. N2 → N3 → wake transitions were associated with high diastolic blood pressure. We observed higher frequencies of alternating (symmetric) patterns (e.g. N2 → N1 → N2, N2 → wake → N2) in sleepy patients both in the development cohort and in a validation cohort (n = 425). In conclusion, effects of obstructive sleep apnea severity and potential confounders on sleep architecture are small, but transition patterns still link sleep fragmentation directly to obstructive sleep apnea‐related clinical outcomes like arterial hypertension and daytime sleepiness.     

Performance of polygenic risk scores for cancer prediction in a racially diverse academic biobank

PurposeGenome-wide association studies have identified hundreds of single nucleotide variations (formerly single nucleotide polymorphisms) associated with several cancers, but the predictive ability of polygenic risk scores (PRSs) is unclear, especially among non-Whites.MethodsPRSs were derived from genome-wide significant single-nucleotide variations for 15 cancers in 20,079 individuals in an academic biobank. We evaluated the improvement in discriminatory accuracy by including cancer-specific PRS in patients of genetically-determined African and European ancestry.ResultsAmong the individuals of European genetic ancestry, PRSs for breast, colon, melanoma, and prostate were significantly associated with their respective cancers. Among the individuals of African genetic ancestry, PRSs for breast, colon, prostate, and thyroid were significantly associated with their respective cancers. The area under the curve of the model consisting of age, sex, and principal components was 0.621 to 0.710, and it increased by 1% to 4% with the inclusion of PRS in individuals of European genetic ancestry. In individuals of African genetic ancestry, area under the curve was overall higher in the model without the PRS (0.723-0.810) but increased by <1% with the inclusion of PRS for most cancers.ConclusionPRS moderately increased the ability to discriminate the cancer status in individuals of European but not African ancestry. Further large-scale studies are needed to identify ancestry-specific genetic factors in non-White populations to incorporate PRS into cancer risk assessment.     

Optimal two‐stage reliability studies

The intraclass correlation is often used to assess the reliability of a measurement system. There is a considerable literature devoted to optimizing the standard assessment plan in which a number of subjects are measured repeatedly. We propose a two‐stage investigation, here called a leveraged plan (LP), where in Stage I, we measure a number of subjects once. Then in Stage II, we select a subset of subjects with extreme initial measurements for repeated measurement. For a fixed total number of measurements, we show that the optimal LP provides a more precise estimate of the intraclass correlation coefficient than does the optimal standard plan (SP). We provide a table for finding the optimal LP given the true intraclass correlation and a specified precision for the estimate. For a fixed total number of measurements N, a nearly optimal LP makes roughly N/2 measurements in Stage I and then selects roughly N/6 extreme subjects to re‐measure thrice each in Stage II. We also compare optimal leveraged with optimal SPs when there is a limit on the number of times each subject can be re‐measured. Copyright © 2009 John Wiley & Sons, Ltd.     

Cancer-related health behaviours and health service use among Inuit and other residents of Canada's north

This article identifies the extent to which demographic, socio-economic and geographic factors account for differences between Inuit and other Northern Canadian residents in health-related behaviours and health service use related to cancer incidence and diagnosis. The study population includes Inuit, Métis, First Nation and non-Aboriginal residents aged 21–65 who live in Nunavut, Northwest Territories, Labrador, Nunavik and Jamésie in northern Quebec, and the northern regions of Saskatchewan and Manitoba. Data are drawn from confidential versions of the 2000–2001 and 2004–2005 Canadian Community Health Surveys and the 2001 Aboriginal People's Survey produced by Statistics Canada. Multivariate Logistic regression analysis is applied to a set of health-related behaviours including cigarette smoking, binge drinking and obesity, and a set of basic health service use measures including consultation with a physician, consultation with a nurse, Pap smear testing and mammography.     

Has Pay-for-Performance Decreased Access for Minority Patients?

Objective. To examine whether the CMS and Premier Inc. Hospital Quality Incentive Demonstration (PHQID), a hospital-based pay-for-performance (P4P) and public quality reporting program, caused participating hospitals (1) to avoid treating minority patients diagnosed with acute myocardial infarction (AMI), heart failure, and pneumonia and (2) to avoid providing coronary artery bypass graft (CABG) to minority patients diagnosed with AMI.
Data Sources. One hundred percent Medicare inpatient claims, denominator files, and provider of service files from 2000 to 2006.
Study Design. We test for differences in the conditional probability of receiving care at PHQID hospitals for AMI, heart failure, and pneumonia before and after implementation of the PHQID between white and minority patients. We also test for differences in the conditional probability that white and minority patients diagnosed with AMI receive CABG in hospitals participating, and not participating, in the PHQID before and after the implementation of the PHQID.
Data Extraction Methods. Data were obtained from CMS.
Principal Findings. We find little evidence that the PHQID reduced access for minority patients: only Other Race beneficiaries had a significant reduction in adjusted admissions to PHQID hospitals in the postperiod, and only for AMI. Only marginally significant (  p <.10) evidence of a reduction in CABG was found, also occurring for Other Race beneficiaries.
Conclusions. Despite minimal evidence of minority patient avoidance in the PHQID, monitoring of avoidance should continue for P4P programs.