Detecting Maternal‐Fetal Genotype Interactions Associated With Conotruncal Heart Defects: A Haplotype‐Based Analysis With Penalized Logistic Regression

Nonsyndromic congenital heart defects (CHDs) develop during embryogenesis as a result of a complex interplay between environmental exposures, genetics, and epigenetic causes. Genetic factors associated with CHDs may be attributed to either independent effects of maternal or fetal genes, or the intergenerational interactions between maternal and fetal genes. Detecting gene‐by‐gene interactions underlying complex diseases is a major challenge in genetic research. Detecting maternal‐fetal genotype (MFG) interactions and differentiating them from the maternal/fetal main effects has presented additional statistical challenges due to correlations between maternal and fetal genomes. Traditionally, genetic variants are tested separately for maternal/fetal main effects and MFG interactions on a single‐locus basis. We conducted a haplotype‐based analysis with a penalized logistic regression framework to dissect the genetic effect associated with the development of nonsyndromic conotruncal heart defects (CTD). Our method allows simultaneous model selection and effect estimation, providing a unified framework to differentiate maternal/fetal main effect from the MFG interaction effect. In addition, the method is able to test multiple highly linked SNPs simultaneously with a configuration of haplotypes, which reduces the data dimensionality and the burden of multiple testing. By analyzing a dataset from the National Birth Defects Prevention Study (NBDPS), we identified seven genes (GSTA1, SOD2, MTRR, AHCYL2, GCLC, GSTM3, and RFC1) associated with the development of CTDs. Our findings suggest that MFG interactions between haplotypes in three of seven genes, GCLC, GSTM3, and RFC1, are associated with nonsyndromic conotruncal heart defects.     

Educational and Organizational Interventions to Improve the Usefulness of Clinical Pharmacological Advice for Personalized Drug Dosing Based on Therapeutic Drug Monitoring

This study was aimed at increasing the clinical usefulness of clinical pharmacological advice (CPA) for personalized drug dosing based on therapeutic drug monitoring (TDM). Educational and organizational interventions focused on improving the knowledge of clinical pharmacology among hospital healthcare workers and reducing the incidence of errors throughout the process were planned. After a pre‐interventional period of risk assessment, different list forms of the types of error occurring in the various phases of the process (Phase 1, request for CPA and blood sampling for TDM; Phase 2, sample delivery to and check in at the CPU; Phase 3, TDM execution and CPA production) were created. In the interventional period, the errors were collected daily and educational programmes were carried out. The pre‐intervention error rate was 19.5%, and resulted significantly higher for the requests coming from the medical wards compared with those from the surgical wards or the ICUs (26.0% versus 10.5% versus 13.7%, p < 0.001). The educational programme trained 303 nurses and 145 physicians. Afterwards, the error percentage progressively dropped (15.5% in the 2nd trimester; 12.3% in the 3rd one; 10.5% in the 4th one). The adopted strategy resulted in significant improvements which may be useful both to improve quality of patient care and to reduce waste in healthcare costs.     

Synthesis,in Vitro Covalent Binding Evaluation,and Metabolism of 14C-Labeled Inhibitors of 11β-HSD1

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A view from the other side: the hope in the eyes of the healer

A physician affected by amyotrophic lateral sclerosis (ALS) explores the meaning of his disease. The deterioration of his physical health and of his independence provided a new and deeper view of healing, as well as a new mission for his medical profession. He has become at the same time a “voice for the voiceless” and a source of hope and inspiration for patients and health professionals alike. Espousing the principle that healing is always possible even when the disease is incurable, the author proposes a three-prong approach to healing: symptom management, allegiance to the patient up to the ends, and common search of meaning. He emphasizes that both patients and health care workers need to be healed.     

Expansion of plasmablasts and loss of memory B cells in peripheral blood from COVID-19 patients with pneumonia

Studies on the interactions between SARS-CoV-2 and humoral immunity are fundamental to elaborate effective therapies including vaccines. We used polychromatic flow cytometry, coupled with unsupervised data analysis and principal component analysis (PCA), to interrogate B cells in untreated patients with COVID-19 pneumonia. COVID-19 patients displayed normal plasma levels of the main immunoglobulin classes, of antibodies against common antigens or against antigens present in common vaccines. However, we found a decreased number of total and naïve B cells, along with decreased percentages and numbers of memory switched and unswitched B cells. On the contrary, IgM⁺ and IgM⁻ plasmablasts were significantly increased. In vitro cell activation revealed that B lymphocytes showed a normal proliferation index and number of dividing cells per cycle. PCA indicated that B-cell number, naive and memory B cells but not plasmablasts clustered with patients who were discharged, while plasma IgM level, C-reactive protein, D-dimer, and SOFA score with those who died. In patients with pneumonia, the derangement of the B-cell compartment could be one of the causes of the immunological failure to control SARS-Cov2, have a relevant influence on several pathways, organs and systems, and must be considered to develop vaccine strategies.     

It's costly punishment,not altruistic: Low midfrontal theta and state anger predict punishment

Punishment in economic games has been interpreted as “altruistic.” However, it was shown that punishment is related to trait anger instead of trait altruism in a third-party dictator game if compensation is also available. Here, we investigated the influence of state anger on punishment and compensation in the third-party dictator game. Therefore, we used movie sequences for emotional priming, including the target states anger, happy, and neutral. We measured the Feedback-Related Negativity (FRN) and midfrontal theta band activation, to investigate an electro-cortical correlate of the processing of fair and unfair offers. Also, we assessed single-trial FRN and midfrontal theta band activation as a predictor for punishment and compensation. We found that punishment was linked to state anger. Midfrontal theta band activation, which has previously been linked to altruistic acts and cognitive control, predicted less punishment. Additionally, trait anger led to enhanced FRN for unfair offers. This led to the interpretation that the FRN depicts the evaluation of fairness, while midfrontal theta band activation captures an aspect of cognitive control and altruistic motivation. We conclude that we need to redefine “altruistic punishment” into “costly punishment,” as no direct link of altruism and punishment is given. Additionally, midfrontal theta band activation complements the FRN and offers additional insights into complex responses and decision processes, especially as a single trial predictor.      

The moderating effect of gender as a protective factor against discrimination in migrants from Latin America and China

This study analysed the association between discrimination and satisfaction with life (SWL) in migrant groups by investigating whether different types of social support (SS; emotional, instrumental, and informational) and networks (family, immigrant and native friends, neighbours, and the community) buffer the negative effects of discrimination on SWL among migrant men and women from different backgrounds. Participants were 631 migrants from Latin America and China residing in Malaga (Spain). We identified behaviour patterns that suggest that SS has different effects on men and women from the same place of origin and similar effects on women and men from different places of origin. In conclusion, the main differences in the effects of SS as a buffer mechanism are not determined by cultural factors. It is more likely that they are determined by differential gender-role socialization, which would lead women to positively value social support.     

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