High fat diet rescues disturbances to metabolic homeostasis and survival in the Id2 null mouse in a sex-specific manner

Inhibitor of DNA binding 2 (ID2) is a helix-loop-helix transcriptional repressor rhythmically expressed in many adult tissues. Our previous studies have demonstrated that Id2 null mice have altered expression of circadian genes involved in lipid metabolism, altered circadian feeding behavior, and sex-specific enhancement of insulin sensitivity and elevated glucose uptake in skeletal muscle and brown adipose tissue. Here we further characterized the Id2−/− mouse metabolic phenotype in a sex-specific context and under low and high fat diets, and examined metabolic and endocrine parameters associated with lipid and glucose metabolism. Under the low-fat diet Id2−/− mice showed decreased weight gain, reduced gonadal fat mass, and a lower survival rate. Under the high-fat diet, body weight and gonadal fat gain of Id2−/− male mice was comparable to control mice and survival rate improved markedly. Furthermore, the high-fat diet treated Id2−/− male mice lost the enhanced glucose tolerance feature observed in the other Id2−/− groups, and there was a sex-specific difference in white adipose tissue storage of Id2−/− mice. Additionally, a distinct pattern of hepatic lipid accumulation was observed in Id2−/− males: low lipids on the low-fat diet and steatosis on the high-fat diet. In summary, these data provides valuable insights into the impact of Id2 deficiency on metabolic homeostasis of mice in a sex-specific manner

Perinatal Depression and Its Impact on Infant Outcomes and Maternal-Nurse SMS Communication in a Cohort of Kenyan Women

Abstract: Background Perinatal depression is broadly defined as depressive symptoms during pregnancy or within the 12 months following delivery, affecting approximately 20-25% of pregnant and postpartum women in low- and middle-income countries. The wide accessibility of mobile phones allows mobile health (mHealth) interventions to be considered a solution to identify perinatal depression and provide appropriate referrals for treatment. This study, nested in a larger SMS communication project, examined the prevalence and correlates of perinatal depression, determined the association between antenatal depression and infant morbidity/mortality, and compared SMS communication patterns between women with and without perinatal depression. Methods This was a prospective longitudinal cohort of pregnant women seeking antenatal services at two public sector health clinics in Kenya. SMS messages were sent to participants with educational content related to their pregnancy and infant health and two-way SMS communication occurred with a nurse. Sociodemographic and obstetric characteristics, SMS messaging behaviors, infant health status, and depressive symptoms were assessed by a standardized questionnaire administered at enrollment (30-36 weeks gestation) and follow-up (14 weeks postpartum). Generalized estimating equation (GEE) with Poisson link was used to evaluate correlates of perinatal depressive symptoms, infant outcomes, and frequency of SMS messaging. Results Of the 572 women with complete follow-up information, 188 (32.9%) screened positive for elevated depressive symptoms (≥10 by EPDS scale) at some time point during pregnancy or postpartum. The strongest predictors of depressive symptoms included abuse during pregnancy, fewer years of schooling, and maternal unemployment. Antenatal depressive symptoms were associated with an increased risk of infant illness or hospitalization (RR = 1.12, 95% CI: 1.11, 1.13). Women with antenatal or persistent perinatal depressive symptoms sent fewer SMS messages during the study period than their counterparts without depression. Conclusions Prevalence of elevated perinatal depressive symptoms was high in this cohort of Kenyan women. Our findings highlight the importance of screening perinatal women for experiences of abuse and symptoms of depression. Differences in messaging frequency between women with vs. without depressive symptoms presents a potential opportunity to provide more support for those perinatal depression

Immunohistochemical Detection of MYC-driven Diffuse Large B-Cell Lymphomas

Diffuse large B cell lymphoma (DLBCL) is a clinically and genetically heterogeneous disease. A small subset of DLBCLs has translocations involving the MYC locus and an additional group has a molecular signature resembling Burkitt lymphoma (mBL). Presently, identification of such cases by morphology is unreliable and relies on cytogenetic or complex molecular methods such as gene transcriptional profiling. Herein, we describe an immunohistochemical (IHC) method for identifying DLBCLs with increased MYC protein expression. We tested 77 cases of DLBCL and identified 15 cases with high MYC protein expression (nuclear staining in >50% of tumor cells). All MYC translocation positive cases had increased MYC protein expression by this IHC assay. In addition, gene set enrichment analysis (GSEA) of the DLBCL transcriptional profiles revealed that tumors with increased MYC protein expression (regardless of underlying MYC translocation status) had coordinate upregulation of MYC target genes, providing molecular confirmation of the IHC results. We then generated a molecular classifier derived from the MYC IHC results in our cases and employed it to successfully classify mBLs from two previously reported independent case series, providing additional confirmation that the MYC IHC results identify clinically important subsets of DLBCLs. Lastly, we found that DLBCLs with high MYC protein expression had inferior overall survival when treated with R-CHOP. In conclusion, the IHC method described herein can be used to readily identify the biologically and clinically distinct cases of MYC-driven DLBCL, which represent a clinically significant subset of DLBCL cases due to their inferior overall survival

Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders

Background: De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder. Methods: To minimise ascertainment bias, we recruited nine additional individuals with CDK13 pathogenic variants from clinical and research exome laboratory sequencing cohorts. Each individual underwent dysmorphology exam and comprehensive medical history review. Results: We demonstrate greater than expected phenotypic heterogeneity, including 33% (3/9) of individuals without structural heart disease on echocardiogram. There was a high penetrance for a unique constellation of facial dysmorphism and global developmental delay, as well as less frequently seen renal and sacral anomalies. Two individuals had novel CDK13 variants (p.Asn842Asp, p.Lys734Glu), while the remaining seven unrelated individuals had a recurrent, previously published p.Asn842Ser variant. Summary of all variants published to date demonstrates apparent restriction of pathogenic variants to the protein kinase domain with clustering in the ATP and magnesium binding sites. Conclusions: Here we provide detailed phenotypic and molecular characterisation of individuals with pathogenic variants in CDK13 and propose management guidelines based upon the estimated prevalence of anomalies identified. Keywords: CDK13, CHDFIDD, De novo variant, Neurodevelopmental disorders, Agenesis of the corpus callosum, Hypertelorism, Developmental delay, Cyclin-dependent kinase, Undiagnosed Diseases Networ

Recent smell loss is the best predictor of COVID-19 among individuals with recent respiratory symptoms

In a preregistered, cross-sectional study we investigated whether olfactory loss is a reliable predictor of COVID-19 using a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n=4148) or negative (C19-; n=546) COVID-19 laboratory test outcome. Logistic regression models identified univariate and multivariate predictors of COVID-19 status and post-COVID-19 olfactory recovery. Both C19+ and C19- groups exhibited smell loss, but it was significantly larger in C19+ participants (mean±SD, C19+: -82.5±27.2 points; C19-: -59.8±37.7). Smell loss during illness was the best predictor of COVID-19 in both univariate and multivariate models (ROC AUC=0.72). Additional variables provide negligible model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms (e.g., fever). Olfactory recovery within 40 days of respiratory symptom onset was reported for ~50% of participants and was best predicted by time since respiratory symptom onset. We find that quantified smell loss is the best predictor of COVID-19 amongst those with symptoms of respiratory illness. To aid clinicians and contact tracers in identifying individuals with a high likelihood of having COVID-19, we propose a novel 0-10 scale to screen for recent olfactory loss, the ODoR-19. We find that numeric ratings ≤2 indicate high odds of symptomatic COVID-19 (4<10). Once independently validated, this tool could be deployed when viral lab tests are impractical or unavailable

More than smell - COVID-19 is associated with severe impairment of smell, taste, and chemesthesis

Recent anecdotal and scientific reports have provided evidence of a link between COVID-19 and chemosensory impairments such as anosmia. However, these reports have downplayed or failed to distinguish potential effects on taste, ignored chemesthesis, generally lacked quantitative measurements, were mostly restricted to data from single countries. Here, we report the development, implementation and initial results of a multi-lingual, international questionnaire to assess self-reported quantity and quality of perception in three distinct chemosensory modalities (smell, taste, and chemesthesis) before and during COVID-19. In the first 11 days after questionnaire launch, 4039 participants (2913 women, 1118 men, 8 other, ages 19-79) reported a COVID-19 diagnosis either via laboratory tests or clinical assessment. Importantly, smell, taste and chemesthetic function were each significantly reduced compared to their status before the disease. Difference scores (maximum possible change+/-100) revealed a mean reduction of smell (-79.7+/- 28.7, mean+/- SD), taste (-69.0+/- 32.6), and chemesthetic (-37.3+/- 36.2) function during COVID-19. Qualitative changes in olfactory ability (parosmia and phantosmia) were relatively rare and correlated with smell loss. Importantly, perceived nasal obstruction did not account for smell loss. Furthermore, chemosensory impairments were similar between participants in the laboratory test and clinical assessment groups. These results show that COVID-19-associated chemosensory impairment is not limited to smell, but also affects taste and chemesthesis. The multimodal impact of COVID-19 and lack of perceived nasal obstruction suggest that SARS-CoV-2 infection may disrupt sensory-neural mechanisms.Additional co-authors: Veronica Pereda-Loth, Shannon B Olsson, Richard C Gerkin, Paloma Rohlfs Domínguez, Javier Albayay, Michael C. Farruggia, Surabhi Bhutani, Alexander W Fjaeldstad, Ritesh Kumar, Anna Menini, Moustafa Bensafi, Mari Sandell, Iordanis Konstantinidis, Antonella Di Pizio, Federica Genovese, Lina Öztürk, Thierry Thomas-Danguin, Johannes Frasnelli, Sanne Boesveldt, Özlem Saatci, Luis R. Saraiva, Cailu Lin, Jérôme Golebiowski, Liang-Dar Hwang, Mehmet Hakan Ozdener, Maria Dolors Guàrdia, Christophe Laudamiel, Marina Ritchie, Jan Havlícek, Denis Pierron, Eugeni Roura, Marta Navarro, Alissa A. Nolden, Juyun Lim, KL Whitcroft, Lauren R. Colquitt, Camille Ferdenzi, Evelyn V. Brindha, Aytug Altundag, Alberto Macchi, Alexia Nunez-Parra, Zara M. Patel, Sébastien Fiorucci, Carl M. Philpott, Barry C. Smith, Johan N Lundström, Carla Mucignat, Jane K. Parker, Mirjam van den Brink, Michael Schmuker, Florian Ph.S Fischmeister, Thomas Heinbockel, Vonnie D.C. Shields, Farhoud Faraji, Enrique Enrique Santamaría, William E.A. Fredborg, Gabriella Morini, Jonas K. Olofsson, Maryam Jalessi, Noam Karni, Anna D'Errico, Rafieh Alizadeh, Robert Pellegrino, Pablo Meyer, Caroline Huart, Ben Chen, Graciela M. Soler, Mohammed K. Alwashahi, Olagunju Abdulrahman, Antje Welge-Lüssen, Pamela Dalton, Jessica Freiherr, Carol H. Yan, Jasper H. B. de Groot, Vera V. Voznessenskaya, Hadar Klein, Jingguo Chen, Masako Okamoto, Elizabeth A. Sell, Preet Bano Singh, Julie Walsh-Messinger, Nicholas S. Archer, Sachiko Koyama, Vincent Deary, Hüseyin Yanik, Samet Albayrak, Lenka Martinec Novákov, Ilja Croijmans, Patricia Portillo Mazal, Shima T. Moein, Eitan Margulis, Coralie Mignot, Sajidxa Mariño, Dejan Georgiev, Pavan K. Kaushik, Bettina Malnic, Hong Wang, Shima Seyed-Allaei, Nur Yoluk, Sara Razzaghi, Jeb M. Justice, Diego Restrepo, Julien W Hsieh, Danielle R. Reed, Thomas Hummel, Steven D Munger, John E Haye

Characterizing perinatal depression and its impact on infant outcomes and maternal-nurse SMS communication in a cohort of Kenyan women

Thesis (Master's)--University of Washington, 2021Objective: To examine the prevalence and correlates of perinatal depression, to determine the association between antenatal depression and infant morbidity/mortality, and to compare SMS communication patterns between women with and without perinatal depression.Background: Perinatal depression is broadly defined as depressive symptoms with onset during pregnancy or within the 12 months following delivery, affecting approximately 20-25% of pregnant and postpartum women in low- and middle-income countries. The broad accessibility of mobile phones allows mHealth interventions to be considered as a solution for health providers to identify and treat perinatal depression. Methods: Prospective longitudinal cohort of pregnant women seeking antenatal services at one of two public sector health clinics in Kenya. Pre-programmed SMS messages were sent to participants with content pertaining to their pregnancy status. Sociodemographic and obstetric characteristics, SMS messaging behaviors, infant health status, and depressive symptoms were assessed by a standardized questionnaire administered at enrollment (30-36 weeks gestation) and follow-up (14 weeks postpartum). Generalized estimating equation (GEE) with Poisson link was used to evaluate correlates of perinatal depression, infant outcomes, and frequency of SMS messaging. Results: Of the 572 women with complete follow-up information, 188 (32.9%) had evidence of perinatal depression at some time point in pregnancy or postpartum. Strongest risk factors for perinatal depression included intimate partner violence, fewer years of schooling, and maternal unemployment. Antenatal depression was associated with an increased risk of infant illness or hospitalization (RR = 1.12, 95% CI: 1.11, 1.13). Women with antenatal or persistent perinatal depression sent fewer SMS messages during the study period than their counterparts without depression. Conclusion: Our analysis demonstrated a relatively high prevalence of perinatal depression in this cohort. Differences in messaging frequency suggest two-way SMS messaging systems may have utility in identifying depressive symptoms throughout the perinatal period, making it feasible to incorporate detection and treatment modalities for mothers with depression via mHealth interventions

Additional file 1 of Perinatal depression and its impact on infant outcomes and maternal-nurse SMS communication in a cohort of Kenyan women

Additional file 1: Supplementary Table A. Baseline Characteristics for Total and Retained Cohorts. Participant baseline characteristics for the 798 participants with complete enrollment data and for the 572 participants with two completed EPDS surveys. Supplementary Table B. Baseline Characteristics of Excluded vs. Retained Cohorts. Comparison of participant baseline characteristics between the 226 participants who were excluded because they did complete a second EPDS survey, and thus did not have a postpartum depression outcome, and the 572 participants included in the study who had two completed EPDS surveys

Ablation of the <i>Id2</i> Gene Results in Altered Circadian Feeding Behavior, and Sex-Specific Enhancement of Insulin Sensitivity and Elevated Glucose Uptake in Skeletal Muscle and Brown Adipose Tissue

<div><p>Inhibitor of DNA binding 2 (ID2) is a helix-loop-helix transcriptional repressor rhythmically expressed in many adult tissues. Our earlier studies have demonstrated a role for ID2 in the input pathway, core clock function and output pathways of the mouse circadian system. We have also reported that <i>Id2</i> null (<i>Id2</i>−/−) mice are lean with low gonadal white adipose tissue deposits and lower lipid content in the liver. These results coincided with altered or disrupted circadian expression profiles of liver genes including those involved in lipid metabolism. In the present phenotypic study we intended to decipher, on a sex-specific basis, the role of ID2 in glucose metabolism and in the circadian regulation of activity, important components of energy balance. We find that <i>Id2</i>−/− mice exhibited altered daily and circadian rhythms of feeding and locomotor activity; activity profiles extended further into the late night/dark phase of the 24-hr cycle, despite mice showing reduced total locomotor activity. Also, male <i>Id2−/−</i> mice consumed a greater amount of food relative to body mass, and displayed less weight gain. <i>Id2−/−</i> females had smaller adipocytes, suggesting sexual-dimorphic programing of adipogenesis. We observed increased glucose tolerance and insulin sensitivity in male <i>Id2−/−</i> mice, which was exacerbated in older animals. FDG-PET analysis revealed increased glucose uptake by skeletal muscle and brown adipose tissue of male <i>Id2</i>−/− mice, suggesting increased glucose metabolism and thermogenesis in these tissues. Reductions in intramuscular triacylglycerol and diacylglycerol were detected in male <i>Id2</i>−/− mice, highlighting its possible mechanistic role in enhanced insulin sensitivity in these mice. Our findings indicate a role for ID2 as a regulator of glucose and lipid metabolism, and in the circadian control of feeding/locomotor behavior; and contribute to the understanding of the development of obesity and diabetes, particularly in shift work personnel among whom incidence of such metabolic disorders is elevated.</p></div

Skeletal muscle triglyceride (TG) and diacylglycerol (DAG) profiles in <i>Id2−/−</i> mice.

<p>A) Total TG content of tibialis anterior muscle (ANOVA: genotype (G), n.s.; sex (S), P<0.05; interaction (I), n.s.). B) Total DAG content of tibialis anterior muscle (G, n.s.; S, P<0.01; I, n.s.). C) DAG species analysis. DAG species are abbreviated as two contributing fatty acyl groups: A, E, S, O, L and P denote arachidonoyl, eicosapentanoyl, stearoyl, oleoyl, linoleoyl and palmitoyl groups, respectively. Values represent mean ± SEM. *p<0.05, **p<0.01 and ***p<0.001 are Turkey post-hoc tests following two way ANOVA for TG, DAG or each DAG species.</p