Gene signature discovery and systematic validation across diverse clinical cohorts for TB prognosis and response to treatment.

While blood gene signatures have shown promise in tuberculosis (TB) diagnosis and treatment monitoring, most signatures derived from a single cohort may be insufficient to capture TB heterogeneity in populations and individuals. Here we report a new generalized approach combining a network-based meta-analysis with machine-learning modeling to leverage the power of heterogeneity among studies. The transcriptome datasets from 57 studies (37 TB and 20 viral infections) across demographics and TB disease states were used for gene signature discovery and model training and validation. The network-based meta-analysis identified a common 45-gene signature specific to active TB disease across studies. Two optimized random forest regression models, using the full or partial 45-gene signature, were then established to model the continuum from Mycobacterium tuberculosis infection to disease and treatment response. In model validation, using pooled multi-cohort datasets to mimic the real-world setting, the model provides robust predictive performance for incipient to active TB risk over a 2.5-year period with an AUROC of 0.85, 74.2% sensitivity, and 78.3% specificity, which approximates the minimum criteria (>75% sensitivity and >75% specificity) within the WHO target product profile for prediction of progression to TB. Moreover, the model strongly discriminates active TB from viral infection (AUROC 0.93, 95% CI 0.91-0.94). For treatment monitoring, the TB scores generated by the model statistically correlate with treatment responses over time and were predictive, even before treatment initiation, of standard treatment clinical outcomes. We demonstrate an end-to-end gene signature model development scheme that considers heterogeneity for TB risk estimation and treatment monitoring.

Expectant fathers' intuitive parenting: associations with parent characteristics and postpartum positive engagement.

This study examined expectant fathers' intuitive parenting behavior and its correlates and associations with fathers' postpartum positive engagement. One hundred eighty-two expectant couples completed the Prenatal Lausanne Trilogue Play in the third trimester of pregnancy. Coders rated expectant fathers' and mothers' intuitive parenting behavior during this procedure. Expectant parents also completed surveys regarding their psychological and demographic characteristics. At 3 months postpartum, fathers completed time diaries that assessed the time that they spent in developmentally appropriate, positive engagement activities with their infants. Examination of correlates of expectant fathers' intuitive parenting behavior revealed that expectant fathers showed lower levels of these behaviors than did expectant mothers, that intuitive parenting behavior was moderately positively associated for mothers and fathers, and that individual differences in expectant fathers' intuitive parenting behavior were associated with parent demographic and psychological characteristics. In particular, expectant fathers showed greater intuitive parenting behavior when they had greater human capital and more progressive beliefs about parent roles, and when their partners had lower parenting self-efficacy. Findings also indicated that expectant fathers' greater intuitive parenting behavior was predictive of fathers' greater subsequent engagement in developmentally appropriate activities at 3 months postpartum, but only when expectant mothers demonstrated low levels of intuitive parenting behavior.

Both T cell priming in lymph node and CXCR3-dependent migration are the key events for predicting the response of atezolizumab.

Anti-PD-L1 antibodies benefit many cancer patients, even those with "non-inflamed tumor". Determining which patients will benefit remains an important clinical goal. In a non-inflamed tumor mouse model, we found that PD-L1 was highly expressed on antigen-presenting cells (APCs) especially on CD103+ CD11c+ dendritic cells in tumor-draining lymph nodes (dLNs), suppressing T-cell priming by APCs. In this model, anti-PD-L1 antibodies enhanced T-cell priming and increased CXCR3+ activated T-cells in dLNs, which was followed by the trafficking of T-cells to tumors in response to CXCR3 ligands. As predictive biomarker, each APCs-related gene expression (AP score) alone or T-cells trafficking-related chemokine gene expression (T score) alone were still less than perfect among the 17 mouse models examined. However a combining score of AP score and T score (AP/T score) precisely identified anti-PD-L1-sensitive tumors. In the phase 3 trial of atezolizumab vs docetaxel in advanced NSCLC patients (OAK), the AP/T score could identify atezolizumab-treated NSCLC patients who achieved significant improvement in overall survival. This biomarker concept would be a clinically valuable for prediction of anti-PD-L1 antibody efficacy.

Molecular determinants of response to PD-L1 blockade across tumor types.

Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis lead to durable clinical responses in subsets of cancer patients across multiple indications, including non-small cell lung cancer (NSCLC), urothelial carcinoma (UC) and renal cell carcinoma (RCC). Herein, we complement PD-L1 immunohistochemistry (IHC) and tumor mutation burden (TMB) with RNA-seq in 366 patients to identify unifying and indication-specific molecular profiles that can predict response to checkpoint blockade across these tumor types. Multiple machine learning approaches failed to identify a baseline transcriptional signature highly predictive of response across these indications. Signatures described previously for immune checkpoint inhibitors also failed to validate. At the pathway level, significant heterogeneity is observed between indications, in particular within the PD-L1+ tumors. mUC and NSCLC are molecularly aligned, with cell cycle and DNA damage repair genes associated with response in PD-L1- tumors. At the gene level, the CDK4/6 inhibitor CDKN2A is identified as a significant transcriptional correlate of response, highlighting the association of non-immune pathways to the outcome of checkpoint blockade. This cross-indication analysis reveals molecular heterogeneity between mUC, NSCLC and RCC tumors, suggesting that indication-specific molecular approaches should be prioritized to formulate treatment strategies.

Who are the Gatekeepers? Predictors of Maternal Gatekeeping.

OBJECTIVE: The goal of this study was to identify determinants of maternal gatekeeping at the transition to parenthood. DESIGN: Participants included 182 different-gender dual-earner couples. During pregnancy, expectant parents completed questionnaires regarding their psychological functioning, attitudes, and expectations, and at 3 months postpartum questionnaires regarding maternal gatekeeping behavior and gate closing attitudes. RESULTS: SEM analyses revealed that mothers were more likely to close the gate to fathers when mothers held greater perfectionistic expectations for fathers' parenting, had poorer psychological functioning, perceived their romantic relationship as less stable, and had higher levels of parenting self-efficacy. In contrast, fathers with lower parenting self-efficacy appeared to elicit greater maternal gate closing behavior. Mothers who engaged in greater gate opening behavior were more religious. CONCLUSIONS: Maternal gatekeeping may be more strongly associated with maternal expectations and psychological functioning than with maternal traditional gender attitudes. Fathers' characteristics are less predictive of maternal gatekeeping than mothers' characteristics.

Associations between prenatal coparenting behavior and observed coparenting behavior at 9-months postpartum.

Coparenting, or the ways partners relate to each other in their roles as parents, is important to child and family functioning. However, it remains unclear whether coparenting begins at or prior to a child's birth. This study tested whether expectant parents' behavior in the Prenatal Lausanne Trilogue Play procedure (PLTP), an assessment designed in Switzerland for examining prebirth coparenting behavior, forecasted postnatal observations of coparenting behavior in a sample of first-time parents in the United States. Participants were 182 dual-earner couples expecting their first child. Couples completed the PLTP in the third trimester of pregnancy and observations of coparenting behavior at 9-months postpartum. Structural equation modeling analyses indicated significant continuity between expectant parents' prenatal coparenting behavior and their observed postpartum coparenting behavior 1 year later. In particular, couples who engaged in higher quality prenatal coparenting behavior demonstrated more supportive and less undermining coparenting behavior at 9-months postpartum, even after controlling for observed prenatal couple behavior and self-reported couple relationship functioning. Thus, this study demonstrated the validity and utility of the PLTP as a window into the development of coparenting, and supported the notion that the coparenting relationship develops prior to the child's birth and is already distinct from the couple relationship.

Comparisons of levels and predictors of mothers' and fathers' engagement with their preschool aged children.

Self-report data from 112 two-parent families were used to compare levels and predictors of four types of mothers' and fathers' engagement with their preschool aged children: socialization, didactic, caregiving, and physical play. Mothers were more involved than fathers in socialization, didactic, and caregiving, whereas fathers were more involved than mothers in physical play. Mothers' greatest engagement was in caregiving, whereas fathers were about equally engaged in didactic, caregiving, and physical play. Mothers who contributed more to family income were less engaged in socialization and caregiving, whereas fathers with nontraditional beliefs about their roles were more engaged in didactic and caregiving. Children with greater temperamental effortful control received more didactic and physical play engagement from mothers. Fathers were more likely to engage in socialization activities with earlier-born children, whereas mothers were more likely to engage in socialization with girls high in effortful control. Mothers were more likely to engage in physical play with boys and with later-born children.

Heat production by 3 implant drill systems after repeated drilling and sterilization.

PURPOSE: The goal was to measure heat generated in bone by 3 implant drill systems after repeated drilling and sterilization. MATERIALS AND METHODS: Temperature was measured with thermocouple technology in vitro using the bovine femoral cortical bone model. Intermittent drilling was accomplished at a constant 2.4-kg load and drill speed of 2,500 rpm. External irrigation at 40 mL/min with normal saline was used. Three implant drill systems-system A (triple twist drills with a relief angle), system B (triple twist drills without a relief angle), and system C (double twist drills with a relief angle)-were evaluated and heat was measured at the final drill in the drilling sequence (4.0 mm or 4.2 mm) at a depth of 15 mm. Thermocouples were placed 0.5 mm from the osteotomy at a depth of 15 mm. Heat measurements were recorded out to 25 uses. RESULTS: Results showed temperature increased with multiple uses. System A and C drills had temperature measurements that were below 47 degrees C, even after 25 uses. System B drills had temperatures that exceeded 47 degrees C from the initial use. Light microscopy showed little drill wear even after 25 uses. CONCLUSIONS: Drill geometry plays a major role in heat production and may explain the increased temperature readings seen in system B. These drills lack relief angles and have the smallest clearance angles of the 3 systems. It also has fewer drills in its drilling sequence compared with systems A and C. This study shows that temperatures increase when drills are used multiple times. Systems A and C had acceptable temperature measurements out to 25 uses. System B drills showed significantly higher heat production with little visual signs of wear.