RECOVER identifies synergistic drug combinations in vitro through sequential model optimization.

For large libraries of small molecules, exhaustive combinatorial chemical screens become infeasible to perform when considering a range of disease models, assay conditions, and dose ranges. Deep learning models have achieved state-of-the-art results in silico for the prediction of synergy scores. However, databases of drug combinations are biased toward synergistic agents and results do not generalize out of distribution. During 5 rounds of experimentation, we employ sequential model optimization with a deep learning model to select drug combinations increasingly enriched for synergism and active against a cancer cell line-evaluating only ∼5% of the total search space. Moreover, we find that learned drug embeddings (using structural information) begin to reflect biological mechanisms. In silico benchmarking suggests search queries are ∼5-10× enriched for highly synergistic drug combinations by using sequential rounds of evaluation when compared with random selection or ∼3× when using a pretrained model.

Changes in Intrapersonal Factors of Participants in the Pregnancy Remote Monitoring Study Who Are at Risk for Pregnancy-Induced Hypertension: Descriptive Quantitative Study.

BACKGROUND: The peripartum period, defined as the period from the beginning of the gestation until 1 year after the delivery, has long been shown to be potentially associated with increased levels of stress and anxiety with regard to one's transition to the status of parent and the accompanying parental tasks. Yet, no research to date has investigated changes in intrapersonal factors during the peripartum period in women at risk for pregnancy-induced hypertension (PIH). OBJECTIVE: The aim of this study is to explore and describe changes in intrapersonal factors in participants at risk for PIH. METHODS: We used an explorative design in which 3 questionnaires were sent by email to 110 participants the day following enrollment in the Pregnancy Remote Monitoring program for pregnant women at risk for PIH. Women were invited to complete the questionnaires at the beginning of their participation in the Pregnancy Remote Monitoring project (mostly at 14 weeks of gestation) and after approaching 32 weeks of gestational age (GA). The Generalized Anxiety Disorder-7 Scale (GAD-7) and the Patient Health Questionnaire-9 were used to assess anxiety and depression, and adaptation of the Pain Catastrophizing Scale was used to measure trait pain catastrophizing. RESULTS: Scores were significantly higher at 32 weeks of GA than at the moment of enrollment (GAD-7 score=7, range 4-11 vs 5, range 3-8; P=.01; and Patient Health Questionnaire-9 score=6, range 4-10 vs 4, range 2-7; P<.001). The subscale scores of the Pain Catastrophizing Scale were all lower at 32 weeks of GA compared with 14 weeks of GA (rumination: 4, range 1-6 vs 5, range 2-9.5; P=.11; magnification: 3, range 1-5.5 vs 4, range 3-7; P=.04; and helplessness: 5, range 2-9 vs 6, range 3.5-12; P=.06). The proportion of women with a risk for depression (GAD-7 score >10) was 13.3% (10/75) at enrollment and had increased to 35.6% (26/75) at 32 weeks of GA. CONCLUSIONS: This study shows that pregnant women at risk for PIH have higher levels of stress and anxiety at 32 weeks of GA than at the moment of enrollment. Further research is recommended to investigate potential strategies to help pregnant women at risk for PIH manage feelings of stress and anxiety. TRIAL REGISTRATION: ClinicalTrials.gov NCT03246737; https://clinicaltrials.gov/study/NCT03246737.

Synthesis and biological evaluation of novel FiVe1 derivatives as potent and selective agents for the treatment of mesenchymal cancers.

Epithelial-mesenchymal transition (EMT) endows stem cell-like properties to cancer cells. Targeting this process represents a potential therapeutic approach to overcome cancer metastasis and chemotherapy resistance. FiVe1 was identified from an EMT-based synthetic lethality screen and was found to inhibit the stem cell-like properties and proliferation of not only cancer cells undergoing EMT, but also more broadly in mesenchymal cancers that include therapeutically intractable soft tissue sarcomas. FiVe1 functions by directly binding to the type III intermediate filament protein vimentin (VIM) in a mode that induces hyperphosphorylation of Ser56, which results in selective disruption of mitosis and induced multinucleation in transformed VIM-expressing mesenchymal cancer cell types. Cell-based potency (IC50 = 1.6 µM, HT-1080 fibrosarcoma), poor solubility (<1 µM) and low oral bioavailability limits the direct application of FiVe1 as an in vivo probe or therapeutic agent. To overcome these drawbacks, we performed structure-activity relationship (SAR) studies and synthesized a set of 35 new compounds, consisting of diverse modifications of the FiVe1 scaffold. Among these compounds, 4e showed a marked improvement in potency (IC50 = 44 nM, 35-fold improvement, HT-1080) and cell type selectivity (19-fold improvement), when compared to FiVe1. Improvements in the potency of 4e, in terms of overall cytotoxicity, directly correlate with VIM Ser56 phosphorylation status and the oral bioavailability and pharmacokinetic profiles of 4e in mouse are superior to FiVe1. Successful optimization also resulted in potent and selective derivatives 11a, 11j and 11k, which exhibited superior pharmacological profiles, in terms of metabolic stability and aqueous solubility. Collectively, these optimization efforts have resulted in the development of promising FiVe1 analogs with potential applications in the treatment of mesenchymal cancers, as well as in the study of VIM-related biology.

Forearm vascular resistance responses to the Valsalva maneuver in healthy young and older adults.

PURPOSE: Effective end-organ peripheral vascular resistance responses are critical to blood pressure control while upright, and prevention of syncope (fainting). The Valsalva maneuver (VM) induces blood pressure decreases that evoke baroreflex-mediated vasoconstriction. We characterized beat-to-beat forearm vascular resistance (FVR) responses to the VM in healthy adults, evaluated the impact of age and sex on these responses, and investigated their association with orthostatic tolerance (OT; susceptibility to syncope). We hypothesized that individuals with smaller FVR responses would be more susceptible to syncope. METHODS: Healthy young (N = 36; 19 women; age 25.4 ± 4.6 years) and older (N = 21; 12 women; age 62.4 ± 9.6 years) adults performed a supine 40 mmHg, 20 s VM. Graded 60° head-up-tilt with combined lower body negative pressure continued to presyncope was used to determine OT. Non-invasive beat-to-beat blood pressure and heart rate (finger plethysmography) were recorded continuously. FVR was calculated as mean arterial pressure (MAP) divided by brachial blood flow velocity (Doppler ultrasound) relative to baseline. RESULTS: The VM produces a distinctive FVR pattern that peaks (+137.1 ± 11.6%) in phase 2B (17.5 ± 0.3 s) as the baroreflex responds to low-pressure perturbations. This response increased with age overall (p < 0.001) and within male (p = 0.030) and female subgroups (p < 0.001). Maximum FVR during the VM was significantly correlated with maximal tilt FVR (r = 0.364; p = 0.0153) and with OT when expressed relative to the MAP decrease in phase 2A (Max FVR (%)/MAP2A-1; r = 0.337; p = 0.0206). CONCLUSION: This is the first characterization of FVR responses to the VM. The VM elicits large baroreflex-mediated increases in FVR; small FVR responses to the VM may indicate susceptibility to syncope.

Assessing reflective functioning in prospective adoptive parents.

The capacity for reflective functioning (RF) or mentalizing of adoptive parents is hypothesized to play an important role in fostering socio-emotional development in adopted children. This paper reports on the development and preliminary validation of the Adoption Expectations Interview (AEI), a semi-structured interview to assess RF in prospective adoptive parents. The AEI was developed based on the Pregnancy Interview, Parent Development Interview, and Working Model of the Child Interview, three interviews that have been used to assess RF in biological parents, to capture RF before child arrival in prospective adoptive parents. In a sample of 96 prospective adoptive parents, the Reflective Functioning Scale, as applied to the AEI (AEI-RFS) showed good reliability, with strong correlations between the different demand items, high internal consistency, and good to excellent inter-rater reliability. A principal component analysis yielded one component, suggesting that the items measured a unidimensional factor. Preliminary evidence for the construct validity of the AEI-RFS was demonstrated by significant associations between the AEI-RFS and well-validated measures of mentalizing, attachment dimensions, and interpersonal functioning.

Relationship Between Adherence to Remote Monitoring and Patient Characteristics: Observational Study in Women With Pregnancy-Induced Hypertension.

BACKGROUND: Pregnancy-induced hypertension (PIH) is associated with high levels of morbidity and mortality in mothers, fetuses, and newborns. New technologies, such as remote monitoring (RM), were introduced in 2015 into the care of patients at risk of PIH in Ziekenhuis Oost-Limburg (Genk, Belgium) to improve both maternal and neonatal outcomes. In developing new strategies for obstetric care in pregnant women, including RM, it is important to understand the psychosocial characteristics associated with adherence to RM to optimize care. OBJECTIVE: The aim of this study was to explore the role of patients' psychosocial characteristics (severity of depression or anxiety, cognitive factors, attachment styles, and personality traits) in their adherence to RM. METHODS: Questionnaires were sent by email to 108 mothers the day after they entered an RM program for pregnant women at risk of PIH. The Generalized Anxiety Disorder Assessment-7 and Patient Health Questionnaire-9 (PHQ-9) were used to assess anxiety and the severity of depression, respectively; an adaptation of the Pain Catastrophizing Scale was used to assess cognitive factors; and attachment and personality were measured with the Experiences in Close Relationships-Revised Scale (ECR-R), the Depressive Experiences Questionnaire, and the Multidimensional Perfectionism Scale, respectively. RESULTS: The moderate adherence group showed significantly higher levels of anxiety and depression, negative cognitions, and insecure attachment styles, especially compared with the over adherence group. The low adherence group scored significantly higher than the other groups on other-oriented perfectionism. There were no significant differences between the good and over adherence groups. Single linear regression showed that the answers on the PHQ-9 and ECR-R questionnaires were significantly related to the adherence rate. CONCLUSIONS: This study demonstrates the relationships between adherence to RM and patient characteristics in women at risk of PIH. Alertness toward the group of women who show less than optimal adherence is essential. These findings call for further research on the management of PIH and the importance of individual tailoring of RM in this patient group. TRIAL REGISTRATION: ClinicalTrials.gov NCT03509272; https://clinicaltrials.gov/ct2/show/NCT03509272.

Making Sense of Adopted Children's Internal Reality Using Narrative Story Stem Techniques: A Mixed-Methods Synthesis.

Background: Extant research on adopted children has consistently shown that early adverse experiences confer vulnerability to myriad developmental problems, which may be mitigated by the "natural intervention" of adoption itself and/or by treatment efforts. Narrative Story Stems Techniques (NSSTs) have been used in research and clinical practice to assess adopted children's developmental profiles in middle childhood. However, no study to date has systematically reviewed this body of literature. Objectives: This paper presents a systematic review of research using NSSTs to make sense of adopted children's internal reality (i.e., perceptions, experiences, and representations), in terms of exploring theoretical perspectives as well as critically synthesizing findings and discussing implications. Methods: State-of-the-art PRISMA guidelines were followed throughout, resulting in the identification of 18 records, comprising six qualitative, 10 quantitative, and two mixed-methods primary papers, reporting on seven unique studies. All records were assessed with regard to methodological quality. Data were extracted and synthesized narratively using an integrated design for mixed-methods synthesis. Results: The findings suggest that, although NSST research with adopted children is still in its infancy, there is relatively robust evidence supporting the use of these techniques to assess and track developmental change in adopted children's attachment representations. In this regard, the non-verbal (aside from the verbal) approach to children's complex internal reality, as well as a more fine-grained (aside from a categorical or dimensional) perspective on children's NSST responses, are highlighted as particularly valuable in tailoring treatment to a particular child's needs and vulnerabilities. Moreover, several promising avenues for future research and clinical application of NSSTs, including the extension to affect-regulatory and mentalizing perspectives, may further our knowledge and understanding of, and thus treatment efforts toward, these often vulnerable children. However, these findings should be interpreted with caution, due to the limited number of studies characterized by considerable methodological heterogeneity. Conclusions: In light of the findings of the present review, we strongly advocate future studies using NSSTs in theoretically and empirically consistent ways, in order to gain a better understanding of adopted children's internal reality in terms of attachment representations, affect-regulatory strategies, and mentalizing processes, and to track changes therein.

Hospitalization-based treatment for postpartum depressed mothers and their babies: rationale, principles, and preliminary follow-up data.

This paper describes the rationale and treatment principles of a mother-infant unit for severely depressed mothers and their infants in Flanders (Belgium). The unit integrates systemic, psychodynamic, and cognitive behavioral treatment approaches, and aims at improvements on three levels: (1) improving mood and interpersonal relationships in depressed mothers, (2) fostering a positive mother infant relationship, and (3) establishing a supportive environment outside the treatment setting for both mother and infant. In addition, we present preliminary data of a 3.5-year naturalistic follow-up study of postpartum depressed mothers (n = 41) admitted at this mother-infant unit between April 2003 and April 2005. Results showed that at 3.5-year follow-up a considerable subgroup of mothers (61%) were functioning relatively well, as indicated by low levels of depressive symptoms, anxiety and anger, negative affect, and relatively high levels of positive affect. Yet, in line with other studies, a relatively large subgroup of mothers (39%) continued to suffer from (severe) depression during follow-up. Using a Life History Calendar method, it was found that, compared to currently nondepressed mothers, mothers who were depressed at follow-up did not have more depressive episodes but had longer depressive episodes, received more psychotherapy after hospitalization, and experienced more negative life events during the 3.5-year follow-up period. Implications of these findings for future research and intervention strategies in postpartum depression are discussed.

Stability and change in levels of depression and personality: a follow-up study of postpartum depressed mothers that were hospitalized in a mother-infant unit.

This prospective longitudinal study investigated the role of the personality dimensions of dependency and self-criticism in the course of depressive symptoms in a sample of inpatient severely postpartum depressed mothers (n = 55). Depressive symptoms and personality were measured during hospitalization and on average 3 1/2 years later. In line with previous research, a considerable subgroup of mothers (39%) reported moderate to severe symptoms of depression at time 2. In addition, although these mothers did not exhibit more depressive episodes during follow-up period compared with mothers with a less chronic course of depression, their depressive episodes were considerably longer, and they had higher levels of severity of depression as well as of dependency and self-criticism at Time 1. Finally, self-criticism, but not dependency, assessed at Time 1, predicted both depression diagnosis and levels of depression at follow-up, supporting a vulnerability model positing that self-criticism confers vulnerability for depression over time.