Teratogenicity is more likely a function of primary and secondary pharmacology than caused by chemically reactive metabolites: a critical evaluation of 40 years of scientific research.

The number of therapeutic drugs known to be human teratogens is actually relatively small. This may reflect the rigorous animal testing and well defined labelling. Some of these drugs were identified to have reactive metabolites and this has been postulated, historically, to be their teratogenic mechanism. These drugs include thalidomide, various anticonvulsants and retinoic acid derivatives.Many of these experiments were conducted in a period where chemically reactive metabolites were being intensely investigated and associated with all forms of toxicity. The legacy of this is that these examples are routinely cited as well established mechanisms.Examination of mechanism leads to the conclusion that the teratogenicity in humans of these compounds is likely due to the primary and secondary pharmacology of the parent drug and stable circulating metabolites and that association of reactive metabolites to this toxicity is unwarranted.

Development of Potent Mcl-1 Inhibitors: Structural Investigations on Macrocycles Originating from a DNA-Encoded Chemical Library Screen.

Evasion of apoptosis is critical for the development and growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family, associated with tumor aggressiveness, poor survival, and drug resistance. Development of Mcl-1 inhibitors implies blocking of protein-protein interactions, generally requiring a lengthy optimization process of large, complex molecules. Herein, we describe the use of DNA-encoded chemical library synthesis and screening to directly generate complex, yet conformationally privileged macrocyclic hits that serve as Mcl-1 inhibitors. By applying a conceptual combination of conformational analysis and structure-based design in combination with a robust synthetic platform allowing rapid analoging, we optimized in vitro potency of a lead series into the low nanomolar regime. Additionally, we demonstrate fine-tuning of the physicochemical properties of the macrocyclic compounds, resulting in the identification of lead candidates 57/59 with a balanced profile, which are suitable for future development toward therapeutic use.

Risk Factors for Severe Maternal Morbidity Among Women Enrolled in Mississippi Medicaid.

Importance: Mississippi has one of the highest rates of severe maternal morbidity (SMM) in the US, and SMMs have been reported to be more frequent among Medicaid-insured women. A substantial proportion of pregnant women in Mississippi are covered by Medicaid; hence, there is a need to identify potential risk factors for SMM in this population. Objective: To examine the associations of health care access and clinical and sociodemographic characteristics with SMM events among Mississippi Medicaid-enrolled women who had a live birth. Design, Setting, and Participants: A nested case-control study was conducted using 2018 to 2021 Mississippi Medicaid administrative claims database. The study included Medicaid beneficiaries aged 12 to 55 years who had a live birth and were continuously enrolled throughout their pregnancy period and 12 months after delivery. Individuals in the case group had SMM events and were matched to controls on their delivery date using incidence density sampling. Data analysis was performed from June to September 2022. Exposure: Risk factors examined in the study included sociodemographic factors (age and race), health care access (distance from delivery center, social vulnerability index, and level of maternity care), and clinical factors (maternal comorbidity index, first-trimester pregnancy-related visits, and postpartum care). Main Outcomes and Measures: The main outcome of the study was an SMM event. Adjusted odds ratio (aORs) and 95% CIs were calculated using conditional logistic regression. Results: Among 13 485 Mississippi Medicaid-enrolled women (mean [SD] age, 25.0 [5.6] years; 8601 [63.8%] Black; 4419 [32.8%] White; 465 [3.4%] other race [American Indian, Asian, Hispanic, multiracial, and unknown]) who had a live birth, 410 (3.0%) were in the case group (mean [SD] age, 26.8 [6.4] years; 289 [70.5%] Black; 112 [27.3%] White; 9 [2.2%] other race) and 820 were in the matched control group (mean [SD] age, 24.9 [5.7] years; 518 [63.2%] Black; 282 [34.4%] White; 20 [2.4%] other race). Black individuals (aOR, 1.44; 95% CI, 1.08-1.93) and those with higher maternal comorbidity index (aOR, 1.27; 95% CI, 1.16-1.40) had higher odds of experiencing SMM compared with White individuals and those with lower maternal comorbidity index, respectively. Likewise, an increase of 100 miles (160 km) in distance between beneficiaries' residence to the delivery center was associated with higher odds of experiencing SMM (aOR, 1.14; 95% CI, 1.07-1.20). Conclusions and Relevance: The study findings hold substantial implications for identifying high-risk individuals within Medicaid programs and call for the development of targeted multicomponent, multilevel interventions for improving maternal health outcomes in this highly vulnerable population.

Effect of exercise dosages on adiposity indices in overweight girls / Efecto de programas de ejercicio en los índices de adiposidad en niñas con sobrepeso

Objective. The primary purpose of this study was to determine the impact of two exercise dosages on reducing adiposity in minority girls. Materials and methods. Sixty-two overweight Hispanic and African-American girls participated in one of two intense summer interventions in Houston, TX: Intervention A (exposure to about 40 hours physical activities) or Intervention B (exposure to 60 hours of physical activities). Adiposity indices (percent body fat, waist circumference, body mass index) were taken pre- and post-intervention. Results. Intervention B had a significantly greater decrease in adiposity indicators (p= 0.006) when compared to Intervention A. Waist circumference displayed the most significant decrease (p = 0.001). Both interventions significantly increased daily minutes of moderate-to-vigorous physical activity (p= 0.020). Conclusions. Intense physical activity interventions may effectively reduce abdominal fat in minority girls.

Objetivo. Determinar el impacto de dos programas de ejercicio en la reducción de los índices de adiposidad en niñas de grupos minoritarios. Material y métodos. Sesenta y dos niñas latinas y africano-americanas participaron en una de dos intervenciones intensivas durante el verano: la intervención A (exposición a aproximadamente 40 horas de actividad física) o la intervención B (exposición a 60 horas de actividad física) en Houston, TX. Los indicadores de adiposidad (índice de masa corporal, porcentaje de grasa corporal y grasa abdominal) se midieron antes y después de cada intervención. Resultados. La intervención B tuvo una disminución más significativa en el nivel de adiposidad (p=0.006) comparado con la intervención A. La circunferencia abdominal fue la que más disminuyó (p=0.001). Ambas intervenciones aumentaron significativamente la actividad física moderada a intensa (p=0.020). Conclusiones. Las intervenciones cortas e intensas pueden ser efectivas en la reducción de la grasa abdominal en niñas de grupos minoritarios.