Maternal Inflammation at Mid-gestation in Pregnant Rats Impairs Fetal Muscle Growth and Development at Term

Intrauterine growth restriction (IUGR) is a leading cause of perinatal morbidity and mortality. Low birth weight resulting from preterm birth and/or IUGR is an underlying factor in 60–80% of perinatal death worldwide, and is particularly common in developing countries (UNICEF, 2008). Furthermore, studies have linked IUGR and the associated fetal malnutrition to increased incidence of metabolic syndrome in adult life (Barker et al., 1993; Godfrey and Barker, 2000). The “thrifty phenotype hypothesis” developed by David Barker (Hales et al., 1991) states that IUGR-associated fetal malnutrition forces the fetus to spare nutrients by altering tissue-specific metabolism in order to survive. In utero, adaptive changes disproportionately impact skeletal muscle development, growth, and metabolism (Yates et al., 2016). Skeletal muscle is responsible for the majority of insulin-stimulated glucose utilization, and adaptive restriction in muscle growth capacity helps to spare glucose in the IUGR fetus but result in lifelong deficits in muscle mass and metabolic homeostasis (Brown and Hay, 2016). Skeletal muscle growth requires proliferation, differentiation, and fusion of myoblast into new muscle fibers early in gestation and fusion with existing fibers in the third trimester of pregnancy (Zhu et al., 2004). This process can be impaired by inflammation from resident macrophages within skeletal muscle. Classically activated M1 macrophages are pro-inflammatory but can polarize to an anti-inflammatory M2 phenotype that inhibits cytokine production and stimulates tissue repair by producing growth factors (Mantovani et al., 2004; Kharraz et al., 2013). The acute effects of inflammatory factors on myoblast function have been investigated in vitro (Frost et al., 1997; Guttridge et al., 2000), and we postulate that inflammatory stress may have similar effects on fetal myoblasts in utero. Impaired myoblast function and the resulting decrease in muscle growth capacity affect long-term metabolic health. Therefore, the objective of this study was to determine the effect of sustained maternal inflammation at mid-gestation on fetal mortality, muscle growth, and metabolic parameters at term

Oral Treprostinil is Associated with Improved Survival in FREEDOM-EV and its Open-Label Extension

\ua9 2023, The Author(s).Introduction: In the event-driven FREEDOM-EV trial, oral treprostinil delayed clinical worsening in patients with pulmonary arterial hypertension (PAH). Open-label extension studies offer additional data about tolerability, efficacy, and survival, especially for those initially assigned placebo. The aim of the current study was to determine if oral treprostinil changed survival when considering the parent and extension study, if treprostinil provides functional benefits for participants initially assigned to placebo, and if the benefits observed for those treated with treprostinil were durable. Methods: Both active and placebo participants from FREEDOM-EV could enroll in the FREEDOM-EV open-label extension (OLE) study after experiencing an investigator-assessed clinical worsening event or after parent study closure. All participants in the OLE were offered open-label oral treprostinil. Previously assigned placebo participants titrated to maximally tolerated doses; previously assigned treprostinil participants continued dose titration. We repeated assessments including functional class and 6-min walk distance (6MWD) at 12-week intervals and measured N-terminal pro-brain natriuretic peptide (NT-proBNP) at week 48. Survival was estimated by Kaplan–Meier analysis, and we estimated hazard ratio (HR) using Cox proportional hazards. Results: Of 690 FREEDOM-EV participants, 470 enrolled in the OLE; vital status was available for 89% of initial Freedom-EV participants. When considering the combined parent and open-label data, initial assignment to oral treprostinil reduced mortality (HR 0.64, 95% confidence interval 0.46–0.91, p = 0.013); absolute risk reduction was 9%. Participants randomized to placebo who initiated oral treprostinil after clinical worsening and tolerated treatment through week 48 demonstrated favorable shifts in functional class (p < 0.0001), 6MWD improvements of + 84 m (p < 0.0001), and a reduction in NT-proBNP of − 778 pg/mL (p = 0.02), compared to OLE baseline. Modest trends toward benefit were measured for those initially assigned placebo who did not have clinical worsening, and 132/144 (92%) of treprostinil assigned participants without clinical worsening remained on drug at week 48 in the OLE study. Adverse events were consistent with FREEDOM-EV. Conclusion: Initial treprostinil assignment improved survival in the entire data set; those who began treprostinil after a clinical worsening in the placebo arm and tolerated drug to week 48 enjoyed substantial functional gains. Clinical Trial Registration: ClinicalTrials.gov identifier NCT01560637

Combination therapy with oral treprostinil for pulmonary arterial hypertension. A double-blind placebo-controlled clinical trial

Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown. Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy. Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response. Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56–0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro–brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil–assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12–60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting. Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening. Clinical trial registered with www.clinicaltrials.gov (NCT01560624)

Maternal Inflammation at Mid-gestation in Pregnant Rats Impairs Fetal Muscle Growth and Development at Term

Intrauterine growth restriction (IUGR) is a leading cause of perinatal morbidity and mortality. Low birth weight resulting from preterm birth and/or IUGR is an underlying factor in 60–80% of perinatal death worldwide, and is particularly common in developing countries (UNICEF, 2008). Furthermore, studies have linked IUGR and the associated fetal malnutrition to increased incidence of metabolic syndrome in adult life (Barker et al., 1993; Godfrey and Barker, 2000). The “thrifty phenotype hypothesis” developed by David Barker (Hales et al., 1991) states that IUGR-associated fetal malnutrition forces the fetus to spare nutrients by altering tissue-specific metabolism in order to survive. In utero, adaptive changes disproportionately impact skeletal muscle development, growth, and metabolism (Yates et al., 2016). Skeletal muscle is responsible for the majority of insulin-stimulated glucose utilization, and adaptive restriction in muscle growth capacity helps to spare glucose in the IUGR fetus but result in lifelong deficits in muscle mass and metabolic homeostasis (Brown and Hay, 2016). Skeletal muscle growth requires proliferation, differentiation, and fusion of myoblast into new muscle fibers early in gestation and fusion with existing fibers in the third trimester of pregnancy (Zhu et al., 2004). This process can be impaired by inflammation from resident macrophages within skeletal muscle. Classically activated M1 macrophages are pro-inflammatory but can polarize to an anti-inflammatory M2 phenotype that inhibits cytokine production and stimulates tissue repair by producing growth factors (Mantovani et al., 2004; Kharraz et al., 2013). The acute effects of inflammatory factors on myoblast function have been investigated in vitro (Frost et al., 1997; Guttridge et al., 2000), and we postulate that inflammatory stress may have similar effects on fetal myoblasts in utero. Impaired myoblast function and the resulting decrease in muscle growth capacity affect long-term metabolic health. Therefore, the objective of this study was to determine the effect of sustained maternal inflammation at mid-gestation on fetal mortality, muscle growth, and metabolic parameters at term

Using Technology to Foster Peer Mentoring Relationships: Development of a Virtual Peer Mentorship Model for Broadening Participation of Underrepresented Racial and Ethnic Minority Women in STEM

In this chapter, the authors give an overview of the research literature that provides the impetus for the conceptualization, development, and implementation of a virtual peer mentorship model to support women in developing interest in science, technology, engineering, and mathematics (STEM), intent to persist in STEM, and self-efficacy in STEM. While the benefits of peer mentorship are cited widely within the research literature, few studies have focused on the virtual peer mentors programs, inclusive of training for mentors. Given the persistent disparity in equitable representation of women and minorities in STEM fields, this project focused on training underrepresented racial and ethnic minority women to serve as mentors as part of a larger National Science Foundation funded peer mentorship project