Efficacy, safety, Low density lipoprotein cholesterol lowering, and calculated 10-year cardiovascular risk reduction of alirocumab and evolocumab in addition to maximal tolerated cholesterol lowering therapy: a post-commercialization study.

BACKGROUND: Efficacy and safety of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, alirocumab (ALI) and evolocumab (EVO) have previously been evaluated through controlled clinical trials with selective patient groups. Post-commercially, in patients with heterozygous familial hypercholesterolemia (HeFH) and/or cardiovascular disease (CVD) with suboptimal LDL cholesterol (LDLC) lowering on maximal tolerated cholesterol lowering therapy, we assessed efficacy and safety of ALI and EVO. METHODS: Post-commercially, we started 25 patients on ALI 75 mg, 15 on ALI 150 mg, and 32 on EVO 140 mg bi-weekly added to entry LDLC lowering regimen, with follow-up for a median 24 weeks. History, physical exam, demographics, and adverse event data were collected. Changes in LDLC and AHA and NIH calculated 10-year CVD risks were assessed on ALI and EVO. RESULTS: Of 72 patients, 25 had HeFH only, 25 CVD only, 22 had both, median age was 65 years, 63% females, 38% males, 86% Caucasian, 11% African-Americans, 17% diabetics, 63% on anti-hypertensives, and 7% smokers. At entry, 30 (42%) were on a statin and 42 (58%) could not tolerate any statins. At 24-weeks, median LDLC decreased on ALI 75 mg from 117 to 62 mg/dL (-54%), on ALI 150 mg from 175 to 57 mg/dL (-63%), and on EVO 140 mg from 165 to 69 mg/dL (-63%), p <0.0001 for all. Absolute and percent LDLC reduction did not differ (p >.05) between ALI 150 and EVO 140 mg, but were less on ALI 75 mg vs ALI 150 mg and EVO 140 mg (p <.05). Percent reductions in 10-year CVD risks by AHA and NIH calculators, respectively were ALI 75 mg -22 and -44%, ALI 150 mg -31 and -50%, and EVO 140 mg -29 and -56%, p ≤.002 for all. The three most common adverse events included flu-like myositis 10%, respiratory tract symptoms 8%, and injection site reaction 6%. CONCLUSION: In patients with HeFH and/or CVD, LDLC was lowered by 63% on EVO and ALI 150 mg, and 54% on ALI 75 mg. Adverse events were minimal and tolerable. ALI and EVO represent paradigm shifts in LDLC lowering. Long term, post-commercial safety and efficacy remain to be determined.

Clinical and Imaging Findings in an Infant With Zika Embryopathy.

Recent Zika virus (ZIKV) outbreaks have been associated with an increased incidence of neonatal microcephaly. Subsequently, tropism for the brain was established in human fetal brain tissue. We present the first congenital ZIKV infection in the United States, confirmed by high ZIKV immunoglobulin M antibody titers in serum and cerebrospinal fluid. The phenotypic characteristics of the patient fall within fetal brain disruption sequence, suggesting impaired brain development in the second half of gestation. Brain imaging revealed an almost agyric brain with diffuse parenchymal calcifications, hydrocephalus ex vacuo, and cerebellar hypoplasia. Ophthalmologic examination revealed macular pigment stippling and optic nerve atrophy. Liver, lungs, heart, and bone marrow were not affected. The patient had progressive neurologic deterioration in the first month of life. The discovery of ZIKV infection in human fetal brain tissue along with serologic confirmation proves the vertical transmission of ZIKV. Therefore, ZIKV has joined the group of congenital infections.

Feasibility of a lifestyle intervention for overweight/obese endometrial and breast cancer survivors using an interactive mobile application.

OBJECTIVE: The study aimed to assess a one-month lifestyle intervention delivered via a web- and mobile-based weight-loss application (app) (LoseIt!) using a healthcare-provider interface. METHODS: Early-stage overweight/obese (body mass index [BMI]≥25kg/m(2)) cancer survivors (CS) diagnosed in the past three years, and without recurrent disease were enrolled and received exercise and nutrition counseling using the LoseIt! app. Entry and exit quality of life (FACT-G) and Weight Efficacy Lifestyle Questionnaire (WEL) measuring self-efficacy were measured along with anthropometrics, daily food intake, and physical activity (PA) using the app. RESULTS: Mean participant age was 58.4±10.3years (n=50). Significant reductions (p<0.0006) in anthropometrics were noted between pre- and post-intervention weight (105.0±21.8kg versus 98.6±22.5kg); BMI (34.9±8.7kg/m(2) versus 33.9±8.4kg/m(2)); and waist circumference (108.1±14.9cm versus 103.7±15.1cm). A significant improvement in pre- and post-intervention total WEL score was noted (99.38±41.8 versus 120.19±47.1, p=0.043). No significant differences were noted in FACT-G, macronutrient consumption, and PA patterns. CONCLUSION: These results indicate that a lifestyle intervention delivered via a web- and mobile-based weight-loss app is a feasible option by which to elicit short-term reductions in weight. Though these results parallel the recent survivors of uterine cancer empowered by exercise and healthy diet (SUCCEED) trial, it is notable that they were achieved without encumbering significant cost and barrier-access issues (i.e. time, transportation, weather, parking, etc.).

The Drosophila SERTAD protein Taranis determines lineage-specific neural progenitor proliferation patterns.

Neural progenitors of the Drosophila larval brain, called neuroblasts, can be divided into distinct populations based on patterns of proliferation and differentiation. Type I neuroblasts produce ganglion mother cells (GMCs) that divide once to produce differentiated progeny, while type II neuroblasts produce self-renewing intermediate neural progenitors (INPs) and thus generate lineages containing many more progeny. We identified Taranis (Tara) as an important determinant of type I lineage-specific neural progenitor proliferation patterns. Tara is an ortholog of mammalian SERTAD proteins that are known to regulate cell cycle progression. Tara is differentially-expressed in neural progenitors, with high levels of expression in proliferating type I neuroblasts but no detectable expression in type II lineage INPs. Tara is necessary for cell cycle reactivation in quiescent neuroblasts and for cell cycle progression in type I lineages. Cell cycle defects in tara mutant neuroblasts are due to decreased activation of the E2F1/Dp transcription factor complex and delayed progression through S-phase. Mis-expression of tara in type II lineages delays INP cell cycle progression and induces premature differentiation of INPs into GMCs. Premature INP differentiation can also be induced by loss of E2F1/Dp function and elevated E2F1/Dp expression suppresses Tara-induced INP differentiation. Our results show that lineage-specific Tara expression is necessary for proper brain development and suggest that distinct cell cycle regulatory mechanisms exist in type I versus type II neural progenitors.

Extracellular Matrix Influences Gene Expression and Differentiation of Mouse Trophoblast Stem Cells.

Trophoblast stem (TS) cells were first isolated from the mouse placenta; however, little is known about their maintenance and niche in vivo. TS cells, like other stem cells, have a unique microenvironment in which the extracellular matrix (ECM) is a component. Placental pathology is associated with ECM change. However, how these changes and the individual ECM components impact the maintenance or differentiation of TS cells has not been established. This study identified which ECM component(s) maintain the greatest expression of markers associated with undifferentiated mouse trophoblast stem (mTS) cells and which alter the profile of markers of differentiation based on mRNA analysis. mTS cells cultured on individual ECM components and subsequent quantitative polymerase chain reaction analysis revealed that laminin promoted the expression of markers associated with undifferentiated TS cells, fibronectin promoted gene expression associated with syncytiotrophoblast (SynT) layer II cells, and collagen IV promoted the expression of genes associated with differentiated trophoblast. To investigate whether pathological placental ECM influenced the expression of genes associated with different trophoblast subtypes, the mouse model of streptozotocin (STZ)-induced pancreatic ß cell ablation and diabetes was used. Female mice administered STZ (blood glucose ≥300 mg/dL) or control (blood glucose ≤150 mg/dL) were mated. Placental pathology at embryonic day (E)14.5 was confirmed with reduced fetal blood space area, reduced expression of the pericyte marker αSMA, and decreased expression of ECM proteins. mTS cells cultured on ECM isolated from STZ placenta were associated with reduced expression of undifferentiated mTS markers and increased expression of genes associated with terminally differentiated trophoblast [Gcm-1 and SynA (SynT) and junctional zone Tpbpa and Prl2c2]. Altogether, these results support the value of using ECM isolated from the placenta as a tool for understanding trophoblast contribution to placental pathology.

A modified version of the dimensional change card sort task tests cognitive flexibility in children (Homo sapiens) and cotton-top tamarins (Saguinus oedipus).

A modified Dimensional Change Card Sort (DCCS) task was used to test cognitive flexibility in adult cotton-top tamarins and children aged 19 months to 60 months. Subjects had to infer a rule from the experience of selecting between two cards to earn a reward, and the pairs of stimuli defined the rule (e.g., pick blue ones, not red ones, or pick trucks, not boats). Two different tests measured subjects' ability to shift to a reversal of the rule (intradimensional shift) and to shift to a new rule defined by a dimension previously irrelevant (interdimensional shift). Both adult tamarins and children aged 49-60 months were able to learn the initial rule and switch to a reversal and to a rule based on a different dimension. In contrast, the two younger groups of children, aged 19-36 months and aged 37-48 months, could switch when a reversal was imposed but took significantly longer to learn a new rule on a former irrelevant dimension. Experiment 2 presented a wider set of novel stimuli which shared some features with the original set to further explore the basis of rule learning. The result was that tamarins and 52- to 60-month-old children both chose novel stimuli that fit the rule and had no a priori associative strength, suggesting a rule application not solely based on associative strength. Importantly, novel items introduced some risk for choice, and children showed themselves to be risk-averse, whereas tamarins were risk-prone within a novel context. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Trophoblast-Specific Expression of Hif-1α Results in Preeclampsia-Like Symptoms and Fetal Growth Restriction.

The placenta is an essential organ that is formed during pregnancy and its proper development is critical for embryonic survival. While several animal models have been shown to exhibit some of the pathological effects present in human preeclampsia, these models often do not represent the physiological aspects that have been identified. Hypoxia-inducible factor 1 alpha (Hif-1α) is a necessary component of the cellular oxygen-sensing machinery and has been implicated as a major regulator of trophoblast differentiation. Elevated levels of Hif-1α in the human placenta have been linked to the development of pregnancy-associated disorders, such as preeclampsia and fetal growth restriction. As oxygen regulation is a critical determinant for placentogenesis, we determined the effects of constitutively active Hif-1α, specifically in trophoblasts, on mouse placental development in vivo. Our research indicates that prolonged expression of trophoblast-specific Hif-1α leads to a significant decrease in fetal birth weight. In addition, we noted significant physiological alterations in placental differentiation that included reduced branching morphogenesis, alterations in maternal and fetal blood spaces, and failure to remodel the maternal spiral arteries. These placental alterations resulted in subsequent maternal hypertension with parturitional resolution and maternal kidney glomeruloendotheliosis with accompanying proteinuria, classic hallmarks of preeclampsia. Our findings identify Hif-1α as a critical molecular mediator of placental development and indicate that prolonged expression of Hif-1α, explicitly in placental trophoblasts causes maternal pathology and establishes a mouse model that significantly recapitulates the physiological and pathophysiological characteristics of preeclampsia with fetal growth restriction.

Thrombophilia in 153 Patients With Premature Cardiovascular Disease ≤Age 45.

We assessed contributions of thrombophilia to premature cardiovascular disease (CVD) events (≤ age 45) in 153 patients. Test results of thrombophilia-hypofibrinolysis were obtained in 153 patients with CVD ≤ age 45, 110 healthy normal controls, and 110 patients who had venous thromboembolism (VTE) without CVD. Of the 153 patients with CVD, 121 (79%) had sustained myocardial infarction, 70 (46%) had coronary artery stenting, and 53 (35%) had coronary artery bypass grafts. The first CVD events occurred at ages >20 to 35 in 47 patients and at ages >35 to 45 in 106 patients. At study entry, median low-density lipoprotein cholesterol was 126 mg/dL, 56 (37%) smoked, 56 (37%) had hypertension, and 56 (37%) were diabetic. Cases differed from normal controls for high factor VIII (10 [22%] of 45 vs 7 of 103 [7%], P = .007), high homocysteine (32 [21%] of 151 vs 5 [5%] of 107, P = .0002), low free protein S (5 [11%] of 44 vs 2 [2%] of 96, P = .032), high anticardiolipin antibodies (ACLA) IgM (11 [9%] of 129 vs 2 [2%] of 109, P = .024), high lipoprotein (a) [Lp(a)] (46 [30%] of 151 vs 21 [19%] of 110, P = .038), and the lupus anticoagulant (4 [11%] of 37 vs 2 [2%] of 110, P = .035). There were no differences ( P > .05) between cases and VTE controls except free protein S and Lp(a). Free protein S was more often low in VTE controls (24 [28%] of 85 vs 5 [11%] of 44, P = .03) and Lp(a) was more often high in cases (46 [30%] of 151, VTE controls 12 [17%] of 71, P = .032). In 153 patients with premature CVD ≤ age 45, thrombophilia was pervasive (high factor VIII, homocysteine, ACLA IgM, low free protein S, high Lp(a), and lupus anticoagulant), evidencing thrombotic contribution to premature CVD. Moreover, thrombophilia in patients with premature CVD was comparable to VTE controls, emphasizing the pervasive nature of thrombophilia in premature CVD.

Gestational differences in murine placenta: Glycolytic metabolism and pregnancy parameters.

The placenta is a complex and essential organ composed largely of fetal-derived cells, including several different trophoblast subtypes that work in unison to support nutrient transport to the fetus during pregnancy. Abnormal placental development can lead to pregnancy-associated disorders that often involve metabolic dysfunction. The scope of dysregulated metabolism during placental development may not be fully representative of the in vivo state in defined culture systems, such as cell lines or isolated primary cells. Thus, assessing metabolic function in intact placental tissue would provide a better assessment of placental metabolism. In this study, we describe a methodology for assaying glycolytic function in structurally-intact mouse placental tissue, ex vivo, without culturing or tissue dissociation, that more closely resembles the in vivo state. Additionally, we present data highlighting sex-dependent differences of two mouse strains (C57BL/6 and ICR) in the pre-hypertrophic (E14.5) and hypertrophic (E18.5) placenta. These data establish a foundation for investigation of metabolism throughout gestation and provides a comprehensive assessment of glycolytic function during placental development.

Temporal and spatial expression of glyceraldehyde 3-phosphate dehydrogenase (Gapdh) in the mouse placenta.

Glucose metabolism in trophoblast cells is essential to provide the required energy for the development and function of the placenta. Glyceraldehyde 3-phosphate dehydrogenase (Gapdh), a key enzyme in the glycolysis pathway has been considered ubiquitously expressed in cells. There is, however, a growing body of evidence suggesting that Gapdh has many functions in pathways unrelated to glucose metabolism. In the present study, we show that GAPDH expression and sub-cellular localization changes through gestation in the mouse placenta. Our findings raise the possibility that GAPDH has multiple functions in trophoblast cells and the developing placenta, while also cautioning against its use as an endogenous reference or standard for gene expression in the placenta.

Case report: primary osteonecrosis associated with thrombophilia-hypofibrinolysis and worsened by testosterone therapy.

BACKGROUND: Familial and acquired thrombophilia are often etiologic for idiopathic hip and jaw osteonecrosis (ON), and testosterone therapy (TT) can interact with thrombophilia, worsening ON. CASE PRESENTATION: Case 1: A 62-year-old Caucasian male (previous deep venous thrombosis), on warfarin 1 year for atrial fibrillation (AF), had non-specific right hip-abdominal pain for 2 years. CT scan revealed bilateral femoral head ON without collapse. Coagulation studies revealed Factor V Leiden (FVL) heterozygosity, 4G/4G plasminogen activator inhibitor (PAI) homozygosity, high anti-cardiolipin (ACLA) IgM antibodies, and endothelial nitric oxide (NO) synthase (eNOS) T786C homozygosity (reduced conversion of L-arginine to NO, required for bone health). Apixaban 5 mg twice daily was substituted for warfarin; and L-arginine 9 g/day was started to increase NO. On Apixaban for 8 months, he became asymptomatic. Case 2: A 32-year-old hypogonadal Caucasian male had 10 years of unexplained tooth loss, progressing to primary jaw ON with cavitation 8 months after starting TT gel 50 mg/day. Coagulation studies revealed FVL heterozygosity, PAI 4G/4G homozygosity, and the lupus anticoagulant. TT was discontinued. Jaw pain was sharply reduced within 2 months. CONCLUSIONS: Idiopathic ON, often caused by thrombophilia-hypofibrinolysis, is worsened by TT, and its progression may be slowed or stopped by discontinuation of TT and, thereafter, anticoagulation. Recognition of thrombophilia-hypofibrinolysis before joint collapse facilitates anticoagulation which may stop ON, preserving joints.