Taste-masked formulation of sodium phenylbutyrate (ACER-001) for the treatment of urea cycle disorders.

Urea cycle disorders (UCDs) are a group of rare inherited metabolic diseases caused by a deficiency of one of the enzymes or transporters that constitute the urea cycle. Defects in these enzymes lead to acute accumulation (hyperammonemic crises, HAC) or chronically elevated levels (hyperammonemia) of ammonia in the blood and/or various tissues including the brain, which can cause persistent neurological deficits, irreversible brain damage, coma, and death. Ongoing treatment of UCDs include the use of nitrogen-scavenging agents, such as sodium phenylbutyrate (salt of 4-phenylbutyric acid; NaPBA) or glycerol phenylbutyrate (GPB). These treatments provide an alternative pathway for nitrogen disposal through the urinary excretion of phenylacetylglutamine. ACER-001 is a novel formulation of NaPBA with polymer coated pellets in suspension, which is designed to briefly mask the unpleasant bitter taste of NaPBA and is being developed as a treatment option for patients with UCDs. Four Phase 1 studies were conducted to characterize the bioavailability (BA) and/or bioequivalence (BE) of ACER-001 (in healthy volunteers) and taste assessment relative to NaPBA powder (in taste panelists). ACER-001 was shown to be bioequivalent to NaPBA powder under both fed and fasting conditions. Lower systemic exposure of phenylacetate (PAA) and phenylbutyrate (PBA) was observed when ACER-001 was administered with a high-fat meal relative to a fasting state suggesting that the lower doses of PBA administered under fasting conditions may yield similar efficacy with potentially fewer dose dependent adverse effects relative to higher doses with a meal. ACER-001 appeared to be adequately taste-masked, staying below the aversive taste threshold for the first 3 min after the formulation was prepared and remaining palatable when taken within 5 min.

HIV-Adapted Group Prenatal Care: Assessing Viral Suppression and Postpartum Retention in Care.

Viral suppression and postpartum retention in care have far-reaching health implications for pregnant women living with HIV and their children, yet remain public health challenges. Prenatal care presents a unique opportunity to engage pregnant women in care. The purpose of this study is to evaluate whether group prenatal care is effective in impacting these outcomes for pregnant women living with HIV. A retrospective cohort study was performed of all women living with HIV who obtained prenatal care from a community-based health center between 2013 and 2019. Women who spoke English or Spanish, remained within the system, and had not participated in group prenatal care previously were included. Women self-selected a prenatal care model: 85 selected group care and 109 elected individual care. Group prenatal care followed a standard Centering Pregnancy® curriculum with the addition of HIV-related topics. The primary outcomes of the study were viral suppression (viral load <20 copies/mL) and postpartum retention in care (attending at least one or two visits with HIV primary care within 12 months postpartum). After adjusting for potential confounding factors, women who participated in group prenatal care were significantly more likely to have at least one HIV primary care visit postpartum {adjusted odds ratio (aOR) = 2.71 [95% confidence interval (CI 1.14-6.46)]; p = 0.024}, and had a trend for achieving viral suppression by the time of delivery [aOR = 2.29 (95% CI 0.94-5.55); p = 0.068]. We have demonstrated that group prenatal care for pregnant women living with HIV is feasible and effective, with positive impacts on retention in care and viral suppression, factors that affect long-term outcomes from patients living with HIV.

Evaluation of human immunodeficiency virus-adapted group prenatal care.

BACKGROUND: Efforts to further decrease perinatal transmission of HIV include efforts to improve engagement and retention in prenatal care. Group prenatal care has been reported to have benefits in certain other high-risk groups of pregnant women but has not been previously evaluated in pregnant women living with HIV. OBJECTIVE: This study aimed to evaluate changes in HIV knowledge, stigma, social support, depression, self-efficacy, and medication adherence after HIV-adapted group prenatal care. STUDY DESIGN: All women living with HIV who presented for prenatal care at ≤30 weeks' gestation in Harris Health System (Houston, TX) between September 2013 and December 2017 were offered either group or individual HIV-focused prenatal care. Patients were recruited for the study at their initial prenatal visit. HIV topics, such as HIV facts, disclosure, medication adherence, safe sex and conception, retention in care, and postdelivery baby testing, were added to the standard CenteringPregnancy curriculum (ten 2-hour sessions per pregnancy). Knowledge and attitudes toward factors associated with adherence to HIV treatment regimens (stigma, loneliness, perceived social support, and depressive symptoms) were compared on written pre- and postsurveys. Surveys included 58 items derived from validated scales, with Likert and dichotomous responses. McNemar's test, Wilcoxon signed-rank test, and paired t-tests compared pre- and postsurvey responses. RESULTS: A total of 190 women living with HIV received prenatal care in the clinic during the study period, 93 (49%) of whom participated in CenteringHIV. A total of 66 Centering participants enrolled in the study and 42 of those completed the pre- and postsurveys. Among women in the Centering program who completed pre- and postsurveys, significant differences were noted with improved perceived social support from family (P=.011) and friends (P=.005), decreased depression (Edinburg Postnatal Depression Scale, ≥10; 43% vs 18%; P<.001; Edinburg Postnatal Depression Scale score mean (standard deviation), 9.3 (5.8) pre vs 5.2 (4.9) post; P<.001), and decreased missed medication doses related to depressed mood (P=.014). No statistically significant differences were noted in HIV knowledge, HIV stigma, attitude, or self-efficacy. CONCLUSION: HIV-focused group prenatal care may positively affect perceived social support and depression scores, factors that are closely associated with antiretroviral adherence and retention in the care for pregnant women living with HIV.

Abnormal Vaginal Pap Test After Hysterectomy in Human Immunodeficiency Virus-Infected Women.

OBJECTIVE: To evaluate the prevalence of abnormal vaginal cytology and vaginal intraepithelial neoplasia (VAIN) and vaginal cancer in human immunodeficiency virus (HIV)-infected women with no history of abnormal cytologic screening who had a hysterectomy for conditions other than cervical dysplasia and cancer; and to explore the risk factors associated with VAIN and vaginal cancer. METHODS: A retrospective cohort study was performed identifying 238 women between January 2000 to January 2015 with a history of HIV, previous hysterectomy, and no previous abnormal Pap tests. Medical records from patients with both HIV and history of hysterectomy were reviewed from Thomas Street Health Center and Northwest Community Health Center. RESULTS: Among 238 women, 164(69%) had normal Pap test results, 12(5%) had results showing atypical cells of undermined significance and human papillomavirus-positive, 55(23.1%) had results showing low-grade squamous intraepithelial lesion, and 7(2.9%) had results showing high-grade squamous intraepithelial lesion. No demographic risk factor was associated with abnormal Pap test after hysterectomy. Median follow-up time for the Pap test was 16 years. Of those who underwent vaginal biopsies for an abnormal Pap test, 15(28%) were normal, 23(43%) were VAIN1, 9(16%) were VAIN2, and 7(13%) were VAIN3. No patients had invasive vaginal cancer. CONCLUSION: Over 30% of HIV-infected women who had no pre-hysterectomy history of an abnormal Pap test had abnormal vaginal Pap tests. Among those who had vaginal biopsies, 29% had VAIN2 or VAIN3, suggesting that Pap tests post-hysterectomy in the HIV population may be indicated.

Clinical effects of long-term metreleptin treatment in patients with lipodystrophy.

OBJECTIVE: To evaluate the long-term clinical effect of treatment with metreleptin (an analogue of human leptin) on glycemic and lipid abnormalities and markers of hepatic steatosis in patients with inherited or acquired lipodystrophy. METHODS: Fifty-five patients (36 with generalized lipodystrophy and 19 with partial lipodystrophy) with at least 1 of 3 metabolic abnormalities (diabetes mellitus, fasting triglyceride level ≥200 mg/dL, and insulin resistance) and low leptin levels received subcutaneous injections of metreleptin once or twice daily in an ongoing clinical trial at the National Institutes of Health. RESULTS: At baseline, hemoglobin A1c-8.5% ± 2.1% (mean ± standard deviation [SD])-and triglycerides-479 ± 80 mg/dL (geometric mean ± standard error [SE])-were substantially elevated. Robust and sustained reductions in both variables were evident for the observed patient population during a 3-year metreleptin treatment period (-2.1% ± 0.5% [mean ± SE] and -35.4% ± 13.7% [mean ± SE], respectively). Mean alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were elevated at baseline (100 ± 120 U/L and 71 ± 77 U/L [mean ± SD], respectively) and decreased by -45 ± 19 U/L and -33 ± 14 U/L (mean ± SE), respectively, during the 3-year metreleptin treatment period. Improvements in hemoglobin A1c, triglycerides, ALT, and AST were more pronounced in the subsets of patients having elevated levels at baseline. The most notable adverse events observed in this patient population were likely attributable to underlying metabolic abnormalities or comorbidities. CONCLUSION: Metreleptin treatment substantially reduced glycemic variables, triglycerides, and liver enzymes (ALT and AST) and demonstrated durability of response throughout a 3-year treatment period. These results support metreleptin as a potential treatment for certain metabolic disorders (for example, diabetes mellitus and hypertriglyceridemia) associated with lipodystrophy.

Social isolation rearing affects prefrontal cortical response to ventral tegmental area stimulation.

BACKGROUND: Animals reared in social isolation exhibit attentional deficits that parallel those found in schizophrenia patients. Such disturbances are frequently attributed to a dysfunction of the mesocortical system. Here we investigated whether electrophysiologic characteristics of prefrontal cortical pyramidal neurons or mesocortical responses were changed in isolated animals. METHODS: In vivo intracellular recordings were obtained from prefrontal cortical pyramidal neurons in animals raised in social isolation or in socialized control animals before and after ventral tegmental area stimulation mimicking dopamine cell burst firing. RESULTS: Prefrontal cortical pyramidal neurons recorded from isolated animals showed bimodal characteristics resembling those of their socialized littermates. Stimulation of the ventral tegmental area evoked plateau depolarizations in both groups, but this was accompanied by abnormal firing or a short hyperpolarization in most of the isolated animals. CONCLUSION: These findings suggest that social isolation rearing may affect mesocortical information processing.

Prefrontal cortical cell firing during maintenance, extinction, and reinstatement of goal-directed behavior for natural reward.

The prefrontal cortex (PFC) is important for higher cognitive functioning and the processing of reward-related information. Here, electrophysiological recording procedures were used to examine cell firing in the PFC in rats (n = 12) during water reinforcement sessions consisting of three phases. In phase one (maintenance), animals pressed a lever (fixed ratio 1) for water reinforcement (0.05 ml/press) paired with an auditory stimulus. Of 62 neurons recorded during maintenance, 39 (63%) exhibited one of three types of patterned discharges relative to the reinforced response for water. Specifically, PFC neurons exhibited increases in firing rate within seconds preceding the response (type PR; n = 9 cells) or increases (type RFe; n = 16 cells) or decreases (type RFi; n = 14 cells) in firing rate immediately following response completion. The remaining neurons did not alter their firing profiles relative to the reinforced response (type nonphasic cells; n = 23 cells). In phase two (extinction), lever press responses had no programmed consequences (i.e., water reinforcement and the auditory stimulus were not presented). After 30 min of no responding, phase three (reinstatement) began, during which each lever press response was again associated with water reinforcement paired with the stimulus. Results indicate differential effects of extinction/reinstatement on cell firing rates and patterns dependent on cell type. These findings are discussed with respect to the adaptive nature of PFC activity during goal-directed behaviors for "natural" rewards, and are considered relative to prior studies that examined nucleus accumbens cell firing during a similar behavioral task.

Prefrontal cortical up states are synchronized with ventral tegmental area activity.

The innervation of the prefrontal cortex (PFC) by the ventral tegmental area (VTA) has an important role in incentive-motivation and cognitive functions. Although this projection has been extensively studied, the precise actions of its transmitters, dopamine (DA) and GABA, on PFC pyramidal neurons remain to be determined. We have recently shown that VTA stimulation elicits a sustained depolarization in PFC pyramidal neurons resembling the periodic depolarizations (up states) these neurons exhibit. This response was shortened by a D1 antagonist, suggesting that DA may sustain depolarized up states in PFC neurons. Here, we tested whether spontaneous PFC up states in vivo require spontaneous VTA activity. Intracellular recordings from PFC neurons conducted simultaneously with VTA local field potentials (LFPs) revealed PFC membrane potential fluctuations occurring synchronously with VTA field potential transitions. Extracellular PFC recordings performed simultaneously with VTA LFPs also indicated a high coherence between these two regions, with VTA oscillations trailing PFC oscillations by a few milliseconds. Furthermore, blockade of VTA activity with lidocaine transiently eliminated PFC LFPs, but not PFC cell up states; instead, up states became irregular during intra-VTA lidocaine administration. These results suggest that baseline levels of VTA activity are necessary for synchronizing PFC pyramidal neurons in the up-down oscillations observed in the anesthetized preparation, allowing the emergence of slow EEG components.