HIV Sexual Risk and Syndemics among Women in Three Urban Areas in the United States: Analysis from HVTN 906

Limited data are available on the longitudinal occurrence of syndemic factors among women at risk for HIV infection in the USA and how these factors relate to sexual risk over time. HVTN 906 was a longitudinal study enrolling 799 HIV-uninfected women in three cities. Assessments were done at baseline, 6, 12, and 18 months to assess syndemic factors (low education, low income, unemployment, lack of health insurance, housing instability, substance use, heavy alcohol use, partner violence, incarceration) and sexual risk outcomes. For each sexual risk outcome, a GEE model was fit with syndemic factors or syndemic score (defined as sum of binary syndemics, ranging from 0 to 9), visit, study site, age and race/ethnicity as predictors to examine the multivariable association between syndemic factors and outcomes over time. Odds of unprotected sex while drunk or high were significantly higher when women reported lack of health insurance, substance and heavy alcohol use and partner violence. Housing instability, substance and heavy alcohol use, partner violence and recent incarceration were associated with higher odds of having multiple sexual partners. Odds of sex exchange were significantly higher in the presence of unemployment, housing instability, low education, lack of health insurance, substance and heavy alcohol use, partner violence and incarceration. Housing instability, substance and heavy alcohol use, and partner violence were significantly associated with higher odds of unprotected anal sex. Odds of having a recent STI were significantly higher when women reported housing instability and partner violence. There were significantly higher odds of the reporting of any risk outcomes during follow-up with higher syndemic score. This study highlights a group of women experiencing multiple poor social and health outcomes who need to be the focus of comprehensive interventions.     

Lower Monoamine Oxidase-A Total Distribution Volume in Impulsive and Violent Male Offenders with Antisocial Personality Disorder and High Psychopathic Traits: An [11C] Harmine Positron Emission Tomography Study

Antisocial personality disorder (ASPD) often presents with highly impulsive, violent behavior, and pathological changes in the orbitofrontal cortex (OFC) and ventral striatum (VS) are implicated. Several compelling reasons support a relationship between low monoamine oxidase-A (MAO-A), an enzyme that regulates neurotransmitters, and ASPD. These include MAO-A knockout models in rodents evidencing impulsive aggression and positron emission tomography (PET) studies of healthy subjects reporting associations between low brain MAO-A levels and greater impulsivity or aggression. However, a fundamental gap in the literature is that it is unknown whether brain MAO-A levels are low in more severe, clinical disorders of impulsivity, such as ASPD. To address this issue, we applied [¹¹C] harmine PET to measure MAO-A total distribution volume (MAO-A V_T), an index of MAO-A density, in 18 male ASPD participants and 18 age- and sex-matched controls. OFC and VS MAO-A V_T were lower in ASPD compared with controls (multivariate analysis of variance (MANOVA): F_2,33=6.8, P=0.003; OFC and VS MAO-A V_T each lower by 19%). Similar effects were observed in other brain regions: prefrontal cortex, anterior cingulate cortex, dorsal putamen, thalamus, hippocampus, and midbrain (MANOVA: F_7,28=2.7, P=0.029). In ASPD, VS MAO-A V_T was consistently negatively correlated with self-report and behavioral measures of impulsivity (r=−0.50 to −0.52, all P-values<0.05). This study is the first to demonstrate lower brain MAO-A levels in ASPD. Our results support an important extension of preclinical models of impulsive aggression into a human disorder marked by pathological aggression and impulsivity.     

The UBIAD1 Prenyltransferase Links Menaquione‐4 Synthesis to Cholesterol Metabolic Enzymes

Schnyder corneal dystrophy (SCD) is an autosomal dominant disease characterized by germline variants in UBIAD1 introducing missense alterations leading to deposition of cholesterol in the cornea, progressive opacification, and loss of visual acuity. UBIAD1 was recently shown to synthesize menaquinone‐4 (MK‐4, vitamin K₂), but causal mechanisms of SCD are unknown. We report a novel c.864G>A UBIAD1 mutation altering glycine 177 to glutamic acid (p.G177E) in six SCD families, including four families from Finland who share a likely founder mutation. We observed reduced MK‐4 synthesis by UBIAD1 altered by SCD mutations p.N102S, p.G177R/E, and p.D112N, and molecular models showed p.G177‐mutant UBIAD1 disrupted transmembrane helices and active site residues. We show UBIAD1 interacts with HMGCR and SOAT1, enzymes catalyzing cholesterol synthesis and storage, respectively, using yeast two‐hybrid screening and immunoprecipitation. Docking simulations indicate cholesterol binds to UBIAD1 in the substrate‐binding cleft and substrate‐binding overlaps with GGPP binding, an MK‐4 substrate, suggesting potential competition between these metabolites. Impaired MK‐4 synthesis is a biochemical defect identified in SCD suggesting UBIAD1 links vitamin K and cholesterol metabolism through physical contact between enzymes and metabolites. Our data suggest a role for endogenous MK‐4 in maintaining cornea health and visual acuity.     

Comparison of Common Methodologies for the Determination of Knee Flexor Muscle Strength

BackgroundKnee flexion strength may hold important clinical implications for the determination of injury risk and readiness to return to sport following injury and orthopedic surgery. A wide array of testing methodologies and positioning options are available that require validation prior to clinical integration. The purpose of this study was to 1) investigate the validity and test-retest reliability of isometric knee flexion strength measured by a fixed handheld dynamometer (HHD) apparatus compared to a Biodex Dynamometer (BD), 2) determine the impact of body position (seated versus supine) and foot position (plantar- vs dorsiflexed) on knee flexion peak torque and 3) establish the validity and test-retest reliability of the NordBord Hamstring Dynamometer.Study DesignValidity and reliability study, test-retest design.MethodsForty-four healthy participants (aged 27 ± 4.8 years) were assessed by two raters over two testing sessions separated by three to seven days. Maximal isometric knee flexion in the seated and supine position at 90^o knee flexion was measured with both a BD and an externally fixed HHD with the foot held in maximal dorsiflexion or in plantar flexion. The validity and test-retest reliability of eccentric knee flexor strength on the NordBord hamstring dynamometer was assessed and compared with isometric strength on the BD.ResultsLevel of agreement between HHD and BD torque demonstrated low bias (bias -0.33 Nm, SD of bias 13.5 Nm; 95% LOA 26.13 Nm, -26.79 Nm). Interrater reliability of the HHD was high, varying slightly with body position (ICC range 0.9-0.97, n=44). Isometric knee flexion torque was higher in the seated versus supine position and with the foot dorsiflexed versus plantarflexed. Eccentric knee flexion torque had a high degree of correlation with isometric knee flexion torque as measured via the BD (r=0.61-0.86). The NordBord had high test-retest reliability (0.993 (95%CI 0.983-0.997, n=19) for eccentric knee flexor strength, with an MDC₉₅ of 26.88 N and 28.76 N for the left and right limbs respectively.ConclusionCommon measures of maximal isometric knee flexion display high levels of correlation and test-retest reliability. However, values obtained by an externally fixed HHD are not interchangeable with values obtained via the BD. Foot and body position should be considered and controlled during testing.Level of Evidence2b