Are Sex Differences in Human Brain Structure Associated With Sex Differences in Behavior?

On average, men and women differ in brain structure and behavior, raising the possibility of a link between sex differences in brain and behavior. But women and men are also subject to different societal and cultural norms. We navigated this challenge by investigating variability of sex-differentiated brain structure within each sex. Using data from the Queensland Twin IMaging study (n = 1,040) and Human Connectome Project (n = 1,113), we obtained data-driven measures of individual differences along a male-female dimension for brain and behavior based on average sex differences in brain structure and behavior, respectively. We found a weak association between these brain and behavioral differences, driven by brain size. These brain and behavioral differences were moderately heritable. Our findings suggest that behavioral sex differences are, to some extent, related to sex differences in brain structure but that this is mainly driven by differences in brain size, and causality should be interpreted cautiously.

Sex Differences in Misperceptions of Sexual Interest Can Be Explained by Sociosexual Orientation and Men Projecting Their Own Interest Onto Women.

Sex differences in misperceptions of sexual interest have been well documented; however, it is unclear whether this cognitive bias could be explained by other factors. In the current study, 1,226 participants (586 men, 640 women) participated in a speed-dating task in which they rated their sexual interest in each other as well as the sexual interest they perceived from their partners. Consistent with previous findings, results showed that men tended to overperceive sexual interest from their partners, whereas women tended to underperceive sexual interest. However, this sex difference became negligible when we considered potential mediators, such as the raters' sociosexual orientation and raters' tendency to project their own levels of sexual interest onto their partners. These findings challenge the popular notion that sex differences in misperceptions of sexual interest have evolved as a specialized adaptation to different selection pressures in men and women.

Mating Strategies and the Masculinity Paradox: How Relationship Context, Relationship Status, and Sociosexuality Shape Women's Preferences for Facial Masculinity and Beardedness.

According to the dual mating strategy model, in short-term mating contexts women should forego paternal investment qualities in favor of mates with well-developed secondary sexual characteristics and dominant behavioral displays. We tested whether this model explains variation in women's preferences for facial masculinity and beardedness in male faces. Computer-generated composites that had been morphed to appear ± 50% masculine were rated by 671 heterosexual women (M age = 31.72 years, SD = 6.43) for attractiveness when considering them as a short-term partner, long-term partner, a co-parent, or a friend. They then completed the Revised Sociosexual Inventory (SOI-R) to determine their sexual openness on dimensions of desire, behavior, and attitudes. Results showed that women's preferences were strongest for average facial masculinity, followed by masculinized faces, with feminized faces being least attractive. In contrast to past research, facial masculinity preferences were stronger when judging for co-parenting partners than for short-term mates. Facial masculinity preferences were also positively associated with behavioral SOI, negatively with desire, and were unrelated to global or attitudinal SOI. Women gave higher ratings for full beards than clean-shaven faces. Preferences for beards were higher for co-parenting and long-term relationships than short-term relationships, although these differences were not statistically significant. Preferences for facial hair were positively associated with global and attitudinal SOI, but were unrelated to behavioral SOI and desire. Although further replication is necessary, our findings indicate that sexual openness is associated with women's preferences for men's facial hair and suggest variation in the association between sociosexuality and women's facial masculinity preferences.

Kin recognition and perceived facial similarity.

Facial similarity between individuals informs kinship judgments in third-party kin recognition. Indeed, one study found that similarity and kinship judgments encapsulate the same information (Maloney & Dal Martello, 2006). Yet, another study found that this is not the case when comparing adult face pairs of different sex (DeBruine et al., 2009). We replicated these studies to further clarify the role of facial similarity in kin recognition. We recruited 318 raters, who were shown 50 sibling pairs and 50 age- and sex-matched unrelated pairs ranging from 3 to 17 years old. Each rater was randomly assigned to make either kinship judgments ("related" or "unrelated") or similarity judgments (scale from 0 [not very similar] to 10 [very similar]). The threshold model found that performance in both tasks was equally accurate, with participants detecting child siblings in the kinship task above chance and giving significantly higher similarity ratings to siblings in the similarity task. In both tasks, opposite-sex siblings were perceived to be siblings less often than same-sex siblings, and judgments of unrelated face pairs were not affected by the sex of faces. Conversely, the effect of age difference within pairs of faces differed for the two tasks: a greater age difference decreased all kinship judgments, but only decreased similarity judgments of siblings, not unrelated pairs. In line with DeBruine et al. (2009), these findings suggest that similarity and kinship judgments are highly correlated but not strictly synonymous. The OSF Pre-registration Challenge for this project can be found at osf.io/ps9hy and the data at osf.io/sef9k.

Mothers are sensitive to men's beards as a potential cue of paternal investment.

Mating strategy theories assert that women's preferences for androgen dependent traits in men are stronger when the costs of reduced paternal investment are lowest. Past research has shown that preferences for facial masculinity are stronger among nulliparous and non-pregnant women than pregnant or parous women. In two studies, we examine patterns in women's preferences for men's facial hair - likely the most visually conspicuous and sexually dimorphic of men's secondary sexual traits - when evaluating men's masculinity, dominance, age, fathering, and attractiveness. Two studies were conducted among heterosexual pregnant women, mothers, non-contractive and contraceptive users. Study 1 used a between-subjects sample (N = 2103) and found that mothers had significantly higher preferences for beards when judging fathering than all other women. Pregnant women and mothers also judged beards as more masculine and older, but less attractive, than non-contractive and contraceptive users. Parous women judged beards higher for age, masculinity and fathering, but lower for attractiveness, than nulliparous women. Irrespective of reproductive status, beards were judged as looking more dominant than clean-shaven faces. Study 2 used a within-subjects design (N = 53) among women surveyed during pregnancy and three months post-partum. Judgments of parenting skills were higher for bearded stimuli during pregnancy among women having their first baby, whereas among parous women parenting skills judgments for bearded stimuli were higher post-partum. Our results suggest that mothers are sensitive to beardedness as a masculine secondary sexual characteristic that may denote parental investment, providing evidence that women's mate preferences could reflect sexual selection for direct benefits.

Facial masculinity is only weakly correlated with handgrip strength in young adult women.

OBJECTIVES: Ancestrally, strength is likely to have played a critical role in determining the ability to obtain and retain resources and the allocation of social status among humans. Responses to facial cues of strength are therefore thought to play an important role in human social interaction. Although many researchers have proposed that sexually dimorphic facial morphology is reliably correlated with physical strength, evidence for this hypothesis is somewhat mixed. Moreover, to date, only one study has investigated the putative relationship between facial masculinity and physical strength in women. Consequently, we tested for correlations between handgrip strength and objective measures of face-shape masculinity. METHODS: 531 women took part in the study. We measured each participant's handgrip strength (dominant hand). Sexual dimorphism of face shape was objectively measured from each face photograph using two methods: discriminant analysis and vector analysis. These methods use shape components derived from principal component analyses of facial landmarks to measure the probability of the face being classified as male (discriminant analysis method) or to locate the face on a female-male continuum (vector analysis method). RESULTS: Our analyses revealed that handgrip strength is, at best, only weakly correlated with facial masculinity in women. There was a weak significant association between handgrip strength and one measure of women's facial masculinity. The relationship between handgrip strength and our other measure of women's facial masculinity was not significant. DISCUSSION: Together, these results do not support the hypothesis that face-shape masculinity is an important cue of physical strength, at least in women.

A Data-Driven Test for Cross-Cultural Differences in Face Preferences.

Previous research has shown strong cross-cultural agreement in facial attractiveness judgments. However, these studies all used a theory-driven approach in which responses to specific facial characteristics are compared between cultures. This approach is constrained by the predictions that can be derived from existing theories and can therefore bias impressions of the extent of cross-cultural agreement in face preferences. We directly addressed this problem by using a data-driven, rather than theory-driven, approach to compare facial attractiveness judgments made by Chinese-born participants who were resident in China, Chinese-born participants currently resident in the UK, and UK-born and UK-resident White participants. Analyses of the principal components along which faces naturally varied suggested that Chinese and White UK participants used face information in different ways, at least when judging women's facial attractiveness. In other words, the data-driven approach used in this study revealed some cross-cultural differences in face preferences that were not apparent in studies using theory-driven approaches.

Contribution of shape and surface reflectance information to kinship detection in 3D face images.

Previous research has established that humans are able to detect kinship among strangers from facial images alone. The current study investigated what facial information is used for making those kinship judgments, specifically the contribution of face shape and surface reflectance information (e.g., skin texture, tone, eye and eyebrow color). Using 3D facial images, 195 participants were asked to judge the relatedness of 100 child pairs, half of which were related and half of which were unrelated. Participants were randomly assigned to judge one of three stimulus versions: face images with both surface reflectance and shape information present (reflectance and shape version), face images with shape information removed but surface reflectance present (reflectance version), or face images with surface reflectance information removed but shape present (shape version). Using binomial logistic mixed models, we found that participants were able to detect relatedness at levels above chance for all three stimulus versions. Overall, both individual shape and surface reflectance information contribute to kinship detection, and both cues are optimally combined when presented together. Preprint, preregistration, code, and data are available on the Open Science Framework (osf.io/7ftxd).

Individual-specific mortality is associated with how individuals evaluate future discounting decisions.

How organisms discount the value of future rewards is associated with many important outcomes, and may be a central component of theories of life-history. According to life-history theories, prioritizing immediacy is indicative of an accelerated strategy (i.e. reaching reproductive maturity quickly and producing many offspring at the cost of long-term investment). Previous work extrapolating life-history theories to facultative calibration of life-history traits within individuals has theorized that cues to mortality can trigger an accelerated strategy; however, compelling evidence for this hypothesis in modern humans is lacking. We assessed whether country-level life expectancy predicts individual future discounting behaviour across multiple intertemporal choice items in a sample of 13 429 participants from 54 countries. Individuals in countries with lower life expectancy were more likely to prefer an immediate reward to one that is delayed. Individuals from countries with greater life expectancy were especially more willing to wait for a future reward when the relative gain in choosing the future reward was large and/or the delay period was short. These results suggest that cues to mortality can influence the way individuals evaluate intertemporal decisions, which in turn can inform life-history trade-offs. We also found that older (but not very old) participants were more willing to wait for a future reward when there is a greater relative gain and/or shorter delay period, consistent with theoretical models that suggest individuals are more future-orientated at middle age.

Metabolism and Disposition of a Novel Selective α7 Neuronal Acetylcholine Receptor Agonist ABT-126 in Humans: Characterization of the Major Roles for Flavin-Containing Monooxygenases and UDP-Glucuronosyl Transferase 1A4 and 2B10 in Catalysis.

Mass balance, metabolism, and excretion of ABT-126, an α7 neuronal acetylcholine receptor agonist, were characterized in healthy male subjects (n = 4) after a single 100-mg (100 µCi) oral dose. The total recovery of the administered radioactivity was 94.0% (±2.09%), with 81.5% (±10.2%) in urine and 12.4% (±9.3%) in feces. Metabolite profiling indicated that ABT-126 had been extensively metabolized, with 6.6% of the dose remaining as unchanged parent drug in urine. Parent drug accounted for 12.2% of the administered radioactivity in feces. The primary metabolic transformations of ABT-126 involved aza-adamantane N-oxidation (M1, 50.3% in urine) and aza-adamantane N-glucuronidation (M11, 19.9% in urine). M1 and M11 were also major circulating metabolites, accounting for 32.6% and 36.6% of the drug-related material in plasma, respectively. These results demonstrated that ABT-126 is eliminated primarily by hepatic metabolism, followed by urinary excretion. Enzymatic studies suggested that M1 formation is mediated primarily by human liver flavin-containing monooxygenase (FMO)3 and, to a lesser extent, by human kidney FMO1; M11 is generated mainly by human uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A4, whereas UGT 2B10 also contributes to ABT-126 glucuronidation. Species-dependent formation of M11 was observed in hepatocytes; M11 was formed in human and monkey hepatocytes, but not in rat and dog hepatocytes, suggesting that monkeys constitute an appropriate model for predicting the fate of compounds undergoing significant N-glucuronidation. M1 and M11 are not expected to have clinically relevant on- or off-target pharmacologic activities. In summary, this study characterized ABT-126 metabolites in the circulation and excreta and the primary elimination pathways of ABT-126 in humans.

No Compelling Evidence that Preferences for Facial Masculinity Track Changes in Women's Hormonal Status.

Although widely cited as strong evidence that sexual selection has shaped human facial-attractiveness judgments, findings suggesting that women's preferences for masculine characteristics in men's faces are related to women's hormonal status are equivocal and controversial. Consequently, we conducted the largest-ever longitudinal study of the hormonal correlates of women's preferences for facial masculinity ( N = 584). Analyses showed no compelling evidence that preferences for facial masculinity were related to changes in women's salivary steroid hormone levels. Furthermore, both within-subjects and between-subjects comparisons showed no evidence that oral contraceptive use decreased masculinity preferences. However, women generally preferred masculinized over feminized versions of men's faces, particularly when assessing men's attractiveness for short-term, rather than long-term, relationships. Our results do not support the hypothesized link between women's preferences for facial masculinity and their hormonal status.

Women's preferences for men's beards show no relation to their ovarian cycle phase and sex hormone levels.

According to the ovulatory shift hypothesis, women's mate preferences for male morphology indicative of competitive ability, social dominance, and/or underlying health are strongest at the peri-ovulatory phase of the menstrual cycle. However, recent meta-analyses are divided on the robustness of such effects and the validity of the often-used indirect estimates of fertility and ovulation has been called into question in methodological studies. In the current study, we test whether women's preferences for men's beardedness, a cue of male sexual maturity, androgenic development and social dominance, are stronger at the peri-ovulatory phase of the menstrual cycle compared to during the early follicular or the luteal phase. We also tested whether levels of estradiol, progesterone, and the estradiol to progesterone ratio at each phase were associated with facial hair preferences. Fifty-two heterosexual women completed a two-alternative forced choice preference test for clean-shaven and bearded male faces during the follicular, peri-ovulatory (validated by the surge in luteinizing hormone or the drop in estradiol levels) and luteal phases. Participants also provided for one entire menstrual cycle daily saliva samples for subsequent assaying of estradiol and progesterone. Results showed an overall preference for bearded over clean-shaven faces at each phase of the menstrual cycle. However, preferences for facial hair were not significantly different over the phases of menstrual cycle and were not significantly associated with levels of reproductive hormones. We conclude that women's preferences for men's beardedness may not be related to changes in their likelihood of conception.

Metabolism and Disposition of a Novel B-Cell Lymphoma-2 Inhibitor Venetoclax in Humans and Characterization of Its Unusual Metabolites.

Venetoclax (ABT-199), a B-cell lymphoma-2 (Bcl-2) protein inhibitor, is currently in clinical development for the treatment of hematologic malignancies. We characterized the absorption, metabolism, and excretion of venetoclax in humans. After a single oral dose of [14C]venetoclax to healthy volunteers, the recovery of total radioactive dose was 100%, with feces being the major route of elimination of the administered dose, whereas urinary excretion was minimal (<0.1%). The extent of absorption was estimated to be at least 65%. Venetoclax was primarily cleared by hepatic metabolism (∼66% of the administered dose). ∼33% of the administered dose was recovered as the parent drug and its nitro reduction metabolite M30 [2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-amino-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide] (13%) in feces. Biotransformation of venetoclax in humans primarily involves enzymatic oxidation on the dimethyl cyclohexenyl moiety, followed by sulfation and/or nitro reduction. Nitro reduction metabolites were likely formed by gut bacteria. Unchanged venetoclax was the major drug-related material in circulation, representing 72.8% of total plasma radioactivity. M27 (oxidation at the 6 position of cyclohexenyl ring followed by cyclization at the α-carbon of piperazine ring; 4-[(10aR,11aS)-7-(4-chlorophenyl)-9,9-dimethyl-1,3,4,6,8,10,10a,11a-octahydropyrazino[2,1-b][1,3]benzoxazin-2-yl]-N-[3-nitro-4-(tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide) was identified as a major metabolite, representing 12% of total drug-related material. M27 was primarily formed by cytochrome P450 isoform 3A4 (CYP3A4). Steady-state plasma concentrations of M27 in human and preclinical species used for safety testing suggested that M27 is a disproportionate human metabolite. M27 is not expected to have clinically relevant on- or off-target pharmacologic activities.

Metabolism and Disposition of the Hepatitis C Protease Inhibitor Paritaprevir in Humans.

Paritaprevir (also known as ABT-450), a potent NS3-4A serine protease inhibitor [identified by AbbVie (North Chicago, IL) and Enanta Pharmaceuticals (Watertown, MA)] of the hepatitis C virus (HCV), has been developed in combination with ombitasvir and dasabuvir in a three-direct-acting antiviral agent (DAA) oral regimen for the treatment of patients infected with HCV genotype 1. This article describes the mass balance, metabolism, and disposition of paritaprevir in humans. After the administration of a single 200-mg oral dose of [(14)C]paritaprevir coadministered with 100 mg of ritonavir to four male healthy volunteers, the mean total percentage of the administered radioactive dose recovered was 96.5%, with recovery in individual subjects ranging from 96.0% to 96.9%. Radioactivity derived from [(14)C]paritaprevir was primarily eliminated in feces (87.8% of the dose). Radioactivity recovered in urine accounted for 8.8% of the dose. The biotransformation of paritaprevir in humans involves: 1) P450-mediated oxidation on the olefinic linker, the phenanthridine group, the methylpyrazinyl group, or combinations thereof; and 2) amide hydrolysis at the acyl cyclopropane-sulfonamide moiety and the pyrazine-2-carboxamide moiety. Paritaprevir was the major component in plasma [90.1% of total radioactivity in plasma, AUC from time 0 to 12 hours (AUC0-12hours) pool]. Five minor metabolites were identified in plasma, including the metabolites M2, M29, M3, M13, and M6; none of the metabolites accounted for greater than 10% of the total radioactivity. Paritaprevir was primarily eliminated through the biliary-fecal route followed by microflora-mediated sulfonamide hydrolysis to M29 as a major component in feces (approximately 60% of dose). In summary, the biotransformation and clearance pathways of paritaprevir were characterized, and the structures of metabolites in circulation and excreta were elucidated.

Metabolism and Disposition of Hepatitis C Polymerase Inhibitor Dasabuvir in Humans.

Dasabuvir [also known as ABT-333 or N-(6-(3-(tert-butyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide] is a potent non-nucleoside NS protein 5B polymerase inhibitor of the hepatitis C virus (HCV) and is being developed in combination with paritaprevir/ritonavir and ombitasvir in an oral regimen with three direct-acting antivirals for the treatment of patients infected with HCV genotype 1. This article describes the mass balance, metabolism, and disposition of dasabuvir in humans. After administration of a single oral dose of 400-mg [(14)C]dasabuvir (without coadministration of paritaprevir/ritonavir and ombitasvir) to four healthy male volunteers, the mean total percentage of the administered radioactive dose recovered was 96.6%. The recovery from the individual subjects ranged from 90.8% to 103%. Dasabuvir and corresponding metabolites were predominantly eliminated in feces (94.4% of the dose) and minimally through renal excretion (2.2% of the dose). The biotransformation of dasabuvir primarily involves hydroxylation of the tert-butyl group to form active metabolite M1 [N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide], followed by glucuronidation and sulfation of M1 and subsequent secondary oxidation. Dasabuvir was the major circulating component (58% of total radioactivity) in plasma, followed by metabolite M1 (21%). Other minor metabolites represented < 10% each of total circulating radioactivity. Dasabuvir was cleared mainly through cytochrome P450-mediated oxidation metabolism to M1. M1 and its glucuronide and sulfate conjugates were primarily eliminated in feces. Subsequent oxidation of M1 to the tert-butyl acid, followed by formation of the corresponding glucuronide conjugate, plays a secondary role in elimination. Cytochrome P450 profiling indicated that dasabuvir was mainly metabolized by CYP2C8, followed by CYP3A4. In summary, the biotransformation pathway and clearance routes of dasabuvir were characterized, and the structures of metabolites in circulation and excreta were elucidated.

Metabolism and Disposition of Pan-Genotypic Inhibitor of Hepatitis C Virus NS5A Ombitasvir in Humans.

Ombitasvir (also known as ABT-267) is a potent inhibitor of hepatitis C virus (HCV) nonstructural protein 5A (NS5A), which has been developed in combination with paritaprevir/ritonavir and dasabuvir in a three direct-acting antiviral oral regimens for the treatment of patients infected with HCV genotype 1. This article describes the mass balance, metabolism, and disposition of ombitasvir in humans without coadministration of paritaprevir/ritonavir and dasabuvir. Following the administration of a single 25-mg oral dose of [(14)C]ombitasvir to four healthy male volunteers, the mean total percentage of the administered radioactive dose recovered was 92.1% over the 192-hour sample collection in the study. The recovery from the individual subjects ranged from 91.4 to 93.1%. Ombitasvir and corresponding metabolites were primarily eliminated in feces (90.2% of dose), mainly as unchanged parent drug (87.8% of dose), but minimally through renal excretion (1.9% of dose). Biotransformation of ombitasvir in human involves enzymatic amide hydrolysis to form M23 (dianiline), which is further metabolized through cytochrome P450-mediated oxidative metabolism (primarily by CYP2C8) at the tert-butyl group to generate oxidative and/or C-desmethyl metabolites. [(14)C]Ombitasvir, M23, M29, M36, and M37 are the main components in plasma, representing about 93% of total plasma radioactivity. The steady-state concentration measurement of ombitasvir metabolites by liquid chromatography-mass spectrometry analysis in human plasma following multiple doses of ombitasvir, in combination with paritaprevir/ritonavir and dasabuvir, confirmed that ombitasvir is the main component (51.9% of all measured drug-related components), whereas M29 (19.9%) and M36 (13.1%) are the major circulating metabolites. In summary, the study characterized ombitasvir metabolites in circulation, the metabolic pathways, and the elimination routes of the drug.

Facial averageness and genetic quality: Testing heritability, genetic correlation with attractiveness, and the paternal age effect.

Popular theory suggests that facial averageness is preferred in a partner for genetic benefits to offspring. However, whether facial averageness is associated with genetic quality is yet to be established. Here, we computed an objective measure of facial averageness for a large sample (N = 1,823) of identical and nonidentical twins and their siblings to test two predictions from the theory that facial averageness reflects genetic quality. First, we use biometrical modelling to estimate the heritability of facial averageness, which is necessary if it reflects genetic quality. We also test for a genetic association between facial averageness and facial attractiveness. Second, we assess whether paternal age at conception (a proxy of mutation load) is associated with facial averageness and facial attractiveness. Our findings are mixed with respect to our hypotheses. While we found that facial averageness does have a genetic component, and a significant phenotypic correlation exists between facial averageness and attractiveness, we did not find a genetic correlation between facial averageness and attractiveness (therefore, we cannot say that the genes that affect facial averageness also affect facial attractiveness) and paternal age at conception was not negatively associated with facial averageness. These findings support some of the previously untested assumptions of the 'genetic benefits' account of facial averageness, but cast doubt on others.

Mining Health Social Media with Sentiment Analysis.

With the rapid development of the Internet, more and more users utilize health communities (known as forums) to find health-related information, share their medical stories and experiences, or interact with other people in the communities. In this paper, we propose a framework to analyze the user-generated contents in a health community. The proposed framework contains three phases. First, we extract medical terms, including conditions, symptoms, treatments, effectiveness and side effects to form a virtual document for each question in the community. Next, we modify Latent Dirichlet Allocation (LDA) by adding a weighted scheme, called conLDA, to cluster virtual documents with similar medical term distributions into a conditional topic (C-topic). Finally, we analyze the clustered C-topics by sentiment polarities, and physiological and psychological sentiment. The experiment results show that conLDA outperforms the original LDA, and can cluster relevant medical terms and relevant questions together. The C-topics clustered by conLDA are more thematic than those clustered by the original LDA. The results of sentiment analysis may provide a quick reference and valuable insights for patients, caregivers and doctors.

Patterns of peripheral neuropathy in ART-naïve patients initiating modern ART regimen.

The purpose of this study was to evaluate associations of pre-ART CD4 with peripheral neuropathy (PN) and estimate the prevalence of PN in HIV-positive patients starting modern combination antiretroviral therapy (cART) regimens. ART-naïve subjects initiating cART were followed longitudinally and screened for signs/symptoms of PN. Lower pre-ART CD4 count was associated with post-ART PN. After 7 years (n = 117), the prevalence (95% CI) of PN and SPN were 31% (23, 40%) and 5% (2, 11%) with pre-ART CD4 count >250 copies/µL. PN continues to be identified in HIV-infected individuals on modern cART by targeted assessment but is generally without symptoms.

Contribution of metabolites to P450 inhibition-based drug-drug interactions: scholarship from the drug metabolism leadership group of the innovation and quality consortium metabolite group.

Recent European Medicines Agency (final) and US Food and Drug Administration (draft) drug interaction guidances proposed that human circulating metabolites should be investigated in vitro for their drug-drug interaction (DDI) potential if present at ≥ 25% of the parent area under the time-concentration curve (AUC) (US Food and Drug Administration) or ≥ 25% of the parent and ≥ 10% of the total drug-related AUC (European Medicines Agency). To examine the application of these regulatory recommendations, a group of scientists, representing 18 pharmaceutical companies of the Drug Metabolism Leadership Group of the Innovation and Quality Consortium, conducted a scholarship to assess the risk of contributions by metabolites to cytochrome P450 (P450) inhibition-based DDIs. The group assessed the risk of having a metabolite as the sole contributor to DDI based on literature data and analysis of the 137 most frequently prescribed drugs, defined structural alerts associated with P450 inhibition/inactivation by metabolites, and analyzed current approaches to trigger in vitro DDI studies for metabolites. The group concluded that the risk of P450 inhibition caused by a metabolite alone is low. Only metabolites from 5 of 137 drugs were likely the sole contributor to the in vivo P450 inhibition-based DDIs. Two recommendations were provided when assessing the need to conduct in vitro P450 inhibition studies for metabolites: 1) consider structural alerts that suggest P450 inhibition potential, and 2) use multiple approaches (e.g., a metabolite cut-off value of 100% of the parent AUC and the R(met) strategy) to predict P450 inhibition-based DDIs caused by metabolites in the clinic.