That trial is a measure of executive function requiring inhibition of a prepotent interfering behavioral response. This effect could not be attributed to differences in HIV-related clinical factors. There were no differences between HIV+ women and men with and without depression in tests of psychomotor speed/attention and motor skills. The domain that was most vulnerable among HIV+ depressed women was a measure of executive function that relies on select areas of the cognitive control network , in particular the rostral anterior cingulate cortex and the dorsolateral PFC which are invoked during inhibitory tasks such as Stroop interference42,43. Neurobiological features of depression contributing to cognition include glucose metabolism in the PFC44 and functional alterations of the ACC, during cognitive task performance. An eventrelated functional magnetic resonance imaging study involving an in-scanner version of the Stroop revealed hyperactivity in the rostral ACC and left dorsolateral PFC in patients with unipolar depression versus healthy participants, and those alterations in brain function correlated with Stroop infererence. This pattern of regional hyperactivity can be induced by lowering serotonin levels with tryptophan depletion, and can be reversed with the antidepressant escitalopram. Although causality cannot be determined in the present study, other work suggests that decreased levels of serotonin alter ACC and PFC function to influence performance on inhibitory tasks. These functional brain alterations partially overlap with the HIV-associated alterations in brain circuitry. Multiple neurobiological features of HIV infection,drain trays for plants including chronic neuroinflammation, reduction of trophic factors, and alterations in dopamine and other neurotransmitters can contribute to depression in HIV.

Mechanistically, neuroinflammation and impaired neurogenesis are key features of depression and HIV and are contributors to NCI. Similarly, hypothalamic-pituitaryadrenal axis function alterations can contribute to NCI in depression and HIV. In our previous publication using this same sample, we demonstrated that although HIV+ women show cognitive vulnerabilities in several domains versus HIV+ men , they show no vulnerability in Stroop. The current data show that it is only in the context of depression where they show greater vulnerability on Stroop colorword [interference], a task reliant on the CCN compared to depressed HIV+ men as well as depressed HIV- men and women. Biological explanations for this selective vulnerability may include females greater sensitivity to the negative effects of inflammation-induced depressed mood. Inducing inflammation via endotoxin exposure leads to increased depressed mood and neural activity in the ACC in healthy females but not males. Converging evidence from preclinical models also demonstrate that the adult female brain has more microglia with an activated phenotype versus the male brain. Microglia play a critical role in maintaining homeostasis in the presence of a number of factors including infection or injury. Sexual dimorphisms in genetic variations in the dopaminergic system may also contribute to a female-specific vulnerability in cognitive control. The catechol-O-methyltransferase gene and the dopamine receptor D2 gene interact with sex on cognitive control behavioral measures. Transcriptional signatures in brain regions in the CCN in MDD also differ by sex. Lastly, sex differences in the HPA, and/or immune alterations may contribute to these findings. For example, cortisol levels negatively relate to executive function in HIV- women but not men. The tighter coupling of depression and HIV in women compared to men suggests a tighter coupling of these neural manifestations of HIV and depression in women than men, and consequently might explain the greater cognitive effect of these comorbidities in women than men. There are also non-biological explanations for the decreased executive function among HIV + depressed women versus all other groups. Depressed HIV+ men could have had greater access and availability to mental health services versus depressed HIV+ women, and this treatment may have minimized the cognitive sequelae of depression in men.

That explanation does not, however, account for the specificity of findings to Stroop color-word [interference] but not other tests. Second, depression among female HIV positive individuals may have the greatest adverse effects on cognitively demanding tasks regardless of domain. Of the tasks administered, Stroop color-word [interference] was the most difficult. Third, we used the same CES-D cutoff for men and women though some argue in favor of a lower cut-off for men than women. Whether a different pattern of findings would emerge with sex-specific cutoffs is unknown. Lastly, performance on Stroop color-word [interference] and possibly other outcomes may have been influenced by unusual patterns within the HIV- depressed men who showed lower performance than HIV+ depressed men in several tests . Even if these patterns did not lead to emergence of any other three-way HIV-serostatus X Sex X Depression interactions, they may have led to the lack of two-way HIV-serostatus X Depression interactions. HIV- depressed men were more likely than HIV+ depressed men to be heavy alcohol users, smoke, and use cannabis and cocaine/crack, but those factors did not account for the three-way interaction on Stroop color-word [interference]. HIV+ depressed men may also have had better engagement in care due to their HIV status versus HIV- depressed men. We also found that elevated depression regardless of HIV status or biological sex was negatively associated with psychomotor speed/attention, executive function, and motor skills. Findings are consistent with studies in HIV- individuals demonstrating that primary NCI among depressed individuals are in psychomotor speed/attention and executive function; sex differences were not examined. In HIV, similar patterns are seen among mixed samples of HIV+ and HIVindividuals . Overall, MACS men compared to WIHS women were more likely to report ever being depressed. Furthermore, HIV serostatus was associated with higher depression rates in women while in men depression rates did not differ by HIV-serostatus. This finding seems unexpected because the depression rate is twice as high in women than men. Similarly in the few studies of sex differences in depression among PWH, HIV+ women have higher depression rates and more severe depressive symptoms versus HIV+ men.

In most studies, the sample sizes were smaller than in the present study so this study might provide more reliable estimates. However, men in the present study, had more opportunities to develop depression because they were followed for a longer period of time versus women . When restricting our analysis to crack/ cocaine non-users, men still had higher levels of depression versus women despite having fewer visits than women. A likely explanation for the higher frequency of depression in MACS men includes primarily sexual minority men whereas WIHS includes primarily heterosexual women. In both sexes, the prevalence of depression is higher among sexual minorities versus heterosexuals. The high prevalence of depression in sexual minorities is associated with stress exposure resulting from stigma and lack of social support. In the MACS, men are predominately Black and all are gay or bisexual. Notably, even though depression was more frequent among HIV+ men, the increased frequency among HIV+ men did not increase NCI on any domain versus either depressed HIV+ women or HIV- men. Moreover, accounting for HIV RNA which was higher in depressed HIV+ men than non-depressed HIV+ men did not not account for the pattern of NCI correlates. This study has a number of limitations including the limited cognitive battery , unmeasured confounders ,4 x 8 grow tray and use of a self-report measure of depression. The preferred diagnostic interview to assess depression was unavailable in both cohorts. Additionally, we did not assess other diagnostic comorbidities commonly cooccuring with depression including anxiety and substance use disorders . Finally, while there were differences in the data collection time frame in the two cohorts, it is unlikely that these differences led to a bias towards or against visits completed while a participant was depressed as depressive symptom trajectories are relatively stable in individuals. Despite limitations, few studies have sufficient statistical power to examine whether the depression-NCI associations differ by HIV-serostatus and sex. To our knowledge, this is the largest study in PWH examining sex and depressive symptoms as contributors to NCI in PWH. The importance of this topic is evident in the high frequency of depression and in the finding that overall depression is associated with impairment in psychomotor speed, executive function, and motor function. Focusing on sex differences is important because for women, the association between depression and executive function was particularly strong, increasing the odds of impairment 5-fold. This pattern was the case even though depression rates were higher in men regardless of HIV-serostatus. Findings indicate that depression is an important prevention and treatment target and that improved access to psychiatric and psychological services may help minimize the influence of this comorbidity on NCI. More high school students smoked little cigars and cigarillos than cigarettes in 33 US states in 2015. Concern is growing about co-use of tobacco and marijuana among youth, particularly among African-American youth.In a 2015 survey, for example, one in four Florida high school students reported ever using cigars or cigar wraps to smoke marijuana. One colloquial term for this is a “blunt.” Adolescent cigar smokers were almost ten times more likely than adults to report that their usual brand offers a flavored variety. Since the US ban on flavored cigarettes , the number of unique LCC flavors more than doubled. Anticipating further regulation, the industry increasingly markets flavored LCCs with sensory and other descriptors that are not recognizable tastes.For example, after New York City prohibited the sale of flavored cigars, blueberry and strawberry cigarillos were marketed as blue and pink, but contained the same flavor ingredients as prohibited products. Among the proliferation of such “concept” flavors , anecdotal evidence suggests that references to marijuana are evident. Cigar marketing includes the colloquial term, “blunt”, in brand names and product labels . Other marketing techniques imply that some brands of cigarillos make it easier for users to replace the contents with marijuana.For example, the image of a zipper on the packaging for Splitarillos and claims about “EZ roll” suggest that products are easily manipulated for making blunts.

We use the term “marijuana co-marketing” to refer to such tobacco industry marketing that may promote dual use of tobacco and marijuana and concurrent use . In addition to flavoring, low prices for LCCs also likely increase their appeal to youth. In California, 74% of licensed tobacco retailers sold cigarillos for less than $1 in 2013. Before Boston regulated cigar pack size and price in 2012, the median price for a popular brand of grape-flavored cigars was $1.19. In 2012, 78% of US tobacco retailers sold single cigarillos, which suggests that the problem of cheap, combustible tobacco is widespread. Additionally, the magnitude of the problem is worse in some neighborhoods than others. Popular brands of flavored cigarillos cost significantly less in Washington DC block groups with a higher proportion of African Americans and in California census tracts with lower median household income.For the first time, this study examines neighborhood variation in the maximum pack size of cigarillos priced at $1 or less and assesses the prevalence of marijuana co-marketing in the retail environment for tobacco. School neighborhoods are the focus of this research because 78% of USA teens attend school within walking distance of a tobacco retailer. In addition, emerging research suggests that adolescents’ exposure to retail marketing is associated with greater curiosity about smoking cigars and higher odds of ever smoking blunts. The Table summarizes descriptive statistics for store type and for schools as well as mixed models with these covariates. Nearly half of the LCC retailers near schools were convenience stores with or without gasoline/petrol. Overall, 61.5% of LCC retailers near schools contained at least one type of marijuana co-marketing: 53.2% sold blunt wraps, 27.2% sold cigarillos marketed as blunts and 26.0% sold blunt wraps, blunts or other LCC with a marijuana related “concept” flavor. After adjusting for store type, marijuana co-marketing was more prevalent in school neighborhoods with lower median household income and with a higher proportion of school-age youth. Nearly all LCC retailers sold cigarillos for $1 or less. The largest pack size at that price contained 2 cigarillos on average . The largest packs priced at $1 or less were singles in 10.9% of stores, 2-packs in 46.8%, 3-packs in 19.2%, 4-packs in 5.5%, and 5 or 6 cigarillos in 5.5%. After adjusting for store type, a significantly larger pack size of cigarillos was priced at $1 or less in school neighborhoods with lower median household income and near schools with a lower proportion of Hispanic students .In California, 79% of licensed tobacco retailers near public schools sold LCCs and approximately 6 in 10 of these LCC retailers sold cigar products labeled as blunts or blunt wraps or sold cigar products with a marijuana-related flavor descriptor.