Tryptophan-Kynurenine Pathway Activation and Cognition in Virally Suppressed Women With HIV.

BACKGROUND: Immune and cognitive dysfunction persists even in virally suppressed women with HIV (VS-WWH). Since inflammation and HIV proteins induce the enzyme indoleamine 2,3-dioxygenase (IDO), converting tryptophan (T) to kynurenine (K) while producing downstream neurotoxic metabolites, we investigated IDO activation (KT ratio) in relation to cognition in VS-WWH and demographically similar women without HIV (WWoH). METHODS: Ninety-nine VS-WWH on stable antiretroviral therapy and 102 WWoH (median age 52 vs 54 years; 73% vs 74% Black, respectively) from the New York and Chicago sites of the Women's Interagency HIV Study (WIHS) completed a neuropsychological test battery assessing motor function, processing speed, attention/working memory, verbal fluency, verbal learning and memory, and executive function and had plasma measured for tryptophan-kynurenine metabolites through liquid chromatography-tandem mass spectrometry and monocyte-derived [soluble cluster of differentiation-14 (sCD14), soluble cluster of differentiation-163 (sCD163), monocyte chemoattractant protein-1 (MCP-1)] plus general inflammatory markers [tumor necrosis factor alpha-2 receptor (TNF-R2), high-sensitivity C-reactive protein, high-sensitivity interleukin-6] through enzyme-linked immunosorbent assays between 2017 and 2020. RESULTS: VS-WWH had a higher KT ratio (P < 0.01) and higher sCD14 levels (P < 0.05) compared with WWoH. Higher sCD163 was associated with higher KT ratio (R = 0.29, P < 0.01) and worse fine motor function in VS-WWH; after adjusting for sCD163 and sCD14 in multivariable regressions, higher KT ratio remained significantly associated with impaired fine motor function in VS-WWH only (standardized ß = -0.29, P < 0.05). IDO activation was not associated with cognition in WWoH. CONCLUSIONS: IDO activation (K:T) was associated with worse fine motor control in VS-WWH independent of measured systemic inflammation. Further studies investigating biological mechanisms linking IDO activation to fine motor function among VS-WWH are warranted.

Priorities and barriers for ageing well; results from stakeholder workshops in rural and urban Rwanda.

BACKGROUND: The National Older Person's Policy of 2021 in Rwanda highlights the need for social protection of older populations. However, there is a lack of local knowledge regarding the priorities and challenges to healthy aging faced by older people and their caregivers. OBJECTIVES: This study aimed to identify and compare the needs and priorities of older people and other stakeholders involved in caring for them in rural and urban areas of Rwanda. METHODS: The study was conducted in two locations, Kigali (urban) and Burera district (rural). Each site hosted two separate one-day workshops with older people (≥60 years) and stakeholders (all ages). Discussions were held in plenary and roundtable-groups to generate a list of the top 4 prioritized responses on areas of importance, priorities/enablers to be addressed, and obstacles to living a healthy and active life for older people. The research team identified similarities between stakeholder and older people's responses in each area and a socio-ecological model was used to categorize findings. RESULTS: There were substantial differences in responses between rural and urban areas and between older people and stakeholders. For each question posed, in each rural or urban area, there was only agreement between stakeholders and older people for a maximum of one response. Whereas, when comparing responses from the same participant groups in urban or rural settings, there was a maximum agreement of two responses, with two questions having no agreement in responses at all. Responses across all discussion-areas were mostly categorized within the Societal level, with Individual, Relationship, and Environment featuring less frequently. CONCLUSION: This study highlights the need for contextually curated interventions to address the concerns of older adults and their caregivers in rural and urban settings. An inclusive and multidimensional approach is needed to conquer the barriers that impede healthy aging, with input from various stakeholders.

Tryptophan-kynurenine metabolic pathway and daytime dysfunction in women with HIV.

Sleep disturbances are prevalent in women with HIV (WWH). Tryptophan-kynurenine (T-K) pathway metabolites are associated with alterations in actigraphy derived sleep measures in WWH, although may not always correlate with functional impairment. We investigated the relationship between T-K pathway metabolites and self-reported daytime dysfunction in WWH and women without HIV (WWoH). 141 WWH on stable antiretroviral therapy and 140 demographically similar WWoH enrolled in the IDOze Study had targeted plasma T-K metabolites measured using liquid chromatography-tandem mass spectrometry. We utilized the daytime dysfunction component of the Pittsburgh Sleep Quality Index (PSQI) to assess functional impairment across HIV-serostatus. Lower levels of 5-hydroxytryptophan and serotonin were associated with greater daytime dysfunction in all women. In WWH, daytime dysfunction was associated with increased kynurenic acid (R = 0.26, p < 0.05), and kynurenic acid-tryptophan (KA-T) ratio (R = 0.28, p < 0.01). WWH with daytime dysfunction had a 0.7 log fold increase in kynurenic acid compared to WWH without daytime dysfunction. Kynurenic acid levels and the KA-T ratio were associated with daytime dysfunction in WWH but not in WWoH. Longitudinal studies are needed to establish a causal relationship and directionality between T-K metabolic changes and sleep impairment in WWH.

A web-based positive-affect intervention to reduce stress and improve well-being in women living with HIV - feasibility and acceptability of a single-arm, pilot study.

Women living with HIV (WLWH) experience high rates of depression but are underrepresented in mental health research. Positive emotions are associated with beneficial health outcomes in WLWH and should be a targeted component of psychological interventions in this population. Positive psychological interventions aim to increase positive emotions through the use of simple exercises, such as keeping a gratitude journal. We conducted a single-arm feasibility/acceptability study of a five-week, self-guided, web-based positive affect skills intervention in a sample of WLWH (N = 23) who also participate in a longitudinal observational study, the Women's Interagency HIV Study. The intervention was feasible as measured by home practice and post-intervention assessment completion, and acceptable as measured by exit interview feedback regarding recommendation of the program to friends or others living with HIV. On average, participants completed home practice for about 8 out of 9 skills. The mean response for recommendation of the program to a friend was 9.26/10 (SD = 1.63) and the mean response for recommendation of the program to others living with HIV was 9.68/10 (SD = 0.82). Participant feedback will be used to adapt and enhance the delivery of this intervention. Further studies are needed to assess efficacy and impact on psychological outcomes.

Overnight urinary melatonin levels in women with and without HIV: An observational cohort study.

INTRODUCTION: Despite significant improvements in longevity and quality of life associated with antiretroviral therapy, individuals with HIV still suffer from a higher burden of sleep and circadian disruption and inflammatory-based diseases than individuals without HIV. While melatonin is a hormone that has a role in sleep and circadian regulation and has anti-inflammatory properties, the overnight concentration of the urinary melatonin metabolite has not yet been reported in people with HIV. METHODS: The aim of this study was to compare the overnight urinary melatonin metabolite levels in women aged 35-70 years with HIV (n = 151) to a well-matched comparison group of women without HIV (n = 147). All women wore a wrist actigraphy monitor and completed daily diaries documenting sleep timing and use of medications and drugs or alcohol for 10 days. Participants collected their overnight urine near the end of the monitoring period. RESULTS: Melatonin levels did not differ between women with or without HIV, but more than 40% of women had low levels of melatonin. Higher body mass index predicted lower levels of melatonin, and lower levels of melatonin were associated with lower sleep efficiency as assessed with wrist actigraphy. CONCLUSION: These data lay the foundation for exploration of the longitudinal consequences of endogenous melatonin levels for inflammatory-based diseases in aging women with and without HIV. Future studies should consider the use of supplemental melatonin to improve sleep in women with lower levels of melatonin.

A qualitative study to explore the healthcare-seeking experiences of men who have sex with men (MSM) and transgender women (TGW) in Rwanda.

BACKGROUND: Globally, men who have sex with men (MSM) and transgender women (TGW) encounter many challenging experiences when accessing health services compared to the general population. Stigma, discrimination, and punitive laws against same-sex relationships in some sub-Saharan African countries have made MSM and TGW more prone to depression, suicidal ideation, anxiety disorders, substance abuse, non-communicable diseases, and HIV. None of the prior studies in Rwanda on MSM and TGW had explored their lived experience in accessing health services. Accordingly, this study aimed at exploring the healthcare-seeking experiences of MSM and TGW in Rwanda. METHODS: This study utilized a qualitative research method employing a phenomenological design. Semi-structured in-depth interviews were conducted with 16 MSM and 12 TGW. Participants were recruited via purposive and snowball sampling approaches in five districts in Rwanda." RESULTS: Data were analyzed using a thematic analysis approach. Three main themes emerged from the study: (1) The healthcare experiences of MSM and TGW were generally dissatisfactory, (2) MSM and TGW hesitated to seek care unless they were severely ill, (3) MSM and TGW's perspectives on how to improve their health-seeking behavior. CONCLUSION: MSM and TGW in Rwanda continue to face negative experiences within the healthcare delivery settings. These experiences include mistreatment, refusal of care, stigma, and discrimination. Provision of services for MSM and TGW and On-the-job cultural competence training in the care of MSM and TGW patients is needed. Including the same training in the medical and health sciences curriculum is recommended. Furthermore, awareness and sensitization campaigns to improve the understanding of the existence of MSM and TGW and to foster acceptance of gender and sexual diversity in society are necessary.

The IDOze Study: The Link Between Sleep Disruption and Tryptophan-Kynurenine Pathway Activation in Women With Human Immunodeficiency Virus.

BACKGROUND: Poor sleep is associated with human immunodeficiency virus (HIV), particularly among women with HIV (WWH), although mechanisms are unclear. We explored cross-sectional associations between sleep disruption and tryptophan-kynurenine (T/K) pathway activation, measured by the kynurenine-to-tryptophan ratio (K:T). METHODS: HIV-uninfected women (HIV-) and WWH aged 35-70 years and on stable antiretroviral therapy were included. Sleep metrics were measured using wrist actigraphy. Plasma T/K pathway metabolites were measured using liquid chromatography-tandem mass spectrometry. Multivariate linear regression models examined relationships between K:T and actigraphy-based sleep metrics by HIV status. RESULTS: WWH (n = 153) and HIV- women (n = 151) were demographically similar. Among WWH, median CD4 was 751 cells/µL; 92% had undetectable HIV RNA. Compared to HIV- women, WWH had higher K:T (P < .001) and kynurenine (P = .01) levels but similar tryptophan levels (P = .25). Higher K:T was associated with more wake bouts (P = .001), more time awake after sleep onset (P = .01), and lower sleep efficiency (P = .03) in WWH only. CONCLUSIONS: HIV infection was associated with T/K pathway activation; this activation was associated with poorer sleep efficiency and more fragmented sleep. While longitudinal studies are needed to elucidate the directionality of these associations, these findings may help identify treatments to reduce sleep disruption in WWH by targeting residual inflammation and T/K pathway activation.

Infliximab for the treatment of CNS sarcoidosis: A multi-institutional series.

OBJECTIVE: To describe clinical and imaging responses in neurosarcoidosis to infliximab, a monoclonal antibody against tumor necrosis factor-α. METHODS: Investigators at 6 US centers retrospectively identified patients with CNS sarcoidosis treated with infliximab, including only patients with definite or probable neurosarcoidosis following rigorous exclusion of other causes. RESULTS: Of 66 patients with CNS sarcoidosis (27 definite, 39 probable) treated with infliximab for a median of 1.5 years, the mean age was 47.5 years at infliximab initiation (SD 11.7, range 24-71 years); 56.1% were female; 62.1% were white, 37.0% African American, and 3% Hispanic. Sarcoidosis was isolated to the CNS in 19.7%. Using infliximab doses ranging from 3 to 7 mg/kg every 4-8 weeks, MRI evidence of a favorable treatment response was observed in 82.1% of patients with imaging follow-up (n = 56), with complete remission of active disease in 51.8% and partial MRI improvement in 30.1%; MRI worsened in 1 patient (1.8%). There was clinical improvement in 77.3% of patients, with complete neurologic recovery in 28.8%, partial improvement in 48.5%, clinical stability in 18.2%, worsening in 3%, and 1 lost to follow-up. In 16 patients in remission when infliximab was discontinued, the disease recurred in 9 (56%), typically in the same neuroanatomic location. CONCLUSIONS: Most patients with CNS sarcoidosis treated with infliximab exhibit favorable imaging and clinical treatment responses, including some previously refractory to other immunosuppressive treatments. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with CNS sarcoidosis infliximab is associated with favorable imaging and clinical responses.