Clinical markers of HIV predict redox-regulated neural and behavioral function in the sensorimotor system.

Even in the modern era of combination antiretroviral therapy, aberrations in motor control remain a predominant symptom contributing to age-related functional dependencies (e.g., neurocognitive impairment) in people with HIV (PWH). While recent evidence implicates aberrant mitochondrial redox environments in the modulation of neural oscillatory activity serving motor control in PWH, the contribution of important clinical and demographic factors on this bioenergetic-neural-behavioral pathway is unknown. Herein, we evaluate the predictive capacity of clinical metrics pertinent to HIV (e.g., CD4 nadir, time with viremia) and age on mitochondrial redox-regulated sensorimotor brain-behavior dynamics in 69 virally-suppressed PWH. We used state-of-the-art systems biology and neuroscience approaches, including Seahorse analyzer of mitochondrial energetics, EPR spectroscopy of intracellular oxidant levels, antioxidant activity assays pertinent to superoxide and hydrogen peroxide (H2O2) redox environments, and magnetoencephalographic (MEG) imaging to quantify sensorimotor oscillatory dynamics. Our results demonstrate differential effects of redox systems on the neural dynamics serving motor function in PWH. In addition, measures of immune stability and duration of compromise due to HIV had dissociable effects on this pathway, above and beyond the effects of age alone. Moreover, peripheral measures of antioxidant activity (i.e., superoxide dismutase) fully mediated the relationship between immune stability and current behavioral performance, indicative of persistent oxidative environments serving motor control in the presence of virologic suppression. Taken together, our data suggest that disease-related factors, in particular, are stronger predictors of current redox, neural and behavioral profiles serving motor function, which may serve as effective targets for alleviating HIV-specific alterations in cognitive-motor function in the future.

Medical student attitudes to patient involvement in healthcare decision-making and research.

OBJECTIVE: Patient involvement is used to describe the inclusion of patients as active participants in healthcare decision-making and research. This study aimed to investigate incoming year 1 medical (MBChB) students' attitudes and opinions regarding patient involvement in this context. METHODS: We established a staff-student partnership to formulate the design of an online research survey, which included Likert scale questions and three short vignette scenarios designed to probe student attitudes towards patient involvement linked to existing legal precedent. Incoming year 1 medical students (n=333) were invited to participate in the survey before formal teaching commenced. RESULTS: Survey data (49 participants) indicate that students were broadly familiar with, and supportive of, patient involvement in medical treatment. There was least support for patient involvement in conducting (23.9%), contributing to (37.0%) or communicating research (32.6%), whereas there was unanimous support for patients choosing treatment from a selection of options (100%). CONCLUSION: Incoming members of the medical profession demonstrate awareness of the need to actively involve patients in healthcare decision-making but are unfamiliar with the utility and value of such involvement in research. Further empirical studies are required to examine attitudes to patient involvement in healthcare.

Movement-related beta and gamma oscillations indicate parallels and disparities between Alzheimer's disease and HIV-associated neurocognitive disorder.

People with HIV (PWH) often develop HIV-related neurological impairments known as HIV-associated neurocognitive disorder (HAND), but cognitive dysfunction in older PWH may also be due to age-related disorders such as Alzheimer's disease (AD). Discerning these two conditions is challenging since the specific neural characteristics are not well understood and limited studies have probed HAND and AD spectrum (ADS) directly. We examined the neural dynamics underlying motor processing during cognitive interference using magnetoencephalography (MEG) in 22 biomarker-confirmed patients on the ADS, 22 older participants diagnosed with HAND, and 30 healthy aging controls. MEG data were transformed into the time-frequency domain to examine movement-related oscillatory activity and the impact of cognitive interference on distinct stages of motor programming. Both cognitively impaired groups (ADS/HAND) performed significantly worse on the task (e.g., less accurate and slower reaction time) and exhibited reductions in frontal and cerebellar beta and parietal gamma activity relative to controls. Disease-specific aberrations were also detected such that those with HAND exhibited weaker gamma interference effects than those on the ADS in frontoparietal and motor areas. Additionally, temporally distinct beta interference effects were identified, with ADS participants exhibiting stronger beta interference activity in the temporal cortex during motor planning, along with weaker beta interference oscillations dispersed across frontoparietal and cerebellar cortices during movement execution relative to those with HAND. These results indicate both overlapping and distinct neurophysiological aberrations in those with ADS disorders or HAND in key motor and top-down cognitive processing regions during cognitive interference and provide new evidence for distinct neuropathology.

Resting state network connectivity alterations in HIV: Parallels with aging.

The increasing incidence of age-related comorbidities in people with HIV (PWH) has led to accelerated aging theories. Functional neuroimaging research, including functional connectivity (FC) using resting-state functional magnetic resonance imaging (rs-fMRI), has identified neural aberrations related to HIV infection. Yet little is known about the relationship between aging and resting-state FC in PWH. This study included 86 virally suppressed PWH and 99 demographically matched controls spanning 22-72 years old who underwent rs-fMRI. The independent and interactive effects of HIV and aging on FC were investigated both within- and between-network using a 7-network atlas. The relationship between HIV-related cognitive deficits and FC was also examined. We also conducted network-based statistical analyses using a brain anatomical atlas (n = 512 regions) to ensure similar results across independent approaches. We found independent effects of age and HIV in between-network FC. The age-related increases in FC were widespread, while PWH displayed further increases above and beyond aging, particularly between-network FC of the default-mode and executive control networks. The results were overall similar using the regional approach. Since both HIV infection and aging are associated with independent increases in between-network FC, HIV infection may be associated with a reorganization of the major brain networks and their functional interactions in a manner similar to aging.

Oscillatory markers of neuroHIV-related cognitive impairment and Alzheimer's disease during attentional interference processing.

People with HIV (PWH) frequently experience mild cognitive decline, which is typically attributed to HIV-associated neurocognitive disorder (HAND). However, such declines could also be a sign of early Alzheimer's disease (AD) in older PWH. Distinguishing these two pathologies in PWH is exceedingly difficult, as there is a major knowledge gap regarding their neural and neuropsychological bases. In the current study, we begin to address this knowledge gap by recording magnetoencephalography (MEG) during a flanker interference task in 31 biomarker-confirmed patients on the AD spectrum (ADS), 25 older participants with HAND, and 31 cognitively-normal controls. MEG data was examined in the time-frequency domain using a data-driven approach. Our results indicated that the clinical groups (ADS/HAND) performed significantly worse than controls on the task and exhibited aberrations in interference-related theta and alpha oscillations, some of which were disease-specific. Specifically, patients (ADS/HAND) exhibited weaker interference activity in frontoparietal and cingulate cortices compared to controls, while the ADS group exhibited stronger theta interference than those with HAND in frontoparietal, occipital, and temporal cortices. These results reveal overlapping and distinct patterns of neurophysiological alterations among those with ADS and HAND in attentional processing centers and suggest the existence of unique oscillatory markers of each condition.

Mitochondrial redox environments predict sensorimotor brain-behavior dynamics in adults with HIV.

Despite virologic suppression, people living with HIV (PLWH) remain at risk for developing cognitive impairment, with aberrations in motor control being a predominant symptom leading to functional dependencies in later life. While the neuroanatomical bases of motor dysfunction have recently been illuminated, the underlying molecular processes remain poorly understood. Herein, we evaluate the predictive capacity of the mitochondrial redox environment on sensorimotor brain-behavior dynamics in 40 virally-suppressed PLWH and 40 demographically-matched controls using structural equation modeling. We used state-of-the-art approaches, including Seahorse Analyzer of mitochondrial function, electron paramagnetic resonance spectroscopy to measure superoxide levels, antioxidant activity assays and dynamic magnetoencephalographic imaging to quantify sensorimotor oscillatory dynamics. We observed differential modulation of sensorimotor brain-behavior relationships by superoxide and hydrogen peroxide-sensitive features of the redox environment in PLWH, while only superoxide-sensitive features were related to optimal oscillatory response profiles and better motor performance in controls. Moreover, these divergent pathways may be attributable to immediate, separable mechanisms of action within the redox environment seen in PLWH, as evidenced by mediation analyses. These findings suggest that mitochondrial redox parameters are important modulators of healthy and pathological oscillations in motor systems and behavior, serving as potential targets for remedying HIV-related cognitive-motor dysfunction in the future.

Convergent and divergent oscillatory aberrations during visuospatial processing in HIV-related cognitive impairment and Alzheimer's disease.

Adults with HIV frequently develop a form of mild cognitive impairment known as HIV-associated neurocognitive disorder (HAND), but presumably cognitive decline in older persons with HIV could also be attributable to Alzheimer's disease (AD). However, distinguishing these two conditions in individual patients is exceedingly difficult, as the distinct neural and neuropsychological features are poorly understood and most studies to date have only investigated HAND or AD spectrum (ADS) disorders in isolation. The current study examined the neural dynamics underlying visuospatial processing using magnetoencephalography (MEG) in 31 biomarker-confirmed patients on the ADS, 26 older participants who met criteria for HAND, and 31 older cognitively normal controls. MEG data were examined in the time-frequency domain, and a data-driven approach was utilized to identify the neural dynamics underlying visuospatial processing. Both clinical groups (ADS/HAND) were significantly less accurate than controls on the task and exhibited stronger prefrontal theta oscillations compared to controls. Regarding disease-specific alterations, those with HAND exhibited stronger alpha oscillations than those on the ADS in frontoparietal and temporal cortices. These results indicate both common and unique neurophysiological alterations among those with ADS disorders and HAND in regions serving visuospatial processing and suggest the underlying neuropathological features are at least partially distinct.

Matrigel Tunes H9 Stem Cell-Derived Human Cerebral Organoid Development.

Human cerebral organoids are readily generated from human embryonic stem cells and human induced pluripotent stem cells and are useful in studying human neurodevelopment. Recent work with human cerebral organoids have explored the creation of different brain regions and the impacts of soluble and mechanical cues. Matrigel is a gelatinous, heterogenous mixture of extracellular matrix proteins, morphogens, and growth factors secreted by Engelbreth-Holm-Swarm mouse sarcoma cells. It is a core component of almost all cerebral organoid protocols, generally supporting neuroepithelial budding and tissue polarization; yet, its roles and effects beyond its general requirement in organoid protocols are not well understood, and its mode of delivery is variable, including the embedding of organoids within it or its delivery in soluble form. Given its widespread usage, we asked how H9 stem cell-derived hCO development and composition are affected by Matrigel dosage and delivery method. We found Matrigel exposure influences organoid size, morphology, and cell type composition. We also showed that greater amounts of Matrigel promote an increase in the number of choroid plexus (ChP) cells, and this increase is regulated by the BMP4 pathway. These results illuminate the effects of Matrigel on human cerebral organoid development and the importance of delivery mode and amount on organoid phenotype and composition.

Epigenetic aging is associated with aberrant neural oscillatory dynamics serving visuospatial processing in people with HIV.

BACKGROUND: Despite effective antiretroviral therapy, cognitive impairment and other aging-related comorbidities are more prevalent in people with HIV (PWH) than in the general population. Previous research examining DNA methylation has shown PWH exhibit accelerated biological aging. However, it is unclear how accelerated biological aging may affect neural oscillatory activity in virally suppressed PWH, and more broadly how such aberrant neural activity may impact neuropsychological performance. METHODS: In the present study, participants (n = 134) between the ages of 23 - 72 years underwent a neuropsychological assessment, a blood draw to determine biological age via DNA methylation, and a visuospatial processing task during magnetoencephalography (MEG). Our analyses focused on the relationship between biological age and oscillatory theta (4-8 Hz) and alpha (10 - 16 Hz) activity among PWH (n=65) and seronegative controls (n = 69). RESULTS: PWH had significantly elevated biological age when controlling for chronological age relative to controls. Biological age was differentially associated with theta oscillations in the left posterior cingulate cortex (PCC) and with alpha oscillations in the right medial prefrontal cortex (mPFC) among PWH and seronegative controls. Stronger alpha oscillations in the mPFC were associated with lower CD4 nadir and lower current CD4 counts, suggesting such responses were compensatory. Participants who were on combination antiretroviral therapy for longer had weaker theta oscillations in the PCC. CONCLUSIONS: These findings support the concept of interactions between biological aging and HIV status on the neural oscillatory dynamics serving visuospatial processing. Future work should elucidate the long-term trajectory and impact of accelerated aging on neural oscillatory dynamics in PWH.

Regular cannabis use modulates the impact of HIV on the neural dynamics serving cognitive control.

BACKGROUND: Cannabis use and HIV are independently associated with decrements in cognitive control. However, the combined effects of HIV and regular cannabis use on the brain circuitry serving higher-order cognition are unclear. AIMS: Investigate the interaction between cannabis and HIV on neural interference effects during the flanker task and spontaneous activity in regions underlying higher-order cognition. METHODS: The sample consisted of 100 participants, including people with HIV (PWH) who use cannabis, PWH who do not use cannabis, uninfected cannabis users, and uninfected nonusers. Participants underwent an interview regarding their substance use history and completed the Eriksen flanker task during magnetoencephalography (MEG). MEG data were imaged in the time-frequency domain and oscillatory maps depicting the neural flanker interference effect were probed for group differences. Voxel time series were then assessed for group-level differences in spontaneous activity. RESULTS: Group differences in behavioral performance were identified along with group differences in theta and alpha neural interference responses in higher-order regions across the cortex, with nonusers with HIV generally exhibiting the most aberrant responses. Likewise, time series analyses indicated that nonusers with HIV also had significantly elevated spontaneous alpha activity in the left inferior frontal and dorsolateral prefrontal cortices (dlPFC). Finally, we found that spontaneous and oscillatory alpha activity were significantly coupled in the inferior frontal cortex and dlPFC among cannabis users, but not nonusers. CONCLUSIONS: Regular cannabis use appears to suppress the impact of HIV on spontaneous and oscillatory alpha deficits in the left inferior frontal cortex and dlPFC.

Signatures of somatosensory cortical dysfunction in Alzheimer's disease and HIV-associated neurocognitive disorder.

Alzheimer's disease is the most common type of dementia in the general population, while HIV-associated neurocognitive disorder is the most common neurological comorbidity in those infected with HIV and affects between 40 and 70% of this population. Both conditions are associated with cognitive impairment and have been associated with aberrant functioning in sensory cortices, but far less is known about their disparate effects on neural activity. Identifying such disparate effects is important because it may provide critical data on the similarities and differences in the neuropathology underlying cognitive decline in each condition. In the current study, we utilized magnetoencephalography, extensive neuropsychological testing and a paired-pulse somatosensory gating paradigm to probe differences in somatosensory processing in participants from two ongoing magnetoencephalography studies. The resulting participant groups included 27 cognitively normal controls, 26 participants with HIV-associated neurocognitive disorder and 21 amyloid biomarker-confirmed patients with Alzheimer's disease. The data were imaged using a beamformer and voxel time series were extracted to identify the oscillatory dynamics serving somatosensory processing, as well as the amplitude of spontaneous cortical activity preceding stimulation onset. Our findings indicated that people with Alzheimer's disease and HIV-associated neurocognitive disorder exhibit normal somatosensory gating but have distinct aberrations in other elements of somatosensory cortical function. Essentially, those with Alzheimer's disease exhibited accentuated neural responses to somatosensory stimulation, along with spontaneous gamma activity preceding stimulus onset. In contrast, those with HIV-associated neurocognitive disorder exhibited normal responses to somatosensory stimulation but had sharply elevated spontaneous gamma activity prior to stimulus onset. These distinct aberrations may reflect the impact of different neuropathological mechanisms underlying each condition. Further, given the differential pattern of deficits in somatosensory cortical function, these measures may function as unique biomarkers in each condition and be useful in identifying persons with HIV who may go on to develop Alzheimer's disease.

Case for persuasion in parental informed consent to promote rational vaccine choices.

There have been calls for mandatory vaccination legislation to be introduced into the UK in order to tackle the national and international rise of vaccine-preventable disease. While some countries have had some success associated with mandatory vaccination programmes, the Royal College of Paediatrics and Child Health (RCPCH) insist this is not a suitable option for the UK, a country which has seen historical opposition to vaccine mandates. There is a lack of comprehensive data to demonstrate a direct link between mandatory vaccination legislation and increased uptake. While there are examples whereby there has been an improvement, some studies suggest that comparable results can be obtained by strongly recommending vaccinations instead. The RCPCH insist that healthcare workers are ideally placed to engage and inform parents to make every interaction a 'vaccine opportunity'. This paper calls for a principled, rational approach to interpretations of autonomy which underpin parental informed consent. MacLean's concept of mutual persuasion could be a vehicle to ensuring parents are suitably informed of both the material risks associated with vaccine choices and to consider the rationality of their decisions, while ultimately upholding parental autonomy. It is argued that this, alongside infrastructural improvement, could create a more sustainable, long-term improvement in childhood vaccination rates in the UK than mandatory vaccination.

"It's having something that you've done it for": Applying Self-Determination Theory to participants' motivations in a for-cause physical activity event.

For-cause physical activity events reach many people. Little research has applied Self-Determination Theory to participants' experiences in for-cause physical activity events. This qualitative study explored participants' (n = 18) experiences in 5K for-cause physical activity events and intention to complete future events. Interviews were recorded and transcribed verbatim. Emergent coding assessed responses for themes. Constructs of competence and relatedness were most prevalent and an altruistic desire to support the cause. Participants highlighted feelings of community supporting their intention to complete future events. Overall, experiences aligned with Self-Determination Theory. Future studies may include altruism to understand leveraging opportunities for promoting physical activity.

Towards conjoint solidarity in healthcare.

Solidarity remains an ambiguous concept despite the long political tradition pertaining to concepts of fraternity, togetherness and collective values or goals. In healthcare ethics, it has been under-explored, perhaps due to the perception that it opposes individual autonomy. However, even where autonomy is interpreted as a liberal construct, the solidaristic act may be borne out of free choice, rather than stand in opposition to it. To complement the existing scholarship, the concept of 'conjoint solidarity' in healthcare is proposed. Conjoint solidarity may be defined as 'the shared goal of all healthcare stakeholders (encapsulating all healthcare practitioners and service users) to accept or adopt a duty to assist one another to achieve improved healthcare outcomes'. The practical application of both medical autonomy and conjoint solidarity is through the process of shared decision making. An epistemic approach may be applied to 'pool information' from healthcare practitioners and patients to determine what improved healthcare outcomes are. This collective approach may also serve to address healthcare issues such exclusion, othering, paternalism and conflict of interest. Furthermore, in extending this relational approach to justice, consideration may be given to how improved healthcare may be attained in a manner that allows patients to also play their part. To this end, medical autonomy, conjoint solidarity and relational distributive justice may be considered interdependent constructs, which, when fully utilized, may help improve healthcare.

Measurement of Physical Activity with Wrist-Worn ActiGraph GT3X+ in Older Women.

Higher wear compliance has been seen with wrist placed accelerometers versus hip placed. Performance of wrist placed ActiGraph GT3X+ accelerometer (GT3X+, ActiGraph LLC, Pensacola, FL) in assessing physical activity (PA) remains unclear. PURPOSE: This study examined GT3X+'s performance in measuring PA energy expenditure (PAEE) and classifying PA intensity in older women. METHODS: Women [n = 89, age = 65.6 (4.3)] wore GT3X+ and SenseWear Armband Mini (SWAM, BodyMedia Inc. Pittsburgh, PA) for 2 weeks. Concurrently, doubly labeled water (DLW) determined total daily energy expenditure (TDEE). Resting energy expenditure (REE) was determined by Indirect Calorimetry. Data was processed using manufacturer-provided software. Bivariate correlations, Intra Class Correlations, and Bland-Altman plots were performed to evaluate agreement between GT3X+ and criterion measures for sedentary time, light and moderate-to-vigorous PA (determined by SWAM) and PAEE (determined by SWAM and by DLW and REE). Epoch-by-epoch analysis evaluated discrepancy and agreement of PA intensity classification between GT3X+ and SWAM. RESULTS: For PAEE, GT3X+ showed moderate correlations with criterion measures (r = 0.413, 0.400 with SWAM; r = 0.564, 0.501 with DLW and REE), but Bland-Altman plots showed large variability. When estimating time spent in PA intensity, GT3X+ underestimated sedentary time and overestimated PA intensity compared to SWAM. During epoch-by-epoch analysis, GT3X+ misclassified light intensity PA as moderate-to-vigorous PA 72% of the time. Counts per minute showed strong correlations with criterion measures (r = 0.68, 0.625 for SWAM and DLW and REE respectively). CONCLUSION: Current equations and cut points do not provide accurate measures of PA with wrist-worn GT3X+ in older women.

Reflected appraisals across multiple reference groups: Discrepancies in self and individual delinquency.

We explore the implications of multiple reference groups for symbolic interaction explanations of delinquency. Specifically, we test the idea that dissimilarity in reflected appraisals across reference groups weakens the effect of the appraisals of a single group on behavior. We also assess whether the relative influence of different reflected appraisals is moderated by differences in the amount of time spent in and attachment to the roles taken among specific reference groups. Using data from the National Youth Survey, our findings mostly support symbolic interactionist predictions: Dissimilarity in reference groups' reflected appraisals weakens the influence of a single group's appraisals on behavior. We also found some evidence that, relatively, the more time an individual spends and the more attached they are to a role in a particular reference group, the more strongly correlated the respective appraisals are with delinquent behavior. Contrary to our predictions, we found that relatively strong attachments to one's role with their parents weakens the influence of parental reflected appraisals as a rule violator.

Gray matter volumes discriminate cognitively impaired and unimpaired people with HIV.

BACKGROUND: Current diagnostic criteria of HIV-associated neurocognitive disorders (HAND) rely on neuropsychological assessments. The aim of this study was to evaluate if gray matter volumes (GMV) can distinguish people with HAND, neurocognitively unimpaired people with HIV (unimpaired PWH), and uninfected controls using linear discriminant analyses. METHODS: A total of 231 participants, including 110 PWH and 121 uninfected controls, completed a neuropsychological assessment and an MRI protocol. Among PWH, HAND (n = 48) and unimpaired PWH (n = 62) designations were determined using the widely accepted Frascati criteria. We then assessed the extent to which GMV, corrected for intracranial volume, could accurately distinguish the three groups using linear discriminant analysis. Sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, area under the curve (AUC), and accuracy were computed for each model using the classification results based on GMV compared to the neuropsychological assessment. RESULTS: The best performing model was comprised of bilaterally combined GMV and was stratified by sex. Among males, sensitivity was 85.2% (95% CI: 66.3%-95.8%), specificity was 97.0% (95% CI: 91.6%-99.4%), and the AUC was 0.91 (95% CI: 0.83-0.99). Among females, sensitivity was 100.0% (95% CI: 83.9%-100.0%), specificity was 98.8% (95% CI: 93.4%-100.0%), and the AUC was 0.99 (95% CI: 0.98-1.00). CONCLUSIONS: GMV accurately discriminated HAND from unimpaired PWH and controls. Measures of GMV may be highly sensitive to HAND, and revisions to the Frascati criteria should consider including GMV in conjunction with a neuropsychological assessment to diagnose HAND.

Cannabis use impacts pre-stimulus neural activity in the visual cortices of people with HIV.

People with HIV (PWH) use cannabis at a higher rate than the general population, but the influence on neural activity is not well characterized. Cannabis use among PWH may have a beneficial effect, as neuroinflammation is known to be a critical problem in PWH and cannabis use has been associated with a reduction in proinflammatory markers. Thus, it is important to understand the net impact of cannabis use on brain and cognitive function in PWH. In this study, we collected magnetoencephalographic (MEG) brain imaging data on 81 participants split across four demographically matched groups (i.e., PWH using cannabis, controls using cannabis, non-using PWH, and non-using controls). Participants completed a visuospatial processing task during MEG. Time-frequency resolved voxel time series were extracted to identify the dynamics of oscillatory and pre-stimulus baseline neural activity. Our results indicated strong theta (4-8 Hz), alpha (10-16 Hz), and gamma (62-72 Hz) visual oscillations in parietal-occipital brain regions across all participants. PWH exhibited significant behavioral deficits in visuospatial processing, as well as reduced theta oscillations and elevated pre-stimulus gamma activity in visual cortices, all of which replicate prior work. Strikingly, chronic cannabis use was associated with a significant reduction in pre-stimulus gamma activity in the visual cortices, such that PWH no longer statistically differed from controls. These results provide initial evidence that cannabis use may normalize some neural aberrations in PWH. This study fills an important gap in understanding the impact of cannabis use on brain and cognitive function in PWH.

Neuroinflammatory profiles regulated by the redox environment predicted cognitive dysfunction in people living with HIV: A cross-sectional study.

BACKGROUND: Despite effective combination antiretroviral therapy (cART), people living with HIV (PLWH) remain at risk for developing neurocognitive impairment primarily due to systemic inflammation that persists despite virologic suppression, albeit the mechanisms underlying such inflammation are poorly understood. METHODS: Herein, we evaluate the predictive capacity of the mitochondrial redox environment on circulating neuro- and T-lymphocyte-related inflammation and concomitant cognitive function in 40 virally-suppressed PLWH and 40 demographically-matched controls using structural equation modeling. We used state-of-the-art systems biology approaches including Seahorse Analyzer of mitochondrial function, electron paramagnetic resonance (EPR) spectroscopy to measure superoxide levels, antioxidant activity assays, and Meso Scale multiplex technology to quantify inflammatory proteins in the periphery. FINDINGS: We observed disturbances in mitochondrial function and the redox environment in PLWH compared to controls, which included reduced mitochondrial capacity (t(76) = -1.85, p = 0.034, 95% CI: -∞,-0.13), elevated levels of superoxide (t(75) = 1.70, p = 0.047, 95% CI: 8.01 E 3, ∞) and alterations in antioxidant defense mechanisms (t(74) = 1.76, p = 0.041, 95% CI: -710.92, ∞). Interestingly, alterations in both superoxide- and hydrogen peroxide-sensitive redox environments were differentially predictive of neuro-, but not T-lymphocyte-related inflammatory profiles in PLWH and controls, respectively (ps < 0.026). Finally, when accounting for superoxide-sensitive redox pathways, neuroinflammatory profiles significantly predicted domain-specific cognitive function across our sample (ß = -0.24, p = 0.034, 95% CI: -0.09, -0.004 for attention; ß = -0.26, p = 0.018, 95% CI: -0.10, -0.01 for premorbid function). INTERPRETATION: Our results suggest that precursors to neuroinflammation apparent in PLWH (i.e., mitochondrial function and redox environments) predict overall functionality and cognitive dysfunction and importantly, may serve as a proxy for characterizing inflammation-related functional decline in the future. FUNDING: National Institute of Mental Health, National Institute for Neurological Disorders and Stroke, National Institute on Drug Abuse, National Science Foundation.

Lessons from the vaginal mesh scandal: enhancing the patient-centric approach to informed consent for medical device implantation.

The vaginal mesh scandal, in which thousands of women were irreversibly maimed by polypropylene mesh, revealed multilevel failures in medical device regulation and implantation, demonstrating that patient-centric care has not yet fully transcended from policy into practice. In law, informed consent is considered by a two-stage test: reasonable treatment and patient information disclosure. The standard of reasonable treatment is determined according to what is deemed acceptable in accordance with a body of medical opinion. However, such bodies of medical opinion were vulnerable to external influence from device manufactures. Vaginal mesh manufacturers were found to have had financial links to research, royal colleges, and influential clinicians, which then influenced the basis of the evidence-based practice that often guides such bodies of medical opinion. According to the Independent Medicines and Medical Device Safety Report, patients' mesh complications were also frequently under-reported and patient-based evidence of harm disregarded. Patients were also not sufficiently informed of the material risks or reasonable alternatives to mesh, which is required of the second stage of informed consent pertaining to information disclosure. This paper makes the following recommendations: that conflict of interest disclosure be mandated, that greater value be afforded to patient-based evidence to improve evaluation of treatments, and that information disclosure for informed consent should relate to the risks, benefits, and alternatives to the surgical procedure and medical device. This will ensure that patients can evaluate whether surgeons are offering unbiased treatment options and are also informed of the potential long-term risks associated with device implantation.