Changes in Cerebrospinal Fluid Proteins across the Spectrum of Untreated and Treated Chronic HIV-1 Infection.

Using the Olink Explore 1536 platform, we measured 1,463 unique proteins in 303 cerebrospinal fluid (CSF) specimens from four clinical centers that included uninfected controls and 12 groups of people living with HIV-1 infection representing the spectrum of progressive untreated and treated chronic infection. We present three initial analyses of these measurements: an overview of the CSF protein features of the sample; correlations of the CSF proteins with CSF HIV-1 RNA and neurofilament light chain protein (NfL) concentrations; and comparison of the CSF proteins in HIV-associated dementia ( HAD ) and neurosymptomatic CSF escape ( NSE ). These reveal a complex but coherent picture of CSF protein changes that includes highest concentrations of many proteins during CNS injury in the HAD and NSE groups and variable protein changes across the course of neuroasymptomatic systemic HIV-1 progression, including two common patterns, designated as lymphoid and myeloid patterns, related to the principal involvement of their underlying inflammatory cell lineages. Antiretroviral therapy reduced CSF protein perturbations, though not always to control levels. The dataset of these CSF protein measurements, along with background clinical information, is posted online. Extended studies of this unique dataset will provide more detailed characterization of the dynamic impact of HIV-1 infection on the CSF proteome across the spectrum of HIV-1 infection, and further the mechanistic understanding of HIV-1-related CNS pathobiology.

IgG and kappa free light chain CSF/serum indices: evaluating intrathecal immunoglobulin production in HIV infection in comparison with multiple sclerosis.

OBJECTIVES: To study intrathecal kappa free light chain (KFLC) synthesis in people living with HIV (PLWH) in comparison with multiple sclerosis (MS). METHODS: Cross-sectional analysis including 56 untreated and 150 well treated PLWH, and compared with 58 controls, and 223 MS patients. RESULTS: Elevated serum/cerebrospinal fluid (CSF) IgG and KFLC indices were observed in untreated PLWH. Seventy percent of untreated PLWH had KFLC index above 6.1, a threshold associated with clinically isolated syndrome/MS diagnosis. No association was found between KFCL index and CSF markers of neuronal injury in either PLWH or MS patients. CONCLUSIONS: HIV-related immune system dysfunction is often associated with an elevated KFLC index akin to those observed in MS. HIV infection should be considered as a differential diagnosis for patients presenting with neurological symptoms and increased intrathecal immunoglobulin synthesis.

Levels of Physical Activity, Enjoyment, Self-Efficacy for Exercise, and Social Support Before and After Metabolic and Bariatric Surgery: a Longitudinal Prospective Observational Study.

INTRODUCTION: Physical activity (PA) after metabolic and bariatric surgery (MBS) can influence weight loss, health status, and quality of life. Known mediators to participate in PA are enjoyment, self-efficacy, and social support. Little is known about PA behavior in MBS individuals. The aim of this study was to explore levels of PA and the PA mediators enjoyment, self-efficacy, and social support before and after MBS and to investigate changes over time. METHODS: Adults scheduled to undergo MBS were recruited from a Swedish university hospital. Accelerometer-measured and self-reported PA, body weight, and PA mediators were collected at baseline and at 12 to 18 months post-surgery. RESULTS: Among 90 individuals included, 50 completed the follow-up assessment and had valid accelerometer data. Sedentary time (minutes/day) was unchanged, but sedentary time as percentage of wear time decreased significantly from 67.2% to 64.5% (p<0.05). Time spent in light PA and total PA increased significantly from 259.3 to 288.7 min/day (p < 0.05) and from 270.5 to 303.5 min/day (p < 0.01), respectively. Step counts increased significantly from 6013 to 7460 steps/day (p < 0.01). There was a significant increase in self-reported PA, enjoyment, self-efficacy for exercise, and positive social support from family. The increase in PA mediators did not lead to a significant change in time spent in moderate to vigorous PA. CONCLUSION: The increase in PA-mediators was not associated with an increase in moderate to vigorous PA, but the strengthened PA mediators suggest potential for an increase in moderate to vigorous PA in patients undergoing MBS.

Mapping the World Health Organization Disability Assessment Schedule (WHODAS 2.0) onto SF-6D Using Swedish General Population Data.

BACKGROUND AND OBJECTIVE: Mapping algorithms can be used for estimating quality-adjusted life years (QALYs) when studies apply non-preference-based instruments. In this study, we estimate a regression-based algorithm for mapping between the World Health Organization Disability Assessment Schedule (WHODAS 2.0) and the preference-based instrument SF-6D to obtain preference estimates usable in health economic evaluations. This was done separately for the working and non-working populations, as WHODAS 2.0 discriminates between these groups when estimating scores. METHODS: Using a dataset including 2258 participants from the general Swedish population, we estimated the statistical relationship between SF-6D and WHODAS 2.0. We applied three regression methods, i.e., ordinary least squares (OLS), generalized linear models (GLM), and Tobit, in mapping onto SF-6D from WHODAS 2.0 at the overall-score and domain levels. Root mean squared error (RMSE) and mean absolute error (MAE) were used for validation of the models; R2 was used to assess model fit. RESULTS: The best-performing models for both the working and non-working populations were GLM models with RMSE ranging from 0.084 to 0.088, MAE ranging from 0.068 to 0.071, and R2 ranging from 0.503 to 0.608. When mapping from the WHODAS 2.0 overall score, the preferred model also included sex for both the working and non-working populations. When mapping from the WHODAS 2.0 domain level, the preferred model for the working population included the domains mobility, household activities, work/study activities, and sex. For the non-working population, the domain-level model included the domains mobility, household activities, participation, and education. CONCLUSIONS: It is possible to apply the derived mapping algorithms for health economic evaluations in studies using WHODAS 2.0. As conceptual overlap is incomplete, we recommend using the domain-based algorithms over the overall score. Different algorithms must be applied depending on whether the population is working or non-working, due to the characteristics of WHODAS 2.0.

Cohort profile: a longitudinal study of HIV infection in the central nervous system with focus on cerebrospinal fluid - the Gothenburg HIV CSF Study Cohort.

PURPOSE: In order to enable long-term follow-up of the natural course of HIV infection in the central nervous system, a longitudinal cohort study with repeated cerebrospinal fluid (CSF) analyses at intervals over time was initiated in 1985. When antiretrovirals against HIV were introduced in the late 1980s, short-term and long-term effects of various antiretroviral treatment (ART) regimens were added to the study. PARTICIPANTS: All adult people living with HIV (PLWH) who were diagnosed at or referred to the Department of Infectious Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden were asked to participate in the Gothenburg HIV CSF Study Cohort. PLWH with neurological symptoms or other clinical symptoms of HIV, as well as those with no symptoms of HIV infection, were included. Most participants were asymptomatic, which distinguishes this cohort from most other international HIV CSF studies. In addition, HIV-negative controls were recruited. These included people on HIV pre-exposure prophylaxis who served as lifestyle-matched controls to HIV-infected men who have sex with men. Since lumbar puncture (LP) is an invasive procedure, some PLHW only consented to participate in one examination. Furthermore, at the beginning of the study, several participants were lost to follow-up having died from AIDS. Of 662 PLWH where an initial LP was done, 415 agreed to continue with follow-up. Among the 415, 56 only gave permission to be followed with LP for less than 1 year, mainly to analyse the short-term effect of ART. The remaining 359 PLWH were followed up with repeated LP for periods ranging from >1 to 30 years. This group was defined as the 'longitudinal cohort'. So far, on 7 April 2022, 2650 LP and samplings of paired CSF/blood had been performed, providing a unique biobank. FINDINGS TO DATE: A general finding during the 37-year study period was that HIV infection in the central nervous system, as mirrored by CSF findings, appears early in the infectious course of the disease and progresses slowly in the vast majority of untreated PLWH. Combination ART has been highly effective in reducing CSF viral counts, inflammation and markers of neural damage. Minor CSF signs of long-term sequels or residual inflammatory activity and CSF escape (viral CSF blips) have been observed during follow-up. The future course of these changes and their clinical impact require further studies. FUTURE PLANS: PLWH today have a life expectancy close to that of non-infected people. Therefore, our cohort provides a unique opportunity to study the long-term effects of HIV infection in the central nervous system and the impact of ART and is an ongoing study.

Cost-Effectiveness of Prolonged Physical Activity on Prescription in Previously Non-Complying Patients: Impact of Physical Activity Mediators.

In Sweden, physical activity on prescription (PAP) is used to support patients in increasing their levels of physical activity (PA). The role of healthcare professionals in supporting PA behavior change requires optimization in terms of knowledge, quality and organization. This study aims to evaluate the cost-effectiveness of support from a physiotherapist (PT) compared to continued PAP at a healthcare center (HCC) for patients who remained insufficiently active after 6-month PAP treatment at the HCC. The PT strategy was constituted by a higher follow-up frequency as well as by aerobic physical fitness tests. The analysis was based on an RCT with a three-year time horizon, including 190 patients aged 27-77 with metabolic risk factors. The cost per QALY for the PT strategy compared to the HCC strategy was USD 16,771 with a societal perspective (including individual PA expenses, production loss and time cost for exercise, as well as healthcare resource use) and USD 33,450 with a healthcare perspective (including only costs related to healthcare resource use). Assuming a willingness-to-pay of USD 57,000 for a QALY, the probability of cost-effectiveness for the PT strategy was 0.5 for the societal perspective and 0.6 for the healthcare perspective. Subgroup analyses on cost-effectiveness based on individual characteristics regarding enjoyment, expectations and confidence indicated potential in identifying cost-effective strategies based on mediating factors. However, this needs to be further explored. In conclusion, both PT and HCC interventions are similar from a cost-effectiveness perspective, indicating that both strategies are equally valuable in healthcare's range of treatments.

Residual Central Nervous System Immune Activation Is Not Prevented by Antiretroviral Therapy Initiated During Early Chronic HIV Infection.

Background: Antiretroviral therapy (ART) initiated during acute infection can potentially impact the central nervous system (CNS) reservoir, but the differential long-term effects of ART initiation during early or late chronic infection are unknown. Methods: We included neuroasymptomatic people with human immunodeficiency virus (HIV) with suppressive ART initiated during chronic (>1 year since transmission) HIV with archived cerebrospinal fluid (CSF) and serum samples after 1 and/or ≥3 years of ART from a cohort study. CSF and serum neopterin was measured using a commercial immunoassay (BRAHMS, Germany). Results: In total, 185 people with HIV (median, 79 [interquartile range, 55-128] months on ART) were included. A significant inverse correlation was found between CD4+ T-cell count and CSF neopterin only at baseline (r = -0.28, P = .002), but not after 1 (r = -0.026, P = .8) or ≥3 (r -0.063, P = .5) years of ART. No significant differences were seen in CSF or serum neopterin concentrations between different pretreatment CD4+ T-cell strata after 1 or ≥3 (median, 6.6) years of ART. Conclusions: In people with HIV initiating ART during chronic infection, occurrence of residual CNS immune activation was not correlated with pretreatment immune status, even when treatment was initiated at high CD4+ T-cell counts, suggesting that the CNS reservoir, once established, is not differentially affected by the timing of ART initiation during chronic infection.

The Cost-Effectiveness of a Dance and Yoga Intervention for Girls with Functional Abdominal Pain Disorders.

BACKGROUND: Functional abdominal pain disorders (FAPDs) affect children worldwide, being more prevalent among girls. The individual and societal burdens of the disease are substantial, and evidence-based interventions are needed. Non-pharmacological treatments have generally produced promising results, with dance and yoga specifically having potential as an effective treatment option. Beside efficacy, the cost-effectiveness of interventions is important when prioritizing and allocating public resources. OBJECTIVE: This study evaluated the cost-effectiveness of an 8-month dance and yoga intervention for girls with functional abdominal pain or irritable bowel syndrome, based on a randomized control trial called 'Just in TIME'. METHODS: The intervention, performed in Sweden, was studied using a decision analysis tool, i.e., a decision tree within the trial followed by a Markov model with a time horizon of 10 years. The base case considered healthcare costs as well as productivity losses, measuring the effects in gained quality-adjusted life-years (QALYs) and presenting an incremental cost-effectiveness ratio (ICER). RESULTS: The base case results show that the intervention, compared with current practice, was the dominant strategy from both the 12-month and long-term perspectives. The sensitivity analyses indicated that the long-term, but not the short-term, findings were robust for different assumptions and changes in parameter estimates, resulting in ICERs similar to those of the base case scenario. CONCLUSIONS: Offering dance and yoga to young girls with FAPDs generates small QALY gains and monetary savings compared with standard healthcare and is likely cost-effective. These findings make a valuable contribution to an area where evidence-based and cost-effective treatment interventions are needed. CLINICAL TRIALS REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT02920268; Name: Just in TIME-Intervention With Dance and Yoga for Girls With Recurrent Abdominal Pain.

The effect of vitamin B supplementation on neuronal injury in people living with HIV: a randomized controlled trial.

Effective antiretroviral therapy has radically changed the course of the HIV pandemic. However, despite efficient therapy, milder forms of neurocognitive symptoms are still present in people living with HIV. Plasma homocysteine is a marker of vitamin B deficiency and has been associated with cognitive impairment. People living with HIV have higher homocysteine concentrations than HIV-negative controls, and we have previously found an association between plasma homocysteine concentration and CSF concentration of neurofilament light protein, a sensitive marker for ongoing neuronal injury in HIV. This prompted us to perform this randomized controlled trial, to evaluate the effect of vitamin B supplementation on neuronal injury in a cohort of people living with HIV on stable antiretroviral therapy. At the Department of Infectious Diseases at Sahlgrenska University Hospital in Gothenburg, Sweden, 124 virally suppressed people living with HIV were screened to determine eligibility for this study. Sixty-one fulfilled the inclusion criteria by having plasma homocysteine levels at or above 12 µmol/l. They were randomized (1:1) to either active treatment (with cyanocobalamin 0.5 mg, folic acid 0.8 mg and pyridoxine 3.0 mg) q.d. or to a control arm with a cross over to active treatment after 12 months. Cognitive function was measured repeatedly during the trial, which ran for 24 months. We found a significant correlation between plasma neurofilament light protein and plasma homocysteine at screening (n = 124, r = 0.35, P < 0.0001). Plasma homocysteine levels decreased by 35% from a geometric mean of 15.7 µmol/l (95% confidence interval 14.7-16.7) to 10.3 µmol/l (95% confidence interval 9.3-11.3) in the active treatment arm between baseline and Month 12. No significant change was detected in the control arm during the same time period [geometric mean 15.2 (95% confidence interval 14.3-16.2) versus geometric mean 16.5 µmol/l (95% confidence interval 14.7-18.6)]. A significant difference in change in plasma homocysteine levels was seen between arms at 12 months [-40% (95% confidence interval -48 to -30%), P < 0.001]. However, no difference between arms was seen in either plasma neurofilament light protein levels [-6.5% (-20 to 9%), P = 0.39], or cognitive measures [-0.08 (-0.33 to 0.17), P = 0.53]. Our results do not support a vitamin B-dependent cause of the correlation between neurofilament light protein and homocysteine. Additional studies are needed to further elucidate this matter.

Digitally distributed Yoga Intervention in Breast Cancer Rehabilitation (DigiYoga CaRe): protocol for a randomised controlled trial.

INTRODUCTION: Breast cancer is the most prevalent cancer among women. The treatment is extensive; in addition to surgery, various combinations of radiation therapy, chemotherapy and antibody and endocrine treatment can be applied. Cancer-related fatigue (CRF) is high in patients with breast cancer, peaking during chemotherapy, but may persist for several years. Physical activity has proven to be effective in reducing CRF in breast cancer rehabilitation, but many patients tend to be less active after the diagnosis. Yoga has a previously demonstrated effect on energy levels and digitally distributed yoga intervention can potentially increase accessibility in pandemic times and facilitate participation for patients susceptible to infection and those living far from organised rehabilitation opportunities. The purpose of this study, Digital Yoga Intervention in Cancer Rehabilitation (DigiYoga CaRe) is to investigate whether a 12-week digitally distributed yoga intervention can reduce CRF and stress, improve health-related quality of life (HRQL) and affect pro-inflammatory and metabolic markers in patients with breast cancer. METHODS AND ANALYSIS: This multicentre study will adopt a randomised controlled design including 240 persons after their breast cancer surgery. They will be randomised to a 12-week digitally distributed yoga intervention or to a control group. The intervention group practice yoga two times a week, one yoga class live-streamed to the patient's computer or mobile device and one prerecorded video class for self-training. The controls receive standardised care, gift cards for flowers and access to yoga video links after the data collection has ended. The primary analysis will be performed following the principle of intention to treat. Data will be collected by questionnaires, blood samples, accelerometers and interviews. ETHICS AND DISSEMINATION: The DigiYoga CaRe study was approved by the Regional Ethical Review Board in Lund. The final results of this study will be disseminated to conference, patient and public involvements and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT04812652.

The effects of a 5-year physical activity on prescription (PAP) intervention in patients with metabolic risk factors.

BACKGROUND: Increased physical activity (PA) has positive effects on health and longevity. In Swedish healthcare, the physical activity on prescription (PAP) method reportedly increases patients' PA levels for up to 12 months, but long-term follow ups are lacking. As it remains difficult to maintain lifestyle changes, our aim was to evaluate adherence and clinical effects at a 5-year follow-up of PAP treatment in primary healthcare. METHODS: This longitudinal, prospective cohort study included 444 patients, (56% female), aged 27-85 years, with at least one metabolic risk factor. Participants were offered PAP by nurses or physiotherapists. The PAP intervention included an individualised dialogue, a PA recommendation by written prescription, and individually adjusted follow-up over 5 years, according to the Swedish PAP model. Patient PA level, metabolic risk factors, and health related quality of life (HRQoL) were measured at baseline and at the 6-month, 1.5-year, 2.5-year, 3.5-year, and 5-year follow-ups. Estimated latent growth curves were used to examine levels and rates of change in the outcomes. RESULTS: The study dropout rate was 52%, with 215 of 444 patients completing the 5-year follow-up. At follow-up, the mean PA level had increased by 730 MET-minutes per week or 3 hours of moderate-intensity PA/week when compared to baseline. During the 5-year intervention, we observed significant positive changes (p ≤ 0.05) in 9 of 11 metabolic risk factors and HRQoL parameters: body mass index, waist circumference, systolic and diastolic blood pressure, fasting plasma glucose, triglycerides, cholesterol, high-density lipoprotein, and mental component summary. CONCLUSION: This first evaluation of a 5-year PAP intervention in primary care demonstrated positive long-term (5 years) effects regarding PA level, metabolic health, and HRQoL. The recorded long-term adherence was ~50%, which is in line with medical treatment. Despite limitations, PAP can have long-term effects in an ordinary primary care setting.

Viral Antigen and Inflammatory Biomarkers in Cerebrospinal Fluid in Patients With COVID-19 Infection and Neurologic Symptoms Compared With Control Participants Without Infection or Neurologic Symptoms.

Importance: Neurologic symptoms are common in COVID-19, but the central nervous system (CNS) pathogenesis is unclear, and viral RNA is rarely detected in cerebrospinal fluid (CSF). Objective: To measure viral antigen and inflammatory biomarkers in CSF in relation to neurologic symptoms and disease severity. Design, Setting, and Participants: This cross-sectional study was performed from March 1, 2020, to June 30, 2021, in patients 18 years or older who were admitted to Sahlgrenska University Hospital, Gothenburg, Sweden, with COVID-19. All patients had CSF samples taken because of neurologic symptoms or within a study protocol. Healthy volunteer and prepandemic control groups were included. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: Outcomes included CSF SARS-CoV-2 nucleocapsid antigen (N-Ag) using an ultrasensitive antigen capture immunoassay platform and CSF biomarkers of immune activation (neopterin, ß2-microglobulin, and cytokines) and neuronal injury (neurofilament light protein [NfL]). Results: Forty-four patients (median [IQR] age, 57 [48-69] years; 30 [68%] male; 26 with moderate COVID-19 and 18 with severe COVID-19 based on the World Health Organization Clinical Progression Scale), 10 healthy controls (median [IQR] age, 58 [54-60] years; 5 [50%] male), and 41 patient controls (COVID negative without evidence of CNS infection) (median [IQR] age, 59 [49-70] years; 19 [46%] male) were included in the study. Twenty-one patients were neuroasymptomatic and 23 were neurosymptomatic (21 with encephalopathy). In 31 of 35 patients for whom data were available (89%), CSF N-Ag was detected; viral RNA test results were negative in all. Nucleocapsid antigen was significantly correlated with CSF neopterin (r = 0.38; P = .03) and interferon γ (r = 0.42; P = .01). No differences in CSF N-Ag concentrations were found between patient groups. Patients had markedly increased CSF neopterin, ß2-microglobulin, interleukin (IL) 2, IL-6, IL-10, and tumor necrosis factor α compared with controls. Neurosymptomatic patients had significantly higher median (IQR) CSF interferon γ (86 [47-172] vs 21 [17-81] fg/mL; P = .03) and had a significantly higher inflammatory biomarker profile using principal component analysis compared with neuroasymptomatic patients (0.54; 95% CI, 0.03-1.05; P = .04). Age-adjusted median (IQR) CSF NfL concentrations were higher in patients compared with controls (960 [673-1307] vs 618 [489-786] ng/L; P = .002). No differences were seen in any CSF biomarkers in moderate compared with severe disease. Conclusions and Relevance: In this study of Swedish adults with COVID-19 infection and neurologic symptoms, compared with control participants, viral antigen was detectable in CSF and correlated with CNS immune activation. Patients with COVID-19 had signs of neuroaxonal injury, and neurosymptomatic patients had a more marked inflammatory profile that could not be attributed to differences in COVID-19 severity. These results highlight the clinical relevance of neurologic symptoms and suggest that viral components can contribute to CNS immune responses without direct viral invasion.

Blood biomarkers for HIV infection with focus on neurologic complications-A review.

Although clinical examinations, neuroimaging, and cerebrospinal fluid analyses are the most important ways to evaluate the impact of HIV infection on the brain and in diagnosis of opportunistic infections, several blood biomarkers including HIV RNA concentrations, CD4 +T-cell count, and neurofilament light chain protein (NfL) concentration, along with tests for opportunistic infections can provide important information for clinical decisions.

The value of powered mobility scooters from the perspective of elderly spouses of the users - a qualitative study.

PURPOSE: To explore spouses' experiences of the value of mobility scooters prescribed to their partner. MATERIAL AND METHODS: A descriptive design with a qualitative approach was used. Thirteen spouses (11 females) aged 65-86 years participated. Semi-structured interviews were conducted when the spouse's partner had had the mobility scooter for 4-6 months. The interviews were analysed using qualitative content analysis. RESULTS: The interviews showed primarily that the spouses experienced that their everyday lives and life situation had improved since their partner had received a mobility scooter. They reported that they could engage in activities of their own choice to a greater extent. The prescription of a mobility scooter to their partner had also yielded a sense of freedom related to shared activities. On the other hand, the spouses described some of the scooter's limitations. Three categories emerged: a sense of freedom related to the spouse's own activities, a sense of freedom related to shared activities and a somewhat restricted freedom. CONCLUSION: Prescription of a powered mobility scooter was of value to the users' spouses because it facilitated independent and shared activities and participation in the community. The value was mainly expressed as a sense of freedom when doing things on their own or together with their partner. Spouses are key persons in the rehabilitation of people with mobility restrictions. Their views on the assistive device may influence the rehabilitation process. Knowledge of spouses' experiences is thus crucial, as this may influence the future rehabilitation outcome.IMPLICATIONS FOR REHABILITATIONA powered mobility scooter prescribed to one partner eases everyday life and increases activity and participation for the spouse, which in turn may further improve the quality of life for the scooter user.The spouses' perspectives on their partners' mobility scooter use could be helpful in developing the design of the mobility device and in the prescription process.A mobility scooter has an added value by giving a sense of freedom and freedom to choose for the spouse as well as the scooter user.

Cerebrospinal Fluid Viral Load Across the Spectrum of Untreated Human Immunodeficiency Virus Type 1 (HIV-1) Infection: A Cross-Sectional Multicenter Study.

BACKGROUND: The aim of this large multicenter study was to determine variations in cerebrospinal fluid (CSF) HIV-RNA in different phases of untreated human immunodeficiency virus type 1 (HIV-1) infection and its associations with plasma HIV-RNA and other biomarkers. METHODS: Treatment naive adults with available CSF HIV-RNA quantification were included and divided into groups representing significant disease phases. Plasma HIV-RNA, CSF white blood cell count (WBC), neopterin, and albumin ratio were included when available. RESULTS: In total, 1018 patients were included. CSF HIV-RNA was in median (interquartile range [IQR]) 1.03 log10 (0.37-1.86) copies/mL lower than in plasma, and correlated with plasma HIV-RNA (r = 0.44, P < .01), neopterin concentration in CSF (r = 0.49, P < .01) and in serum (r = 0.29, P < .01), CSF WBC (r = 0.34, P < .01) and albumin ratio (r = 0.25, P < .01). CSF HIV-RNA paralleled plasma HIV-RNA in all groups except neuroasymptomatic patients with advanced immunodeficiency (CD4 < 200) and patients with HIV-associated dementia (HAD) or opportunistic central nervous system (CNS) infections. Patients with HAD had the highest CSF HIV-RNA (in median [IQR] 4.73 (3.84-5.35) log10 copies/mL). CSF > plasma discordance was found in 126 of 972 individuals (13%) and varied between groups, from 1% in primary HIV, 11% in neuroasymptomatic groups, up to 30% of patients with HAD. CONCLUSIONS: Our study confirms previous smaller observations of variations in CSF HIV-RNA in different stages of HIV disease. Overall, CSF HIV-RNA was approximately 1 log10 copies/mL lower in CSF than in plasma, but CSF discordance was found in a substantial minority of subjects, most commonly in patients with HAD, indicating increasing CNS compartmentalization paralleling disease progression.

Effects on health-related quality of life in the randomized, controlled crossover trial ADIRA (Anti-inflammatory Diet In Rheumatoid Arthritis).

BACKGROUND: Patients with Rheumatoid Arthritis (RA) often report impaired health-related quality of life (HrQoL) such as difficulties in daily life, pain, fatigue and an affected social life. Even when lowering disease activity, pharmacological treatment does not always resolve these factors. OBJECTIVE: To investigate if a proposed anti-inflammatory diet improves HrQoL in patients with RA. DESIGN: In this controlled crossover trial, 50 patients were randomized to start with either an intervention diet (anti-inflammatory) or a control diet (usual Swedish intake) for ten weeks followed by a wash out period before switching to the other diet. Participants received food equivalent to ~1100 kcal/day, five days/week, and instructions to consume similarly for the remaining meals. HrQoL was evaluated using Health Assessment Questionnaire (HAQ), 36-item Short Form Survey (SF-36), Visual Analogue Scales (VAS) for pain, fatigue and morning stiffness, and a time scale for morning stiffness. RESULTS: Forty-seven participants completed ≥1 diet period and were included in the main analyses. No significant difference between intervention and control diet at end of diet periods was observed for any outcome. However, significant improvements were obtained for SF-36 Physical Functioning (mean:5.79, SE: 2.12, 95% CI: 1.58, 10.01) during the intervention diet period. When excluding participants with anti-rheumatic medication changes, the differences between diet periods increased for most outcomes, favoring the intervention diet period, and the difference for SF-36 Physical Functioning became significant (n = 25, mean:7.90, 95% CI:0.56, 15.24, p = 0.036). CONCLUSIONS: In main analyses, the proposed anti-inflammatory diet did not significantly improve HrQoL for patients with RA compared to control diet. In sub-analyses, significant improvements in physical functioning were detected. Larger studies with consistent medication use and in populations more affected by the disease may be needed to obtain conclusive evidence.

Increased immune activation and signs of neuronal injury in HIV-negative people on preexposure prophylaxis.

OBJECTIVE: Persistent immune activation in the central nervous system and systemically are common in people living with HIV (PLHIV) despite antiretroviral therapy. It is not known whether this is generated by HIV replication or by other components such as coinfections and lifestyle-related factors. DESIGN: The aim of this study was to determine the importance of different factors; it is crucial to find well matched HIV-negative controls. In this context, HIV-negative persons on preexposure prophylaxis (PrEP) may constitute a suitable control group to PLHIV with similar lifestyle-related factors. METHODS: Cerebrospinal fluid (CSF) and blood were collected from 40 HIV-negative persons on PrEP and 20 controls without PrEP. Biomarkers of immune activation, blood--brain barrier (BBB) integrity and neuronal injury were analysed. RESULTS: CSF and serum ß2-microglobulin, serum neopterin and CSF neurofilament light protein were higher in persons on PrEP compared with controls. Furthermore, persons on PrEP had higher CSF/plasma albumin ratio, and matrix metalloproteinase-3 concentrations, indicating BBB dysfunction. Of persons on PrEP, 90% were cytomegalovirus (CMV)-positive compared to 65% of the controls. CMV-positive individuals as a group had higher levels of serum ß2-microglobulin than CMV-negative individuals (P < 0.05). Drug users had higher serum ß2-microglobulin compared to nonusers (P < 0.01). CONCLUSION: HIV-negative persons on PrEP had higher levels of biomarkers for immune activation, BBB impairment and neuronal injury, compared with volunteers without PrEP. Moreover, serum ß2-microglobulin was higher in CMV-positive than in CMV-negative individuals and in drug users compared with nonusers. These findings are important to consider when analysing immune activation and CNS injury in PLHIV, and emphasize the importance of appropriate controls.

Compartmentalization of cerebrospinal fluid inflammation across the spectrum of untreated HIV-1 infection, central nervous system injury and viral suppression.

OBJECTIVE: To characterize the evolution of central nervous system (CNS) inflammation in HIV-1 infection applying a panel of cerebrospinal fluid (CSF) inflammatory biomarkers to grouped subjects representing a broad spectrum of systemic HIV-1 immune suppression, CNS injury and viral control. METHODS: This is a cross-sectional analysis of archived CSF and blood samples, assessing concentrations of 10 functionally diverse soluble inflammatory biomarkers by immunoassays in 143 HIV-1-infected subjects divided into 8 groups: untreated primary HIV-1 infection (PHI); four untreated groups defined by their blood CD4+ T lymphocyte counts; untreated patients presenting with subacute HIV-associated dementia (HAD); antiretroviral-treated subjects with ≥1 years of plasma viral suppression; and untreated elite controllers. Twenty HIV-1-uninfected controls were included for comparison. Background biomarkers included blood CD4+ and CD8+ T lymphocytes, CSF and blood HIV-1 RNA, CSF white blood cell (WBC) count, CSF/blood albumin ratio, CSF neurofilament light chain (NfL), and CSF t-tau. FINDINGS: HIV-1 infection was associated with a broad compartmentalized CSF inflammatory response that developed early in its course and changed with systemic disease progression, development of neurological injury, and viral suppression. CSF inflammation in untreated individuals without overt HAD exhibited at least two overall patterns of inflammation as blood CD4+ T lymphocytes decreased: one that peaked at 200-350 blood CD4+ T cells/µL and associated with lymphocytic CSF inflammation and HIV-1 RNA concentrations; and a second that steadily increased through the full range of CD4+ T cell decline and associated with macrophage responses and increasing CNS injury. Subacute HAD was distinguished by a third inflammatory profile with increased blood-brain barrier permeability and robust combined lymphocytic and macrophage CSF inflammation. Suppression of CSF and blood HIV-1 infections by antiretroviral treatment and elite viral control were associated with reduced CSF inflammation, though not fully to levels found in HIV-1 seronegative controls.

Adolescent depression, early psychiatric comorbidities, and adulthood welfare burden: a 25-year longitudinal cohort study.

PURPOSE: Depression at all ages is recognized as a global public health concern, but less is known about the welfare burden following early-life depression. This study aimed to (1) estimate the magnitude of associations between depression in adolescence and social transfer payments in adulthood; and (2) address the impact of major comorbid psychopathology on these associations. METHODS: This is a longitudinal cohort study of 539 participants assessed at age 16-17 using structured diagnostic interviews. An ongoing 25-year follow-up linked the cohort (n = 321 depressed; n = 218 nondepressed) to nationwide population-based registries. Outcomes included consecutive annual data on social transfer payments due to unemployment, work disability, and public assistance, spanning from age 18 to 40. Parameter estimations used the generalized estimating equations approach. RESULTS: Adolescent depression was associated with all forms of social transfer payments. The estimated overall payment per person and year was 938 USD (95% CI 551-1326) over and above the amount received by nondepressed controls. Persistent depressive disorder was associated with higher recipiency across all outcomes, whereas the pattern of findings was less clear for subthreshold and episodic major depression. Moreover, depressed adolescents presenting with comorbid anxiety and disruptive behavior disorders evidenced particularly high recipiency, exceeding the nondepressed controls with an estimated 1753 USD (95% CI 887-2620). CONCLUSION: Adolescent depression is associated with considerable public expenditures across early-to-middle adulthood, especially for those exposed to chronic/persistent depression and psychiatric comorbidities. This finding suggests that the clinical heterogeneity of early-life depression needs to be considered from a longer-term societal perspective.

CSF Biomarkers in Patients With COVID-19 and Neurologic Symptoms: A Case Series.

OBJECTIVE: To explore whether hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and neurologic symptoms have evidence of CNS infection, inflammation, and injury using CSF biomarker measurements. METHODS: We assessed CSF SARS-CoV-2 RNA along with CSF biomarkers of intrathecal inflammation (CSF white blood cell count, neopterin, ß2-microglobulin, and immunoglobulin G index), blood-brain barrier integrity (albumin ratio), and axonal injury (CSF neurofilament light chain protein [NfL]) in 6 patients with moderate to severe coronavirus disease 2019 (COVID-19) and neurologic symptoms who had undergone a diagnostic lumbar puncture. Neurologic symptoms and signs included features of encephalopathies (4 of 6), suspected meningitis (1 of 6), and dysgeusia (1 of 6). SARS-CoV-2 infection was confirmed by real-time PCR analysis of nasopharyngeal swabs. RESULTS: SARS-CoV-2 RNA was detected in the plasma of 2 patients (cycle threshold [Ct] value 35.0-37.0) and in CSF at low levels (Ct 37.2, 38.0, 39.0) in 3 patients in 1 but not in a second real-time PCR assay. CSF neopterin (median 43.0 nmol/L) and ß2-microglobulin (median 3.1 mg/L) were increased in all. Median immunoglobulin G index (0.39), albumin ratio (5.35), and CSF white blood cell count (<3 cells/µL) were normal in all, while CSF NfL was elevated in 2 patients. CONCLUSION: Our results in patients with COVID-19 and neurologic symptoms suggest an unusual pattern of marked CSF inflammation in which soluble markers were increased but white cell response and other immunologic features typical of CNS viral infections were absent. While our initial hypothesis centered on CNS SARS-CoV-2 invasion, we could not convincingly detect SARS-CoV-2 as the underlying driver of CNS inflammation. These features distinguish COVID-19 CSF from other viral CNS infections and raise fundamental questions about the CNS pathobiology of SARS-CoV-2 infection.