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 contributed by 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 CSF proteins in HIV-associated dementia (HAD) and neurosymptomatic CSF escape (NSE). These reveal a complex but coherent picture of CSF protein changes with highest concentrations of many proteins during CNS injury in the HAD and NSE groups and variable protein changes across the course of systemic HIV-1 progression that included two common patterns, designated as lymphoid and myeloid patterns, related to 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 supplement this report to provide more detailed characterization of the dynamic impact of HIV-1 infection on the CSF proteome across the spectrum of HIV-1 infection, advancing 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.

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.

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.

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.

What is the time cost of exercise? Cost of time spent on exercise in a primary health care intervention to increase physical activity.

BACKGROUND: In health care interventions aimed at increased physical activity, the individual's time spent on exercise is a substantial input. Time costs should therefore be considered in cost-effectiveness analyses. The aim of this study was to estimate the cost of time spent on exercise among 333 primary health care patients with metabolic risk factors receiving physical activity on prescription. METHODS: Based on a theoretical framework, a yardstick was constructed with experience of work (representing claim of salary as compensation) as the lower anchor-point, and experience of leisure activity forgone due to extended exercise time (no claim) as the higher anchor-point. Using this yardstick experience of exercise can be valued. Another yardstick was constructed with experience of cleaning at home in combination with willingness to pay for cleaning as the lowest anchor-point. RESULTS: The estimated costs of exercise time were between 14 and 37% of net wages, with physical activity level being the most important factor in determining the cost. Among sedentary individuals, the time cost was 21-51% of net wages while among individuals performing regular exercise it was 2-10%. When estimating the cost of time spent on exercise in a cost-effectiveness analysis, experience of exercise, work, leisure activity forgone, and cleaning at home (or other household work that may be relevant to purchase) should be measured. The individual's willingness to pay for cleaning at home and their net salary should also be measured. CONCLUSIONS: When using a single valuation of cost of time spent on exercise in health care interventions, for employed participants 15-30% of net salary should be used. Among unemployed individuals, lower cost estimation should be applied. Better precision in cost estimations can be achieved if participants are stratified by physical activity levels.Trial registration The study was conducted as a survey of existing clinical physical activity on prescription work, and was approved by the Regional Ethical Review Board in Gothenburg, Sweden (ref: 678-14).

Cerebrospinal fluid levels of glial marker YKL-40 strongly associated with axonal injury in HIV infection.

BACKGROUND: HIV-1 infects the central nervous system (CNS) shortly after transmission. This leads to a chronic intrathecal immune activation. YKL-40, a biomarker that mainly reflects activation of astroglial cells, has not been thoroughly investigated in relation to HIV. The objective of our study was to characterize cerebrospinal fluid (CSF) YKL-40 in chronic HIV infection, with and without antiretroviral treatment (ART). METHODS: YKL-40, neopterin, and the axonal marker neurofilament light protein (NFL) were analyzed with ELISA in archived CSF samples from 120 HIV-infected individuals (85 untreated neuroasymptomatic patients, 7 with HIV-associated dementia, and 28 on effective ART) and 39 HIV-negative controls. RESULTS: CSF YKL-40 was significantly higher in patients with HIV-associated dementia compared to all other groups. It was also higher in untreated neuroasymptomatic individuals with CD4 cell count < 350 compared to controls. Significant correlations were found between CSF YKL-40 and age (r = 0.38, p < 0.001), CD4 (r = - 0.36, p < 0.001), plasma HIV RNA (r = 0.35, p < 0.001), CSF HIV RNA (r = 0.35, p < 0.001), CSF neopterin (r = 0.40, p < 0.001), albumin ratio (r = 0.44, p < 0.001), and CSF NFL (r = 0.71, p < 0.001). Age, CD4 cell count, albumin ratio, and CSF HIV RNA were found as independent predictors of CSF YKL-40 concentrations in multivariable analysis. In addition, CSF YKL-40 was revealed as a strong independent predictor of CSF NFL together with age, CSF neopterin, and CD4 cell count. CONCLUSIONS: CSF YKL-40 is a promising biomarker candidate for understanding the pathogenesis of HIV in the CNS. The strong correlation between CSF YKL-40 and NFL suggests a pathogenic association between astroglial activation and axonal injury, and implies its utility in assessing the prognostic value of YKL-40.

Factors associated with blood culture positivity in patients with complicated skin and skin structure infection-a population-based study.

Skin and skin structure infection (SSSI) is classified as complicated (cSSSI) if it involves deep subcutaneous tissue or requires surgery. Factors associated with blood culture sampling and bacteremia have not been established in patients with cSSSI. Moreover, the benefit of information acquired from positive blood culture is unknown. The aim of this study was to address these important issues. In this retrospective population-based study from two Nordic cities, a total of 460 patients with cSSSI were included. Blood cultures were drawn from 258 (56.1%) patients and they were positive in 61 (23.6%) of them. Factors found to be associated with more blood culture sampling in multivariate analysis were diabetes, duration of symptoms shorter than 2 days and higher C-reactive protein (CRP) level. Whereas factors associated with less frequent blood culture sampling were peripheral vascular disease and a surgical wound infection. In patients from whom blood cultures were taken, alcohol abuse was the only factor associated with culture positivity, as CRP level was not. Patients with a positive blood culture had antibiotic streamlining more often than non-bacteremic patients. A high rate of blood culture positivity in patients with cSSSI was observed. Factors related to more frequent blood culture sampling were different from those associated with a positive culture.

Which patients benefit from physical activity on prescription (PAP)? A prospective observational analysis of factors that predict increased physical activity.

BACKGROUND: There is robust evidence that regular physical activity (PA) has positive health effects. However, the best PA methods and the most important correlates for promoting PA remain unclear. Physical activity on prescription (PAP) aims to increase the patient's motivation for and level of PA. This study investigated possible predictive baseline correlates associated with changes in the PA level over a 6-month period of PAP treatment in order to identify the primary care patients most likely to benefit from a PAP intervention. METHODS: The study included 444 patients with metabolic risk factors who were aged 27 to 85 years and physically inactive. The patients received PAP treatment that included individual counseling plus an individually-tailored PA recommendation with a written prescription and individualised structured follow-up for 6 months. Eight baseline correlates of PA were analysed against the PA level at the 6-month follow-up in a predictor analysis. RESULTS: Five baseline correlates predicted the PA level at the 6-month follow-up: self-efficacy expectations for changing PA; the patient's preparedness and confidence regarding readiness to change PA; a BMI <  30; and a positive valued physical health. The proportion of patients increasing the PA level and achieving a PA level that was in accordance with public health recommendations was higher with a positive valued baseline correlate. The odds of achieving the recommended PA level increased substantially when 2 to 4 predictive correlates were present. PA levels increased to a greater extent among patients with low PA at baseline than patients with high PA at baseline, especially in combination with 2 to 4 positively-valued correlates (87-95% vs. 62-75%). CONCLUSIONS: This study identified potential predictive correlates of an increased PA level after a 6-month PAP intervention. This contributes to our understanding of PAP and could help individualise PAP support. The proportion of patients with the lowest PA level at baseline increased their PA level in a higher extent (84%) and thus may benefit the most from PAP. These results have clinical implications for behavioural change in those patients having the greatest health gains by increasing their PA level. TRIAL REGISTRATION: ClinicalTrials.gov ; NCT03586011 . Retrospectively registered on July 17, 2018.

Cost-effectiveness and quality of life of a diet intervention postpartum: 2-year results from a randomized controlled trial.

BACKGROUND: Pregnancy has been identified as a contributor to obesity. We have shown that a diet intervention postpartum produced a 2-y weight loss of 8%. Here, we present the impact of the diet intervention on cost-effectiveness and explore changes in quality of life (QOL). METHODS: A total of 110 postpartum women with overweight/obesity were randomly assigned to diet (D-group) or control (C-group). D-group received a 12-wk diet intervention within primary health care followed by monthly emails up to the 1-y follow-up. C-group received a brochure. Changes in QOL were measured using the 36-item Short Form Health Survey and EQ-5D. The analysis of cost-effectiveness was a cost-utility analysis with a health care perspective and included costs of intervention for stakeholder, quality-adjusted life-years (QALYs) gained and savings in health care. The likelihood of cost-effectiveness was examined using the net monetary benefit method. RESULTS: The D-group increased their QOL more than the C-group at 12 wk. and 1 y, with pronounced differences for the dimensions general health and mental health, and the mental component summary score (all p < 0.05). Cost per gained QALY was 1704-7889 USD. The likelihood for cost-effectiveness, based on a willingness to pay 50,000 USD per QALY, was 0.77-1.00. CONCLUSIONS: A diet intervention that produced clinically relevant postpartum weight loss also resulted in increased QOL and was cost-effective. TRIAL REGISTRATION: Clinical trials, NCT01949558 , 2013-09-24.

Anti-Human Immunodeficiency Virus Antibodies in the Cerebrospinal Fluid: Evidence of Early Treatment Impact on Central Nervous System Reservoir?

Background: Despite effective antiretroviral therapy (ART), human immunodeficiency virus (HIV) likely persists in the central nervous system (CNS) in treated individuals. We examined anti-HIV antibodies in cerebrospinal fluid (CSF) and blood as markers of persistence. Methods: Human immunodeficiency virus antibodies were measured in paired CSF and serum before and after long-term treatment of chronic (n = 10) and early infection (n = 12), along with untreated early infection (n = 10). Results: Treatment of chronic infection resulted in small reductions of anti-HIV antibodies in CSF and serum despite >10 years of suppressive ART. In untreated early infection, anti-HIV antibodies emerged in blood by day 30, whereas CSF antibodies reached similar levels 2 weeks later. Compared with long-term treatment of chronic infection, early ART initiation reduced CSF antibodies by 43-fold (P > .0001) and blood antibodies by 7-fold (P = .0003). Two individuals receiving pre-exposure prophylaxis and then ART early after infection failed to develop antibodies in CSF or blood, whereas CSF antibodies were markedly reduced in the Berlin patient. Conclusions: To the extent that differential CSF and blood antibodies indicate HIV persistence, these data suggest a relative delay in establishment of the CNS compared with the systemic HIV reservoir that provides an opportunity for early treatment to have a greater impact on the magnitude of long-term CNS infection.

Cost-effectiveness of antibiotic prophylaxis in elective cesarean section.

BACKGROUND: The proportion of pregnant women delivered by cesarean section has increased steadily during the past three decades. The risk of infection is 10-fold augmented after elective cesarean section compared to vaginal delivery. Antibiotic prophylaxis may reduce endometritis by 62% and superficial wound infection by 38% after elective cesarean section. International guidelines recommend antibiotic prophylaxis in elective cesarean section, but this procedure is not routinely followed in Sweden. Studies of costs of antibiotic prophylaxis in cesarean section show conflicting results and are based on substantially different incidence of postoperative infections. No study of costs of antibiotic prophylaxis in elective cesarean section in a Swedish or Nordic context has been pursued. The aim of this study was to investigate if antibiotic prophylaxis is cost-reducing in elective cesarean section in Örebro County, Sweden. METHODS: All women undergoing elective cesarean in the Region Örebro County health care system during 2011-2012 were eligible for inclusion. Postoperative infections and risk factors for infections were registered. A hypothetical situation in which all participants had received antibiotic prophylaxis was compared to the actual situation, in which none of them had received antibiotic prophylaxis. The reduction in the risk of postoperative infections resulting from antibiotic prophylaxis was based on a meta-analysis. Costs for in-patient care of postoperative infections were extracted from the accounting system, and costs for out-patient care were calculated according to standard costs. Costs for antibiotic prophylaxis were calculated and compared with the cost reduction that would be implied by the introduction of such prophylaxis. RESULTS: The incidences of deep and superficial surgical site infection were 3.5% and 1.3% respectively. Introduction of antibiotic prophylaxis would reduce health care costs by 31 Euro per cesarean section performed (95% credible interval 4-58 Euro). The probability of cost-saving was 99%. CONCLUSIONS: Antibiotic prophylaxis in elective cesarean section is cost-reducing in this health care setting. Our results indicate that the introduction of antibiotic prophylaxis in elective cesarean section can also be cost-saving in low infection rate settings.Trial registration Ethical approval was given by the Regional Ethical Review Board in Uppsala (registration number 2013/484).

Blood-Brain Barrier Disruption Is Initiated During Primary HIV Infection and Not Rapidly Altered by Antiretroviral Therapy.

Background: We explored the establishment of abnormal blood-brain barrier (BBB) permeability and its relationship to neuropathogenesis during primary human immunodeficiency virus (HIV) infection by evaluating the cerebrospinal fluid (CSF) to serum albumin quotient (QAlb) in patients with primary HIV infection. We also analyzed effects of initiating combination antiretroviral therapy (cART). Methods: The QAlb was measured in longitudinal observational studies of primary HIV infection. We analyzed trajectories of the QAlb before and after cART initiation, using mixed-effects models, and associations between the QAlb and the CSF level of neurofilament light chain (NFL), the ratio of N-acetylaspartate to creatinine levels (a magnetic resonance spectroscopy neuronal integrity biomarker), and neuropsychological performance. Results: The baseline age-adjusted QAlb was elevated in 106 patients with primary HIV infection (median time of measurement, 91 days after infection), compared with that in 64 controls (P = .02). Before cART initiation, the QAlb increased over time in 84 participants with a normal baseline QAlb (P = .006) and decreased in 22 with a high baseline QAlb (P = .011). The QAlb did not change after a median cART duration of 398 days, initiated at a median interval of 225 days after infection (P = .174). The QAlb correlated with the NFL level at baseline (r = 0.497 and P < .001) and longitudinally (r = 0.555 and P < .001) and with the ratio of N-acetylaspartate to creatinine levels in parietal gray matter (r = -0.352 and P < .001 at baseline and r = -0.387 and P = .008 longitudinally) but not with neuropsychological performance. Conclusion: The QAlb rises during primary HIV infection, associates with neuronal injury, and does not significantly improve over a year of treatment. BBB-associated neuropathogenesis in HIV-infected patients may initiate during primary infection.

Quality of life and trust among young people with narcolepsy and their families, after the Pandemrix® vaccination: protocol for a case-control study.

BACKGROUND: The extensive vaccination programme against swine flu resulted in an increased incidence of narcolepsy among children and adolescents. There is a need to explore if these young persons' experiences have affected their trust in healthcare, their willingness to participate in future prevention programmes, and their contacts with the healthcare system. The overall aim is to identify factors important for the life-situation of children and adolescents with narcolepsy and their families, and factors that correlate with trust in healthcare. METHODS/DESIGN: Data will be collected via questionnaires from all available children with narcolepsy following the vaccination and their families, as well as a control group of children with diabetes and their families. Longitudinal descriptive interviews will also be conducted with a selection of 20-25 children and their families. Techniques from media research will be used for Internet-based data collection and analysis of information relating to narcolepsy from social media. DISCUSSION: This project will use the situation of young persons with narcolepsy after the swine flu vaccination as a case to build a model that can be used in situations where trust in healthcare is essential. This model will be based on findings from the included studies on how trust is influenced by support, quality of life, burden of disease, impact on family, and use of social media. The model developed in this project will be beneficial in future situations where trust in healthcare is essential, such as new pandemic outbreaks but also for "everyday" adherence to health advice.

Osteomyelitis Risk in Patients With Transfemoral Amputations Treated With Osseointegration Prostheses.

BACKGROUND: Percutaneous anchoring of femoral amputation prostheses using osseointegrating titanium implants has been in use for more than 25 years. The method offers considerable advantages in daily life compared with conventional socket prostheses, however long-term success might be jeopardized by implant-associated infection, especially osteomyelitis, but the long-term risk of this complication is unknown. QUESTIONS/PURPOSES: (1) To quantify the risk of osteomyelitis, (2) to characterize the clinical effect of osteomyelitis (including risk of implant extraction and impairments to function), and (3) to determine whether common patient factors (age, sex, body weight, diabetes, and implant component replacements) are associated with osteomyelitis in patients with transfemoral amputations treated with osseointegrated titanium implants. METHODS: We retrospectively analyzed our first 96 patients receiving femoral implants (102 implants; mean implant time, 95 months) treated at our center between 1990 and 2010 for osteomyelitis. Six patients were lost to followup. The reason for amputation was tumor, trauma, or ischemia in 97 limbs and infection in five. All patients were referred from other orthopaedic centers owing to difficulty with use or to be fitted with socket prostheses. If found ineligible for this implant procedure no other treatment was offered at our center. Osteomyelitis was diagnosed by medical chart review of clinical signs, tissue culture results, and plain radiographic findings. Proportion of daily prosthetic use when osteomyelitis was diagnosed was semiquantitatively graded as 1 to 3. Survivorship free from implant- associated osteomyelitis and extraction attributable to osteomyelitis respectively was calculated using the Kaplan-Meier estimator. Indication for extraction was infection not responsive to conservative treatment with or without minor débridement or loosening of implant. RESULTS: Implant-associated osteomyelitis was diagnosed in 16 patients corresponding to a 10-year cumulative risk of 20% (95% CI 0.12-0.33). Ten implants were extracted owing to osteomyelitis, with a 10-year cumulative risk of 9% (95% CI 0.04-0.20). Prosthetic use was temporarily impaired in four of the six patients with infection who did not undergo implant extraction. With the numbers available, we did not identify any association between age, BMI, or diabetes with osteomyelitis; however, this study was underpowered on this endpoint. CONCLUSION: The increased risk of infection with time calls for numerous measures. First, patients should be made aware of the long-term risks, and the surgical team should have a heightened suspicion in patients with method-specific presentation of possible infection. Second, several research questions have been raised. Will the surgical procedure, rehabilitation, and general care standardization since the start of the program result in lower infection rates? Will improved diagnostics and early treatment resolve infection and prevent subsequent extraction? Although not supported in this study, it is important to know if most infections arise as continuous bacterial invasion from the skin and implant interface and if so, how this can be prevented? LEVEL OF EVIDENCE: Level IV, therapeutic study.

Asymptomatic Cerebrospinal Fluid HIV-1 Viral Blips and Viral Escape During Antiretroviral Therapy: A Longitudinal Study.

We examined longitudinal cerebrospinal fluid (CSF) samples (median, 5 samples/patients; interquartile range [IQR], 3-8 samples/patient) in 75 neurologically asymptomatic human immunodeficiency virus (HIV)-infected patients receiving antiretroviral therapy. Twenty-seven patients (36%) had ≥1 CSF HIV RNA load of >20 copies/mL (23% had ≥1 load of >50 copies/mL), with a median HIV RNA load of 50 copies/mL (IQR, 32-77 copies/mL). In plasma, 42 subjects (52%) and 22 subjects (29%) had an HIV RNA load of >20 and >50 copies/mL, respectively. Two subjects had an increasing virus load in consecutive CSF samples, representing possible CSF escape. Of 418 samples, 9% had a CSF HIV RNA load of >20 copies/mL (5% had a load of >50 copies/mL) and 19% had a plasma HIV RNA load of >20 copies/mL (8% had a load of >50 copies/mL). A CSF-associated virus load of >20 copies/mL was associated with higher CSF level of neopterin. In conclusion, CSF escape was rare, and increased CSF HIV RNA loads usually represented CSF virus load blips.

Soluble CD14 in cerebrospinal fluid is associated with markers of inflammation and axonal damage in untreated HIV-infected patients: a retrospective cross-sectional study.

BACKGROUND: HIV-associated cognitive impairment has declined since the introduction of combination antiretroviral treatment (cART). However, milder forms of cognitive impairment persist. Inflammation in the cerebrospinal fluid (CSF) has been associated with cognitive impairment, and CSF neurofilament light chain protein (NFL) and CSF neopterin concentrations are increased in those patients. Microbial translocation in HIV infection has been suggested to contribute to chronic inflammation, and lipopolysaccharide (LPS) and soluble CD14 (sCD14) are markers of microbial translocation and the resulting monocyte activation, respectively. We hypothesised that microbial translocation contributes to inflammation and axonal damage in the central nervous system (CNS) in untreated HIV infection. METHODS: We analyzed paired samples of plasma and CSF from 62 HIV-infected, untreated patients without cognitive symptoms from Sahlgrenska University Hospital, Gothenburg, Sweden. Measurements of neopterin and NFL in CSF were available from previous studies. Plasma and CSF sCD14 was measured using ELISA (R&D, Minneapolis, MN), and plasma and CSF LPS was measured using LAL colorimetric assay (Lonza, Walkersville, MD, USA). Univariate and multivariate regression analyses were performed. RESULTS: LPS in plasma was associated with plasma sCD14 (r = 0.31, P = 0.015), and plasma sCD14 was associated with CSF sCD14 (r = 0.32, P = 0.012). Furthermore, CSF sCD14 was associated with NFL (r = 0.32, P = 0.031) and neopterin (r = 0.32, P = 0.012) in CSF. LPS was not detectable in CSF. In a multivariate regression model CSF sCD14 remained associated with NFL and neopterin after adjusting for age, CD4+ cell count, and HIV RNA in CSF. CONCLUSIONS: In a group of untreated, HIV-infected patients LPS was associated with sCD14 in plasma, and plasma sCD14 was associated CSF sCD14. CSF sCD14 were associated with markers of CNS inflammation and axonal damage. This suggest that microbial translocation might be a driver of systemic and CNS inflammation. However, LPS was not detectable in the CSF, and since sCD14 is a marker of monocyte activation sCD14 may be increased due to other causes than microbial translocation. Further studies regarding cognitive impairment and biomarkers are warranted to fully understand causality.

An example of genetically distinct HIV type 1 variants in cerebrospinal fluid and plasma during suppressive therapy.

We sequenced the genome of human immunodeficiency virus type 1 (HIV-1) recovered from 70 cerebrospinal fluid (CSF) specimens and 29 plasma samples and corresponding samples obtained before treatment initiation from 17 subjects receiving suppressive therapy. More CSF sequences than plasma sequences were hypermutants. We determined CSF sequences and plasma sequences in specimens obtained from 2 subjects after treatment initiation. In one subject, we found genetically distinct CSF and plasma sequences, indicating that they came from HIV-1 from 2 different compartments, one potentially the central nervous system, during suppressive therapy. In addition, there was little evidence of viral evolution in the CSF during therapy, suggesting that continuous virus replication is not the major cause of viral persistence in the central nervous system.

Progressive increase in central nervous system immune activation in untreated primary HIV-1 infection.

BACKGROUND: Central nervous system (CNS) inflammation is a mediator of brain injury in HIV infection. To study the natural course of CNS inflammation in the early phase of infection, we analyzed longitudinal levels of soluble and cellular markers of inflammation in cerebrospinal fluid (CSF) and blood, beginning with primary HIV-1 infection (PHI). METHODS: Antiretroviral-naïve subjects identified as having PHI (less than one year since HIV transmission) participated in phlebotomy and lumbar puncture at baseline and at variable intervals thereafter. Mixed-effects models were used to analyze longitudinal levels of CSF neopterin and percentages of activated cluster of differentiation (CD)4+ and CD8+ T-cells (co-expressing CD38 and human leukocyte antigen-D-related (HLA-DR)) in blood and CSF. RESULTS: A total of 81 subjects were enrolled at an average of 100 days after HIV transmission and had an average follow-up period of 321 days, with the number of visits ranging from one to 13. At baseline, the majority of subjects had CSF neopterin concentrations above the upper limit of normal. The baseline concentration was associated with the longitudinal trajectory of CSF neopterin. In subjects with baseline levels of less than 21 nmol/L, a cutoff value obtained from a mixed-effects model, CSF neopterin increased by 2.9% per 10 weeks (n = 33; P <0.001), whereas it decreased by 6.7% in subjects with baseline levels of more than 21 nmol/L (n = 11; P = 0.001). In a subset with available flow cytometry data (n = 42), the percentages of activated CD4+ and CD8+ T-cells in CSF increased by 0.8 (P <0.001) and 0.73 (P = 0.02) per 10 weeks, respectively. CONCLUSIONS: Neopterin levels and the percentages of activated CD4+ and CD8+ T-cells in CSF progressively increase in most subjects without treatment during early HIV-1 infection, suggesting an accrual of intrathecal inflammation, a major contributor to neuropathology in HIV infection.

Cost-utility analysis of a randomized controlled weight loss trial among lactating overweight/obese women.

BACKGROUND: Overweight and obesity among young, adult women are increasing problems in Sweden as in many other countries. The postpartum period may be a good opportunity to improve eating habits and lose weight in a sustainable manner. The aim was to make a cost-utility analysis of a dietary behavior modification treatment alongside usual care, compared to usual care alone, among lactating overweight and obese women. METHODS: This study was a cost-utility analysis based on a randomized controlled and longitudinal clinical diet intervention. Between 2007-2010, 68 women living in Sweden were, after baseline measurement at 8-12 weeks postpartum, randomly assigned to a 12-week dietary behavior modification treatment or control group. Inclusion criteria were: self-reported pre-pregnancy body mass index (BMI) 25-35 kg/m2, non-smoker, singleton term delivery, birth weight > 2500 g, intention to breastfeed for 6 mo and no diseases (mother and child). The women in the intervention group received 1.5 hour of individual counseling at study start and 1 hour at follow-up home visits after 6 weeks of intervention, with support through cell phone text messages every two wk. Dietary intervention aimed to reduce dietary intake by 500 kcal/day. The control group received usual care. Weight results have previously been reported. Here we report on analyses carried out during 2012-2013 of cost per quality adjusted life years (QALY), based on the changes in quality of life measured by EQ-5D-3 L and SF-6D. Likelihood of cost-effectiveness was calculated using Net Monetary Benefit method. RESULTS: Based on conservative assumptions of no remaining effect after 1 year follow-up, the diet intervention was cost-effective. Costs per gained QALY were 8 643 - 9 758 USD. The likelihood for cost-effectiveness, considering a willingness to pay 50 000 USD for a QALY, was 87-93%. CONCLUSIONS: The diet intervention is cost-effective. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01343238 Registered April 27, 2011.The regional ethics committee in Gothenburg, Sweden, approved the study on November 15, 2006.