Prevalence and Incidence of Nonmotor Symptoms in Individuals with and Without Parkinson’s Disease

Background The prevalence ratio (PR) and incidence rate ratio (IRR) of nonmotor symptoms (NMS) were calculated for early Parkinson\u27s disease (PD) versus non-PD from 2 observational studies. Methods NMS were assessed through the self-reported Non-Motor Symptom Questionnaire in the online Fox Insight study and through self- and clinician-rated scales in the Parkinson\u27s Progression Marker Initiative (PPMI) study. Age- and sex-adjusted/matched PR and IRR were estimated for each NMS by PD status using Poisson regression. Results Most NMS occurred more frequently in PD. Among 15,194 Fox Insight participants, sexual dysfunction had the largest adjusted PR (12.4 [95% CI, 6.9–22.2]) and dysgeusia/hyposmia had the largest adjusted IRR over a 2-year median follow-up (17.0 [95% CI, 7.8–37.1]). Among 607 PPMI participants, anosmia had the largest PR (16.6 [95% CI, 6.1–44.8]). During the 7-year median follow-up, hallucinations had the largest IRR (13.5 [95% CI, 6.3–28.8]). Conclusion Although many NMS are more common in early PD than in non-PD, their occurrence may differ with time (hallucinations) or data collection methods (sexual dysfunction)

Bone mineral density reductions after tenofovir disoproxil fumarate initiation and changes in phosphaturia: a secondary analysis of ACTG A5224s

Background: It is unknown if the greater reductions in bone mineral density (BMD) associated with initiation of tenofovir disoproxil fumarate compared with abacavir in previously untreated HIV-infected participants in the ACTG A5224s clinical trial were associated with potentially worsening tenofovir-related phosphaturia. Methods: We correlated changes in BMD at the hip and spine with changes in phosphaturia [transtubular reabsorption of phosphorus (TRP) and tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR)] from entry through week 96 in those initiating tenofovir ( n  =   134) versus abacavir ( n  =   135) with efavirenz or atazanavir/ritonavir in A5224s. We also correlated changes in BMD with tenofovir AUC measured between weeks 4 and 24. Results: Changes in TRP and TmP/GFR through week 96 between the tenofovir and abacavir arms were not significantly different (both P  ≥   0.70) and did not differ with use of efavirenz versus atazanavir/ritonavir. There were no significant correlations between changes in either TRP or TmP/GFR and with either hip or spine BMD in the tenofovir arms. Tenofovir AUC was significantly correlated with changes in hip BMD, but not spine BMD, at week 24 ( r  =   -0.22, P  =   0.028) and week 48 ( r  =   -0.26, P  =   0.010), but not at week 96 ( r  =   -0.14, P  =   0.18). Conclusions: Changes in phosphaturia were not different between the tenofovir and abacavir arms in A5224s. Changes in hip and spine BMD with tenofovir were not related to changes in phosphaturia. However, tenofovir exposure was weakly associated with changes in hip BMD through week 48

Histology of human tubulo-interstitial nephritis associated with antibodies to renal basement membranes

Histology of human tubulo-interstitial nephritis associated with antibodies to renal basement membranes. Twenty-seven patients with diffuse “crescentic” glomerulonephritis (CSGN) were identified in 1,174 renal biopsies from nephritic patients. Patients were assigned to three groups on the basis of the immunofluorescent study of renal biopsy specimens and serologic findings. Group I included eight patients with antibodies to glomerular (anti-GBM) and tubular (anti-TBM) basement membranes; group II had eight patients with only anti-GBM antibodies; and group III had eleven patients with CSGN unassociated with antibodies to either GBM or TBM. Patients with anti-GBM/anti-TBM antibodies (group I) had severe tubulointerstitial (TI) nephritis, as characterized by the infiltration of polymorphonuclear leukocytes and macrophages along the TBM and peritubular vessels. In some patients, focal proliferation of epithelial cells of proximal convoluted tubules (PCT), gaps or extensive destruction of TBM, lesions in the walls of small peritubular vessels, and interstitial giant cells were also observed. Patients with anti-GBM antibodies (group II) had mild to moderate interstitial cellular infiltration and mild tubular changes. Five patients with CSGN not associated with antibodies to renal basement membranes (group III) had mild to moderate interstitial cellular infiltration and tubular changes. A sixth patient, with Wegener's disease had severe granulomatous TI lesions. The results of this study show that TI nephritis is most frequent and severe when anti-TBM antibodies are demonstrable and suggest that anti-TBM antibodies contribute to the development of TI lesions.Histologie de la néphrite tubulo-interstitielle humaine associée à la présence d'anticorps anti-membrane basale. Vingt-sept malades atteints de glomérulonéphrite diffuse avec des croissants (CSGN) ont été identifiés à partir de 1174 biopsies rénales réalisées chez des malades atteints de néphrite. Les malades ont été répartis en trois groupes sur la base de l'étude en immunofluorescence des biopsies rénales et des constatations sérologiques. Le groupe I comprend huit malades qui ont des anticorps anti-membrane basale glomérulaire (anti-GBM) et tubulaire (anti-TBM), le groupe II comprend huit malades qui n'ont que l'anti-GBM et le groupe III comprend onze malades atteints de CSGN mais qui n'ont ni les anti-GBM ni les anti-TBM. Les malades qui ont les deux anticorps (groupe I) ont une néphropathie tubulointerstitielle sévère caractérisée par des infiltrats leucocytaires et macrophagiques le long des membranes basales tubulaires et des vaisseaux péri-tubulaires. Chez quelques malades, la prolifération focale des cellules épithéliales du tube contourné proximal (PCT), des solutions de continuité ou des destructions étendues de la basale tubulaire, des lésions des parois des vaisseaux péritubulaires de petit calibre et des cellules interstitielles géantes sont aussi observées. Les malades qui ont des anticorps anti-GBM (groupe II) ont une infiltration interstitielle et des modifications tubulaires modérées. Cinq malades atteints de CSGN sans anticorps anti-membranes basales (groupe III) ont une infiltration interstitielle et des modifications tubulaires modérées. Un sixième malade atteint de maladie de Wegener a des lésions tubulo-interstitielles granulomateuses sévères. Le résultat de cette étude démontre que la néphropathie tubulo-interstitielle est plus fréquente et plus sévère quand les anticorps anti-TBM sont mis en évidence et suggèrent que les anticorps anti-TBM contribuent au développement des lésions tubulo-interstitielles

Predicting ambulatory capacity in Parkinson's disease to analyze progression, biomarkers, and trial design

Background: In Parkinson's disease (PD), gait and balance is impaired, relatively resistant to available treatment and associated with falls and disability. Predictive models of ambulatory progression could enhance understanding of gait/balance disturbances and aid in trial design. Objectives: To predict trajectories of ambulatory abilities from baseline clinical data in early PD, relate trajectories to clinical milestones, compare biomarkers, and evaluate trajectories for enrichment of clinical trials. Methods: Data from two multicenter, longitudinal, observational studies were used for model training (Tracking Parkinson's, n = 1598) and external testing (Parkinson's Progression Markers Initiative, n = 407). Models were trained and validated to predict individuals as having a “Progressive” or “Stable” trajectory based on changes of ambulatory capacity scores from the Movement Disorders Society Unified Parkinson's Disease Rating Scale parts II and III. Survival analyses compared time-to-clinical milestones and trial outcomes between predicted trajectories. Results: On external evaluation, a support vector machine model predicted Progressive trajectories using baseline clinical data with an accuracy, weighted-F1 (proportionally weighted harmonic mean of precision and sensitivity), and sensitivity/specificity of 0.735, 0.799, and 0.688/0.739, respectively. Over 4 years, the predicted Progressive trajectory was more likely to experience impaired balance, loss of independence, impaired function and cognition. Baseline dopamine transporter imaging and select biomarkers of neurodegeneration were significantly different between predicted trajectory groups. For an 18-month, randomized (1:1) clinical trial, sample size savings up to 30% were possible when enrollment was enriched for the Progressive trajectory versus no enrichment. Conclusions: It is possible to predict ambulatory abilities from clinical data that are associated with meaningful outcomes in people with early PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Effect of scavenger receptor BI antagonist ITX5061 in patients with hepatitis C virus infection undergoing liver transplantation

Hepatitis C virus (HCV) entry inhibitors have been hypothesized to prevent infection of the liver after transplantation. ITX5061 is a Scavenger Receptor B-I (SR-BI) antagonist that blocks HCV entry and infection in vitro. We assessed the safety and efficacy of ITX5061 to limit HCV infection of the graft. The study included 23 HCV infected patients undergoing liver transplantation. The first 13 "control" patients did not receive drug. The subsequent 10 patients received ITX5061 150 mg immediately pre- and post-transplant, and daily for 1 week thereafter. ITX5061 pharmacokinetics and plasma HCV RNA were quantified. Viral genetic diversity was measured by ultradeep pyrosequencing. ITX5061 was well tolerated with measurable plasma concentrations during therapy. Whilst the median HCV RNA reduction was greater in ITX treated patients at all time points in the first week after transplantation there was no difference in the overall change in the area over the HCV RNA curve in the 7-day treatment period. However, in genotype 1 infected patients treatment was associated with a sustained reduction in HCV RNA levels compared to the control group (area over the HCV RNA curve analysis, p=0.004). Ultradeep pyrosequencing revealed a complex and evolving pattern of HCV variants infecting the graft during the first week. ITX5061 significantly limited viral evolution where the median divergence between day 0 and day 7 was 3.5% in the control group compared to 0.1% in the treated group.CONCLUSIONS: ITX5061 reduces plasma HCV RNA post transplant notably in genotype 1 infected patients and slows viral evolution. Following liver transplantation the likely contribution of extrahepatic reservoirs of HCV necessitates combining entry inhibitors such as ITX5061 with inhibitors of replication in future studies. Clinicaltrials.gov NCT01292824. This article is protected by copyright. All rights reserved.</p

Precompetitive data sharing as a catalyst to address unmet needs in Parkinson's disease

Parkinson's disease is a complex heterogeneous disorder with urgent need for disease-modifying therapies. Progress in successful therapeutic approaches for PD will require an unprecedented level of collaboration. At a workshop hosted by Parkinson's UK and co-organized by Critical Path Institute's (C-Path) Coalition Against Major Diseases (CAMD) Consortiums, investigators from industry, academia, government and regulatory agencies agreed on the need for sharing of data to enable future success. Government agencies included EMA, FDA, NINDS/NIH and IMI (Innovative Medicines Initiative). Emerging discoveries in new biomarkers and genetic endophenotypes are contributing to our understanding of the underlying pathophysiology of PD. In parallel there is growing recognition that early intervention will be key for successful treatments aimed at disease modification. At present, there is a lack of a comprehensive understanding of disease progression and the many factors that contribute to disease progression heterogeneity. Novel therapeutic targets and trial designs that incorporate existing and new biomarkers to evaluate drug effects independently and in combination are required. The integration of robust clinical data sets is viewed as a powerful approach to hasten medical discovery and therapies, as is being realized across diverse disease conditions employing big data analytics for healthcare. The application of lessons learned from parallel efforts is critical to identify barriers and enable a viable path forward. A roadmap is presented for a regulatory, academic, industry and advocacy driven integrated initiative that aims to facilitate and streamline new drug trials and registrations in Parkinson's disease

Outcomes by Sex Following Treatment Initiation With Atazanavir Plus Ritonavir or Efavirenz With Abacavir/Lamivudine or Tenofovir/Emtricitabine

Background. We aimed to evaluate treatment responses to atazanavir plus ritonavir (ATV/r) or efavirenz (EFV) in initial antiretroviral regimens among women and men, and determine if treatment outcomes differ by sex

Inflammation investigated as a source of pharmacokinetic variability of atazanavir in AIDS Clinical Trials Group protocol A5224s.

BACKGROUND:Inflammation is associated with the downregulation of drug metabolizing enzymes and transporters. Thus, we investigated the chronic inflammatory state associated with HIV infection as a source of pharmacokinetic variability of atazanavir. We also explored the association of total bilirubin concentrations with markers of inflammation and endothelial activation. METHODS:Apparent oral clearance (CL/F) of atazanavir was estimated from plasma samples collected from participants in AIDS Clinical Trials Group Study A5202. Several inflammatory and endothelial activation biomarkers were measured at baseline and weeks 24 and 96 as part of metabolic substudy A5224s: high-sensitivity C-reactive protein (hsCRP), interleukin-6, tumour necrosis factor-α and its soluble receptors, soluble vascular cellular and intracellular adhesion molecules and total bilirubin. Statistical analysis was performed by a matrix of correlation coefficients between atazanavir CL/F and biomarker concentrations measured at week 24. The correlation between atazanavir clearance and percentage change in bilirubin from baseline to weeks 24 and 96, and between biomarkers and bilirubin concentrations at each week were also evaluated. RESULTS:Among 107 participants, there were no significant correlations observed between atazanavir CL/F and inflammatory and endothelial activation biomarkers measured at week 24 (P≥0.24). As expected, bilirubin increased with increasing exposure to atazanavir (rho=-0.25, P=0.01). Bilirubin concentrations were inversely correlated (P&lt;0.01) with each of the biomarkers except hsCRP. CONCLUSIONS:Atazanavir CL/F did not correlate with the inflammatory biomarkers changes. Inflammatory-mediated inhibition of cytochrome P450 3A may have been attenuated due to atazanavir-associated increases of bilirubin, which has known anti-inflammatory properties