Peginterferon beta‐1a was efficacious in a Phase 3 relapsing multiple sclerosis trial, and its safety profile was consistent with other beta interferons. This study evaluated the impact of renal ...impairment on the pharmacokinetics and pharmacodynamics (neopterin elevation; a biomarker of pharmacological activity induced by interferon beta‐1a) of peginterferon beta‐1a following a single subcutaneous dose at 63 μg (n = 5) or 125 μg (n = 30). The results showed a fractional increase in area‐under‐the‐concentration‐time curve (AUC 30–53%) and peak serum concentration (Cmax 26–42%) in subjects with mild, moderate, and severe renal impairment, versus healthy subjects; AUC and Cmax were similar for healthy subjects and end‐stage‐renal‐disease patients receiving hemodialysis. Pharmacokinetic simulation showed that the steady state concentration overlapped in the majority of healthy subjects and subjects with severe renal impairment. Neopterin baseline, peak concentration, and AUC increased as renal function decreased. Peginterferon beta‐1a was well tolerated in all groups. These results do not warrant peginterferon beta‐1a dose adjustment in subjects with renal impairment.
Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder that is caused by expansion of a CAG-repeat tract in the huntingtin gene and characterized by motor impairment, ...cognitive decline, and neuropsychiatric disturbances. Neuropathological studies show that disease progression follows a characteristic pattern of brain atrophy, beginning in the basal ganglia structures. The HD Regulatory Science Consortium (HD-RSC) brings together diverse stakeholders in the HD community-biopharmaceutical industry, academia, nonprofit, and patient advocacy organizations-to define and address regulatory needs to accelerate HD therapeutic development. Here, the Biomarker Working Group of the HD-RSC summarizes the cross-sectional evidence indicating that regional brain volumes, as measured by volumetric magnetic resonance imaging, are reduced in HD and are correlated with disease characteristics. We also evaluate the relationship between imaging measures and clinical change, their longitudinal change characteristics, and within-individual longitudinal associations of imaging with disease progression. This analysis will be valuable in assessing pharmacodynamics in clinical trials and supporting clinical outcome assessments to evaluate treatment effects on neurodegeneration.
Social Audits were carried out to understand people's perception about the outcomes of public services in thirty-two flagship schemes of the outcome budget exercise in Maharashtra. The mandate of the ...Public Verification Exercise (PVE) was to make state budgets sensitive to the outcomes that directly affect people's everyday lives, especially those in which they encounter state machinery. The paper reveals how the concepts of social audit were adapted into a PVE jointly conducted by the state government departments and a public university. The paper discusses the origins of social audit and recent trends of using social audits as instruments of accountability in the wake of democratic decentralisation and devolution of powers to local bodies. In doing so, the paper critically examines two schemes implemented in Maharashtra and poses more questions on the ongoing debates on the notions of public accountability itself that differs across stakeholder groups. Adapted from the source document.
Data are needed on the potential long-term prognostic association of serum neurofilament light in multiple sclerosis (MS).
To evaluate serum neurofilament light as a biomarker associated with ...long-term disease outcomes in clinically isolated syndrome.
This post hoc cohort study used data from the Controlled High-Risk Avonex Multiple Sclerosis Prevention Study, a 36-month, multicenter, placebo-controlled interferon β-1a randomized clinical trial conducted from April 1996 to March 2000, and its long-term (5- and 10-year) extension study from February 2001 to March 2009. Participants included individuals with a symptomatic initial demyelinating event and brain magnetic resonance imaging (MRI) lesions suggestive of MS. Data were analyzed from April 2017 through 2019.
The variable of interest was naturally occurring serum neurofilament light concentration.
Gadolinium-enhancing (Gd+) lesion number, T2 lesion volume, and brain parenchymal fraction, a measure of brain atrophy were measured at baseline and 5 and 10 years. Multivariate regression models evaluated whether age, sex, and baseline covariates, including serum neurofilament light, brain parenchymal fraction, Expanded Disability Status Scale, Gd+ lesion count, and T2 lesion volume, were associated with brain parenchymal fraction changes over 5 and 10 years.
Among 308 included participants (mean SD age, 33.2 7.6 years; 234 76.0% women), baseline serum neurofilament light concentrations were associated with Gd+ lesions (Spearman r = 0.41; P < .001) and T2 lesion volume (Spearman r = 0.42; P < .001). Among covariates for brain parenchymal fraction change, serum neurofilament light concentration had the greatest correlation with change in brain parenchymal fraction at 5 years (Spearman r = -0.38; P < .001) and was the only variable associated with brain parenchymal fraction at 10 years (Spearman r = -0.45; P < .001). Participants in the highest vs lowest baseline serum neurofilament light tertiles showed brain parenchymal fraction reduction at 5 years (-1.83% 95% CI, -1.49% to -2.18% vs -0.95% 95% CI, -0.78% to -1.12%; P < .001) and 10 years (-3.54% 95% CI, -2.90% to -4.17% vs -1.90% 95% CI, -1.43% to -2.37%; P < .001). At 5 years, 6 of 45 participants (13.3%) in the highest neurofilament tertile and 2 of 52 participants (3.8%) in the lowest neurofilament tertile achieved an Expanded Disability Status Scale score of 3.5 or greater.
This cohort study found that higher baseline serum neurofilament light levels were associated with increased brain atrophy over 5 and 10 years. These findings suggest that serum neurofilament light could be a biomarker associated with disease severity stratification in early MS and may help to guide intervention.
Related adhesion focal tyrosine kinase (RAFTK) (also known as PYK2) is a cytoplasmic tyrosine kinase related to the focal adhesion kinase (FAK) p125FAK. RAFTK is rapidly phosphorylated on tyrosine ...residues in response to various stimuli, such as tumor necrosis factor-α, changes in osmolarity, elevation in intracellular calcium concentration, lysophosphatidic acid, and bradykinin. Overexpression of RAFTK induces activation of c-Jun amino-terminal kinase (also known as stress-activated protein kinase), mitogen-activated protein kinase (MAPK), and p38 MAPK. The present studies demonstrate that RAFTK binds constitutively to the protein tyrosine phosphatase SHPTP1. In contrast to PTP1B, overexpression of wild-type SHPTP1 blocks tyrosine phosphorylation of RAFTK. The results further demonstrate that RAFTK is a direct substrate of SHPTP1 in vitro. Moreover, treatment of PC12 cells with bradykinin is associated with inhibition in tyrosine phosphorylation of RAFTK in the presence of SHPTP1. Furthermore, in contrast to the phosphatase-dead SHPTP1 C453S mutant, overexpression of wild-type SHPTP1 blocks interaction of RAFTK with the SH2-domain of c-Src and inhibits RAFTK-mediated MAPK activation. Significantly, cotransfection of RAFTK with SHPTP1 did not inhibit RAFTK-mediated c-Jun amino-terminal kinase activation. Taken together, these findings suggest that SHPTP1 plays a negative role in PYK2/RAFTK signaling by dephosphorylating RAFTK.
It is a common refrain that public investments made in Integrated Child Development Scheme (ICDS) fails to bring any marked reduction in undernutrition rates among children in Maharashtra. The ...problem seems to be not of inadequate allocations, but of inefficient spending. The outcome budget initiative for the ICDS scheme provides strategies to maximise resource utilisation for tangible and equitable outcomes. The paper does not analyse the performance of the ICDS scheme in the state, but describes methods of outcome budgeting audit that led to an outcome based planning and budgeting for the scheme. The paper delineates some prerequisites before attempting an outcome budget for a scheme in addition to constraints and challenges of attempting this methodology. Adapted from the source document.
Jeevandayi Arogya Yojana, recently re-launched and renamed as Rajiv Gandhi Jeevandayi Arogya Yojana is a unique and popular health scheme in Maharashtra. The scheme has been in operation since the ...last fifteen years and provides for free surgeries to Below Poverty Line (BPL) patients in the state. An outcome based analysis of the scheme as discussed in this paper reveals the extent to which the scheme is able to reach out to the poor, thus enabling them to access tertiary care. The paper provides lessons on the implementation of outcome methodology for a health scheme that may be useful to other agencies and governments interested in outcome budgeting. Adapted from the source document.
Peginterferon beta-1a was efficacious in a Phase 3 relapsing multiple sclerosis trial, and its safety profile was consistent with other beta interferons. This study evaluated the impact of renal ...impairment on the pharmacokinetics and pharmacodynamics (neopterin elevation; a biomarker of pharmacological activity induced by interferon beta-1a) of peginterferon beta-1a following a single subcutaneous dose at 63 μg (n = 5) or 125 μg (n = 30). The results showed a fractional increase in area-under-the-concentration-time curve (AUC 30–53%) and peak serum concentration (C
max
26–42%) in subjects with mild, moderate, and severe renal impairment, versus healthy subjects; AUC and C
max
were similar for healthy subjects and end-stage-renal-disease patients receiving hemodialysis. Pharmacokinetic simulation showed that the steady state concentration overlapped in the majority of healthy subjects and subjects with severe renal impairment. Neopterin baseline, peak concentration, and AUC increased as renal function decreased. Peginterferon beta-1a was well tolerated in all groups. These results do not warrant peginterferon beta-1a dose adjustment in subjects with renal impairment.
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