Opicapone, a Novel Catechol-O-methyl Transferase Inhibitor, for Treatment of Parkinson\u27s Disease Off Episodes

Parkinson\u27s Disease (PD) is a common neurodegenerative disorder and the leading cause of disability. It causes significant morbidity and disability through a plethora of symptoms, including movement disorders, sleep disturbances, and cognitive and psychiatric symptoms. The traditional pathogenesis theory of PD involves the loss of dopaminergic neurons in the substantia nigra (SN). Classically, treatment is pursued with an assortment of medications that are directed at overcoming this deficiency with levodopa being central to most treatment plans. Patients taking levodopa tend to experience off episodes with decreasing medication levels, causing large fluctuations in their symptoms. These off episodes are disturbing and a source of morbidity for these patients. Opicapone is a novel, peripherally acting Catechol-O-methyl transferase (COMT) inhibitor that is used as adjunctive therapy to carbidopa/levodopa for treatment and prevention of off episodes. It has been approved for use as an adjunct to levodopa since 2016 in Europe and has recently (April 2020) gained FDA approval for use in the USA. By inhibiting COMT, opicapone slows levodopa metabolism and increases its availability. Several clinical studies demonstrated significant improvement in treatment efficacy and reduction in duration of off episodes. The main side effect demonstrated was dyskinesia, mostly with the 100mg dose, which is higher than the approved, effective dose of 50mg. Post-marketing surveillance and analysis are required to further elucidate its safety profile and contribute to patient selection. This paper reviews the seminal and latest evidence in the treatment of PD off episodes with the novel drug Opicapone, including efficacy, safety, and clinical indications

Murine Gammaherpesvirus 68 LANA Acts on Terminal Repeat DNA To Mediate Episome Persistence

Murine gammaherpesvirus 68 (MHV68) ORF73 (mLANA) has sequence homology to Kaposi’s sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA). LANA acts on the KSHV terminal repeat (TR) elements to mediate KSHV episome maintenance. Disruption of mLANA expression severely reduces the ability of MHV68 to establish latent infection in mice, consistent with the possibility that mLANA mediates episome persistence. Here we assess the roles of mLANA and MHV68 TR (mTR) elements in episome persistence. mTR-associated DNA persisted as an episome in latently MHV68-infected tumor cells, demonstrating that the mTR elements can serve as a cis-acting element for MHV68 episome maintenance. In some cases, both control vector and mTR-associated DNAs integrated into MHV68 episomal genomes. Therefore, we also assessed the roles of mTRs as well as mLANA in the absence of infection. DNA containing both mLANA and mTRs in cis persisted as an episome in murine A20 or MEF cells. In contrast, mTR DNA never persisted as an episome in the absence of mLANA. mLANA levels were increased when mLANA was expressed from its native promoters, and episome maintenance was more efficient with higher mLANA levels. Increased numbers of mTRs conferred more efficient episome maintenance, since DNA containing mLANA and eight mTR elements persisted more efficiently in A20 cells than did DNA with mLANA and two or four mTRs. Similar to KSHV LANA, mLANA broadly associated with mitotic chromosomes but relocalized to concentrated dots in the presence of episomes. Therefore, mLANA acts on mTR elements to mediate MHV68 episome persistence

Building a data sharing model for global genomic research

Data sharing models designed to facilitate global business provide insights for improving transborder genomic data sharing. We argue that a flexible, externally endorsed, multilateral arrangement , combined with an objective third-party assurance mechanism, can effectively balance privacy with the need to share genomic data globally

Understanding the relationship between the Centers for Medicare and Medicaid Services’ Hospital Compare star rating, surgical case volume, and short‐term outcomes after major cancer surgery

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138844/1/cncr30866.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138844/2/cncr30866_am.pd

Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy

To continue evaluation of the long-term efficacy and safety of eteplirsen, a phosphorodiamidate morpholino oligomer designed to skip DMD exon 51 in patients with Duchenne muscular dystrophy (DMD). Three-year progression of eteplirsen-treated patients was compared to matched historical controls (HC). METHODS: Ambulatory DMD patients who were 657 years old and amenable to exon 51 skipping were randomized to eteplirsen (30/50mg/kg) or placebo for 24 weeks. Thereafter, all received eteplirsen on an open-label basis. The primary functional assessment in this study was the 6-Minute Walk Test (6MWT). Respiratory muscle function was assessed by pulmonary function testing (PFT). Longitudinal natural history data were used for comparative analysis of 6MWT performance at baseline and months 12, 24, and 36. Patients were matched to the eteplirsen group based on age, corticosteroid use, and genotype. RESULTS: At 36 months, eteplirsen-treated patients (n = 12) demonstrated a statistically significant advantage of 151m (p < 0.01) on 6MWT and experienced a lower incidence of loss of ambulation in comparison to matched HC (n = 13) amenable to exon 51 skipping. PFT results remained relatively stable in eteplirsen-treated patients. Eteplirsen was well tolerated. Analysis of HC confirmed the previously observed change in disease trajectory at age 7 years, and more severe progression was observed in patients with mutations amenable to exon skipping than in those not amenable. The subset of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping. INTERPRETATION: Over 3 years of follow-up, eteplirsen-treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC. Ann Neurol 2016;79:257-271

Cross-species conservation of episome maintenance provides a basis for in vivo investigation of Kaposi's sarcoma herpesvirus LANA

Copyright: © 2017 Habison et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Many pathogens, including Kaposi's sarcoma herpesvirus (KSHV), lack tractable small animal models. KSHV persists as a multi-copy, nuclear episome in latently infected cells. KSHV latency-associated nuclear antigen (kLANA) binds viral terminal repeat (kTR) DNA to mediate episome persistence. Model pathogen murine gammaherpesvirus 68 (MHV68) mLANA acts analogously on mTR DNA. kLANA and mLANA differ substantially in size and kTR and mTR show little sequence conservation. Here, we find kLANA and mLANA act reciprocally to mediate episome persistence of TR DNA. Further, kLANA rescued mLANA deficient MHV68, enabling a chimeric virus to establish latent infection in vivo in germinal center B cells. The level of chimeric virus in vivo latency was moderately reduced compared to WT infection, but WT or chimeric MHV68 infected cells had similar viral genome copy numbers as assessed by immunofluorescence of LANA intranuclear dots or qPCR. Thus, despite more than 60 Ma of evolutionary divergence, mLANA and kLANA act reciprocally on TR DNA, and kLANA functionally substitutes for mLANA, allowing kLANA investigation in vivo. Analogous chimeras may allow in vivo investigation of genes of other human pathogens.This work was supported in part by National Institutes of Health grants CA082036 (NCI), DE025208, and DE024971 (both NIDCR), to KMK, FCT PTDC/IMI-MIC/0980/2014 to JPS, FCT Harvard Medical School Portugal Program in Translational Research (HMSP-ICT/0021/2010) to JPS, KMK, CEM, Instituto de Medicina Molecular Directors Fund to JPS, and iNOVA4Health Research Unit (LISBOA-01-0145-FEDER-007344) FCT/FEDER (PT2020 Partnership Agreement) to CEM. M.P.M is supported by a fellowship from Fundação para a Ciência e Tecnologia (FCT), Portugal.info:eu-repo/semantics/publishedVersio

Recommendations for change in infection prevention programs and practice

Fifty years of evolution in infection prevention and control programs have involved significant accomplishments related to clinical practices, methodologies, and technology. However, regulatory mandates, and resource and research limitations, coupled with emerging infection threats such as the COVID-19 pandemic, present considerable challenges for infection preventionists. This article provides guidance and recommendations in 14 key areas. These interventions should be considered for implementation by United States health care facilities in the near future

Categorizing natural history trajectories of ambulatory function measured by the 6-minute walk distance in patients with Duchenne muscular dystrophy

High variability in patients' changes in 6 minute walk distance (6MWD) over time has complicated clinical trials of treatment efficacy in Duchenne muscular dystrophy (DMD). We assessed whether boys with DMD could be grouped into classes that shared similar ambulatory function trajectories as measured by 6MWD. Ambulatory boys aged 5 years or older with genetically confirmed DMD who were enrolled in a natural history study at 11 care centers throughout Italy were included. For each boy, standardized assessments of 6MWD were available at annual intervals spanning 3 years. Trajectories of 6MWD vs. age and trajectories of 6MWD vs. time from enrollment were examined using latent class analysis. A total of 96 boys were included. At enrollment, the mean age was 8.3 years (mean 6MWD: 374 meters). After accounting for age, baseline 6MWD, and steroid use, four latent trajectory classes were identified as explaining 3-year 6MWD outcomes significantly better than a single average trajectory. Patient trajectories of 6MWD change from enrollment were categorized as having fast decline (n\ue2\u80\u89=\ue2\u80\u8925), moderate decline (n\ue2\u80\u89=\ue2\u80\u8919), stable function (n\ue2\u80\u89=\ue2\u80\u8937), and improving function (n\ue2\u80\u89=\ue2\u80\u8915) during the 3-year follow-up. After accounting for trajectory classes, the standard deviation of variation in 6MWD was reduced by approximately 40%. The natural history of ambulatory function in DMD may be composed of distinct trajectory classes. The extent to which trajectories are associated with novel and established prognostic factors warrants further study. Reducing unexplained variation in patient outcomes could help to further improve DMD clinical trial design and analysis

Placing Joseph Banks in the North Pacific

The South Pacific was a fulcrum of Joseph Banks's maritime world and global networks. The North Pacific was a distance and intangible fringe. This article is concerned with how Banks should be ‘placed’ in the North Pacific. It tracks how Banks's activities have been delineated in terms of languages and categories of global and local, and centre and margin, and then considers the historical and geographical specifics apposite to his connection to the North Pacific. In this setting, ideas of place (as location and assignment) and capital (as a circulatory and everyday practice of exchange and opportunism) come into view and question the distinction between science and commerce in Banks historiography. The article considers a diverse group of non-Indigenous figures – explorers, traders, cartographers, scientists, collectors – operating in the North Pacific in the 1780s and 1790s whose initiatives and missives passed across Banks's desk, and assesses their place in Banks's archive by drawing on Peter Sloterdijk's ideas about the interiorising and exteriorising logic of capital.PostprintPeer reviewe

Adolescent and adult first time mothers' health seeking practices during pregnancy and early motherhood in Wakiso district, central Uganda

<p>Abstract</p> <p>Background</p> <p>Maternal health services have a potentially critical role in the improvement of reproductive health. In order to get a better understanding of adolescent mothers'needs we compared health seeking practices of first time adolescent and adult mothers during pregnancy and early motherhood in Wakiso district, Uganda.</p> <p>Methods</p> <p>This was a cross-sectional study conducted between May and August, 2007 in Wakiso district. A total of 762 women (442 adolescents and 320 adult) were interviewed using a structured questionnaire. We calculated odds ratios with their 95% CI for antenatal and postnatal health care seeking, stigmatisation and violence experienced from parents comparing adolescents to adult first time mothers. STATA V.8 was used for data analysis.</p> <p>Results</p> <p>Adolescent mothers were significantly more disadvantaged in terms of health care seeking for reproductive health services and faced more challenges during pregnancy and early motherhood compared to adult mothers. Adolescent mothers were more likely to have dropped out of school due to pregnancy (OR = 3.61, 95% CI: 2.40–5.44), less likely to earn a salary (OR = 0.43, 95%CI: 0.24–0.76), and more likely to attend antenatal care visits less than four times compared to adult mothers (OR = 1.52, 95%CI: 1.12–2.07). Adolescents were also more likely to experience violence from parents (OR = 2.07, 95%CI: 1.39–3.08) and to be stigmatized by the community (CI = 1.58, 95%CI: 1.09–2.59). In early motherhood, adolescent mothers were less likely to seek for second and third vaccine doses for their infants [Polio2 (OR = 0.73, 95% CI: 0.55–0.98), Polio3 (OR = 0.70: 95% CI: 0.51–0.95), DPT2 (OR = 0.71, 95% CI: 0.53–0.96), DPT3 (OR = 0.68, 95% CI: 0.50–0.92)] compared to adult mothers. These results are compelling and call for urgent adolescent focused interventions.</p> <p>Conclusion</p> <p>Adolescents showed poorer health care seeking behaviour for themselves and their children, and experienced increased community stigmatization and violence, suggesting bigger challenges to the adolescent mothers in terms of social support. Adolescent friendly interventions such as pregnancy groups targeting to empower pregnant adolescents providing information on pregnancy, delivery and early childhood care need to be introduced and implemented.</p