Persistence of pharmacological treatment into adulthood, in UK primary care, for ADHD patients who started treatment in childhood or adolescence

Background ADHD guidelines in the UK suggest that children and adults who respond to pharmacological treatment should continue for as long as remains clinically effective, subject to regular review. To what extent patients persist with treatment from childhood and adolescence into adulthood is not clear. This study aims to describe, in UK primary care, the persistence of pharmacological treatment for patients with ADHD who started treatment aged 6–17 years and to estimate the percentage of patients who continued treatment from childhood and adolescence into adulthood. Methods The Health Improvement Network (THIN) database was used to identify patients with ADHD who received their first prescription for methylphenidate/ dexamfetamine/atomoxetine, aged 6–17 years. Patients were monitored until their ‘censored date’ (the earliest of the following dates: date the last prescription coded in the database ended, end of the study period (31st December 2008), date at which they transferred out of their practice, date of death, the last date the practice contributed data to the database). Persistence of treatment into adulthood was estimated using Kaplan Meier analysis. Results 610 patients had follow-up data into adulthood. 213 patients (93.4% male) started treatment between 6–12 years; median treatment duration 5.9 years. 131 (61.5%) stopped before 18 years, 82 (38.5%) were still on treatment age ≥18 years. 397 patients (86.4% male) started treatment between 13–17 years; median treatment duration was 1.6 years. 227 (57.2%) stopped before 18 years, 170 (42.8%) were still on treatment age ≥18 years. The number of females in both age categories was too small to formally test for differences between genders in persistence of treatment. Conclusion Persistence of treatment into adulthood is lower (~40%) compared with published rates of persistence of the condition (~65% when symptomatic definition of remission used). Due to the limited number of patients with data past 18 years, it is important that ongoing monitoring of prescribing into later adulthood is undertaken, particularly to observe the effects of recommendations in new guidelines

Joining the conspiracy? Negotiating ethics and emotions in researching (around) AIDS in southern Africa

AIDS is an emotive subject, particularly in southern Africa. Among those who have been directly affected by the disease, or who perceive themselves to be personally at risk, talking about AIDS inevitably arouses strong emotions - amongst them fear, distress, loss and anger. Conventionally, human geography research has avoided engagement with such emotions. Although the ideal of the detached observer has been roundly critiqued, the emphasis in methodological literature on 'doing no harm' has led even qualitative researchers to avoid difficult emotional encounters. Nonetheless, research is inevitably shaped by emotions, not least those of the researchers themselves. In this paper, we examine the role of emotions in the research process through our experiences of researching the lives of 'Young AIDS migrants' in Malawi and Lesotho. We explore how the context of the research gave rise to the production of particular emotions, and how, in response, we shaped the research, presenting a research agenda focused more on migration than AIDS. This example reveals a tension between universalised ethics expressed through ethical research guidelines that demand informed consent, and ethics of care, sensitive to emotional context. It also demonstrates how dualistic distinctions between reason and emotion, justice and care, global and local are unhelpful in interpreting the ethics of research practice

Errors in chromosome segregation during oogenesis and early embryogenesis

Errors in chromosome segregation occurring during human oogenesis and early embryogenesis are very common. Meiotic chromosome development during oogenesis is subdivided into three distinct phases. The crucial events, including meiotic chromosome pairing and recombination, take place from around 11 weeks until birth. Oogenesis is then arrested until ovulation, when the first meiotic division takes place, with the second meiotic division not completed until after fertilization. It is generally accepted that most aneuploid fetal conditions, such as trisomy 21 Down syndrome, are due to maternal chromosome segregation errors. The underlying reasons are not yet fully understood. It is also clear that superimposed on the maternal meiotic chromosome segregation errors, there are a large number of mitotic errors taking place post-zygotically during the first few cell divisions in the embryo. In this chapter, we summarise current knowledge of errors in chromosome segregation during oogenesis and early embryogenesis, with special reference to the clinical implications for successful assisted reproduction

Application of Consensus Scoring and Principal Component Analysis for Virtual Screening against β-Secretase (BACE-1)

BACKGROUND: In order to identify novel chemical classes of β-secretase (BACE-1) inhibitors, an alternative scoring protocol, Principal Component Analysis (PCA), was proposed to summarize most of the information from the original scoring functions and re-rank the results from the virtual screening against BACE-1. METHOD: Given a training set (50 BACE-1 inhibitors and 9950 inactive diverse compounds), three rank-based virtual screening methods, individual scoring, conventional consensus scoring and PCA, were judged by the hit number in the top 1% of the ranked list. The docking poses were generated by Surflex, five scoring functions (Surflex_Score, D_Score, G_Score, ChemScore, and PMF_Score) were used for pose extraction. For each pose group, twelve scoring functions (Surflex_Score, D_Score, G_Score, ChemScore, PMF_Score, LigScore1, LigScore2, PLP1, PLP2, jain, Ludi_1, and Ludi_2) were used for the pose rank. For a test set, 113,228 chemical compounds (Sigma-Aldrich® corporate chemical directory) were docked by Surflex, then ranked by the same three ranking methods motioned above to select the potential active compounds for experimental test. RESULTS: For the training set, the PCA approach yielded consistently superior rankings compared to conventional consensus scoring and single scoring. For the test set, the top 20 compounds according to conventional consensus scoring were experimentally tested, no inhibitor was found. Then, we relied on PCA scoring protocol to test another different top 20 compounds and two low micromolar inhibitors (S450588 and 276065) were emerged through the BACE-1 fluorescence resonance energy transfer (FRET) assay. CONCLUSION: The PCA method extends the conventional consensus scoring in a quantitative statistical manner and would appear to have considerable potential for chemical screening applications

Neurotoxic reactive astrocytes are induced by activated microglia

Reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease, but their role is poorly understood. Here we show that a subtype of reactive astrocytes, which we termed A1, is induced by classically activated neuroinflammatory microglia. We show that activated microglia induce A1 astrocytes by secreting Il-1α, TNF and C1q, and that these cytokines together are necessary and sufficient to induce A1 astrocytes. A1 astrocytes lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons and oligodendrocytes. Death of axotomized CNS neurons in vivo is prevented when the formation of A1 astrocytes is blocked. Finally, we show that A1 astrocytes are abundant in various human neurodegenerative diseases including Alzheimer’s, Huntington’s and Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis. Taken together these findings help to explain why CNS neurons die after axotomy, strongly suggest that A1 astrocytes contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders, and provide opportunities for the development of new treatments for these diseases.This work was supported by grants from the National Institutes of Health (R01 AG048814, B.A.B.; RO1 DA15043, B.A.B.; P50 NS38377, V.L.D. and T.M.D.) Christopher and Dana Reeve Foundation (B.A.B.), the Novartis Institute for Biomedical Research (B.A.B.), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (B.A.B.), the JPB Foundation (B.A.B., T.M.D.), the Cure Alzheimer’s Fund (B.A.B.), the Glenn Foundation (B.A.B.), the Esther B O’Keeffe Charitable Foundation (B.A.B.), the Maryland Stem Cell Research Fund (2013-MSCRFII-0105-00, V.L.D.; 2012-MSCRFII-0268-00, T.M.D.; 2013-MSCRFII-0105-00, T.M.D.; 2014-MSCRFF-0665, M.K.). S.A.L. was supported by a postdoctoral fellowship from the Australian National Health and Medical Research Council (GNT1052961), and the Glenn Foundation Glenn Award. L.E.C. was funded by a Merck Research Laboratories postdoctoral fellowship (administered by the Life Science Research Foundation). W.-S.C. was supported by a career transition grant from NEI (K99EY024690). C.J.B. was supported by a postdoctoral fellowship from Damon Runyon Cancer Research Foundation (DRG-2125-12). L.S. was supported by a postdoctoral fellowship from the German Research Foundation (DFG, SCHI 1330/1-1)

Elimination of Rhodnius prolixus in Central America

Rhodnius prolixus is one of the main vectors of Trypanosoma cruzi, causative agent of Chagas disease. In Central America, it was first discovered in 1915 in El Salvador, from where it spread northwest to Guatemala and Mexico, and southeast to Nicaragua and Costa Rica, arriving also in Honduras in the late 1950s. Indoor residual spraying (IRS) by the antimalaria services of Costa Rica prevented its spread southwards, and similar IRS programmes appear to have eliminated it from El Salvador by the late 1970s. In 1997, by resolution of the Ministers of Health of the seven Central American countries, a multinational initiative against Chagas disease (IPCA) was launched with one of the specific objectives being the elimination of R. prolixus from the region. As a result, more and more infested areas were encountered, and progressively sprayed using an IRS strategy already deployed against Triatoma infestans in the southern cone countries of South America. In 2008, Guatemala became the first of these countries to be formally certified as free of Chagas disease transmission due to R. prolixus. The other infested countries have since been similarly certified, and none of these has reported the presence of R. prolixus since June 2010. Further surveillance is required, but current evidence suggests that R. prolixus may now been eliminated from throughout the mesoamerican region, with a corresponding decline in the incidence of T. cruzi infections

The potential of antisense oligonucleotide therapies for inherited childhood lung diseases.

Antisense oligonucleotides are an emerging therapeutic option to treat diseases with known genetic origin. In the age of personalised medicines, antisense oligonucleotides can sometimes be designed to target and bypass or overcome a patient's genetic mutation, in particular those lesions that compromise normal pre-mRNA processing. Antisense oligonucleotides can alter gene expression through a variety of mechanisms as determined by the chemistry and antisense oligomer design. Through targeting the pre-mRNA, antisense oligonucleotides can alter splicing and induce a specific spliceoform or disrupt the reading frame, target an RNA transcript for degradation through RNaseH activation, block ribosome initiation of protein translation or disrupt miRNA function. The recent accelerated approval of eteplirsen (renamed Exondys 51™) by the Food and Drug Administration, for the treatment of Duchenne muscular dystrophy, and nusinersen, for the treatment of spinal muscular atrophy, herald a new and exciting era in splice-switching antisense oligonucleotide applications to treat inherited diseases. This review considers the potential of antisense oligonucleotides to treat inherited lung diseases of childhood with a focus on cystic fibrosis and disorders of surfactant protein metabolism

Multi-ancestry genome-wide association meta-analysis of Parkinson’s disease

\ua9 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations