Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Multiple Sclerosis, Relapses, and the Mechanism of Action of Adrenocorticotropic Hormone

Relapses in multiple sclerosis (MS) are disruptive and frequently disabling for patients, and their treatment is often a challenge to clinicians. Despite progress in the understanding of the pathophysiology of MS and development of new treatments for long-term management of MS, options for treating relapses have not changed substantially over the past few decades. Corticosteroids, a component of the HPA axis that modulate immune responses and reduce inflammation, are currently the mainstay of relapse treatment. Adrenocorticotropic hormone (ACTH) gel is another treatment option. Although it has long been assumed that the efficacy of ACTH in treating relapses depends on the peptide’s ability to increase endogenous corticosteroid production, evidence from research on the melanocortin system suggests that steroidogenesis may only partly account for ACTH influences. Indeed, the melanocortin peptides (ACTH and α-, β-, γ-melanocyte-stimulating hormones [MSH]) and their receptors (MCRs) exert multiple actions, including modulation of inflammatory and immune mediator production. Melanocortin receptors are widely distributed within the central nervous system and in peripheral tissues including immune cells (eg, macrophages). This suggests that the mechanism of action of ACTH includes not only steroid-mediated indirect effects, but also direct anti-inflammatory and immune-modulating actions via the melanocortin system. An increased understanding of the role of the melanocortin system, particularly ACTH, in the immune and inflammatory processes underlying relapses may help to improve relapse management

Assessing Relapse in Multiple Sclerosis Questionnaire: Results of a Pilot Study

There is need for a brief but comprehensive objective assessment tool to help clinicians evaluate relapse symptoms in patients with multiple sclerosis (MS) and their impact on daily functioning, as well as response to treatment. The 2-part Assessing Relapse in Multiple Sclerosis (ARMS) questionnaire was developed to achieve these aims. Part 1 consists of 7 questions that evaluate relapse symptoms, impact on activities of daily living (ADL), overall functioning, and response to treatment for previous relapses. Part 2 consists of 7 questions that evaluate treatment response in terms of symptom relief, functioning, and tolerability. The ARMS questionnaire has been evaluated in 103 patients with MS. The most commonly reported relapse symptoms were numbness/tingling (67%), fatigue (58%), and leg/foot weakness (55%). Over half of patients reported that ADL or overall functioning were affected very much (47%) or severely (11%) by relapses. Prescribed treatments for relapses included intravenous and/or oral corticosteroids (87%) and adrenocorticotropic hormone (13%). Nearly half of patients reported that their symptoms were very much (33%) or completely resolved (16%) following treatment. The most commonly reported adverse events were sleep disturbance (45%), mood changes (33%), weight gain (29%), and increased appetite (26%). Systematic assessment of relapses and response to relapse treatment may help clinicians to optimize outcomes for MS patients

Analysis of Pregnancy Outcomes Following Exposure to Intramuscular Interferon Beta-1a: The AVONEX® Pregnancy Exposure Registry

Abstract Background and Objectives There is a lack of well-controlled US studies of intramuscular (IM) interferon beta (IFNβ)-1a use in pregnant women with multiple sclerosis; however, in the European Medicines Agency region, IFNβ formulations may be considered during pregnancy if clinically needed based on data from European Union cohort registries. The AVONEX Pregnancy Exposure Registry was established to prospectively study the effects of IM IFNβ-1a on the risk of birth defects and spontaneous pregnancy loss in a US population. Methods Pregnant women with multiple sclerosis exposed to IM IFNβ-1a within ~ 1 week of conception or during the first trimester were included. Participants were followed until there was a pregnancy outcome, live-born infants were followed until age 8–12 weeks. Data were collected on IM IFNβ-1a exposure, demographics, patient characteristics, medical history, and pregnancy outcomes, including live births (with or without birth defect), spontaneous abortions/miscarriages and fetal death/stillbirth, elective abortions (with and without birth defect), and ectopic pregnancies. A population-based birth defect surveillance program, the Metropolitan Atlanta Congenital Defects Program (MACDP), served as the primary external control group for evaluating the risk of birth defects. Results Three-hundred and two patients with a median (range) age of 31.0 (16–48) years and a median (range) gestational age at the time of enrollment of 10.1 (4–39) weeks were evaluable. Most patients (n = 278/302; 92%) reported IM IFNβ-1a exposure in the week before conception and most (n = 293/302; 97%) discontinued treatment before the end of the first trimester. Of 306 pregnancy outcomes, there were 272 live births, 28 spontaneous abortions of 266 pregnancies enrolled before 22 weeks’ gestation (rate 10.5%; 95% confidence interval 7.2–15.0), five elective abortions, and one stillbirth. There were 17 adjudicator-confirmed major birth defects of 272 live births (rate 6.3%; 95% confidence interval 3.8–10.0); the pattern of birth defects observed was not suggestive of a relationship to prenatal IM IFNβ-1a exposure. Conclusions This large US registry study suggests IM IFNβ-1a exposure during early pregnancy was not clinically associated with adverse pregnancy outcomes in women with multiple sclerosis. These findings help inform clinicians and patients in weighing the risks and benefits of IM IFNβ-1a use during pregnancy. Clinical Trial Registration ClinicalTrials.gov: NCT00168714, 15 September, 2005

Adherence in multiple sclerosis (ADAMS): Classification, relevance, and research needs. A meeting report

Background: Adherence to medical interventions is a global problem. With an increasing amount of partially effective but expensive drug treatments adherence is increasingly relevant in multiple sclerosis (MS). Perceived lack of efficacy and side effects as well as neuropsychiatric factors such as forgetfulness, fatigue and depression are major determinants. However, research on adherence to behavioural interventions as part of rehabilitative interventions has only rarely been studied. Methods: In a one-day meeting health researchers as well as patient representatives and other stakeholders discussed adherence issues in MS and developed a general draft research agenda within a focus group session. Results: The focus group addressed four major areas: (1) focussing patients and their informal team; (2) studying health care professionals; (3) comparing practice across cultures; and (4) studying new adherence interventions. Conclusions: A focus on patient preferences as well as a non-judgemental discussion on adherence issues with patients should be at the core of adherence work

sj-docx-1-mso-10.1177_20552173231203816 - Supplemental material for Tolerability of subcutaneous ofatumumab with long-term exposure in relapsing multiple sclerosis

Supplemental material, sj-docx-1-mso-10.1177_20552173231203816 for Tolerability of subcutaneous ofatumumab with long-term exposure in relapsing multiple sclerosis by John Kramer, Ralf Linker, David Paling, Adam Czaplinski, Olaf Hoffmann, V Wee Yong, Noreen Barker, Amy Perrin Ross, Elisabeth Lucassen, Mohammad Gufran, Xixi Hu, Ronald Zielman, Gustavo Seifer and Patrick Vermersch in Multiple Sclerosis Journal – Experimental, Translational and Clinical</p

Sixty years of global progress in managed aquifer recharge

Sessanta anni di progressi a livello globale nella ricarica delle falde acquifere in condizioni controllate Riassunto Gli ultimi 60 anni sono stati testimoni di prelievi e fenomeni di sovrasfruttamento delle falde senza precedenti, come pure dello sviluppo di nuove tecnologie per il trattamento delle acque. Questi fattori hanno guidato i progressi nelle applicazioni della ricarica intenzionale degli acquiferi, nota in lingua inglese come managed aquifer recharge – MAR (in italiano tradotto in “ricarica delle falde in condizioni controllate”). Questo articolo è il primo tentativo conosciuto dagli Autori che ha l’obiettivo di quantificare a scala globale il volume prodotto attraverso tecniche MAR, di illustrare i progressi compiuti nelle varie tipologie di MAR e di mettere questi in relazione con gli avanzamenti nella ricerca e nella regolamentazione. Di fronte al cambiamento del clima e all’aumento dell’intensità degli eventi climatici estremi, le tecniche MAR rappresentano una strategia di gestione delle acque sempre più importante, insieme alla gestione della domanda, per mantenere, migliorare e proteggere i sistemi acquiferi sotto pressione e per salvaguardare e migliorare la qualità delle acque. In questo arco di tempo, la ricerca scientifica relativa alla progettazione idraulica degli impianti, agli studi con traccianti, alla gestione dei fenomeni di intasamento, all’efficienza di recupero ed. alle modifiche della qualità delle acque sotterranee, ha supportato i miglioramenti pratici nei sistemi MAR e ha prodotto benefici in senso più ampio in idrogeologia. I pozzi di ricarica hanno largamente contribuito ad incrementare il ravvenamento degli acquiferi, in particolare nelle aree urbane e nella gestione delle acque di miniera. Negli ultimi anni sono state intraprese ricerche sulla governance, le pratiche operative, l’affidabilità, l’economicità, la valutazione del rischio e l’accettazione pubblica dei sistemi MAR. Dagli anni ‘60, la realizzazione di sistemi MAR è progredita ad un tasso del 5% all’anno, ma non sta tenendo il passo con l’aumento dei prelievi delle acque sotterranee. Attualmente si stima che i sistemi MAR forniscano circa 10 km3/anno, circa il 2.4% dei prelievi di acque sotterranee nei paesi che riportano la presenza di impianti MAR (o ~1.0% del prelievo globale di acque sotterranee). Si ritiene, sulla base dei dati provenienti dai paesi in cui l’uso di questa tecnica è avanzato, che i volumi immagazzinati attraverso i sistemi MAR potranno arrivare a superare il 10% dei prelievi globali, sostenendo la disponibilità, affidabilità e qualità delle risorse idriche.The last 60&nbsp;years has seen unprecedented groundwater extraction and overdraft as well as development of new technologies for water treatment that together drive the advance in intentional groundwater replenishment known as managed aquifer recharge (MAR). This paper is the first known attempt to quantify the volume of MAR at global scale, and to illustrate the advancement of all the major types of MAR and relate these to research and regulatory advancements. Faced with changing climate and rising intensity of climate extremes, MAR is an increasingly important water management strategy, alongside demand management, to maintain, enhance and secure stressed groundwater systems and to protect and improve water quality. During this time, scientific research—on hydraulic design of facilities, tracer studies, managing clogging, recovery efficiency and water quality changes in aquifers—has underpinned practical improvements in MAR and has had broader benefits in hydrogeology. Recharge wells have greatly accelerated recharge, particularly in urban areas and for mine water management. In recent years, research into governance, operating practices, reliability, economics, risk assessment and public acceptance of MAR has been undertaken. Since the 1960s, implementation of MAR has accelerated at a rate of 5%/year, but is not keeping pace with increasing groundwater extraction. Currently, MAR has reached an estimated 10&nbsp;km3/year, ~2.4% of groundwater extraction in countries reporting MAR (or ~1.0% of global groundwater extraction). MAR is likely to exceed 10% of global extraction, based on experience where MAR is more advanced, to sustain quantity, reliability and quality of water supplies