Favorable Antiviral Effect of Metformin on Severe Acute Respiratory Syndrome Coronavirus 2 Viral Load in a Randomized, Placebo-Controlled Clinical Trial of Coronavirus Disease 2019.

BACKGROUND: Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%. METHODS: COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction. RESULTS: The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95% confidence interval [CI], -1.05 to -.06; P = .027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72; 95% CI, .55 to .94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI, .36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo. CONCLUSIONS: In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology. CLINICAL TRIALS REGISTRATION: NCT04510194.

Genome-Wide Mapping of Gene-Phenotype Relationships in Experimentally Evolved Populations.

Model organisms subjected to sustained experimental evolution often show levels of phenotypic differentiation that dramatically exceed the phenotypic differences observed in natural populations. Genome-wide sequencing of pooled populations then offers the opportunity to make inferences about the genes that are the cause of these phenotypic differences. We tested, through computer simulations, the efficacy of a statistical learning technique called the "fused lasso additive model" (FLAM). We focused on the ability of FLAM to distinguish between genes which are differentiated and directly affect a phenotype from differentiated genes which have no effect on the phenotype. FLAM can separate these two classes of genes even with relatively small samples (10 populations, in total). The efficacy of FLAM is improved with increased number of populations, reduced environmental phenotypic variation, and increased within-treatment among-replicate variation. FLAM was applied to SNP variation measured in both twenty-population and thirty-population studies of Drosophila subjected to selection for age-at-reproduction, to illustrate the application of the method.

Drosophila transcriptomics with and without ageing.

The genomic basis of ageing still remains unknown despite being a topic of study for many years. Here, we present data from 20 experimentally evolved laboratory populations of Drosophila melanogaster that have undergone two different life-history selection regimes. One set of ten populations demonstrates early ageing whereas the other set of ten populations shows postponed ageing. Additionally, both types of populations consist of five long standing populations and five recently derived populations. Our primary goal was to determine which genes exhibit changes in expression levels by comparing the female transcriptome of the two population sets at two different time points. Using three different sets of increasingly restrictive criteria, we found that 2.1-15.7% (82-629 genes) of the expressed genes are associated with differential ageing between population sets. Conversely, a comparison of recently derived populations to long-standing populations reveals little to no transcriptome differentiation, suggesting that the recent selection regime has had a larger impact on the transcriptome than its more distant evolutionary history. In addition, we found very little evidence for significant enrichment for functional attributes regardless of the set of criteria used. Relative to previous ageing studies, we find little overlap with other lists of aging related genes. The disparity between our results and previously published results is likely due to the high replication used in this study coupled with our use of highly differentiated populations. Our results reinforce the notion that the use of genomic, transcriptomic, and phenotypic data to uncover the genetic basis of a complex trait like ageing can benefit from experimental designs that use highly replicated, experimentally-evolved populations.

Iodination of Dimethenamid in Chloraminated Water: Active Iodinating Agents and Distinctions between Chlorination, Bromination, and Iodination.

Few studies have elucidated the agent(s) that generate iodinated disinfection byproducts during drinking water treatment. We present a kinetic investigation of iodination of dimethenamid (DM), a model compound lacking acid-base speciation. Water chemistry parameters (pH, [Cl-], [Br-], [I-], and [pH buffer]) were systematically varied. As pH increased (4-9), DM iodination rate decreased. Conventional wisdom considers hypoiodous acid (HOI) as the predominant iodinating agent; nevertheless, HOI (pKHOI = 10.4) could not have produced this result, as its concentration is essentially invariant from pH 4-9. In contrast, [H2OI+] and [ICl] both decrease as pH increases. To distinguish their contributions to DM iodination, [Cl-] was added at constant pH and ionic strength. Although chloride addition did increase the iodination rate, the reaction order in [Cl-] was fractional (≤0.36). The contribution of ICl to DM iodination remained below 47% under typical drinking water conditions ([Cl-] ≤ 250 mg/L), implicating H2OI+ as the predominant iodinating agent. Distinctions between DM iodination versus chlorination or bromination include a more pronounced role for the hypohalous acidium ion (H2OX+), negligible contributions by hypohalous acid and molecular halogen (X2), and a more muted influence of XCl, leading to lesser susceptibility to catalysis by chloride.

Effects of evolutionary history on genome wide and phenotypic convergence in Drosophila populations.

BACKGROUND: Studies combining experimental evolution and next-generation sequencing have found that adaptation in sexually reproducing populations is primarily fueled by standing genetic variation. Consequently, the response to selection is rapid and highly repeatable across replicate populations. Some studies suggest that the response to selection is highly repeatable at both the phenotypic and genomic levels, and that evolutionary history has little impact. Other studies suggest that even when the response to selection is repeatable phenotypically, evolutionary history can have significant impacts at the genomic level. Here we test two hypotheses that may explain this discrepancy. Hypothesis 1: Past intense selection reduces evolutionary repeatability at the genomic and phenotypic levels when conditions change. Hypothesis 2: Previous intense selection does not reduce evolutionary repeatability, but other evolutionary mechanisms may. We test these hypotheses using D. melanogaster populations that were subjected to 260 generations of intense selection for desiccation resistance and have since been under relaxed selection for the past 230 generations. RESULTS: We find that, with the exception of longevity and to a lesser extent fecundity, 230 generations of relaxed selection has erased the extreme phenotypic differentiation previously found. We also find no signs of genetic fixation, and only limited evidence of genetic differentiation between previously desiccation resistance selected populations and their controls. CONCLUSION: Our findings suggest that evolution in our system is highly repeatable even when populations have been previously subjected to bouts of extreme selection. We therefore conclude that evolutionary repeatability can overcome past bouts of extreme selection in Drosophila experimental evolution, provided experiments are sufficiently long and populations are not inbred.

Validation of The Individualized Neuromuscular Quality of Life in Japanese patients with myotonic dystrophy.

INTRODUCTION: The Individualized Neuromuscular Quality of Life (INQoL) is used to measure the quality of life (QoL) of patients with neuromuscular disease. We conducted this study to translate and validate the Japanese version of the INQoL in patients with myotonic dystrophy. METHODS: Forward and backward translation, patient testing, and psychometric validation were performed. We used the 36-Item Short Form Health Survey (SF-36) and the modified Rankin scale for concurrent validation. RESULTS: The Japanese INQoL was administered to 90 adult patients. The coefficients for internal consistency and test-retest reliability were adequately high in most domains (Cronbach α 0.88-0.96 and intraclass coefficient 0.64-0.99). INQoL domains were moderately to strongly associated with relevant SF-36 subscales (Spearman's ρ -0.23 to -0.74). Symptom severity, disease duration, employment status, and use of a ventilator influenced overall QoL. DISCUSSION: The INQoL is a reliable and validated measure of QoL for Japanese patients with myotonic dystrophy. Muscle Nerve, 2018.

Fourth-Generation HIV Testing.

A 72-year-old man presented to the emergency department with fevers, night sweats, and rash 3 days after condomless vaginal intercourse. Results of a fourth-generation HIV test were positive and HIV-1-/2 antibody differentiation testing was negative. How would you interpret these results?

What explains high life satisfaction in men living with Duchenne muscular dystrophy? A preliminary study to inform psychological intervention.

INTRODUCTION: There are increasing numbers of men with Duchenne muscular dystrophy (mDMD). For those who struggle to live with the condition, psychological interventions may be helpful. However, it is unclear how these should be tailored for mDMD. To inform intervention, this study assessed whether 2 well-validated psychological models (Leventhal's Self-Regulatory Model; Psychological Flexibility Model) could explain variation in life satisfaction (LS). METHODS: Sixteen mDMD, aged 18-43 years, completed an online survey comprised of questionnaire measures of LS, mood, and both psychological models: Illness Perceptions (Leventhal's Self-Regulatory Model); engagement in meaningful activity, and acceptance/awareness of difficult thoughts and feelings (Psychological Flexibility Model). A median split enabled comparison of high and low LS groups. RESULTS: Those with higher LS were characterized by the ability to undertake personally meaningful activity in acceptance of difficult thoughts and feelings. CONCLUSIONS: Results supported the Psychological Flexibility Model. However, methodological limitations mean that these findings should be considered preliminary. Muscle Nerve 56: 163-166, 2017.

A protocol to develop clinical guidelines for inclusion-body myositis.

INTRODUCTION: Inclusion-body myositis (IBM) is a late-onset idiopathic inflammatory myopathy associated with selective and progressive muscle weakness and atrophy. Current clinical management of IBM is largely supportive due to its uncertain etiology and lack of effective treatment. Establishing a consensus of opinion on questions relating to diagnosis and management of IBM is expected to help reduce inconsistencies in the care and resources allocated to those living with this condition. METHODS: A protocol has been developed to produce best practice clinical guidelines for IBM based on a combination of published research and expert consensus. CONCLUSIONS: In this study we describe the proposed protocol for developing methods for producing robust and transparent clinical guidance on aspects of diagnosis, drug treatment, physical and practical management, respiration, nutrition and cardiac management, psychosocial management, and multidisciplinary care.

The death spiral: predicting death in Drosophila cohorts.

Drosophila research has identified a new feature of aging that has been called the death spiral. The death spiral is a period prior to death during which there is a decline in life-history characters, such as fecundity, as well as physiological characters. First, we review the data from the Drosophila and medfly literature that suggest the existence of death spirals. Second, we re-analyze five cases with such data from four laboratories using a generalized statistical framework, a re-analysis that strengthens the case for the salience of the death spiral phenomenon. Third, we raise the issue whether death spirals need to be taken into account in the analysis of functional characters over age, in aging research with model species as well as human data.

Four steps toward the control of aging: following the example of infectious disease.

The biotechnological task of controlling human aging will evidently be complex, given the failure of all simple strategies for accomplishing this task to date. In view of this complexity, a multi-step approach will be necessary. One precedent for a multi-step biotechnological success is the burgeoning control of human infectious diseases from 1840 to 2000. Here we break down progress toward the control of infectious disease into four key steps, each of which have analogs for the control of aging. (1) Agreement about the fundamental nature of the medical problem. (2) Public health measures to mitigate some of the factors that exacerbate the medical problem. (3) Early biotechnological interventions that ward off the more tractable disease etiologies. (4) Deep understanding of the underlying biology of the diseases involved, leading in turn to comprehensive control of the medical problems that they pose. Achievement of all four of these steps has allowed most people who live in Western countries to live largely free of imminent death due to infectious disease. Accomplishing the equivalent feat for aging over this century should lead to a similar outcome for aging-associated disease. Neither infection nor aging will ever be entirely abolished, but they can both be rendered minor causes of death and disability.

Genome-wide analysis of a long-term evolution experiment with Drosophila.

Experimental evolution systems allow the genomic study of adaptation, and so far this has been done primarily in asexual systems with small genomes, such as bacteria and yeast. Here we present whole-genome resequencing data from Drosophila melanogaster populations that have experienced over 600 generations of laboratory selection for accelerated development. Flies in these selected populations develop from egg to adult ∼20% faster than flies of ancestral control populations, and have evolved a number of other correlated phenotypes. On the basis of 688,520 intermediate-frequency, high-quality single nucleotide polymorphisms, we identify several dozen genomic regions that show strong allele frequency differentiation between a pooled sample of five replicate populations selected for accelerated development and pooled controls. On the basis of resequencing data from a single replicate population with accelerated development, as well as single nucleotide polymorphism data from individual flies from each replicate population, we infer little allele frequency differentiation between replicate populations within a selection treatment. Signatures of selection are qualitatively different than what has been observed in asexual species; in our sexual populations, adaptation is not associated with 'classic' sweeps whereby newly arising, unconditionally advantageous mutations become fixed. More parsimonious explanations include 'incomplete' sweep models, in which mutations have not had enough time to fix, and 'soft' sweep models, in which selection acts on pre-existing, common genetic variants. We conclude that, at least for life history characters such as development time, unconditionally advantageous alleles rarely arise, are associated with small net fitness gains or cannot fix because selection coefficients change over time.

Interventions for dysphagia in long-term, progressive muscle disease.

BACKGROUND: Normal swallowing function is divided into oral, pharyngeal, and oesophageal phases. The anatomy and physiology of the oral cavity facilitates an oral preparatory phase of swallowing, in which food and liquid are pushed towards the pharynx by the tongue. During pharyngeal and oesophageal phases of swallowing, food and liquid are moved from the pharynx to the stomach via the oesophagus. Our understanding of swallowing function in health and disease has informed our understanding of how muscle weakness can disrupt swallowing in people with muscle disease. As a common complication of long-term, progressive muscle disease, there is a clear need to evaluate the current interventions for managing swallowing difficulties (dysphagia). This is an update of a review first published in 2004. OBJECTIVES: To assess the effects of interventions for dysphagia in people with long-term, progressive muscle disease. SEARCH METHODS: On 11 January 2016, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, AMED, LILACS, and CINAHL. We checked references in the identified trials for additional randomised and quasi-randomised controlled trials. We also searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform on 12 January 2016 for ongoing or completed but unpublished clinical trials. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials that assessed the effect of interventions for managing dysphagia in adults and children with long-term, progressive muscle disease, compared to other interventions, placebo, no intervention, or standard care. Quasi-randomised controlled trials are trials that used a quasi-random method of allocation, such as date of birth, alternation, or case record number. Review authors previously excluded trials involving people with muscle conditions of a known inflammatory or toxic aetiology. In this review update, we decided to include trials of people with sporadic inclusion body myositis (IBM) on the basis that it presents as a long-term, progressive muscle disease with uncertain degenerative and inflammatory aetiology and is typically refractory to treatment. DATA COLLECTION AND ANALYSIS: We applied standard Cochrane methodological procedures. MAIN RESULTS: There were no randomised controlled trials (RCTs) that reported results in terms of the review's primary outcome of interest, weight gain or maintenance. However, we identified one RCT that assessed the effect of intravenous immunoglobulin on swallowing function in people with IBM. The trial authors did not specify the number of study participants who had dysphagia. There was also incomplete reporting of findings from videofluoroscopic investigations, which was one of the review's secondary outcome measures. The study did report reductions in the time taken to swallow, as measured using ultrasound. No serious adverse events occurred during the study, although data for the follow-up period were lacking. It was also unclear whether the non-serious adverse events reported occurred in the treatment group or the placebo group. We assessed this study as having a high risk of bias and uncertain confidence intervals for the review outcomes, which limited the overall quality of the evidence. Using GRADE criteria, we downgraded the quality of the evidence from this RCT to 'low' for efficacy in treating dysphagia, due to limitations in study design and implementation, and indirectness in terms of the population and outcome measures. Similarly, we assessed the quality of the evidence for adverse events as 'low'. From our search for RCTs, we identified two other non-randomised studies, which reported the effects of long-term intravenous immunoglobulin therapy in adults with IBM and lip-strengthening exercises in children with myotonic dystrophy type 1. Headaches affected two participants treated with long-term intravenous immunoglobulin therapy, who received a tailored dose reduction; there were no adverse events associated with lip-strengthening exercises. Both non-randomised studies identified improved outcomes for some participants following the intervention, but neither study specified the number of participants with dysphagia or demonstrated any group-level treatment effect for swallowing function using the outcomes prespecified in this review. AUTHORS' CONCLUSIONS: There is insufficient and low-quality RCT evidence to determine the effect of interventions for dysphagia in long-term, progressive muscle disease. Clinically relevant effects of intravenous immunoglobulin for dysphagia in inclusion body myositis can neither be confirmed or excluded using the evidence presented in this review. Standardised, validated, and reliable outcome measures are needed to assess dysphagia and any possible treatment effect. Clinically meaningful outcomes for dysphagia may require a shift in focus from measures of impairment to disability associated with oral feeding difficulties.

The potential of psychological interventions to improve quality of life and mood in muscle disorders.

Quality of life (QoL) and mood are reduced in many patients with muscle disorders. Psychological variables appear to be contributors to both QoL and mood, suggesting that psychological interventions could improve these outcomes, yet research in this area is sparse. We review the roles of psychological variables, plus context and disease severity, in explaining QoL. A cognitive-behavioral model of disease self-management, with acceptance as the central component, is discussed. This model is then used to describe how psychological interventions derived from cognitive behavioral therapy (CBT), in particular Acceptance and Commitment Therapy (ACT), might be applied to address the issues of distress, nonadherence to treatments, pain, and fatigue in people with muscle disorders.

The individualized neuromuscular quality of life questionnaire: cultural translation and psychometric validation for the Dutch population.

INTRODUCTION: In this study we describe the translation and psychometric evaluation of the Dutch Individualized Neuromuscular Quality of Life (INQoL) questionnaire. METHODS: Backward and forward translation of the questionnaire was executed, and psychometric properties were assessed on the basis of reliability and validity. RESULTS: Two hundred six patients were included in the study. Reliability analyses resulted in Cronbach alpha values of >0.70 for all subdomains. Known-group validity showed a significant correlation between INQoL scores and severity as well as age for the majority of subdomains. Item-total correlation for overall quality of life was satisfactory. Concurrent validity with the SF-36 and EQ-5D was good (range of Spearman correlation coefficients -0.43 to -0.76). CONCLUSIONS: This study resulted in a questionnaire that is appropiate for use in the Dutch-speaking population to measure quality of life among patients with a wide variety of muscle disorders. This confirms and extends data obtained in the UK, US, Italy, and Serbia.

Treatment for inclusion body myositis.

BACKGROUND: Inclusion body myositis (IBM) is a late-onset inflammatory muscle disease (myopathy) associated with progressive proximal and distal limb muscle atrophy and weakness. Treatment options have attempted to target inflammatory and atrophic features of this condition (for example with immunosuppressive and immunomodulating drugs, anabolic steroids, and antioxidant treatments), although as yet there is no known effective treatment for reversing or minimising the progression of inclusion body myositis. In this review we have considered the benefits, adverse effects, and costs of treatment in targeting cardinal effects of the condition, namely muscle atrophy, weakness, and functional impairment. OBJECTIVES: To assess the effects of treatment for IBM. SEARCH METHODS: On 7 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register for Controlled Trials (CENTRAL), MEDLINE, and EMBASE. Additionally in November 2014 we searched clinical trials registries for ongoing or completed but unpublished trials. SELECTION CRITERIA: We considered randomised or quasi-randomised trials, including cross-over trials, of treatment for IBM in adults compared to placebo or any other treatment for inclusion in the review. We specifically excluded people with familial IBM and hereditary inclusion body myopathy, but we included people who had connective tissue and autoimmune diseases associated with IBM, which may or may not be identified in trials. We did not include studies of exercise therapy or dysphagia management, which are topics of other Cochrane systematic reviews. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. MAIN RESULTS: The review included 10 trials (249 participants) using different treatment regimens. Seven of the 10 trials assessed single agents, and 3 assessed combined agents. Many of the studies did not present adequate data for the reporting of the primary outcome of the review, which was the percentage change in muscle strength score at six months. Pooled data from two trials of interferon beta-1a (n = 58) identified no important difference in normalised manual muscle strength sum scores from baseline to six months (mean difference (MD) -0.06, 95% CI -0.15 to 0.03) between IFN beta-1a and placebo (moderate-quality evidence). A single trial of methotrexate (MTX) (n = 44) provided moderate-quality evidence that MTX did not arrest or slow disease progression, based on reported percentage change in manual muscle strength sum scores at 12 months. None of the fully published trials were adequately powered to detect a treatment effect. We assessed six of the nine fully published trials as providing very low-quality evidence in relation to the primary outcome measure. Three trials (n = 78) compared intravenous immunoglobulin (combined in one trial with prednisone) to a placebo, but we were unable to perform meta-analysis because of variations in study analysis and presentation of trial data, with no access to the primary data for re-analysis. Other comparisons were also reported in single trials. An open trial of anti-T lymphocyte immunoglobulin (ATG) combined with MTX versus MTX provided very low-quality evidence in favour of the combined therapy, based on percentage change in quantitative muscle strength sum scores at 12 months (MD 12.50%, 95% CI 2.43 to 22.57). Data from trials of oxandrolone versus placebo, azathioprine (AZA) combined with MTX versus MTX, and arimoclomol versus placebo did not allow us to report either normalised or percentage change in muscle strength sum scores. A complete analysis of the effects of arimoclomol is pending data publication. Studies of simvastatin and bimagrumab (BYM338) are ongoing. All analysed trials reported adverse events. Only 1 of the 10 trials interpreted these for statistical significance. None of the trials included prespecified criteria for significant adverse events. AUTHORS' CONCLUSIONS: Trials of interferon beta-1a and MTX provided moderate-quality evidence of having no effect on the progression of IBM. Overall trial design limitations including risk of bias, low numbers of participants, and short duration make it difficult to say whether or not any of the drug treatments included in this review were effective. An open trial of ATG combined with MTX versus MTX provided very low-quality evidence in favour of the combined therapy based on the percentage change data given. We were unable to draw conclusions from trials of IVIg, oxandrolone, and AZA plus MTX versus MTX. We need more randomised controlled trials that are larger, of longer duration, and that use fully validated, standardised, and responsive outcome measures.

ANTECEDENTES: La miositis por cuerpos de inclusión (MCI) es una enfermedad muscular inflamatoria (miopatía) de aparición tardía asociada con atrofia muscular y debilidad progresivas de los miembros proximales y distales. Las opciones de tratamiento se han intentado dirigir a las características inflamatorias y atróficas de esta afección (por ejemplo, con fármacos inmunosupresores e inmunomoduladores, esteroides anabólicos y tratamientos antioxidantes), aunque hasta ahora no hay un tratamiento eficaz conocido para la reversión o la reducción de la progresión de la miositis por cuerpos de inclusión. En esta revisión se han considerado los efectos beneficiosos, los efectos adversos y los costos del tratamiento dirigido a los efectos fundamentales de la afección, a saber, la atrofia muscular, la debilidad y el deterioro funcional. OBJETIVOS: Evaluar los efectos del tratamiento para la MCI. MÉTODOS DE BÚSQUEDA: El 7 octubre 2014, se hicieron búsquedas en el registro especializado del Grupo Cochrane de Enfermedades Neuromusculares (Cochrane Neuromuscular Disease Group), en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL), MEDLINE y en EMBASE. Además, en noviembre 2014 se realizaron búsquedas de ensayos en curso o terminadas pero no publicados en los registros de ensayos clínicos. CRITERIOS DE SELECCIÓN: Se consideraron para inclusión en la revisión los ensayos aleatorios o cuasialeatorios, incluidos los ensayos cruzados (crossover), del tratamiento para la MCI en adultos en comparación con placebo u otro tratamiento. Se excluyeron específicamente los pacientes con MCI familiar y miopatía por cuerpos de inclusión hereditaria, pero se incluyeron los pacientes con enfermedades del tejido conjuntivo y autoinmunitarias asociadas con MCI, que pueden o no identificarse en los ensayos. No se incluyeron los estudios de terapia con ejercicios o tratamiento de la disfagia, que son los temas de otras revisiones sistemáticas Cochrane. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Se utilizaron procedimientos metodológicos Cochrane estándar. RESULTADOS PRINCIPALES: La revisión incluyó diez ensayos (249 participantes) que utilizaron diferentes regímenes de tratamiento. Siete de los diez ensayos evaluaron agentes únicos y tres evaluaron agentes combinados. Muchos de los estudios no presentaron datos suficientes para el informe del resultado primario de la revisión, que fue el cambio porcentual en la puntuación de fuerza muscular a los seis meses. Los datos agrupados de dos ensayos de interferón beta­1a (n = 58) no identificaron diferencias importantes en las puntuaciones normalizadas de la suma de la fuerza muscular manual desde el inicio hasta los seis meses (diferencia de medias [DM] ­0,06; IC del 95%: ­0,15 a 0,03) entre IFN beta­1a y placebo (pruebas de calidad moderada). Un único ensayo de metotrexato (MTX) (n = 44) proporcionó pruebas de calidad moderada de que el MTX no detuvo ni enlenteció la progresión de la enfermedad, sobre la base del cambio porcentual informado en las puntuaciones de la suma de la fuerza muscular manual a los 12 meses. Ninguno de los ensayos publicados completamente tuvo poder estadístico suficiente para detectar un efecto del tratamiento. Se consideró que seis de los nueve ensayos publicados completamente aportaron pruebas de calidad muy baja con respecto a la medida de resultado primaria. Tres ensayos (n = 78) compararon la inmunoglobulina intravenosa (combinada en un ensayo con prednisona) con placebo, pero no fue posible realizar el metanálisis debido a las variaciones en el análisis de los estudios y a la presentación de los datos del ensayo, sin acceso a los datos primarios para el reanálisis. Otras comparaciones también se informaron en ensayos individuales. Un ensayo abierto de inmunoglobulina anti­linfocitos T (IgAT) combinada con MTX versus MTX proporcionó pruebas de calidad muy baja a favor del tratamiento combinado, sobre la base del cambio porcentual en las puntuaciones cuantitativas de la suma de la fuerza muscular a los 12 meses (DM 12,50%; IC del 95%: 2,43 a 22,57). Los datos de los ensayos de oxandrolona versus placebo, azatioprina (AZA) combinada con MTX versus MTX y arimoclomol versus placebo no permitieron informar sobre el cambio porcentual o normalizado en las puntuaciones de la suma de la fuerza muscular. Un análisis completo de los efectos del arimoclomol está pendiente de la publicación de los datos. Están en curso estudios de simvastatina y bimagrumab (BYM338). Todos los ensayos analizados informaron eventos adversos. Solamente uno de los diez ensayos interpretó la significación estadística de los eventos adversos. Ninguno de los ensayos incluyó criterios preespecificados para los eventos adversos significativos. CONCLUSIONES DE LOS AUTORES: Los ensayos de interferón beta­1a y MTX proporcionaron pruebas de calidad moderada de que no tienen efectos sobre la progresión de la MCI. Las limitaciones generales del diseño de los ensayos, que incluyen el riesgo de sesgo, los escasos números de participantes y la corta duración, hacen difícil determinar si alguno de los tratamientos farmacológicos incluidos en esta revisión fue eficaz. Un ensayo abierto de ATG combinada con MTX versus MTX aportó pruebas de calidad muy baja a favor del tratamiento combinado sobre la base de los datos de cambio porcentual facilitados. No fue posible establecer conclusiones de los ensayos de IgIV, oxandrolona y AZA más MTX versus MTX. Se necesitan más ensayos controlados aleatorios de mayor tamaño, con una duración más prolongada y que utilicen medidas de resultado completamente validadas, estandarizadas y de interés.

Technical Modifications to Prevent Massive Hemothorax Following Sternal Plating.

We report two cases of life-threatening massive hemothorax after titanium plate fixation. We propose a modification of this technique using smaller plates that span the sternal bone but do not encroach upon the cartilage of the ribcage.

Activity rating scales in adult muscle disease: what do they actually measure?

INTRODUCTION: There is a diversity of rating scales that assess function in muscle disease. Definitive knowledge of the content covered by these scales would help in making choices. METHODS: We searched for activity rating scales used for muscle disease and assessed their content by linking scale items to the International Classification of Functioning, Disability and Health (ICF) and the muscle regions they cover. RESULTS: Of the 119 scales found, 19 muscle disease-specific and 9 generic scales were prioritized for analysis. These 28 scales contained 457 items, from which 1145 concepts were identified and 160 were unique. Of these concepts, 97.8% could be linked to the ICF, most to the activities and participation domain (68.7%), followed by environmental factors (22.5%) and body functions (6.6%). Global muscle function was assessed most frequently, followed by lower and upper extremity function. CONCLUSIONS: This content comparison should allow for a better-informed choice of activity rating scales for muscle disease.