Introduction
Exercise can provide numerous benefits to haemophilia patients, including bleeding reduction in muscles and joints.
Aim
This systematic review (SR) aims to evaluate the effects of ...physical exercise on pain and the musculoskeletal function of patients with hemophilia.
Methods
Literature searches of Pubmed, Web of Science, PEDro, Cochrane, Clinical Trials SciELO and Lilacs were performed. The risks of bias were measured using the JADAD scale.
Results
Nine controlled clinical trials were included in the SR.
Conclusion
Physical exercise can promote a reduction in the perception of pain and can increase ROM and muscle strength in haemophilia patients. Future RCTs with greater methodological rigor that focus on the parameters used to prescribe exercises are necessary.
Although β-lactams are considered to have a safe therapeutic profile, neurotoxicity has been reported. The aim of this study was to assess the association between β-lactam concentrations and ...neurological alterations in septic ICU patients.
Retrospective study on all ICU patients who were treated with meropenem (MEM), piperacillin-tazobactam (TZP) or ceftazidime/cefepime (CEF) and in whom at least one β-lactam trough concentration (C min) was determined. Drug levels were measured using high-performance liquid chromatography; C min was normalized to the clinical breakpoint of Pseudomonas aeruginosa (as determined by EUCAST) for each drug (C min/MIC). Changes in neurological status were evaluated using changes in the neurological sequential organ failure assessment score (ΔnSOFA) using the formula: ΔnSOFA = nSOFA(day of TDM) - nSOFA(ICU admission). Worsening neurological status (NWS) was defined as a ΔnSOFA ≥ 1 for an nSOFA on admission of 0-2.
We collected 262 C min in 199 patients (130 MEM, 85 TZP, 47 CEF). Median APACHE II score and GCS on admission were 17 and 15, respectively. Overall ICU mortality was 27 %. There were no differences in the occurrence of NWS between antibiotics (39% for MEM, 32% for TZP and 35% for CEF). The occurrence of NWS increased with increasing C min/MIC ranges (P = 0.008); this correlation was found for TZP (P = 0.05) and MEM (P = 0.01), but not for CEF. C min/MIC was an independent predictive factor for NWS (OR 1.12 1.04-1.20).
We found a correlation between high β-lactam trough concentrations and increased occurrence of neurological deterioration in septic ICU patients. Although our data cannot determine causality, monitoring of β-lactam levels should be considered when deterioration of neurological status occurs during critical illness.
Comprehensive cost-effectiveness analyses of introducing varicella and/or herpes zoster vaccination in the Swedish national vaccination programme.
Cost-effectiveness analyses based on epidemiological ...results from a specifically developed transmission model.
National vaccination programme in Sweden, over an 85- or 20-year time horizon depending on the vaccination strategy.
Hypothetical cohorts of people aged 12 months and 65-years at baseline.
Four alternative vaccination strategies; 1, not to vaccinate; 2, varicella vaccination with one dose of the live attenuated vaccine at age 12 months and a second dose at age 18 months; 3, herpes zoster vaccination with one dose of the live attenuated vaccine at 65 years of age; and 4, both vaccine against varicella and herpes zoster with the before-mentioned strategies.
Accumulated cost and quality-adjusted life years (QALY) for each strategy, and incremental cost-effectiveness ratios (ICER).
It would be cost-effective to vaccinate against varicella (dominant), but not to vaccinate against herpes zoster (ICER of EUR 200,000), assuming a cost-effectiveness threshold of EUR 50,000 per QALY. The incremental analysis between varicella vaccination only and the combined programme results in a cost per gained QALY of almost EUR 1.6 million.
The results from this study are central components for policy-relevant decision-making, and suggest that it was cost-effective to introduce varicella vaccination in Sweden, whereas herpes zoster vaccination with the live attenuated vaccine for the elderly was not cost-effective-the health effects of the latter vaccination cannot be considered reasonable in relation to its costs. Future observational and surveillance studies are needed to make reasonable predictions on how boosting affects the herpes zoster incidence in the population, and thus the cost-effectiveness of a vaccination programme against varicella. Also, the link between herpes zoster and sequelae need to be studied in more detail to include it suitably in health economic evaluations.
HER2-positive (+) breast cancers, defined by HER2 overexpression and/or amplification, are often addicted to HER2 to maintain their malignant phenotype. Yet, some HER2+ tumors do not benefit from ...anti-HER2 therapy. We hypothesize that HER2 amplification levels and PI3K pathway activation are key determinants of response to HER2-targeted treatments without chemotherapy.
Baseline HER2+ tumors from patients treated with neoadjuvant lapatinib plus trastuzumab with endocrine therapy for estrogen receptor (ER)+ tumors in TBCRC006 (NCT00548184) were evaluated in a central laboratory for HER2 amplification by fluorescence in situ hybridization (FISH) (n=56). HER2 copy number (CN) and FISH ratios, and PI3K pathway status, defined by PIK3CA mutations or PTEN levels by immunohistochemistry were available for 41 tumors. Results were correlated with pathologic complete response (pCR; no residual invasive tumor in breast).
Thirteen of the 56 patients (23%) achieved pCR. None of the 11 patients with HER2 ratio <4 and/or CN <10 achieved pCR, whereas 13/45 patients (29%) with HER2 ratio ≥4 and/or CN ≥10 attained pCR (P=0.0513). Of the 18 patients with tumors expressing high PTEN or wild-type (WT) PIK3CA (intact PI3K pathway), 7 (39%) achieved pCR, compared with 1/23 (4%) with PI3K pathway alterations (P=0.0133). Seven of the 16 patients (44%) with HER2 ratio ≥4 and intact PI3K pathway achieved pCR, whereas only 1/25 (4%) patients not meeting these criteria achieved pCR (P=0.0031).
Our findings suggest that there is a clinical subtype in breast cancer with high HER2 amplification and intact PI3K pathway that is especially sensitive to HER2-targeted therapies without chemotherapy. A combination of HER2 FISH ratio and PI3K pathway status warrants validation to identify patients who may be treated with HER2-targeted therapy without chemotherapy.
ABSTRACT
Spatially resolved images of debris discs are necessary to determine disc morphological properties and the scattering phase function (SPF) thatantifies the brightness of scattered light as a ...function of phase angle. Current high-contrast imaging instruments have successfully resolved several dozens of debris discs around other stars, but few studies have investigated trends in the scattered-light, resolved population of debris discs in a uniform and consistent manner. We have combined Karhunen-Loeve Image Projection (KLIP) with radiative-transfer disc forward modelling in order to obtain the highest-quality image reductions and constrain disc morphological properties of eight debris discs imaged by the Gemini Planet Imager at H-band with a consistent and uniformly applied approach. In describing the scattering properties of our models, we assume a common SPF informed from solar system dust scattering measurements and apply it to all systems. We identify a diverse range of dust density properties among the sample, including critical radius, radial width, and vertical width. We also identify radially narrow and vertically extended discs that may have resulted from substellar companion perturbations, along with a tentative positive trend in disc eccentricity with relative disc width. We also find that using a common SPF can achieve reasonable model fits for discs that are axisymmetric and asymmetric when fitting models to each side of the disc independently, suggesting that scattering behaviour from debris discs may be similar to Solar system dust.
Gene expression in skeletal muscle of older individuals may reflect compensatory adaptations in response to oxidative damage that preserve tissue integrity and maintain function. Identifying ...associations between oxidative stress response gene expression patterns and mitochondrial function, physical performance, and muscle mass in older individuals would further our knowledge of mechanisms related to managing molecular damage that may be targeted to preserve physical resilience. To characterize expression patterns of genes responsible for the oxidative stress response, RNA was extracted and sequenced from skeletal muscle biopsies collected from 575 participants (≥70 years old) from the Study of Muscle, Mobility, and Aging. Expression levels of 21 protein‐coding RNAs related to the oxidative stress response were analyzed in relation to six phenotypic measures, including maximal mitochondrial respiration from muscle biopsies (Max OXPHOS), physical performance (VO2 peak, 400‐m walking speed, and leg strength), and muscle size (thigh muscle volume and whole‐body D3Cr muscle mass). The mRNA level of the oxidative stress response genes most consistently associated across outcomes are preferentially expressed within the mitochondria. Higher expression of mRNAs that encode generally mitochondria located proteins SOD2, TRX2, PRX3, PRX5, and GRX2 were associated with higher levels of mitochondrial respiration and VO2 peak. In addition, greater SOD2, PRX3, and GRX2 expression was associated with higher physical performance and muscle size. Identifying specific mechanisms associated with high functioning across multiple performance and physical domains may lead to targeted antioxidant interventions with greater impacts on mobility and independence.
Identifying associations between oxidative stress response gene expression patterns and mitochondrial function, physical performance, and muscle mass in older individuals would further our knowledge of mechanisms related to functional decline. We performed gene expression in 575 skeletal muscle biopsies collected as part of the Study of Muscle, Mobility, and Aging, a large, longitudinal study of ≥70 year old people. Associations were identified between expression levels of 21 canonical mitochondrial and extramitochondrial antioxidant genes and muscle mitochondrial function (Max OXPHOS), physical performance (VO2 peak, 400‐m walking speed, and leg strength), and muscle size (thigh muscle volume and whole‐body D3Cr muscle mass). Higher expression of mRNAs that encode mitochondria located proteins were associated with higher levels of mitochondrial respiration, VO2 peak, walking speed, and muscle size.
Autophagy is essential for proteostasis, energetic balance, and cell defense and is a key pathway in aging. Identifying associations between autophagy gene expression patterns in skeletal muscle and ...physical performance outcomes would further our knowledge of mechanisms related with proteostasis and healthy aging. Muscle biopsies were obtained from participants in the Study of Muscle, Mobility, and Aging (SOMMA). For 575 participants, RNA was sequenced and expression of 281 genes related to autophagy regulation, mitophagy, and mTOR/upstream pathways was determined. Associations between gene expression and outcomes including mitochondrial respiration in muscle fiber bundles (MAX OXPHOS), physical performance (VO2 peak, 400 m walking speed, and leg power), and thigh muscle volume, were determined using negative binomial regression models. For autophagy, key transcriptional regulators including TFE3 and NFKB‐related genes (RELA, RELB, and NFKB1) were negatively associated with outcomes. On the contrary, regulators of oxidative metabolism that also promote overall autophagy, mitophagy, and pexophagy (PPARGC1A, PPARA, and EPAS1) were positively associated with multiple outcomes. In line with this, several mitophagy, fusion, and fission‐related genes (NIPSNAP2, DNM1L, and OPA1) were also positively associated with outcomes. For mTOR pathway and related genes, expression of WDR59 and WDR24, both subunits of GATOR2 complex (an indirect inhibitor of mTORC1), and PRKAG3, which is a regulatory subunit of AMPK, were negatively correlated with multiple outcomes. Our study identifies autophagy and selective autophagy such as mitophagy gene expression patterns in human skeletal muscle related to physical performance, muscle volume, and mitochondrial function in older persons which may lead to target identification to preserve mobility and independence.
Our study identifies autophagy and selective autophagy (mitophagy) gene expression patterns in human skeletal muscle related to physical performance, muscle volume, and mitochondrial function in older persons.
Although the use of pesticides in inner-city homes of the United States is of considerable magnitude, little is known about the potentially adverse health effects of such exposure. Recent animal data ...suggest that exposure to pesticides during pregnancy and early life may impair growth and neurodevelopment in the offspring. To investigate the relationship among prenatal pesticide exposure, paraoxonase (PON1) polymorphisms and enzyme activity, and infant growth and neurodevelopment, we are conducting a prospective, multiethnic cohort study of mothers and infants delivered at Mount Sinai Hospital in New York City. In this report we evaluate the effects of pesticide exposure on birth weight, length, head circumference, and gestational age among 404 births between May 1998 and May 2002. Pesticide exposure was assessed by a prenatal questionnaire administered to the mothers during the early third trimester as well as by analysis of maternal urinary pentachlorophenol levels and maternal metabolites of chlorpyrifos and pyrethroids. Neither the questionnaire data nor the pesticide metabolite levels were associated with any of the fetal growth indices or gestational age. However, when the level of maternal PON1 activity was taken into account, maternal levels of chlorpyrifos above the limit of detection coupled with low maternal PON1 activity were associated with a significant but small reduction in head circumference. In addition, maternal PON1 levels alone, but not PON1 genetic polymorphisms, were associated with reduced head size. Because small head size has been found to be predictive of subsequent cognitive ability, these data suggest that chlorpyrifos may have a detrimental effect on fetal neurodevelopment among mothers who exhibit low PON1 activity.
ABSTRACT Some circumstellar disks, called transitional or hybrid disks, present characteristics of both protoplanetary disks (significant amount of gas) and debris disks (evolved structures around ...young main-sequence stars, composed of second generation dust, from collisions between planetesimals). Therefore, they are ideal astrophysical laboratories to witness the last stages of planet formation. The circumstellar disk around HD 141569A was intensively observed and resolved in the past from space, but also from the ground. However, the recent implementation of high contrast imaging systems has opened up new opportunities to re-analyze this object. We analyzed Gemini archival data from the Near-infrared Coronagraphic Imager obtained in 2011 in the H band, using several angular differential imaging techniques (classical ADI, LOCI, KLIP). These images reveal the complex structures of this disk with an unprecedented resolution. We also include archival Hubble Space Telescope images as an independent data set to confirm these findings. Using an analysis of the inner edge of the disk, we show that the inner disk is almost axisymmetrical. The measurement of an offset toward the east observed by previous authors is likely due to the fact that the eastern part of this disk is wider and more complex in substructure. Our precise reanalysis of the eastern side shows several structures, including a splitting of the disk and a small finger detached from the inner edge to the southeast. Finally, we find that the arc at 250 AU is unlikely to be a spiral, at least not at the inclination derived from the first ring, but instead could be interpreted as a third belt at a different inclination. If the very symmetrical inner disk edge is carved by a companion, the data presented here put additional constraints on its position. The observed very complex structures will be confirmed by the new generation of coronagraphic instrument (GPI, SPHERE). However, a full understanding of this system will require gas observations at millimetric wavelengths.
Methotrexate (MTX) is the cornerstone medication in the treatment of rheumatoid arthritis (RA). We examined whether single nucleotide polymorphisms (SNPs) in enzymes of the folic acid pathway ...(folylpoly-gamma-glutamate synthetase FPGS, gamma-glutamyl hydrolase GGH, and methylenetetrahydrofolate reductase MTHFR) associate with significant adverse events (SigAE).
Patients (n=319) enrolled in the Veterans Affairs RA (VARA) registry taking MTX were genotyped for HLA-DRB1-SE and the following SNPs: FPGS (rs7033913, rs10760503, rs10106), GGH (12548933, rs7010484, rs4617146, rs719235, rs11988534), MTHFR (rs1801131, rs1801133). AE were abstracted from the medical record using a structured instrument. SigAE were defined as an AE leading to MTX discontinuation. Covariates included: age, gender, race, RA antibody status, tobacco, RA disease duration between diagnosis and MTX course, Charlson-Deyo comorbidity index, glucocorticoids, use of prior RA medications, and mean 4-variable disease activity score. Cox regression was performed to determine factors associated with time-to-SigAE. A p-value ≤ 0.005 established significance in the final model.
The presence of ≥ 1 copy of the minor allele in MTHFR rs1801131 was associated with an increased hazard ratio (HR) of SigAE (HR 3.05, 95% CI 1.48-6.29, p-value 0.003 and HR 3.88, 95% CI 1.62-9.28, p-value 0.002 for heterozygotes and homozygotes for the minor allele, respectively). An interaction term, between FPGS rs7033913 heterozygotes and GGH rs11988534 homozygotes for the minor allele, had a p-value <0.0001.
RA subjects taking MTX may have decreased time-to-SigAE with ≥ 1 copy of the minor allele in MTHFR rs1801131. Further investigation is warranted, as these SNPs may indicate susceptibility to MTX toxicity.
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