2,935 research outputs found
Genetic modifiers of ambulation in the CINRG duchenne natural history study.
No full textWe studied the effects of LTBP4 and SPP1 polymorphisms on age at loss of ambulation (LoA) in a multiethnic Duchenne muscular dystrophy cohort (DMD). We genotyped SPP1 rs28357094 and LTBP4 haplotype in 283/340 participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). Median ages at LoA were compared by Kaplan-Meier analysis and log-rank test. We controlled polymorphism analyses for concurrent effects of glucocorticoid corticosteroid (GC) treatment (time-varying Cox regression), and for population stratification (multidimensional scaling of genome-wide markers). Hispanic and South Asian participants (n = 18, 41) lost ambulation 2.7 and 2 years earlier than Caucasian (p = 0.003, <0.001). The TG/GG genotype at SPP1 rs28357094 was associated to 1.2-year earlier median LoA (p = 0.048). This difference was greater (1.9 years, p = 0.038) in GC-treated participants, whereas no difference was observed in untreated. Cox regression confirmed a significant effect of SPP1 genotype in GC-treated participants (HR 1.61, p = 0.016). LTBP4 genotype showed a direction of association with age at LoA as previously reported, but not statistically significant. After controlling for population stratification, we confirmed a strong effect of LTBP4 genotype in Caucasians (2.4 years, p = 0.024). Median age at LoA with the protective LTBP4 genotype in this cohort was 15.0 years, 16.0 if GC-treated. In conclusion, SPP1 rs28357094 acts as a pharmacodynamic biomarker of GC response, and LTBP4 haplotype modifies age at LoA in the CINRG-DNHS cohort. Adjustment for GC treatment and population stratification appears crucial in assessing genetic modifiers in DMD
Safety and effectiveness of ataluren: comparison of results from the STRIDE Registry and CINRG DMD Natural History Study
No full textAim: Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, multicenter registry providing real-world evidence regarding ataluren use in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). We examined the effectiveness of ataluren + standard of care (SoC) in the registry versus SoC alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS), DMD genotype-phenotype/-ataluren benefit correlations and ataluren safety. Patients & methods: Propensity score matching was performed to identify STRIDE and CINRG DNHS patients who were comparable in established disease progression predictors (registry cut-off date, 9 July 2018). Results & conclusion: Kaplan-Meier analyses demonstrated that ataluren + SoC significantly delayed age at loss of ambulation and age at worsening performance in timed function tests versus SoC alone (p ≤ 0.05). There were no DMD genotype-phenotype/ataluren benefit correlations. Ataluren was well tolerated. These results indicate that ataluren + SoC delays functional milestones of DMD progression in patients with nmDMD in routine clinical practice. ClinicalTrials.gov identifier: NCT02369731
Treatment with Ataluren for Duchene Muscular Dystrophy
No full textInvestigators from Europe and the USA, representing the STRIDE Registry and Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS), examined the effectiveness of ataluren and standard of care in the Registry versus stand of care alone in the CINRG DNHS
Safety and effectiveness of ataluren in patients with nonsense mutation DMD in the STRIDE Registry compared with the CINRG Duchenne Natural History Study (2015-2022): 2022 interim analysis
No full textOBJECTIVE: Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, international, multicenter registry of real-world ataluren use in individuals with nonsense mutation Duchenne muscular dystrophy (nmDMD) in clinical practice. This updated interim report (data cut-off: January 31, 2022), describes STRIDE patient characteristics and ataluren safety data, as well as the effectiveness of ataluren plus standard of care (SoC) in STRIDE versus SoC alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS). METHODS: Patients are followed up from enrollment for at least 5 years or until study withdrawal. Propensity score matching was performed to identify STRIDE and CINRG DNHS patients who were comparable in established predictors of disease progression. RESULTS: As of January 31, 2022, 307 patients were enrolled from 14 countries. Mean (standard deviation [SD]) ages at first symptoms and at genetic diagnosis were 2.9 (1.7) years and 4.5 (3.7) years, respectively. Mean (SD) duration of ataluren exposure was 1671 (56.8) days. Ataluren had a favorable safety profile; most treatment-emergent adverse events were mild or moderate and unrelated to ataluren. Kaplan-Meier analyses demonstrated that ataluren plus SoC significantly delayed age at loss of ambulation by 4 years (p < 0.0001) and age at decline to %-predicted forced vital capacity of < 60% and < 50% by 1.8 years (p = 0.0021) and 2.3 years (p = 0.0207), respectively, compared with SoC alone. CONCLUSION: Long-term, real-world treatment with ataluren plus SoC delays several disease progression milestones in individuals with nmDMD. NCT02369731; registration date: February 24, 2015
Discourse on formation of investigators’ competencies
No full textOne of the most important aims of law enforcement agencies is crime investigation and
prevention. Consequently, one of the main activities of the law enforcement agencies, especially in the
pre-trial investigation sphere, is to optimise the organisation of the pre-trial investigation in order to
save the experienced skilled and competent specialists. The author of this research offers a new
approach and analyses the qualification and competence of the pre-trial investigation subjects not only
in terms of personnel management, but all elements of the model of pre-trial investigation to make
pre-trial investigation organisation more effective. It should be noted that the content of an
investigators‘ qualification or levels of competence are still not determined or strictly regulated and
this is the reason for many discussions in this area. These discussions surround what qualification and level of competence the investigators should have in pre-trial investigation, what general and special
competencies they should acquire and how the content of the competencies should be determined. In the present article the author analyses the investigators‘ qualification and competence as a
presumption that it is an essential aspect of an effective pre-trial investigation. Analysing this question
the author compares other subjects such as the regulation of qualifications and levels of competence of
the prosecutors and pre-trial investigation judges. The author also identifies the problem of how to
define an investigators qualification and level of competence making recommendations to create a
Description of Investigators Competencies. Qualification requirements should be determined in this
legal act and general, occupational and special competencies should be identified with the content also
being determined within this framework. Formation of the Description of Investigators‘ Competencies
should determine not only the content of the investigators‘ required level of competence but also this
process should be consistent with the assessment and career development of investigators‘ including
the process of gaining the investigators‘ qualification. The aim of this research is to identify the problems associated with defining an investigators‘
qualification and levels of competence and to propose recommendations on how this could be
achieved. The subject of this research is limited to only looking at investigators‘ qualification and
level of competence. The author is using a qualitative method for this research based upon the contents of documents.
The author will analysis eight legal acts related to the qualification and competence of pre-trial
investigation and fifty different investigators‘ job descriptions.Straipsnyje nagrinėjama ikiteisminio tyrimo pareigūnų (tyrėjų) kvalifikacija ir kompetencija kaip viena iš veiksmingo ikiteisminio tyrimo organizavimo prielaidų. Analizuojant tyrėjų kvalifikacijos ir kompetencijos turinį ir jo reglamentavimą, lyginama kitų ikiteisminio tyrimo subjektų – prokurorų ir ikiteisminio tyrimo teisėjų – kvalifikacijos ir kompetencijos turinio reglamentavimo ypatumai, identifikuojamos tyrėjų kvalifikacijos ir kompetencijos apibrėžties problemos ir pateikiami sprendimo būdai – siūlomas ikiteisminio tyrimo pareigūnų (tyrėjų) kompetencijų aprašas, kuriame būtų tiksliai nustatyti tyrėjų kvalifikaciniai reikalavimai, identifikuotos bendrosios, profesinės ir specialiosios kompetencijos ir apibrėžtas šių kompetencijų turinys. Ikiteisminio tyrimo pareigūnų kompetencijų aprašo suformavimas sudarytų galimybę ne tik aiškiai apibrėžti tyrėjo kompetencijos turinį, bet ir šį procesą nuosekliai susieti su tyrėjo veiklos vertinimu, karjera ir kvalifikacijos tobulinimu. Straipsnį sudaro įvadas ir dvi dalys. Pirmoje dalyje nagrinėjama tyrėjo kvalifikacijos apibrėžties problematika, gretinama ikiteisminio tyrimo pareigūno, prokuroro ir teisėjo kvalifikacijos apibrėžtys. Šioje dalyje siūloma tiksliai nustatyti ir apibrėžti tyrėjo kvalifikacinius reikalavimus. Antrojoje dalyje analizuojama tyrėjo kompetencijos turinys. Nagrinėjant prokurorų, teisėjų kompetencijos turinį ir jo reglamentavimo ypatumus, siūloma sudaryti tyrėjo kompetencijų aprašą, kuriame būtų tiksliai apibrėžtas tyrėjo kompetencijos turinys
Sepsis-driven temporal variability in cytokine secretion and heart rate is potentiated by withdrawing vagal innervation: Evidence of higher order neuroimmunological communication via the cholinergic anti-inflammatory pathway in the ovine fetus near term
No full textFetal brain-gut communication is disrupted during sepsis and associated with a higher degree of intestinal inflammation: Implications for non-evasive monitoring
No full textInternet technologies relevant to private investigators’ working practices
No full textMuch has been written and discussed especially in the various US media and in legislative organs, about how the Internet is used illegally (hacking, stalking for instance), but hardly if any research has been done as to how the investigative industry employs the new medium to its benefit. The author described in this thesis how private investigators (PIs) execute their profession these days using the facilities the Internet avail them in contrast to the time before the dawn of the Internet. This contrast is also investigated in an international context, an important part of the thesis, drawn from the author's 32 years of international business experience and that of PIs worldwide. The availability of the various online facilities in different countries are compared. To better understand the new medium, and its facilities a short outline of the Internet’s history, it’s set up in general and for the use of PIs in particular is supplied. PIs also face limitations in their daily work, limitations originating from online, legal, educational, financial and international causes. The new medium not only helps PIs in their investigative, but also in their office work. Finally PIs' wishes for new tools to facilitate their daily investigative work and their outlook as to where the new medium will head are also discussed
A signature of fetal systemic inflammatory response in the temporal pattern of heart rate variability measures
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