Statistical analyses and quality of individual participant data network meta-analyses were suboptimal: a cross-sectional study

Background Network meta-analyses using individual participant data (IPD-NMAs) have been increasingly used to compare the effects of multiple interventions. Although there have been many studies on statistical methods for IPD-NMAs, it is unclear whether there are statistical defects in published IPD-NMAs and whether the reporting of statistical analyses has improved. This study aimed to investigate statistical methods used and assess the reporting and methodological quality of IPD-NMAs. Methods We searched four bibliographic databases to identify published IPD-NMAs. The methodological quality was assessed using AMSTAR-2 and reporting quality assessed based on PRISMA-IPD and PRISMA-NMA. We performed stratified analyses and correlation analyses to explore the factors that might affect quality. Results We identified 21 IPD-NMAs. Only 23.8% of the included IPD-NMAs reported statistical techniques used for missing participant data, 42.9% assessed the consistency, and none assessed the transitivity. None of the included IPD-NMAs reported sources of funding for trials included, only 9.5% stated pre-registration of protocols, and 28.6% assessed the risk of bias in individual studies. For reporting quality, compliance rates were lower than 50.0% for more than half of the items. Less than 15.0% of the IPD-NMAs reported data integrity, presented the network geometry, or clarified risk of bias across studies. IPD-NMAs with statistical or epidemiological authors often better assessed the inconsistency (P = 0.017). IPD-NMAs with a priori protocol were associated with higher reporting quality in terms of search (P = 0.046), data collection process (P = 0.031), and syntheses of results (P = 0.006). Conclusions The reporting of statistical methods and compliance rates of methodological and reporting items of IPD-NMAs were suboptimal. Authors of future IPD-NMAs should address the identified flaws and strictly adhere to methodological and reporting guidelines

Size characterization of manganese species from liver extracts using size exclusion chromatography inductively coupled plasma mass spectrometry

International audienceIncreased Mn levels are known to damage the central nervous system, resulting in motoric abnormalities and psychic disorder and finallyresulting even in symptoms similar to Parkinson’s disease. Monomethyl-Mn-pentadienyl-tricarbonyl is used as anti-knock agent and consequentlyMn compounds are exhausted into air from automobiles. With additional inhalative Mn exposure, finally an Mn overflow of the liver is known,resulting in increasedMntransport to other organs, predominantly to the brain. Specific Mn-species then seem to be generated in liver, however, theirspeciation is still not investigated. This paper focuses on experiments to get more information on Mn species with respect to a size characterizationof the Mn species in liver. Liver extracts were analyzed using a mass calibrated size exclusion chromatography (SEC) column being coupled toinductively coupled plasma mass spectrometry (ICP-MS) detection. As an important prerequisite, the stability of Mn species in the liver extractsduring storage was investigated as well. It turned out that short term storage of the extract (under Ar atmosphere) at 4 ◦C seems to be bestsuited. Storage for several days even at −20 ◦C demonstrated already considerable changes in species pattern. Further investigations focused onimprovements in detection during hyphenation using dynamic reaction cell (DRC) technology for Mn detection. The signal to noise (S/N) ratiowas increased up to a factor of 15 when using DRC technology compared to conventional ICP-MS without DRC. The analysis of liver extractswith a mass calibrated SEC column coupled to inductively coupled plasma-dynamic reaction cell-mass spectrometry (ICP-DRC-MS) showed Mnassociated to ca. 36% to a peak covering a mass range 100–260 kDa, approximately 9% was found in a peak having the mass range 37–77 kDa,46% in a peak having the mass range 13–36 kDa and ca. 7% in the low molecular mass (LMM) range

Analysis of size characterized manganese species from liver extracts using capillary zone electrophoresis coupled to inductively coupled plasma mass spectrometry (CZE-ICP-MS)

Mn is of toxicological concern because overexposure can lead to progressive, permanent neurodegenerative damage. Monomethyl-Mnpentadienyl-tricarbonyl (MMT) is used as an anti-knock agent in fuel. Exhausted Mn compounds are absorbed in the lung and transported tothe liver. Extended exposure causes an overflow of the liver with Mn species moving e.g. to the brain, causing irreversible central nervous system(CNS) disorders like Manganism.This paper focuses on experiments for getting more information on Mn species in liver extracts. The investigations are performed with respect to(1) a size characterization and (2) a subsequent identification of the Mn species in liver extracts using preparative size exclusion chromatography(SEC) followed by capillary zone electrophoresis coupled to inductively coupled plasma mass spectrometry (CZE-ICP-MS). First, extracts wereanalyzed using a mass calibrated SEC column coupled to ICP-MS detection. The chromatogram showed the 55Mn-trace and proved main Mn elutionbetween ca. 60–150 kDa. Second, liver extracts were fractionated on the same SEC column, however, now the effluent was directed to a fractioncollector. This resulted in fractions containing pre-purified, size characterized Mn species per fraction. It turned out that the Mn concentrations perfraction reflected roughly the previous on-line Mn trace. Third, the fractions were subject to CZE-ICP-MS, where the MS was operated additionallywith dynamic reaction cell (DRC) technique. From size characterization (with SEC coupled on-line to ICP-MS or connected to a fraction collectorand subsequent Mn determination in fractions) it was shown that most Mn species from liver extract were of high molecular mass (HMM)nature as they eluted mostly between 50 and 80 min, corresponding to ca. 60–150 kDa. With the two-dimensional speciation approach employingfirst SEC and then CZE-ICP-DRC-MS together with standard addition method, a series of Mn species was identified. Mn species predominantlywere Mn-enzymes e.g. arginase, isocitric dehydrogenase, galactosyltransferase, prolidase, pyruvate carboxylase and oxalate oxidase. A typical Mntransporter– Mn-albumin – was also seen, whilst Mn-transferrin obviously was degraded during SEC separation. This Mn-compound (independentwhether as a standard or from liver extract) was not stable during SEC even at the finally chosen physiological conditions

Digenic inheritance of mutations in the cardiac troponin (TNNT2) and cardiac beta myosin heavy chain (MYH7) as the cause of severe dilated cardiomyopathy

Familial dilated cardiomyopathy (DCM) is characterized by ventricular dilation and depressed myocardial performance. It is a genetically heterogeneous disorder associated with mutations in over 60 genes. We carried out whole exome sequencing in combination with cardiomyopathy-related gene-filtering on two affected family members to identify the possible causative mutation in a consanguineous Iranian family with DCM. Two novel variants in cardiomyopathy-related genes were identified: c.247 A > C; p.N83H in the Troponin T Type 2 gene (TNNT2) and c.2863G > A; p.D955N in the Myosin Heavy Polypeptide 7 gene (MYH7). Sanger sequencing and co-segregation analysis in the remaining family members supported the coexistence of these digenic mutations in affected members of the family. Carriers of either variant alone were asymptomatic. In summary, we find that digenic inheritance of two novel variants in DCM related genes is associated with a severe form of DCM. Exome sequencing has been shown to be very useful in identifying pathogenic mutations in cardiomyopathy families, and this report emphasizes the importance of comprehensive screening of DCM related genes, even after the identification of a single disease-causing mutation

Life without Geminin

The interplay of proliferation and differentiation is essential for normal development and organogenesis. Geminin is a cell cycle regulator which controls licensing of origins for DNA replication, safeguarding genomic stability. Geminin has also been shown to regulate cellular decisions of self-renewal versus commitment of neuronal progenitor cells. We discuss here our recent analysis of mice with conditional inactivation of the Geminin gene in the immune system. Our data indicate that Geminin is not indispensable for every cell division: in the absence of Geminin, development of progenitor T-cells appears largely unaffected. In contrast, rapid cell divisions, taking place in vitro upon TCR receptor activation or in vivo during homeostatic proliferation, are defective