Factor VIII (FVIII) inhibitor formation is a major clinical concern during replacement therapy in patients with hemophilia A. Immune tolerance induction (ITI) is the only therapeutic approach to attempt inhibitor eradication and establishment of long-term immune tolerance to FVIII. Hemophilia Inhibitor Previously Untreated Patient (PUP) Study (HIPS) was a prospective clinical trial to investigate changes in the immune system of PUPs with severe hemophilia A. Five patients who developed persistent FVIII inhibitors during HIPS entered an ITI extension arm (HIPS-ITI). During HIPS-ITI, inhibitor patients received ITI with the same FVIII product (a single source of recombinant, human full-length FVIII) used in HIPS until successful tolerance, declared failure, or a maximum of 2 years after HIPS-ITI enrollment, whichever came first. Blood samples and clinical data were collected monthly. Longitudinal FVIII-binding antibody signatures, associated binding specificities, and apparent affinities were determined for each patient at each sampling time point. ITI was successful or partially successful in 2 patients and failed in 3. Both groups presented with distinct FVIII-specific antibody signatures. ITI success required the disappearance of FVIII inhibitors, which was associated with the eradication or sustained titer minimization of high-affinity FVIII-specific antibodies, particularly of the immunoglobulin G1 (IgG1) and IgG4 subclasses. In contrast, ITI failure, as reflected by FVIII inhibitor persistence, was associated with persistent high-affinity FVIII-specific antibodies. Interestingly, 1 patient with partial ITI success and 1 patient with ITI failure developed apparent oligoreactive FVIII-binding antibodies during ITI. The explanation of the true nature of these antibodies requires more comprehensive follow-ups in future studies. This trial was registered at www.clinicaltrials.gov as #NCT01652027.

• MeSH
• Factor VIII therapeutic use   MeSH
• Hemophilia A * therapy   MeSH
• Hemostatics * therapeutic use   MeSH
• Immunoglobulin G therapeutic use   MeSH
• Immune Tolerance MeSH
• Humans MeSH
• Prospective Studies MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Preventing factor VIII (FVIII) inhibitors following replacement therapies with FVIII products in patients with hemophilia A remains an unmet medical need. Better understanding of the early events of evolving FVIII inhibitors is essential for risk identification and the design of novel strategies to prevent inhibitor development. The Hemophilia Inhibitor Previously Untreated Patients (PUPs) Study (HIPS; www.clinicaltrials.gov #NCT01652027) is the first prospective cohort study to evaluate comprehensive changes in the immune system during the first 50 exposure days (EDs) to FVIII in patients with severe hemophilia A. HIPS participants were enrolled prior to their first exposure to FVIII or blood products ("true PUPs") and were evaluated for different immunological and clinical parameters at specified time points during their first 50 EDs to a single source of recombinant FVIII. Longitudinal antibody data resulting from this study indicate that there are 4 subgroups of patients expressing distinct signatures of FVIII-binding antibodies. Subgroup 1 did not develop any detectable FVIII-binding immunoglobulin G (IgG) antibodies. Subgroup 2 developed nonneutralizing, FVIII-binding IgG1 antibodies, but other FVIII-binding IgG subclasses were not observed. Subgroup 3 developed transient FVIII inhibitors associated with FVIII-binding IgG1 antibodies, similar to subgroup 2. Subgroup 4 developed persistent FVIII inhibitors associated with an initial development of high-affinity, FVIII-binding IgG1 antibodies, followed by IgG3 and IgG4 antibodies. Appearance of FVIII-binding IgG3 was always associated with persistent FVIII inhibitors and the subsequent development of FVIII-binding IgG4. Some of the antibody signatures identified in HIPS could serve as candidates for early biomarkers of FVIII inhibitor development.

• MeSH
• Biomarkers MeSH
• Factor VIII MeSH
• Hemophilia A * drug therapy   MeSH
• Hemostatics * MeSH
• Immunoglobulin G MeSH
• Humans MeSH
• Prospective Studies MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Local extinction and recolonization events can shape genetic structure of subdivided animal populations. The gray wolf (Canis lupus) was extirpated from most of Europe, but recently recolonized big part of its historical range. An exceptionally dynamic expansion of wolf population is observed in the western part of the Great European Plain. Nonetheless, genetic consequences of this process have not yet been fully understood. We aimed to assess genetic diversity of this recently established wolf population in Western Poland (WPL), determine its origin and provide novel data regarding the population genetic structure of the grey wolf in Central Europe. We utilized both spatially explicit and non-explicit Bayesian clustering approaches, as well as a model-independent, multivariate method DAPC, to infer genetic structure in large dataset (881 identified individuals) of wolf microsatellite genotypes. To put the patterns observed in studied population into a broader biogeographic context we also analyzed a mtDNA control region fragment widely used in previous studies. In comparison to a source population, we found slightly reduced allelic richness and heterozygosity in the newly recolonized areas west of the Vistula river. We discovered relatively strong west-east structuring in lowland wolves, probably reflecting founder-flush and allele surfing during range expansion, resulting in clear distinction of WPL, eastern lowland and Carpathian genetic groups. Interestingly, wolves from recently recolonized mountainous areas (Sudetes Mts, SW Poland) clustered together with lowland, but not Carpathian wolf populations. We also identified an area in Central Poland that seems to be a melting pot of western, lowland eastern and Carpathian wolves. We conclude that the process of dynamic recolonization of Central European lowlands lead to the formation of a new, genetically distinct wolf population. Together with the settlement and establishment of packs in mountains by lowland wolves and vice versa, it suggests that demographic dynamics and possibly anthropogenic barriers rather than ecological factors (e.g. natal habitat-biased dispersal patterns) shape the current wolf genetic structure in Central Europe.

• MeSH
• Bayes Theorem MeSH
• Ecosystem * MeSH
• Genetic Variation MeSH
• Haplotypes genetics   MeSH
• Animal Migration physiology   MeSH
• Microsatellite Repeats genetics   MeSH
• DNA, Mitochondrial genetics   MeSH
• Genetics, Population * MeSH
• Cluster Analysis MeSH
• Wolves genetics   MeSH
• Geography MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Europe MeSH

An important message taken from human genome sequencing projects is that the human population exhibits approximately 99.9% genetic similarity. Variations in the remaining parts of the genome determine our identity, trace our history and reveal our heritage. The precise delineation of phenotypically causal variants plays a key role in providing accurate personalized diagnosis, prognosis, and treatment of inherited diseases. Several computational methods for achieving such delineation have been reported recently. However, their ability to pinpoint potentially deleterious variants is limited by the fact that their mechanisms of prediction do not account for the existence of different categories of variants. Consequently, their output is biased towards the variant categories that are most strongly represented in the variant databases. Moreover, most such methods provide numeric scores but not binary predictions of the deleteriousness of variants or confidence scores that would be more easily understood by users. We have constructed three datasets covering different types of disease-related variants, which were divided across five categories: (i) regulatory, (ii) splicing, (iii) missense, (iv) synonymous, and (v) nonsense variants. These datasets were used to develop category-optimal decision thresholds and to evaluate six tools for variant prioritization: CADD, DANN, FATHMM, FitCons, FunSeq2 and GWAVA. This evaluation revealed some important advantages of the category-based approach. The results obtained with the five best-performing tools were then combined into a consensus score. Additional comparative analyses showed that in the case of missense variations, protein-based predictors perform better than DNA sequence-based predictors. A user-friendly web interface was developed that provides easy access to the five tools' predictions, and their consensus scores, in a user-understandable format tailored to the specific features of different categories of variations. To enable comprehensive evaluation of variants, the predictions are complemented with annotations from eight databases. The web server is freely available to the community at http://loschmidt.chemi.muni.cz/predictsnp2.

• MeSH
• Databases, Nucleic Acid MeSH
• Databases, Protein MeSH
• Genetic Variation MeSH
• Genome, Human MeSH
• Genomics statistics & numerical data   MeSH
• Polymorphism, Single Nucleotide * MeSH
• Humans MeSH
• Software * MeSH
• Computational Biology MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a promising tool to study and modulate brain plasticity. OBJECTIVE: Our aim was to investigate the effects of rTMS on cognitive functions in patients with mild cognitive impairment and Alzheimer's disease (MCI/AD) and assess the effect of gray matter (GM) atrophy on stimulation outcomes. METHODS: Twenty MCI/AD patients participated in the proof-of-concept controlled study. Each patient received three sessions of 10 Hz rTMS of the right inferior frontal gyrus (IFG), the right superior temporal gyrus (STG), and the vertex (VTX, a control stimulation site) in a randomized order. Cognitive functions were tested prior to and immediately after each session. The GM volumetric data of patients were: 1) compared to healthy controls (HC) using source-based morphometry; 2) correlated with rTMS-induced cognitive improvement. RESULTS: The effect of the stimulated site on the difference in cognitive scores was statistically significant for the Word part of the Stroop test (ST-W, p = 0.012, linear mixed models). As compared to the VTX stimulation, patients significantly improved after both IFG and STG stimulation in this cognitive measure. MCI/AD patients had significant GM atrophy in characteristic brain regions as compared to HC (p = 0.029, Bonferroni corrected). The amount of atrophy correlated with the change in ST-W scores after rTMS of the STG. CONCLUSION: rTMS enhanced cognitive functions in MCI/AD patients. We demonstrated for the first time that distinct pattern of GM atrophy in MCI/AD diminishes the cognitive effects induced by rTMS of the temporal neocortex.

• MeSH
• Alzheimer Disease complications   MeSH
• Analysis of Variance MeSH
• Cognition Disorders * etiology   pathology   therapy   MeSH
• Humans MeSH
• Cerebral Cortex physiology   MeSH
• Neuropsychological Tests MeSH
• Psychiatric Status Rating Scales MeSH
• Gray Matter pathology   physiopathology   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Transcranial Magnetic Stimulation methods   MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

There are numerous tools available to assess the risk of bias in individual studies in a systematic review. These tools have different structures, including scales and checklists, which may or may not separate their items by domains. There are also various approaches and guides for the process, scoring, and interpretation of risk of bias assessments, such as value judgments, quality scores, and relative ranks. The objective of this commentary, which is part of the JBI Series on Risk of Bias, is to discuss some of the distinctions among different tool structures and approaches to risk of bias assessment and the implications of these approaches for systematic reviewers.

• MeSH
• Checklist * MeSH
• Humans MeSH
• Research Design * MeSH
• Bias MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Systematic Review MeSH

Dual reporters encoding two distinct proteins within the same mRNA have had a crucial role in identifying and characterizing unconventional mechanisms of eukaryotic translation. These mechanisms include initiation via internal ribosomal entry sites (IRESs), ribosomal frameshifting, stop codon readthrough and reinitiation. This design enables the expression of one reporter to be influenced by the specific mechanism under investigation, while the other reporter serves as an internal control. However, challenges arise when intervening test sequences are placed between these two reporters. Such sequences can inadvertently impact the expression or function of either reporter, independent of translation-related changes, potentially biasing the results. These effects may occur due to cryptic regulatory elements inducing or affecting transcription initiation, splicing, polyadenylation and antisense transcription as well as unpredictable effects of the translated test sequences on the stability and activity of the reporters. Unfortunately, these unintended effects may lead to misinterpretation of data and the publication of incorrect conclusions in the scientific literature. To address this issue and to assist the scientific community in accurately interpreting dual-reporter experiments, we have developed comprehensive guidelines. These guidelines cover experimental design, interpretation and the minimal requirements for reporting results. They are designed to aid researchers conducting these experiments as well as reviewers, editors and other investigators who seek to evaluate published data.

• MeSH
• Eukaryota genetics   MeSH
• Humans MeSH
• RNA, Messenger genetics   metabolism   MeSH
• Protein Biosynthesis genetics   MeSH
• Genes, Reporter * MeSH
• Guidelines as Topic MeSH
• Research Design standards   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

The foundations for critical appraisal of literature have largely progressed through the development of epidemiologic research methods and the use of research to inform medical teaching and practice. This practical application of research is referred to as evidence-based medicine and has delivered a standard for the health care profession where clinicians are equally as engaged in conducting scientific research as they are in the practice of delivering treatments. Evidence-based medicine, now referred to as evidence-based health care, has generally been operationalized through empirically supported treatments, whereby the choice of treatments is substantiated by scientific support, usually by means of an evidence synthesis. As evidence synthesis methodology has advanced, guidance for the critical appraisal of primary research has emphasized a distinction from the assessment of internal validity required for synthesized research. This assessment is conceptualized and branded in various ways in the literature, such as risk of bias, critical appraisal, study validity, methodological quality, and methodological limitations. This paper provides a discussion of the definitions and characteristics of these terms, concluding with a recommendation for JBI to adopt the term "risk of bias" assessment.

• MeSH
• Humans MeSH
• Research Design * MeSH
• Bias MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: The lack of a consensus definition of neonatal sepsis and a core outcome set (COS) proves a substantial impediment to research that influences policy and practice relevant to key stakeholders, patients and parents. METHODS: A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In the included studies, the described outcomes were extracted in accordance with the provisions of the Core Outcome Measures in Effectiveness Trials (COMET) handbook and registered. RESULTS: Among 884 abstracts identified, 90 randomised controlled trials (RCTs) were included in this review. Only 30 manuscripts explicitly stated the primary and/or secondary outcomes. A total of 88 distinct outcomes were recorded across all 90 studies included. These were then assigned to seven different domains in line with the taxonomy for classification proposed by the COMET initiative. The most frequently reported outcome was survival with 74% (n = 67) of the studies reporting an outcome within this domain. CONCLUSIONS: This systematic review constitutes one of the initial phases in the protocol for developing a COS in neonatal sepsis. The paucity of standardised outcome reporting in neonatal sepsis hinders comparison and synthesis of data. The final phase will involve a Delphi Survey to generate a COS in neonatal sepsis by consensus recommendation. IMPACT: This systematic review identified a wide variation of outcomes reported among published RCTs on the management of neonatal sepsis. The paucity of standardised outcome reporting hinders comparison and synthesis of data and future meta-analyses with conclusive recommendations on the management of neonatal sepsis are unlikely. The final phase will involve a Delphi Survey to determine a COS by consensus recommendation with input from all relevant stakeholders.

• MeSH
• Delphi Technique MeSH
• Outcome Assessment, Health Care MeSH
• Humans MeSH
• Infant, Newborn MeSH
• Neonatal Sepsis * diagnosis   therapy   MeSH
• Randomized Controlled Trials as Topic MeSH
• Treatment Outcome MeSH
• Research Design * MeSH
• Check Tag
• Humans MeSH
• Infant, Newborn MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Systematic Review MeSH

A comprehensive guide to all practical procedures and technical measures required to ensure the safety of drinking-water supplies in small communities and periurban areas of developing countries. Now in its second edition, the book has been vastly expanded in line with broadened appreciation for the many factors that influence water quality and determine its impact on health. Revisions and additions also reflect considerable new knowledge about the specific technical and social interventions that have the greatest chance of success in situations where resources are scarce and logistic problems are formidable. Since quality controls may be especially difficult to implement in small communities, the book concentrates on the most essential requirements, emphasizing the crucial need to ensure microbiological safety. Details range from advice on how to design simple pictorial reporting forms for sanitary inspections, to guidance on setting priorities for remedial action, from a comparison of different methods for the analysis of coliform bacteria, to drawings of measures for protecting water sources. Throughout numerous checklists, charts, diagrams, and model forms are used to enhance the volume\'s practical value. The book has eight chapters, organized to reflect the key stages in the development of surveillance. Chapter one explains how the basic principles of surveillance and control apply to small-community supplies and alerts readers to several unique problems that need to be overcome. Planning and implementation are discussed in the second chapter, which gives particular attention to the distinct yet complementary responsibilities of the water supply agency and the public health protection agency. Subsequent chapters offer advice on the nature, scope and timing of sanitary inspections, describe the most appropriate methods for sampling water and assessing its hygienic quality, and explain how the resulting data can be used to improve the quality, coverage, quantity, cost, and continuity of the water supply. The most extensive chapter describes and illustrates numerous technical interventions for preventing or correcting hazards associated with water from different sources, procedures for water treatment, and methods used to treat and store water in households. Additional strategies for improvement are covered in the remaining chapters, which outline methods of hygiene education in communities and discuss the important role of legislation and regulation. Further practical guidance is provided in a series of annexes, which give examples of sanitary inspection and hazard scoring forms for 11 different types of water supply, list responsibilities for different categories of surveillance staff, and provide illustrated step-by-step instructions for several sampling methods and analytical tests for use in laboratories and the field.

• MeSH
• Water Microbiology MeSH
• Environmental Monitoring MeSH
• National Health Programs MeSH
• Developing Countries MeSH
• Water Supply MeSH
• Water Pollution prevention & control   MeSH

• Conspectus
• Veřejné zdraví a hygiena
• NML Fields
• environmentální vědy
• environmentální vědy
• environmentální vědy
• NML Publication type
• publikace WHO