bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Biological Aspects of Inhibitor Development
Authors: Tuddenham E.G.D. 
Published: July 2024

AbstractMutation genotype studies have led to a number of interesting observations about the role of the different types of mutations in inhibitor development. Searchable information on mutations, phenotype data, models, etc., are available on the internet at http://europium.mrc.rpms.ac.uk. A relatively high incidence of inhibitors occurs in patients with deletion mutations. Stop mutations are also associated with a high incidence of inhibitors, although there is anomalous distribution of the inhibitors associated with different stop codons. Inhibitors have been associated with a small number of missense mutations. Missense mutations are of great interest from the structure/function viewpoint; in many instances, a missense mutation which results in reduced function of a circulating protein can be mapped onto a model structure and inferences can be made about the effects on the functionality of the protein. A model of the A domains of FVIII is available, but as yet, no structure is available on which to model the C domain of FVIII. Stop codons appear to have a different incidence of inhibitor formation compared to other types of mutations. It is concluded that while genotype mutation studies have led to a number of interesting observations about the role of the different types of mutations in inhibitor development, though more questions have been raised than answers provided to date.
Epitope Specificity and Inactivation Mechanisms of Factor VIII Inhibitor Antibodies
Authors: Scandella Dorothea 
Published: July 2024

AbstractThe domain specificity of anti‐factor VIII (FVIII) inhibitor antibodies was determined in assays using FVIII domains generated by thrombin cleavage or expressed as recombinant polypeptides to neutralise the inhibitor. The results revealed the existence of three major types of inhibitors, and various combinations of these antibodies were found in haemophilic and autoantibody patients. Anti‐A2 domain inhibitors prevent normal function of the FVIII/factor IXa (FIXa)/phospholipid complex in an unknown manner. Binding of FVIII to phospholipid and to von Willebrand factor is blocked by anti‐C2 domain antibodies, and the binding of FVIII to FIXa is prevented by anti‐A3 domain antibodies. A rare type of inhibitor prevents release of activated FVIII from von Willebrand factor (vWf), and another probably interferes with FVIII binding to factor X (FX) because it shares the epitope of a monoclonal antibody with this property.
Anti‐ldiotypic Antibodies: From Regulation to Therapy of Factor VIII Inhibitors
Authors: Saint‐Remy Jean‐Marie R. , Jacquemin Marc G. , Gilles Jean Guy 
Published: July 2024

AbstractEvidence has recently accumulated showing that antiidiotype antibodies specific to anti‐FVIII antibodies are present in the plasma of healthy individuals and of haemophilia A patients with or without inhibitors, where they can neutralise the FVIII inhibitory activity. Additionally, patients successfully desensitised towards FVIII have an increased production of anti‐idiotypic antibodies with no significant reduction in anti‐FVIII antibodies. We review here possible strategies for modulating the anti‐FVIII immune response by idiotypic interactions.
Comparison of the International Immune Tolerance Registry and the North American Immune Tolerance Registry
Authors: Kroner Barbara L. 
Published: July 2024

AbstractTwo immune tolerance registries – the International Immune Tolerance Study Group (ITSG) and North American Immune Tolerance Study (NAITS) – are compared and findings from combined data reported. The registries differed with respect to data collection tools, location, host and environmental factors, start date distribution and treatment products. The success and failure rates were similar in the two studies. There was a highly significant association between maximum historical titre and immune tolerance success; the success rate decreased as the historical titre increased. There was a significant association between inhibitor titre immediately prior to treatment and the probability for treatment success, and between outcome and time from diagnosis to treatment in the ITSG (of borderline significance in the NAITS). There was a significant association between outcome and dose, though the direction of the associations was not the same. In the ITSG, success was associated with doses greater than or equal to 200 IU/kg/day, while in the NAITS, greater success was observed with doses of less than 50 IU/kg/day. There was no association between outcome and treatment product. Data from the two registries were combined to produce a table for calculating the chance of successful treatment by historical titre, pretreatment titre, and dose.
Induction of Immune Tolerance in Haemophilia A Inhibitor Patients by the ‘Bonn Protocol‘: Predictive Parameter for Therapy Duration and Outcome
Authors: Oldenburg J. , Schwaab R. , Brackmann H.H. 
Published: July 2024

AbstractThe treatment of inhibitors is one of the most challenging fields in haemophilia care. The present study reports the results of 60 haemophilia A inhibitor patients treated according to the ‘Bonn Protocol’ and evaluates predictors for the duration and outcome of therapy. Successful immune tolerance could be achieved in 52 patients (86.7%) while the therapy failed in eight patients (13.3%). The immune tolerance achieved was longlasting in all 52 patients, with no inhibitor relapse in up to 20‐years follow‐up. The course of ITT was influenced by several factors. Interruptions of treatment during the ITT course led to a substantial prolongation of ITT duration (median 39.9 months vs 14.1 months in continuously treated patients). Infections of intravenous central lines appeared to be frequently coincided with ITT prolongation and sometimes even ITT failure. Further negative predictors towards the ITT duration were high inhibitor titres at enrolment or during ITT. There was also a tendency towards longer ITT duration in patients exhibiting the prevalent intron 22 inversion. As a consequence of our data treatment interruptions and infections of intravenous central lines should be avoided during the course of ITT. Furthermore our data suggest, that ITT should be started at low inhibitor titres preferably with a high factor VIII dosage protocol.
Immune Tolerance Protocols Using Low‐Dose Factor VIII: A Review of the Literature
Authors: Sultan Y. 
Published: July 2024

AbstractLow‐dose immune tolerance protocols use doses of factor VIII of less than 50 IU/kg/day to induce immune tolerance. Such protocols are chosen for a variety of reasons including cost, patient acceptability and ease of administration. Early published reports of low‐dose protocols appeared in 1981, described small numbers of patients and moderate success. It was proposed that such protocols might modify inhibitor responses from high to low. Later reports are sparse and clinical success is again moderate. Useful treatment and expectation guidelines have emerged from experience with these protocols, and improvements for patients with inhibitors can be achieved. Consideration of immunological success, however, raises doubts about whether real immune tolerance is achieved with such protocols.
Extracorporeal Immunoadsorption for the Treatment of Haemophilia Patients with Inhibitors to Factor VIII or IX
Authors: Knöbl Paul , Derfler Kurt 
Published: July 2024

AbstractBackground and Objectives: This article reviews the relevance of immunoadsorption in the treatment of haemophilic patients with inhibitors. Materials and Methods: Immunosorba (sepharose‐bound staphylococcal protein A) and Ig‐Therasorb (sepharose‐bound polycional sheep antibodies to human immunoglobulin) columns are suitable for the clinical use of immunoadsorption. They allow the processing of large plasma volumes (>7,000 ml) without relevant side‐effects. Results: A haemophilic patient was treated with the Malmö protocol, another was admitted with intracerebral bleeding. Immunoadsorption reduced the inhibitor titer by 70–90%. Conclusions: Immunoadsorption can be used in cases of acute bleeding, before surgery, acquired factor VIII (FVIII) antibodies, and before the start of immune tolerance therapy. We suggest the inclusion of this method in immune tolerance protocols in order to improve levels, recovery, and half‐life of FVIII and to save concentrates.
Successful Immune Tolerance Treatment with Monoclonal or Recombinant Factor VIII Concentrates in High Responding Inhibitor Patients
Authors: Rocino Angiola , de Biasi Raffaello 
Published: July 2024

AbstractVery high purity factor VIII (FVI1I) concentrates (plasma‐derived or produced by recombinant‐DNA technology) were used to achieve immune tolerance in five patients with high‐responding inhibitors to FVIII. The mean time required for inhibitor disappearance was 5 months. Four out of five patients showed normalisation of the half‐life of infused FVIII after 8–18 months of treatment with 100 IU FVIII/kg body weight administered once daily. Highly purified FVIII products thus appear to be suitable for achieving immune tolerance without negative effects on endogenous von Willebrand factor levels and activity.
The incidence and pathophysiology of atopic dermatitis
Authors: Thestrup‐Pedersen Kristian 
Published: July 2024

AbstractAimTo review our present knowledge about atopic dermatitis and try to formulate a working hypothesis about disease mechanisms.SubjectAtopic dermatitis and disease mechanisms.MethodsLiterature review.ResultsAtopic dermatitis is a skin disorder which develops within the first years of life, is active for a number of years and then resolves in most affected individuals. Although no single disease‐associated gene locus has been found, observations among monozygous and dizygous twins suggest that atopic dermatitis is first and foremost a genetically determined disease. Atopic dermatitis is associated with an abnormal dryness of the skin due to a deficient skin barrier function. Although it seems to be a genetically determined ectodermal disorder, it includes immune deviations such as T lymphocyte accumulation in the skin leading to chronic relapsing eczema. In some patients increased serum IgE is found and type 1 allergies are common. However, the immune deviations are not always associated with type I or type IV allergies. If allergies were of primary importance for disease development, it is hard to explain why the eczema disappears despite the presence of environmental allergens. Some kind of “maturation step” is likely involved in the down‐regulation of eczema.Many epidemiological studies indicate that the incidence of atopic dermatitis has doubled or tripled over the last two decades. This is difficult to explain, if the disease is mostly genetically determined. However, it could be explained, if atopic dermatitis is considered a dysmaturation of the immune system and that the expression of a genetically determined dysmaturation can be influenced by the age of the mother ‐ comparable to what is found concerning the risk of developing Down's syndrome.ConclusionThis review summarizes known facts and puts foreward a working hypothesis that atopic dermatitis may be a genetically determined dysmaturation of the T lymphocyte system. T lymphocytes mature primarily in the thymus via positive and negative selection processes. This includes contact between pre‐T cells and the thymic epithelium, which is derived from the ectoderm. We hypothesize that the maturation of the T cell immune system is disturbed, resulting in a faulty selection of T lymphocytes in the thymus. “Dys”‐matured T cells leave the thymus to continue growth in the skin. The cells are eventually eradicated by immune surveillance in the patient. Because of the increased proliferation of “dysmature” T cells, a cytokine imbalance occurs, and in some patients this leads to the development of type 1 allergies.
The role of the staphylococci in dermatology
Authors: Noble W.C. 
Published: July 2024

AbstractAimTo describe the prevalence of Staphylococcus aureus in atopic dermatitis.SubjectAtopic dermatitis and Staphylococcus aureus.ResultsAmongst the staphylococci, only S. aureus is implicated in skin infection. Much localised infection, such as folliculitis or furunculosis, is endogenous, that is the result of infection with organisms carried in the nose or at specific skin sites. In contrast impetigo and scalded skin syndrome are chiefly exogenous in origin. Secondary infection, for example in atopic dermatitis, is also associated with nasal and skin carriage. Much remains to be learned of the pathogenesis of staphylococcal infection and much current interest derives from the superantigenic activity of the exotoxins and toxic shock toxin.ConclusionStaphylococcus aureus occurs with increased incidence on the skin of patients with atopic dermatitis. It could be responsible for activating eczema via secretion of exotoxins.
The treatment of atopic dermatitis with topical fusidic acid and hydrocortisone acetate
Authors: Ramsay Colin A. , Savoie J.M. , Gilbert Martin , Gidon Martie , Kidson Paul 
Published: July 2024

AbstractAimTo compare the clinical efficacy of a cream combination containing 2% fusidic acid and 1% hydrocortisone acetate in the treatment of patients with mild to moderate atopic dermatitis.SubjectAtopic dermatitis and efficacy of antibacterial and antiinflammatory topical therapy.MethodsRandomized, double blind, prospective, parallel group trials.ResultsStudy 1, involving 186 patients, compared the combination 2% fusidic acid and 1% hydrocortisone acetate with 1% hydrocortisone cream. Analysis was performed on patients who had pathogens at entry and on the total patient population. Study II, involving 68 patients, compared the combinaison 2% fusidic acid and 1% hydrocortisone acetate with 2% fusidic acid cream. Analysis was the same as in study I.Results of study I in patients with pathogens at baseline showed a significant difference in favour of the combination (P = 0.04) in terms of the primary efficacy criterion which was a combination of clinical and bacteriological efficacy measures. When all patients in the study were analyzed there was no significant difference between the two groups. The combination was significantly more effective in removing pathogens than 1% hydrocortisone cream (P < 0.0001).Results of study II in all patients showed that the combination was significantly better than 2% fusidic acid cream (P = 0.04) in terms of the primary efficacy criterion, Both preparations were highly successful in eradicating pathogens.Pooled analysis of studies 1 and II showed a difference with respect to the primary efficacy criterion among the 3 preparations in the order Fucidin 2% plus HC 1% cream > HC 1% cream > Fucidin 2% cream in all patients and in those with pathogens (P = 0.007 for all patients and P = 0.01 for those with pathogens). Similarly, regarding the reduction in sign/symptom score a significant difference among the 3 preparations existed (P = 0.009 for all patients and P = 0.01 for those with pathogens). Adverse events with the combination were minimal.Conclusion2% fusidic acid and 1% hydrocortisone acetate cream is an effective therapy in patients with mild to moderate degrees of atopic dermatitis.
The role of Staphylococcus aureus in atopic eczema: treatment strategies
Authors: Cork Michael J. 
Published: July 2024

AbstractSubjectTherapy of atopic dermatitis.AimTo outline treatment strategies for atopic dermatitis patients.MethodsDescription of therapeutic principles of atopic dermatitis.ResultsAtopic eczema arises as a result of the interaction of environmental factors with an abnormal immune system in a genetically predisposed individual. Also the skin of patients with atopic eczema carries high levels of Staphylococcus aureus, which correlate with the severity of the eczema. Staphylococcus aureus releases a toxin with superanligenic actions which initiates a vicious circle in atopic eczema. Therapy of atopic eczema will he more effective if it breaks the vicious circle at two points. Topical steroids inhibit the action and production of pro‐inflammatory mediators breaking the circle at one point. Intensive emollient therapy and antibiotic steroid combinations reduce the number of Staphylococcus aureus and the penetratioin of the toxins through the skin, thereby breaking the circle at a second point.ConclusionUsing the approach of reducing both the effects of cytokines and of superantigens, it is possible to reduce the potency and quantity of topical steroids applied and therefore their cutaneous adverse effects.
The role of ‘familiarity’ and ‘normality’ in supporting transition to end of life care in paediatric oncology: A qualitative study
Authors: Kelly Daniel , Closs Mia , McAndrew Rachel , Smith Pam 
Published: July 2024

AbstractAimThe aim of this study was to explore factors that helped when a child with cancer transitioned to end of life care in a hospital setting.DesignQualitative exploratory design using reflexive thematic analysis.MethodsIn‐depth, semi‐structured interviews were carried out with 7 sets of bereaved parents and 10 health professionals from one specialist paediatric oncology centre. Results were shared with professionals to help shape services in a new children's hospital.ResultsThree themes were identified: ‘change and facing the unknown’, ‘the comfort of feeling normal’ and ‘knowing and being known’. Bereaved parents described a gradual awareness of the deterioration of their child's condition and the need for trust in health professionals. Professionals described the process as challenging but were guided by the needs of children and parents. Supportive and trusting relationships with professionals helped parents to cope with the transition.ConclusionWe identified practices that helped create a culture that supported parents and professionals involved in caring for children facing death from cancer. These were rooted in feeling supported and working to provide the best end of life care for children.Summary StatementGiven that the death of a child is a uniquely challenging event, this study indicates that the clinical setting can assist via the promotion of familiarity (supporting families over time) and normality (allowing family‐focused activities). These were helpful to parents and to professionals. However, professionals need emotional support when working with these families.Reporting MethodThe study adhered to the Consolidated Criteria for Reporting Qualitative Research.Patient or Public ContributionThe project steering group included one bereaved parent (who was not involved in the study), one consultant paediatric oncologist and one hospital chaplain.
An international survey of recalcitrant and recurrent tinea of the glabrous skin—A potential indicator of antifungal resistance
Authors: Khan Sidra S. , Hay Roderick , Saunte Ditte Marie L. 
Published: July 2024

AbstractBackgroundThere has been a global rise in cases of dermatophytosis and, in particular, recalcitrant and recurrent cases on tinea of the glabrous skin. This phenomenon, particularly prevalent in India, has been linked to the concerning rise of antifungal resistance. The challenge is amplified by a dearth of comprehensive, international data to understand the global scope and characteristics of such cases.ObjectivesThis study aims to collate international insights, focusing on areas outside Europe (as this was previously published), to map the extent and characteristics of clinical and, where possible, laboratory confirmed tinea of the glabrous skin through an online survey administered to dermatologists globally.MethodsAn online survey was distributed from February 2022 to July 2023 and captured data on respondents' experience of recalcitrant and recurrent tinea of the glabrous skin over the preceding 3 years.ResultsA total of 260 responses were received spreads across 36 countries, excluding Europe. In total, 91.7% reported seeing cases of recalcitrant or recurrent tinea of the glabrous skin over the preceding 3 years. Common anatomical sites affected were the trunk and groin. T. mentagrophytes and T. rubrum were the predominant species implicated, and there were low rates of laboratory confirmed dermatophyte resistance.ConclusionsThe high rates of reported recalcitrant and recurrent tinea of the glabrous skin underscore an urgent need for global collaborative efforts and enhanced diagnostic measures. The findings advocate for the establishment of a standardized global disease registry, regulation of over‐the‐counter antifungal and steroid combinations, correlation of clinical suspicion with laboratory confirmed drug resistance and exploration of alternative therapeutic strategies to mitigate the burgeoning challenge of dermatophyte resistance.
The genome history of Bacillus thuringiensis subsp. tenebrionis: From discovery to present day product
Authors: Schäfer Lea , Jehle Johannes A. , Kleespies Regina G. , Wennmann Jörg T. 
Published: July 2024

AbstractBacillus thuringiensis subsp. tenebrionis (Btt) was discovered in 1982 and has been used as a biological control agent against the Colorado potato beetle (Leptinotarsa decemlineata) since the early 1990s. In this study, we sequenced, assembled and analysed the genome of strain DSM 2803, which is the patent deposit of the original Btt isolate BI 256‐82. A high‐quality reference genome is provided that allows investigating the genomic changes throughout the commercial history of Btt. Strain DSM 2803 (BI 256‐82) is particularly interesting since the subspecies description of ‘tenebrionis’ is based on it and because it represents the genomic origin of the commercial Btt strain currently used in plant protection. Comparative genome analysis of six Btt strains derived from BI 256‐82 revealed that the genomes were generally highly similar. However, some plasticity in the profile of extrachromosomal elements was detected, including recombination‐dependent plasmid differences and the presence/absence of a circular plasmid‐like prophage.
The role of Anchoviella spp. as forage species in different stages of reservoir development in the upper Tocantins River, Central Brazil
Authors: Ferreira Vitor Manuel Barros , Albrecht Míriam Pilz 
Published: July 2024

AbstractWe report the spatiotemporal increase in abundance of Anchoviella spp. (Engraulidae) through the diet of fish consumers after reservoir formation in the upper Tocantins River, Central Brazil. The increase in the abundance of this planktivorous fish evidences the growing importance of autochthonous herbivory food chains as the reservoir stabilized in this novel lentic ecosystem. These changes would otherwise remain unnoticed only through fish sampling, highlighting the importance of assessing trophic interactions to understand responses to damming at the community and ecosystem levels.