Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss

Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss

Strategies for the Quantification of Endogenously Present Small Molecules in Biological Samples

The quantification of endogenously present compounds in biological samples demands appropriately validated methods, in particular because increasing research efforts are aimed at studying the impact of such compounds on human health and disease. International regulatory agencies, such as the Food and Drug Administration (FDA) and the European Medicine Agency (EMA), have published a vast number of guidelines concerning bioanalytical method validation over recent decades. Compared with the quantification of exogenous compounds, these guidelines have remained rather vague and unclear when it comes to the quantification of endogenous compounds. Nonetheless, the continuous expansion of studies devoted to the search for endogenous disease markers in the human metabolome has incited the regulatory bodies to include endogenous compounds in a draft of an updated International Conference on Harmonization (ICH) guideline on bioanalytical method validation. In light of these recent developments, the main objective of this review article is to provide a clear summary of the different methods that can be used to quantify endogenous small molecules. Because of the increased use of mass spectrometry (MS) in the field of bioanalysis, a special focus will be placed on quantification by liquid chromatography (LC)–MS. Practical recommendations to face this bioanalytical challenge, in particular in terms of method validation, will also be provided.http://www.chromatographyonline.com/status: Published onlin

Development of a HILIC-MS/MS method for the quantification of histamine and its main metabolites in human urine samples

An LC-MS/MS method was developed enabling the separation and quantification of histamine and its main metabolites (imidazole acetaldehyde, imidazole acetic acid, methyl imidazole acetic acid, methyl histamine, acetyl histamine) in urine samples. A fast separation was achieved in 10 min on two HILIC columns connected in series by adopting a linear gradient followed by an isocratic hold. The sample preparation consisted of a simple dilution step wherein 10 μL of urine was diluted with acetonitrile (ACN) to a final volume comprising 95% ACN. For methyl imidazole acetic acid, an additional dilution step was incorporated due to its high natural levels. Hereafter, the samples were stored at -20 °C and centrifuged prior to injection. Matrix matched calibrators were unavailable due to the endogenous occurrence of the compounds of interest. The occurrence of matrix effects and the lack of labeled internal standards prompted the use of the standard addition method as a viable alternative to solvent calibration. The validation of the method entailed matrix effects, accuracy and precision and was performed in compliance with the recent guidelines on endogenous compounds issued by the International Conference of Harmonization (ICH). The method was then adopted for the quantification of histamine and its metabolites in human urine samples collected from healthy volunteers and patients suffering from gastrointestinal discomfort.status: publishe

Patient-centered care coordination, education and counseling of patients treated with oral anticancer drugs : an importance-performance analysis

Purpose: To analyse the importance and performance of key elements in patient-centered care coordination, education and counseling of patients treated with oral anticancer drugs. Method: In four Belgian non-academic hospitals, the importance and performance of a set of 82 key elements was cross-sectionally evaluated by primary and secondary healthcare professionals and by patients. These key elements were divided in 6 themes: coordination of care, style and content of patient contacts, medication counseling at treatment initiation, follow-up of treatment, psychosocial support, and involvement of family and friends. Participants were asked to indicate for each key element if it was implemented in the current care process for patients on oral anticancer drugs ('yes', 'no', 'I don't know') and if they considered it important that the component was implemented or would be in the future ('yes' or 'no'). Three levels of performance were defined, based on the number of participants who had answered 'yes' or 'no': 'systematically performed' (>= 90% of participants), 'not systematically performed' (>= 75% and <90%) and 'not performed' (<75%). Importance-rates were based on the number of 'yes' or 'no'. Results: In total, 85 participants evaluated the key elements. More than half of key elements, 13/82 (15.9%) and 35/82 (42.6%) respectively, were considered as 'not' or 'not systematically performed'. The majority of these elements concerned coordination of care, medication counseling at treatment initiation and follow-up of treatment. Especially key elements on involving primary care and on discussing adherence had low performance rates. Nearly all key elements were assigned an importance score of >= 90%. Conclusions: Performance of key elements of patient-centered care coordination, education and counseling of patients treated with oral anticancer drugs proved moderate. Our findings suggest that strategies are needed to prioritize and operationalize key elements to coordinate transmural care and to provide effective education and counseling

Patient-centered care coordination, education and counseling of patients treated with oral anticancer drugs: An importance-performance analysis

PURPOSE: To analyse the importance and performance of key elements in patient-centered care coordination, education and counseling of patients treated with oral anticancer drugs. METHOD: In four Belgian non-academic hospitals, the importance and performance of a set of 82 key elements was cross-sectionally evaluated by primary and secondary healthcare professionals and by patients. These key elements were divided in 6 themes: coordination of care, style and content of patient contacts, medication counseling at treatment initiation, follow-up of treatment, psychosocial support, and involvement of family and friends. Participants were asked to indicate for each key element if it was implemented in the current care process for patients on oral anticancer drugs ('yes', 'no', 'I don't know') and if they considered it important that the component was implemented or would be in the future ('yes' or 'no'). Three levels of performance were defined, based on the number of participants who had answered 'yes' or 'no': 'systematically performed' (≥90% of participants), 'not systematically performed' (≥75% and <90%) and 'not performed' (<75%). Importance-rates were based on the number of 'yes' or 'no'. RESULTS: In total, 85 participants evaluated the key elements. More than half of key elements, 13/82 (15.9%) and 35/82 (42.6%) respectively, were considered as 'not' or 'not systematically performed'. The majority of these elements concerned coordination of care, medication counseling at treatment initiation and follow-up of treatment. Especially key elements on involving primary care and on discussing adherence had low performance rates. Nearly all key elements were assigned an importance score of ≥90%. CONCLUSIONS: Performance of key elements of patient-centered care coordination, education and counseling of patients treated with oral anticancer drugs proved moderate. Our findings suggest that strategies are needed to prioritize and operationalize key elements to coordinate transmural care and to provide effective education and counseling.status: publishe

Local immune response to food antigens drives meal-induced abdominal pain

Up to 20% of people worldwide develop gastrointestinal symptoms following a meal1, leading to decreased quality of life, substantial morbidity and high medical costs. Although the interest of both the scientific and lay communities in this issue has increased markedly in recent years, with the worldwide introduction of gluten-free and other diets, the underlying mechanisms of food-induced abdominal complaints remain largely unknown. Here we show that a bacterial infection and bacterial toxins can trigger an immune response that leads to the production of dietary-antigen-specific IgE antibodies in mice, which are limited to the intestine. Following subsequent oral ingestion of the respective dietary antigen, an IgE- and mast-cell-dependent mechanism induced increased visceral pain. This aberrant pain signalling resulted from histamine receptor H1-mediated sensitization of visceral afferents. Moreover, injection of food antigens (gluten, wheat, soy and milk) into the rectosigmoid mucosa of patients with irritable bowel syndrome induced local oedema and mast cell activation. Our results identify and characterize a peripheral mechanism that underlies food-induced abdominal pain, thereby creating new possibilities for the treatment of irritable bowel syndrome and related abdominal pain disorders

Local immune response to food antigens drives meal-induced abdominal pain

Up to 20% of people worldwide develop gastrointestinal symptoms following a meal(1), leading to decreased quality of life, substantial morbidity and high medical costs. Although the interest of both the scientific and lay communities in this issue has increased markedly in recent years, with the worldwide introduction of gluten-free and other diets, the underlying mechanisms of food-induced abdominal complaints remain largely unknown. Here we show that a bacterial infection and bacterial toxins can trigger an immune response that leads to the production of dietary-antigen-specific IgE antibodies in mice, which are limited to the intestine. Following subsequent oral ingestion of the respective dietary antigen, an IgE- and mast-cell-dependent mechanism induced increased visceral pain. This aberrant pain signalling resulted from histamine receptor H-1-mediated sensitization of visceral afferents. Moreover, injection of food antigens (gluten, wheat, soy and milk) into the rectosigmoid mucosa of patients with irritable bowel syndrome induced local oedema and mast cell activation. Our results identify and characterize a peripheral mechanism that underlies food-induced abdominal pain, thereby creating new possibilities for the treatment of irritable bowel syndrome and related abdominal pain disorders. In mice, oral tolerance to food antigens can break down after enteric infection, and this leads to food-induced pain resembling irritable bowel syndrome in humans

Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss

Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss.publishedVersionPeer reviewe