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This article contends that intersensory experiences of the plague are key to comprehending how the inhabitants of seventeenth-century London understood outbreaks of epidemic disease. Interplay between the senses influenced how people understood the processes of disease transmission, the vulnerability of bodies to contract disease and disease prevention. Previous research into the sensory histories of the plague has focused on smell and touch as isolated sensory phenomena. In doing so, studies have tended to suggest that the plague was understood as either an airborne or contagious disease. An intersensory approach reveals that this binary between miasma and contagion was not so clear cut. People navigated their relationships with their bodies, neighbours and the city via a complex web of understandings of epidemic disease, many of which were born out of interactions between the senses.

In tackling the widespread problem of bullying victimisation, researchers have acknowledged the value of focusing on changing bullying-related beliefs and using peer-based interventions. In three studies (N = 419, 237 intervention and 182 controls), we tested the effectiveness of the CATZ cross-age teaching programme by inviting small groups of 11-year-olds to incorporate information supporting positive beliefs (concerning non-physical forms of bullying, the value of disclosing being bullied to adults, and helping victims) into a lesson they devised for themselves and to deliver that to small groups of 9-year-olds. Specifically, we examined if the intervention would promote that (i) non-physical forms of bullying are unacceptable (study 1), (ii) disclosing bullying to adults and getting the right kind of help have value and importance (study 2), and (iii) victims can be assisted in safe ways (study 3). Self-reports of nine specific aspects of these beliefs were collected from CATZ tutors and age-matched controls prior to and following the intervention, and at five-week follow-up in one study, using both open and closed questions. Results indicated significant positive effects of CATZ on all nine outcome variables, with mostly medium and high effect sizes. These findings support the use of CATZ to foster positive anti-bullying beliefs, and issues related to its wider uptake are discussed.

Antibody drug conjugates are a class of biotherapeutic proteins which have been extensively developed in recent years resulting in new approvals and improved standard of care for cancer patients. Among the numerous strategies of conjugating cytotoxic payloads to monoclonal antibodies, insertion of a cysteine residue at position 239 (C239i) achieves a tightly controlled, site specific drug to antibody ratio. Tailored analytical tools are required to direct the development of processes capable of manufacturing novel antibody scaffolds with the desired product quality. Here, we describe the development of a high throughput, 12-minute, mass spectrometry based method capable of monitoring four distinct quality attributes simultaneously: variations in the thiol state of the inserted cysteines, N-linked glycosylation, reduction of inter-chain disulphide bonds, and polypeptide fragmentation. When deployed, the method provided new insight into the properties of C239i antibody intermediate and its manufacturing processes. First, C239i forms exclusively oxidised thiol states within the bioreactor, of which a variant containing an additional disulphide bond was invariably produced and remained relatively constant throughout the fed-batch process; reduced thiol variants were introduced upon harvest. Second, close to twenty percent of N-linked glycans contained sialic acid, substantially higher than anticipated for wildtype IgG1. Lastly, previously unreported polypeptide fragmentation sites were identified in the C239i constant (C 2) domain and the relationship between fragmentation and glycoform explored. This work illustrates the utility of applying a high-throughput liquid chromatography mass spectrometry (LC-MS) multi-attribute monitoring method to support the development of engineered antibody scaffolds.

Data Availability Statement: Deidentified VOC output could be shared (with no end date) subject to the approval of a proposal and completion of a data-sharing agreement and/or ethical approval. Copyright: © 2022 by the authors. Colorectal symptoms are common but only infrequently represent serious pathology, including colorectal cancer (CRC). A large number of invasive tests are presently performed for reassurance. We investigated the feasibility of urinary volatile organic compound (VOC) testing as a potential triage tool in patients fast-tracked for assessment for possible CRC. A prospective, multicenter, observational feasibility study was performed across three sites. Patients referred to NHS fast-track pathways for potential CRC provided a urine sample that underwent Gas Chromatography-Mass Spectrometry (GC-MS), Field Asymmetric Ion Mobility Spectrometry (FAIMS), and Selected Ion Flow Tube Mass Spectrometry (SIFT-MS) analysis. Patients underwent colonoscopy and/or CT colonography and were grouped as either CRC, adenomatous polyp(s), or controls to explore the diagnostic accuracy of VOC output data supported by an artificial neural network (ANN) model. 558 patients participated with 23 (4%) CRC diagnosed. 59% of colonoscopies and 86% of CT colonographies showed no abnormalities. Urinary VOC testing was feasible, acceptable to patients, and applicable within the clinical fast track pathway. GC-MS showed the highest clinical utility for CRC and polyp detection vs. controls (sensitivity = 0.878, specificity = 0.882, AUROC = 0.896) but it is labour intensive. Urinary VOC testing and analysis are feasible within NHS fast-track CRC pathways. Clinically meaningful differences between patients with cancer, polyps, or no pathology were identified suggesting VOC analysis may have future utility as a triage tool. National Institute for Health Research, Research for Patient Benefit Scheme grant number PB-PG-0416-20022.

Background: There is growing awareness of the unique etiology, biology, clinical presentation and progression of Invasive lobular breast cancer (ILC), but additional research is needed to assure translation of findings into management and treatment guidelines. We performed a survey to: 1) analyze the landscape of the current understanding of ILC, and 2) identify consensus research questions on ILC. Methods: The IRB-approved survey was developed with input from representatives of three major stakeholder groups - breast cancer clinicians/researchers, laboratory-based researchers, and advocates/patients. We fielded the survey from March to May 2022 using targeted email and via social media. Results: 1,774 participants answered at least one question and 1,310 finished the survey. Participants are from 66 countries from all continents (except Antarctica). Respondents self-identified as clinicians (mostly medical oncologists and surgeons) (N=413), researchers (N=376), and breast cancer patients (1,121), with some belonging to more than one category. 26% of the patients who participated in the survey belong to advocate groups. Only 46% of clinicians reported being confident in describing the differences between ILC and no special type (NST) (invasive ductal) breast cancer. Knowledge of histology was seen as important (73%), affecting their treatment decisions (51%), and refined treatment guidelines would be valuable for patients with ILC in the future (76%). 85% of clinicians have never powered a clinical trial to allow subset analysis for histological subtypes, but the majority would consider it. 88% would participate in a consortium to conduct clinical trials on ILC. The top two most important research questions were: 1) determining mechanisms of endocrine resistance, and, 2) identifying novel therapeutic targets, repurposing existing drugs and progressing them to clinical trials. Of the researchers, 48% reported being confident in describing differences between ILC and NST. They reported that ILCs are inadequately presented in large genomic data sets (52%), and that ILC models are insufficient (42%). Only 13% of respondents have inadequate access to tissue or blood from patients with ILC. The top two most important research questions identified by the laboratory researchers overlapped with those identified by the clinicians, i.e. understanding of endocrine resistance and identifying novel drugs that can be tested in clinical trials. The majority of patients (52%) thought that their health care providers did not explain unique features of ILC, and that in general communication was limited. When asked about top research question, they chose: 1) Improvement of ILC screening/early detection, and, 2) Identifying new and specific imaging tools for ILC. When comparing top priority topics across six research domains, there was a high degree of consistency, especially among clinicians and researcher, but less so when compared with the breast cancer patients (Table 1). Conclusion: In summary, we have gathered timely and representative information from an international community of clinicians, researchers, and patients/advocates that we expect will lay the foundation for a community-informed collaborative research agenda, with the goal of improving the management and personalizing treatment for patients with ILC. Table 1. Ratings by all three stakeholder groups of the most critical and impactful ILC research topics. Top box scores between stakeholder groups were compared using chi-square analysis. Citation Format: Steffi Oesterreich, Leigh Pate, ADRIAN V. LEE, Rachel C. Jankowitz, Patrick Derksen, Rita Mukhtar, Otto Metzger, Matthew J. Sikora, Christopher Li, Christos Sotiriou, Gary Ulaner, Jorge Reis-Filho, Nancy E Davidson, Karen Van Baelen, Laurie Hutcheson, Siobhan Freeney, Flora Migyanka, Claire Turner, Todd Bear, Christine Desmedt. An international survey on invasive lobular breast cancer (ILC) reveals gaps in knowledge and top priority research areas [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-10.

Simple Summary This commentary reflects a collaborative effort between international Invasive Lobular Carcinoma (ILC)-focused breast cancer researchers, clinicians and patient advocate leaders. It offers a perspective on the progress made in ILC research in recent years and discusses the recent rise in patient advocate involvement to advance ILC research, raise awareness and educate about this disease. It outlines several distinct challenges in conducting ILC research and describes opportunities and suggestions for ways researchers, clinicians and advocates can work together to advance ILC research to develop new therapies and refine the care offered to patients. Abstract Breast cancer research and therapies have significantly advanced in recent years. However, Invasive Lobular Carcinoma (ILC), the second most common histological type of breast cancer and the sixth most frequently diagnosed cancer of women, has not always benefited from critical analysis, missing opportunities to better understand this important subtype. Recent progress understanding the biological and behavioral differences of ILC demonstrates that it is a unique subtype of breast cancer which can respond differently to common therapies. These new insights have increased interest in researching lobular breast disease. Concurrently, the formation of motivated patient-led advocacy organizations working in partnership with basic, translational and clinical researchers creates new opportunities, including connecting a dispersed patient population to research, encouraging new research funding and connecting patient advocates to researchers to advance common goals. This commentary will explore the unprecedented opportunity to drive multidisciplinary, multicenter and international collaborative research into lobular breast cancer that builds on recent research progress. Collaborative research partnerships that include advocates can result in a better understanding of ILC, identify targeted therapies and refine standard of care therapies that are currently equally applied to all breast cancers, resulting in improvements in the diagnosis, treatment and follow-up care for patients with ILC.

Background Flat foot (pes planus) describes a reduction or absence of the medial longitudinal arch (MLA) of the foot, with or without additional deformities of the foot and ankle. Flat feet are relatively common in childhood, affecting up to 14% of children. Flexible flat feet can be part of a normal developmental profile, and foot arches usually develop with age, although there is a wide range of normal variation. Up to 25% of the total population has a deficient MLA in at least one foot; therefore, it is likely a general practitioner (GP) will encounter this issue relatively frequently in their practice. Objective This article outlines a method for paediatric pes planus assessment and management. A multidisciplinary approach involving GPs, rehabilitation physicians, orthopaedic surgeons, physiotherapists, orthotists and podiatrists is discussed. Discussion Paediatric pes planus treatment has long been a contentious topic, with a lack of clarity in the literature regarding which children require treatment and the efficacy of intervention. However, there is increasing evidence that non-surgical interventions, such as orthoses and physiotherapy, may be beneficial for certain groups of children.

The rail infrastructure controller in Great Britain recognised that more work was required to allow a robust and consistent demonstration that appropriate health and safety risk assessments are being undertaken throughout each stage of the contracting process. In response to this requirement, the authors were engaged to assist the rail infrastructure client with the development of a new risk-based contractor management and assurance process. Bowtie diagrams were selected as a key component of this process to represent: Key safety risks associated with rail construction projects; Potential causes and consequences of unwanted events; Good practice in risk barriers/controls. To test the suitability of Bowties for risk communication to contractors, three key hazards were identified for Bowtie analysis. These and the specific top events selected were as follows: Hazard: Working at height – from scaffold, ladders, mobile elevating working platforms, mobile towers or ledges; Top event: Falls from height – to surface; Hazard: Working in vicinity of uninsulated conductors and supply points; Top event: Contact with live/charged equipment >60 V; Hazard: Working on or near the line; Top event: Personnel in path of oncoming train. A one-day Bowtie development workshop was held for each of the hazards selected. These were attended by client personnel with the required knowledge and expertise of the hazard and associated barrier measures, ensuring the necessary levels of input and consultation. Feedback to date on the Bowtie approach has been positive, both within the client and contractor organisations. Bowties provide a method of communicating the client’s expectations about levels of protection to infrastructure project contractors and address the following key requirements: Allow contractors to understand risk management requirements in detail and to price jobs accordingly; Enable identification of gaps in the barrier of key risks and facilitate implementation of best practice; Can be used by the client as a project safety assurance tool to check the risk management measures in place against those defined in the Bowtie; Demonstrate to the regulator that the client is communicating a clear ‘safety story’ throughout a project. This paper describes the Bowtie development process in accordance with Ten Golden Rules including how human factors can be incorporated in a systematic and meaningful way. It will demonstrate how the Bowties developed within this project represent in a clear and accessible manner what constitutes industry best practice with regard to controlling important safety risks in construction projects.

In this paper we report a method for the comparative analysis of volatile organic compounds (VOCs) at physiologically representative concentrations by different analytical methods Standard aqueous solutions of acetone, ethanol, methanol, 1-propanol, 2-propanol and acetaldehyde were prepared by adding a specific mass of compound to a known volume of water, calculated using published Henry’s law constants for individual compounds. Headspace concentrations are thus known from established partitioning from dilute aqueous phase in accordance with Henry’s law. Selected Ion Flow Tube Mass Spectrometry (SIFT-MS), Proton Transfer Reaction Mass Spectrometry (PTR-MS), and Gas Chromatography–Mass Spectrometry (GC–MS) coupled to thermal desorption have been used to study and evaluate the performance of the instruments in the analysis of these VOCs. These analytical techniques have been widely used in the identification and quantification of trace concentrations of VOCs in biological samples. Quantitative determination of VOC concentration was achieved and the performance of the instruments compared with one another. Calibration curves are given within the range 101–103 ppbv.

The analysis of volatile organic compounds (VOCs) as a non-invasive method for disease monitoring, such as type 2 diabetes (T2D) has shown potential over the years although not yet set in clinical practice. Longitudinal studies to date are limited and the understanding of the underlying VOC emission over the age is poorly understood. This study investigated longitudinal changes in VOCs present in faecal headspace in two mouse models of T2D – Cushing’s syndrome and single Afmid knockout mice. Longitudinal changes in bodyweight, blood glucose levels and plasma insulin concentration were also reported. Faecal headspace analysis was carried out using selected ion flow tube mass spectrometry (SIFT-MS) and thermal desorption coupled to gas chromatography-mass spectrometry (TD-GC-MS). Multivariate data analysis of the VOC profile showed differences mainly in acetic acid and butyric acid able to discriminate the groups Afmid and Cushing’s mice. Moreover, multivariate data analysis revealed statistically significant differences in VOCs between Cushing’s mice/wild-type (WT) littermates, mainly short-chain fatty acids (SCFAs), ketones, and alcohols, and longitudinal differences mainly attributed to methanol, ethanol and acetone. Afmid mice did not present statistically significant differences in their volatile faecal metabolome when compared to their respective WT littermates. The findings suggested that mice developed a diabetic phenotype and that the altered VOC profile may imply a related change in gut microbiota, particularly in Cushing’s mice. Furthermore, this study provided major evidence of age-related changes on the volatile profile of diabetic mice.

Contains fulltext : 206572.pdf (Publisher’s version ) (Open Access) We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

peer-reviewed Faecal VOCs (volatile organic compounds) were compared in horses and ponies before and after 6 weeks on Spring pasture and with and without a dietary supplement (ERME). The supplement was derived from malted barley and contained enzymes which degrade complex carbohydrates, including amylase, maltase, glucanases and fructanases. VOCs of faecal samples were analysed by selected ion flow tube mass spectrometry (SIFT-MS) and the results showed that the faecal microbiome was altered in different ways both by feeding on Spring pasture and by the dietary supplement. The composition of the equine gut microbiome (EGM) is therefore potentially a reflection of dietary constituents, both pasture and supplements; any metabolomic approach should take this into account since the EGM may have modulating effects on physiological parameters such as diabetes and obesity.

Beetroot juice (BJ), a source of nitrate, was added to the diet of thoroughbred racehorses for a four-week period. Analysis of nitrate/nitrite in plasma showed no significant differences between control and dosed groups. SIFT/MS (selected ion-flow tube/mass spectrometry) was used to analyse the faecal metabolome. The levels and types of volatile organic compounds (VOCs) were compared using headspace sampling of faeces from control and beetroot-supplemented equines, However, there were no significant differences apart from raised levels of acetonitrile in samples from the animals dosed with BJ. The conclusion was that racehorses appear not to have nitrate transporters and that addition of BJ to equine diets would not improve performance

© 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.

Immune Thrombocytopenia is an organ specific autoimmune disorder. It was believed that food intolerance may be a factor in ITP, affecting platelet count. This study investigated whether dietary modification could lead to an increase in platelet count in patients with ITP. IgE and IgG tests were conducted along with platelet counts to see if the role of food in ITP could be better understood. This study found that dietary modification did not affect platelet count in ITP patients. This suggests food intolerance does not cause chronic ITP.

Root canal irrigation with sodium hypochlorite (NaOCl) is an indispensable part of the chemomechanical preparation of infected root canals in Endodontology. However, there is limited information on the emergence of toxic or hazardous volatile compounds (VOCs) from the interaction of NaOCl with the infected content of tooth biomaterials. The aim of this study was to assess the formation of VOCs and disinfection by-products (DBPs) following the interaction of NaOCl 2.5% v/v with a model system of different sources of natural organic matter (NOM) present in infected root canals, including dentine powder, planktonic multi-microbial suspensions (Propionibacterium acnes, Staphylococcus epidermidis, Actinomyces radicidentis, Streptococcus mitis and Enterococcus faecalis strain OMGS3202), bovine serum albumin 4%w/v and their combination. NaOCl was obtained from a stock solution with iodometric titration. Ultrapure water served as negative control. Samples were stirred at 37°C in aerobic and anaerobic conditions for 30min to approximate a clinically realistic time. Centrifugation was performed and the supernatants were collected and stored at -800 C until analysis. The reaction products were analysed in real time by selected ion flow tube mass spectrometry (SIFT-MS) in triplicates. SIFT-MS analysis showed that the released VOCs included chlorinated hydrocarbons, particularly chloroform, together with unexpected higher levels of some nitrogenous compounds, especially acetonitrile. No difference was observed between aerobic and anaerobic conditions. The chemical interaction of NaOCl with NOM resulted in the formation of toxic chlorinated VOCs and DBPs. SIFT-MS analysis proved to be an effective analytical method. The risks from the rise of toxic compounds require further consideration in dentistry.

© 2019 Elsevier B.V. Antibiotic resistance is set to be an unprecedented threat to modern medicine. ‘Sniffing’ bacteria potentially offers a rapid way to determine susceptibility. A successful proof-of-principle study is described, using thermal desorption-gas chromatography-mass spectrometry (TD–GC–MS) to ‘smell’ cephalexin and ciprofloxacin resistant and sensitive Urinary Tract Infection (UTI)-causing bacteria. 578 peaks at unique retention times were detected from 86 chromatograms of 18 bacterial isolates (E. coli, K. pneumoniae and P. aeruginosa). The isolates were grown with and without the presence of antibiotic. Chi-square analysis found 9 compounds that differed significantly between cephalexin sensitive and resistant isolates, and 22 compounds that differed significantly between ciprofloxacin sensitive and resistant isolates, at p ≤ 0.05. When antibiotic was added to the media, more differences were found in the cephalexin group, attributed to lysis, but not in the ciprofloxacin group. Further work with large sample sizes will potentially enable the development of diagnostic algorithms using presence/absence of particular compounds of interest.

Previous studies have indicated that volatile organic compounds specific to bladder cancer may exist in urine headspace, raising the possibility that they may be of diagnostic value for this particular cancer. To further examine this hypothesis, urine samples were collected from patients diagnosed with either bladder cancer or a non‐cancerous urological disease/infection, and from healthy volunteers, from which the volatile metabolomes were analysed using gas chromatography mass spectrometry. The acquired data were subjected to a specifically designed pattern recognition algorithm, involving cross‐model validation. The best diagnostic performance, achieved with independent test data provided by healthy volunteers and bladder cancer patients, was 89% overall accuracy (90% sensitivity and 88% specificity). Permutation tests showed that these were statistically significant, providing further evidence of the potential for volatile biomarkers to form the basis of a non‐invasive diagnostic technique.

Purpose – The purpose of this paper is to explore how the next government could develop a better deal in relation to work, pensions and poverty. The paper argues that given the changing face of poverty, the next government should focus on creating better jobs if it is really to encourage people to work longer and save more for retirement. Furthermore, it could do more to support those who are currently under-saving for retirement. Design/methodology/approach – The paper draws on evidence from a number of recent qualitative and quantitative JRF research reports and government statistical data. Findings – The paper suggests policy recommendations for the next government focused on creating better jobs and helping those on lower incomes increase their pension pots. This includes: ensuring that the minimum wages is set with regard to the changing price of essentials and changing average earnings; raising awareness of the Living Wage and playing a leadership role; industrial strategies for low paid sectors; mid-life career reviews and increased rights for those aged 60 and over; the redistribution of tax relief on pension contributions and the auto-escalation of workplace pensions. Originality/value – This paper looks at the issue of an ageing society, work and pensions through a poverty lens.

The developed world has seen an alarming increase in the incidence of gastrointestinal diseases, among the most common of which is Crohn’s disease (CD) in the young. The current “gold standard” techniques for diagnosis are often costly, time consuming, inefficient, invasive, and offer poor sensitivities and specificities. This paper compares the performances of three hyphenated instrumental techniques that have been suggested as rapid methods for the non‐invasive diagnosis of CD from urine. These techniques are gas chromatography‐mass spectrometry (GC‐MS), high performance liquid chromatography‐mass spectrometry (HPLC‐MS) and selected ion flow tube mass spectrometry (SIFT‐MS). Each of these techniques is followed by multivariate classification to provide a diagnosis based on the acquired data. The most promising results for potentially diagnosing CD was via HPLC‐MS. An overall classification accuracy of 73% (74% specificity; 73% sensitivity) was achieved for differentiating CD from healthy controls, statistically significant at 95% confidence.

Experiments into the relationship between diet and health have been an area of high interest for a long time. In this study, we investigate the application of multivariate data analysis to differentiate between rat populations fed on two different diets: normal rat diet (control) and Western affluent diet (WAD). Two sets of data were acquired and analysed: one from a biochemical clinical analyser, taking measurements of blood-based biochemical markers; the other from the analysis of the volatile organic compounds (VOCs) emitted from faecal samples from the same animals using selected ion flow tube mass spectrometry (SIFT-MS). Five classes were considered: weanlings, 12 month controls, 12 month WADs, 18 month controls, and 18 month WADs. Data from the biochemical analyser, weanlings and 18 month WAD fed rats showed significant differences from the other measurement classes. This was shown in both the exploratory analysis and through multivariate classification. Classification of control diet versus WAD diets suggested there are differences between classes with 92% accuracy for the 12 month classes and 91% for the 18 month classes. Cholesterol markers, especially as low density lipoprotein-cholesterol (LDL), were the main factor in influencing WAD samples. The data from the SIFT-MS analysis also produced very good classification accuracies. Classification of control diet versus WAD diets using the H3O(+) precursor ion data suggested there are differences between classes with 71% accuracy for the 12 month classes and 100% for the 18 month classes. These findings confirm that total cholesterol and LDL-cholesterol are elevated in the 18 month WAD-fed rats. We therefore suggest that the analysis of VOCs from faecal samples in conjunction with multivariate data analysis may be a useful alternative to blood analysis for the detection of parameters of health.

Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.

One of the most common volatile organic compounds (VOCs) group is monoterpenes. Monoterpenes share the molecular formula C10H16, they are usually cyclic and have a pleasant smell. The most common monoterpenes are limonene (present in citrus fruits) and α-pinene (present in conifers’ resin). Different monoterpenes have different chemical, biological and ecological properties thus it is experimentally very important to be able to differentiate between them in real time. Real time instruments such as Proton Transfer Reaction-Time of Flight-Mass Spectrometry (PTR-ToF-MS), offer a real time solution for monoterpene measurement but at the cost of selectivity resulting in all monoterpenes being seen at the same m/z. In this work we used Selective Reagent Ion-Time of Flight-Mass Spectrometry (SRI/PTR-ToF-MS) in order to explore the differences in ion branching when different ionizations (H3O+, NO+ and O2 +) and different drift tube reduced field energies (E/N) were used. We report a comprehensive ion library with many unique features, characteristic for individual monoterpenes.

Breath analysis is a promising field with great potential for non-invasive diagnosis of a number of disease states. Analysis of the concentrations of volatile organic compounds (VOCs) in breath with an acceptable accuracy are assessed by means of using analytical techniques with high sensitivity, accuracy, precision, low response time, and low detection limit, which are desirable characteristics for the detection of VOCs in human breath. “Breath fingerprinting”, indicative of a specific clinical status, relies on the use of multivariate statistics methods with powerful in-built algorithms. The need for standardisation of sample collection and analysis is the main issue concerning breath analysis, blocking the introduction of breath tests into clinical practice. This review describes recent scientific developments in basic research and clinical applications, namely issues concerning sampling and biochemistry, highlighting the diagnostic potential of breath analysis for disease diagnosis. Several considerations that need to be taken into account in breath analysis are documented here, including the growing need for metabolomics to deal with breath profiles.

Gastrointestinal diseases such as irritable bowel syndrome, Crohn’s disease (CD) and ulcerative colitis are a growing concern in the developed world. Current techniques for diagnosis are often costly, time consuming, inefficient, of great discomfort to the patient, and offer poor sensitivities and specificities. This paper describes the development and evaluation of a new methodology for the non-invasive diagnosis of such diseases using a combination of gas chromatography mass spectrometry (GC–MS) and chemometrics. Several potential sample matrices were tested: blood, breath, faeces and urine. Faecal samples provided the only statistically significant results, providing discrimination between CD and healthy controls with an overall classification accuracy of 85 % (78 % specificity; 93 % sensitivity). Differentiating CD from other diseases proved more challenging, with overall classification accuracy dropping to 79 % (83 % specificity; 68 % sensitivity). This diagnostic performance compares well with the gold standard technique of colonoscopy, suggesting that GC–MS may have potential as a non-invasive screening tool.

Background: The aim of this study was to determine whether volatile organic compounds (VOCs) present in the headspace of feces could be used to diagnose or distinguish between chronic diseases of the gastrointestinal tract and apparently healthy volunteers. Methods: A total of 87 people were recruited, divided between 4 categories: healthy volunteers (n = 19), Crohn's disease (n = 22), ulcerative colitis (n = 20), and irritable bowel syndrome (n = 26). They each supplied fecal samples before, and except for the healthy volunteers, after treatment. Fecal samples were incubated in a sample bag with added purified air at 40[degrees]C and headspace samples were taken and concentrated on thermal sorption tubes. Gas chromatography-mass spectrometry then desorbed and analyzed these. The concentrations of a selection of high-abundance compounds were determined and assessed for differences in concentration between the groups. Results: Crohn's disease samples showed significant elevations in the concentrations of ester and alcohol derivates of short-chain fatty acids and indole compared with the other groups; indole and phenol were elevated in ulcerative colitis and irritable bowel syndrome but not at a statistically significant level. After treatment, the levels of many of the VOCs were significantly reduced and were more similar to those concentrations in healthy controls. Conclusions: The abundance of a number of VOCs in feces differs markedly between Crohn's disease and other gastrointestinal conditions. Following treatment, the VOC profile is altered to more closely resemble that of healthy volunteers.

© 2013 Bentham Science Publishers.SIFT-MS is used for the first time in profiling the volatile organic profile in faecal headspace in two groups of horses admitted to an equine hospital, one group with acute intestinal disease (colic) affecting the large colon, plus a control group of similarly managed horses admitted for non-gastrointestinal/metabolic reasons (e.g. acute orthopaedic injury). Compounds in faecal headspace which show statistically significant concentration differences between the groups are acetone and methanol. In addition, some ions at various m/z values show significantly different ion counts between the groups. Further information may be gleaned by using multivariate statistics in evaluating the differences between the two horse groups. Principal components analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were evaluated for reducing the dimensionality of the SIFT-MS data, and OPLS-DA was found to be best at discriminating between the groups, particularly with SIFT-MS data acquired using the H3O+ precursor ion. Analysis of these data also show the significance of ammonia as a discriminating ion. These results show that SIFT-MS may potentially be used on the headspace of horse faecal samples for detecting altered microbial fermentation associated with acute intestinal disease of the colon.

Objectives Grading of Recommendations Assessment, Development and Evaluation (GRADE) is a system for rating the confidence in estimates of effect and grading guideline recommendations. It promotes evaluation of the quality of the evidence for each outcome and an assessment of balance between desirable and undesirable outcomes leading to a judgment about the strength of the recommendation. In 2007, the National Institute for Health and Clinical Excellence began introducing GRADE across its clinical guideline program to enable separation of judgments about the evidence quality from judgments about the strength of the recommendation. Study Design and Setting We describe the process of implementing GRADE across guidelines. Results Use of GRADE has been positively received by both technical staff and guideline development group members. Conclusion A shift in thinking about confidence in the evidence was required leading to a more structured and transparent approach to decision making. Practical problems were also encountered; these have largely been resolved, but some areas require further work, including the application of imprecision and presenting results from analyses considering more than two alternative interventions. The use of GRADE for nonrandomized and diagnostic accuracy studies needs to be refined.

ITP is an organ-specific autoimmune disorder characterised by a low platelet count whose cause is uncertain. A possible factor is food intolerance, although much of the information linking this with ITP is anecdotal. The role of food intolerance in ITP was studied by replacing a normal diet with an elemental diet (E028), but this did not increase platelet counts. Clear differences, however, were apparent between the volatile organic compounds (VOCs) in the urine headspace of patients with ITP and those present in healthy volunteers, which leads to speculation that abnormal metabolic activity of the intestinal microbiome may be a factor causing ITP. However, further work is needed to confirm this. There were also differences between the VOCs of patients on a normal diet and those on the elemental diet, and in this case, the VOCs involved are very likely to be of bacterial origin, as their production is affected by dietary manipulation. Many of these VOCs are known to be toxic.

The need for improved rapid diagnostic tests for tuberculosis disease has prompted interest in the volatile organic compounds (VOCs) emitted by Mycobacterium tuberculosis complex bacteria. We have investigated VOCs emitted by Mycobacterium bovis BCG grown on Lowenstein–Jensen media using selected ion flow tube mass spectrometry and thermal desorption-gas chromatography-mass spectrometry. Compounds observed included dimethyl sulphide, 3-methyl-1-butanol, 2-methyl-1-propanol, butanone, 2-methyl-1-butanol, methyl 2-methylbutanoate, 2-phenylethanol and hydrogen sulphide. Changes in levels of acetaldehyde, methanol and ammonia were also observed. The compounds identified are not unique to M. bovis BCG, and further studies are needed to validate their diagnostic value. Investigations using an ultra-rapid gas chromatograph with a surface acoustic wave sensor (zNose) demonstrated the presence of 2-phenylethanol (PEA) in the headspace of cultures of M. bovis BCG and Mycobacterium smegmatis, when grown on Lowenstein–Jensen supplemented with glycerol. PEA is a reversible inhibitor of DNA synthesis. It is used during selective isolation of gram-positive bacteria and may also be used to inhibit mycobacterial growth. PEA production was observed to be dependent on growth of mycobacteria. Further study is required to elucidate the metabolic pathways involved and assess whether this compound is produced during in vivo growth of mycobacteria.

The book of Hosea uses the rich and unyielding metaphor of a broken marriage to demonstrate the extent to which Ephraim, Israel’s Northern region had been unfaithful to God, her eternally faithful husband. This paper seeks to offer the reader a creative way of approaching its message from a contemporary standpoint. Furthermore, it will centre on the contentious male/female imagery that carries Hosea’s prophecy. In so doing it will invite consideration, not of an often-assumed misogynistic deity but of a relational and wholly relevant God, tangled up with humanity in all its vulnerability and brokenness; God in our midst.

In past years, numerous electronic nose (e-nose) developments have been published describing analyses of solid-, liquid- or gaseous media in microbiological-, environmental-, agricultural- or medical applications. However, little has been reported about complex methodological pitfalls that might be associated with commercially available e-nose technology. In this paper, some of these pitfalls such as temperature, the use of filters and mass flow using different sampling methods (static- and dynamic sampling) are described for two generations of conducting polymer e-noses (ST114/214, CPs, both Scensive Tech. Ltd.). A comparison with metal oxide semiconducting field effect transistor/metal oxide semiconductor (MOSFET/MOS) e-noses regarding stability across replicates and over time was made. Changes in temperature were found to give larger sensor responses, whereas the application of filters led to quantitative and qualitative changes in sensor responses due to a change in mass flow which was also affected by the sampling method. Static sampling provided more stable flows across replicates. Variation was investigated for CPs and MOSFET/MOS e-noses that gave different responses over time and across replicates. These methodological factors cause a lack of stability and reproducibility, demonstrating the pitfalls of e-nose technology and therefore limit their utility for discriminating between samples.