Knowledge of cytology results affects the performance of colposcopy: a crossover study.

OBJECTIVE: To determine whether knowledge of cytology affects the colposcopist's diagnostic accuracy in the identification of cervical intraepithelial neoplasia grade 2 and worse (≥ CIN2). METHOD: In this cross-over study, healthcare professionals interpreted colposcopy images from 80 patient cases with known histological diagnoses. For each case, 2 images taken with a colposcope were provided (native and after acetic acid application). Inclusion criteria consisted of women with a transformation zone type 1 or 2, who had both a cytological and histological diagnosis. Cases were distributed across two online surveys, one including and one omitting the cytology. A wash-out period of six weeks between surveys was implemented. Colposcopists were asked to give their diagnosis for each case as < CIN2 or ≥ CIN2 on both assessments. Statistical analysis was conducted to compare the two interpretations. RESULTS: Knowledge of cytology significantly improved the sensitivity when interpreting colposcopic images, from 51.1% [95%CI: 39.3 to 62.8] to 63.7% [95%CI: 52.1 to 73.9] and improved the specificity from 63.5% [95%CI: 52.3 to 73.5] to 76.6% [95%CI: 67.2 to 84.0]. Sensitivity was higher by 38.6% when a high-grade cytology (ASC-H, HSIL, AGC) was communicated compared to a low-grade cytology (inflammation, ASC-US, LSIL). Specificity was higher by 31% when a low-grade cytology was communicated compared to a high-grade. CONCLUSIONS: Our data suggests that knowledge of cytology increases sensitivity and specificity for diagnosis of ≥ CIN2 lesions at colposcopy. Association between cytology and histology may have contributed to the findings.

The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study.

OBJECTIVE: To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. PATIENTS AND METHODS: This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. RESULTS: Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3-34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1-30.2), UTUC (n = 128) 1.14% (95% CI 0.77-1.52), renal cancer (n = 107) 1.05% (95% CI 0.80-1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32-2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03-1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90-4.15; P < 0.001), male sex 1.30 (95% CI 1.14-1.50; P < 0.001), and smoking 2.70 (95% CI 2.30-3.18; P < 0.001). CONCLUSIONS: A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer.

Understanding Barriers to Novel Data Linkages: Topic Modeling of the Results of the LifeInfo Survey.

BACKGROUND: Novel consumer and lifestyle data, such as those collected by supermarket loyalty cards or mobile phone exercise tracking apps, offer numerous benefits for researchers seeking to understand diet- and exercise-related risk factors for diseases. However, limited research has addressed public attitudes toward linking these data with individual health records for research purposes. Data linkage, combining data from multiple sources, provides the opportunity to enhance preexisting data sets to gain new insights. OBJECTIVE: The aim of this study is to identify key barriers to data linkage and recommend safeguards and procedures that would encourage individuals to share such data for potential future research. METHODS: The LifeInfo Survey consulted the public on their attitudes toward sharing consumer and lifestyle data for research purposes. Where barriers to data sharing existed, participants provided unstructured survey responses detailing what would make them more likely to share data for linkage with their health records in the future. The topic modeling technique latent Dirichlet allocation was used to analyze these textual responses to uncover common thematic topics within the texts. RESULTS: Participants provided responses related to sharing their store loyalty card data (n=2338) and health and fitness app data (n=1531). Key barriers to data sharing identified through topic modeling included data safety and security, personal privacy, requirements of further information, fear of data being accessed by others, problems with data accuracy, not understanding the reason for data linkage, and not using services that produce these data. We provide recommendations for addressing these issues to establish the best practice for future researchers interested in using these data. CONCLUSIONS: This study formulates a large-scale consultation of public attitudes toward this kind of data linkage, which is an important first step in understanding and addressing barriers to participation in research using novel consumer and lifestyle data.

Dietary Compounds Influencing the Sensorial, Volatile and Phytochemical Properties of Bovine Milk.

The main aim of this study was to evaluate the volatile profile, sensory perception, and phytochemical content of bovine milk produced from cows fed on three distinct feeding systems, namely grass (GRS), grass/clover (CLV), and total mixed ration (TMR). Previous studies have identified that feed type can influence the sensory perception of milk directly via the transfer of volatile aromatic compounds, or indirectly by the transfer of non-volatile substrates that act as precursors for volatile compounds. In the present study, significant differences were observed in the phytochemical profile of the different feed and milk samples. The isoflavone formonoetin was significantly higher in CLV feed samples, but higher in raw GRS milk, while other smaller isoflavones, such as daidzein, genistein, and apigenin were highly correlated to raw CLV milk. This suggests that changes in isoflavone content and concentration in milk relate to diet, but also to metabolism in the rumen. This study also found unique potential volatile biomarkers in milk (dimethyl sulfone) related to feeding systems, or significant differences in the concentration of others (toluene, p-cresol, ethyl and methyl esters) based on feeding systems. TMR milk scored significantly higher for hay-like flavor and white color, while GRS and CLV milk scored significantly higher for a creamy color. Milk samples were easily distinguishable by their volatile profile based on feeding system, storage time, and pasteurization.

Prevalence of abnormal semen analysis and levels of adherence with fertility preservation in men undergoing therapy for newly diagnosed cancer: A retrospective study in 2906 patients.

BACKGROUND: Sperm cryopreservation (freezing) should be offered to all men with cancer due to risk of infertility. However, many men with cancer already have impaired spermatogenesis prior to sperm cryopreservation. Furthermore, physical ill-health may hinder attendance of freeze visits. Investigating both the distribution of sperm functions and freeze attendance rates in men with newly diagnosed cancer, may identify patients benefiting from targeted reproductive fertility support. METHODS: We performed a retrospective study of 2906 male patients undergoing sperm cryopreservation prior to cancer therapy at a single UK tertiary centre between 1989 and 2013; all patients were asked to attend three hospital semen collection visits prior to cancer therapy. RESULTS: Fifteen per cent (433/2906) of men with newly diagnosed cancer had severely impaired semen quality (i.e., sperm total motile count, TMC < 1 million) during the first semen collection visit. However, patients with severely impaired semen quality had the poorest attendance of subsequent semen collection visits despite being requested to do so (non-attendance in TMC < 1 million: 43.4%; TMC < 1-30 million: 35.7%, P < 0.05 vs. <1 million; TMC > 30 million: 33.2%, P < 0.01 vs. <1 million). CONCLUSIONS: This study expands understanding of the semen quality of men with newly diagnosed cancer, and their ability to adhere to fertility preservation recommendations. Our data suggest that patients with the poorest semen quality paradoxically suffer the poorest attendance rates of sperm cryopreservation appointments prior to commencing cancer therapy. We suggest that additional support may be of clinical benefit to men with newly diagnosed cancer and TMC < 1 million sperm.

Caffeine, coffee, and appetite control: a review.

Coffee and caffeine consumption has global popularity. However, evidence for the potential of these dietary constituents to influence energy intake, gut physiology, and appetite perceptions remains unclear. The purpose of this review was to examine the evidence regarding coffee and caffeine's influence on energy intake and appetite control. The literature was examined for studies that assessed the effects of caffeine and coffee on energy intake, gastric emptying, appetite-related hormones, and perceptual measures of appetite. The literature review indicated that coffee administered 3-4.5 h before a meal had minimal influence on food and macronutrient intake, while caffeine ingested 0.5-4 h before a meal may suppress acute energy intake. Evidence regarding the influence of caffeine and coffee on gastric emptying, appetite hormones, and appetite perceptions was equivocal. The influence of covariates such as genetics of caffeine metabolism and bitter taste phenotype remain unknown; longer controlled studies are needed.

Associations of coefficient of variation of serum GH with previous radiotherapy, hypopituitarism and cardiac disease in patients with treated acromegaly.

BACKGROUND: Cardiovascular complications represent the biggest cause of mortality in acromegaly. It is therefore important to optimally stratify acromegalic patients according to disease activity and complication risk. GH is secreted in a pulsatile manner from the pituitary gland, but GH pulsatility is not routinely assessed clinically. The coefficient of variation of serum GH (GHCV) during oral glucose tolerance test (OGTT) quantifies the variation of GH secretion in patients with acromegaly, but has not been reported previously. AIM: To investigate whether GHCV during OGTT is associated with clinical parameters predicted to relate with hypothalamo-pituitary dysfunction during acromegaly, such as radiotherapy treatment, pituitary deficiency and cardiac disease. METHODS: GHCV was calculated during 584 OGTTs and compared with nadir serum GH and IGF-1 in 111 acromegalic patients treated at a single centre. RESULTS: Acromegalic patients treated with radiotherapy had a 37% lower level of GHCV when compared to the nonradiotherapy group (mean GHCV: 0·298 ± 0·015, no radiotherapy; 0·189 ± 0·007, radiotherapy; P < 0·001). Neither serum IGF-1 nor nadir GH was significantly altered in the radiotherapy group. Mean GHCV was 50% lower in the acromegalic patients with cardiac failure when compared to acromegalic patients with normal echocardiogram (0·161 ± 0·034 vs 0·297 ± 0·055; P < 0·05). Neither serum IGF-1 nor nadir GH was significantly altered during cardiac failure. CONCLUSION: Our preliminary data suggest that GHCV during OGTT may be reduced during acromegaly in patients with previous radiotherapy, pituitary deficiencies and cardiac disease. Larger studies are required to determine whether GHCV could provide help to assess the morbidity status of patients with treated acromegaly.

Molecular basis for negative regulation of the glucagon receptor.

Members of the class B family of G protein-coupled receptors (GPCRs) bind peptide hormones and have causal roles in many diseases, ranging from diabetes and osteoporosis to anxiety. Although peptide, small-molecule, and antibody inhibitors of these GPCRs have been identified, structure-based descriptions of receptor antagonism are scarce. Here we report the mechanisms of glucagon receptor inhibition by blocking antibodies targeting the receptor's extracellular domain (ECD). These studies uncovered a role for the ECD as an intrinsic negative regulator of receptor activity. The crystal structure of the ECD in complex with the Fab fragment of one antibody, mAb1, reveals that this antibody inhibits glucagon receptor by occluding a surface extending across the entire hormone-binding cleft. A second antibody, mAb23, blocks glucagon binding and inhibits basal receptor activity, indicating that it is an inverse agonist and that the ECD can negatively regulate receptor activity independent of ligand binding. Biochemical analyses of receptor mutants in the context of a high-resolution ECD structure show that this previously unrecognized inhibitory activity of the ECD involves an interaction with the third extracellular loop of the receptor and suggest that glucagon-mediated structural changes in the ECD accompany receptor activation. These studies have implications for the design of drugs to treat class B GPCR-related diseases, including the potential for developing novel allosteric regulators that target the ECDs of these receptors.

Inhibitory mechanism of an allosteric antibody targeting the glucagon receptor.

Elevated glucagon levels and increased hepatic glucagon receptor (GCGR) signaling contribute to hyperglycemia in type 2 diabetes. We have identified a monoclonal antibody that inhibits GCGR, a class B G-protein coupled receptor (GPCR), through a unique allosteric mechanism. Receptor inhibition is mediated by the binding of this antibody to two distinct sites that lie outside of the glucagon binding cleft. One site consists of a patch of residues that are surface-exposed on the face of the extracellular domain (ECD) opposite the ligand-binding cleft, whereas the second binding site consists of residues in the αA helix of the ECD. A docking model suggests that the antibody does not occlude the ligand-binding cleft. We solved the crystal structure of GCGR ECD containing a naturally occurring G40S mutation and found a shift in the register of the αA helix that prevents antibody binding. We also found that alterations in the αA helix impact the normal function of GCGR. We present a model for the allosteric inhibition of GCGR by a monoclonal antibody that may form the basis for the development of allosteric modulators for the treatment of diabetes and other class B GPCR-related diseases.

Self-supervised learning-based cervical cytology for the triage of HPV-positive women in resource-limited settings and low-data regime.

Screening Papanicolaou test samples has proven to be highly effective in reducing cervical cancer-related mortality. However, the lack of trained cytopathologists hinders its widespread implementation in low-resource settings. Deep learning-assisted telecytology diagnosis emerges as an appealing alternative, but it requires the collection of large annotated training datasets, which is costly and time-consuming. In this paper, we demonstrate that the abundance of unlabeled images that can be extracted from Pap smear test whole slide images presents a fertile ground for self-supervised learning methods, yielding performance improvements compared to off-the-shelf pre-trained models for various downstream tasks. In particular, we propose Cervical Cell Copy-Pasting (C3P) as an effective augmentation method, which enables knowledge transfer from public and labeled single-cell datasets to unlabeled tiles. Not only does C3P outperforms naive transfer from single-cell images, but we also demonstrate its advantageous integration into multiple instance learning methods. Importantly, all our experiments are conducted on our introduced in-house dataset comprising liquid-based cytology Pap smear images obtained using low-cost technologies. This aligns with our long-term objective of deep learning-assisted telecytology for diagnosis in low-resource settings.

Cost-effectiveness of two online interventions supporting self-care for eczema for parents/carers and young people.

OBJECTIVE: To estimate the cost-effectiveness of online behavioral interventions (EczemaCareOnline.org.uk) designed to support eczema self-care management for parents/carers and young people from an NHS perspective. METHODS: Two within-trial economic evaluations, using regression-based approaches, adjusting for baseline and pre-specified confounder variables, were undertaken alongside two independent, pragmatic, parallel group, unmasked randomized controlled trials, recruiting through primary care. Trial 1 recruited 340 parents/carers of children aged 0-12 years and Trial 2 337 young people aged 13-25 years with eczema scored ≥ 5 on Patient-Oriented Eczema Measure (POEM). Participants were randomized (1:1) to online intervention plus usual care or usual care alone. Resource use, collected via medical notes review, was valued using published unit costs in UK £Sterling 2021. Quality-of-life was elicited using proxy CHU-9D in Trial 1 and self-report EQ-5D-5L in Trial 2. RESULTS: The intervention was dominant (cost saving and more effective) with a high probability of cost-effectiveness (> 68%) in most analyses. The exception was the complete case cost-utility analysis for Trial 1 (omitting participants with children aged < 2), with adjusted incremental cost savings of -£34.15 (95% CI - 104.54 to 36.24) and incremental QALYs of - 0.003 (95% CI - 0.021 to 0.015) producing an incremental cost per QALY of £12,466. In the secondary combined (Trials 1 and 2) cost-effectiveness analysis, the adjusted incremental cost was -£20.35 (95% CI - 55.41 to 14.70) with incremental success (≥ 2-point change on POEM) of 10.3% (95% CI 2.3-18.1%). CONCLUSION: The free at point of use online eczema self-management intervention was low cost to run and cost-effective. TRIAL REGISTRATION: This trial was registered prospectively with the ISRCTN registry (ISRCTN79282252). URL www.EczemaCareOnline.org.uk .

Automated extraction of clinical measures from videos of oculofacial disorders using machine learning: feasibility, validity and reliability.

OBJECTIVES: To determine the feasibility, validity and reliability of automatically extracting clinically meaningful eyelid measurements from consumer-grade videos of individuals with oculofacial disorders. METHODS: A custom computer program was designed to automatically extract clinical measures from consumer-grade videos. This program was applied to publicly available videos of individuals with oculofacial disorders, and age-matched controls. The primary outcomes were margin reflex distance 1 (MRD1) and 2 (MRD2), blink lagophthalmos, and ocular surface area exposure. Test-retest reliability was evaluated using Bland-Altman analysis to compare the agreement in obtained measures between separate videos of the same individual taken within 48 h of each other. RESULTS: MRD1 was reduced in individuals with ptosis versus controls (2.2 mm versus 3.4 mm, p < 0.001), and increased in individuals with facial nerve palsy (FNP) (3.9 mm, p = 0.049) and thyroid eye disease (TED) (4.1 mm; p = 0.038). Blink lagophthalmos was increased in individuals with FNP (3.7 mm); p < 0.001) and those with TED (0.1 mm, p = 0.003) versus controls (0.0 mm). Ocular surface exposure was reduced in individuals with ptosis compared with controls (12.2 mm2 versus 13.1 mm2; p < 0.001) and increased in TED (13.7 mm2; p 0.002). Bland-Altmann analysis demonstrated 95% limits of agreement for video-derived measures: median MRD1: -1.1 to 1.1 mm; median MRD2: -0.9 to 1.0 mm; blink lagophthalmos: -3.5 to 3.7 mm; and average ocular surface area exposure: -1.6 to 1.6 mm2. CONCLUSIONS: The presented program is capable of taking consumer grade videos of patients with oculofacial disease and providing clinically meaningful and reliable eyelid measurements that show promising validity.

Telecytologic diagnosis of cervical smears for triage of self-sampled human papillomavirus-positive women in a resource-limited setting: concept development before implementation.

INTRODUCTION: Cytology is an option for triaging human papillomavirus (HPV)-positive women. The interpretation of cytologic slides requires expertise and financial resources that are not always available in resource-limited settings. A solution could be offered by manual preparation and digitization of slides on site for real-time remote cytologic diagnosis by specialists. In the present study, we evaluated the operational feasibility and cost of manual preparation and digitization of thin-layer slides and the diagnostic accuracy of screening with virtual microscopy. MATERIALS AND METHODS: Operational feasibility was evaluated on 30 cervical samples obtained during colposcopy. The simplicity of the process and cellularity and quality of digitized thin-layer slides were evaluated. The diagnostic accuracy of digital versus glass slides to detect cervical intraepithelial neoplasia grade 2 or worse was assessed using a cohort of 264 HPV-positive Cameroonian women aged 30 to 49 years. The histologic results served as the reference standard. RESULTS: Manual preparation was found to be feasible and economically viable. The quality characteristics of the digital slides were satisfactory, and the mean cellularity was 6078 squamous cells per slide. When using the atypical squamous cells of undetermined significance or worse threshold for positivity, the diagnostic performance of screening digital slides was not significantly different statistically compared with the same set of slides screened using a light microscope (P = 0.26). CONCLUSIONS: We have developed an innovative triage concept for HPV-positive women. A quality-ensured telecytologic diagnosis could be an effective solution in areas with a shortage of specialists, applying a same day "test-triage-treat" approach. Our results warrant further on-site clinical validation in a large prospective screening trial.

Functional and structural characteristics in patients with diabetic macular oedema after switching from ranibizumab to aflibercept treatment. Three year results in real world settings.

BACKGROUND: Our aim was to examine the long term anatomical and functional outcomes in patients with refractory diabetic macular oedema (DMO) undergoing treatment switch from ranibizumab to aflibercept. METHODS: Retrospective review of patients with DMO undergoing treatment switch from ranibizumab to aflibercept at a single centre between 2015 and 2017. Primary outcomes were best corrected visual acuity (BCVA) and central macular thickness (CMT). RESULTS: 57 eyes from 44 patients were included. Following switch to aflibercept, median (IQR) BCVA improved to 73 (64-77) letters at 3 months (p = 0.0006), to 73 (61-78) letters at 6 months (p = 0.0042), to 73 (65-77) at 9 months (p = 0.0006), and to 73 (63-75) letters at 18 months (p = 0.0444). At 36 months following switch, 12 eyes had gained > 10 letters, 5 eyes had gained 5-9 letters, 25 remained stable (± 5 letters), 7 eyes lost 5-9 letters and 8 eyes lost > 10 letters. A significant reduction in CMT at all trimesters following treatment switch was found except at month 24. CONCLUSIONS: We provide real world data suggesting a sustained anatomical and functional benefit of switching from ranibizumab to aflibercept in the treatment of refractory DMO.

Can Routine Patients Be Safely Discharged After Neodymium-Doped Yttrium Aluminium Garnet Laser Posterior Capsulotomy?

Background Neodymium-doped yttrium aluminium garnet (Nd:YAG) posterior capsulotomy is a common treatment for posterior capsular opacification. Practice varies regarding routine follow-up. In this study, we reviewed follow-up rates and treatment-related complications from a district general hospital's ophthalmology unit to assess areas for improvement and cost-effectiveness. Methodology We conducted a retrospective review of electronic patient records for all patients treated with Nd:YAG capsulotomy in 2019 at our hospital. Primary outcomes included visual acuity, complications, and follow-up data. Secondary outcomes included medication prescribing and the grade of surgeon. Results In total, 912 eyes of 744 patients were included. Overall, 536 (58.8%) eyes were discharged immediately following their laser. Complication rate was 4.3% (39 eyes). Junior training grades had a higher rate of medication prescribing (40/46 eyes; 87.0%) and follow-up (36/40 eyes; 78.3%). Conclusions Certain selected patients may be safely discharged following capsulotomy with safety-netting advice. This strategy increases the capacity to follow-up patients at higher risk of complications. Higher rates of follow-up among junior ophthalmologists offers potential for training.

The Influence of Pasture and Non-pasture-Based Feeding Systems on the Aroma of Raw Bovine Milk.

Aroma-active compounds in raw bovine milk produced from cows fed perennial ryegrass (GRS) or total mixed ration (TMR) consisting of grass silage, maize silage, and concentrates were identified by direct immersion sorptive extraction (DI Hi-Sorb), coupled with gas-chromatography-mass spectrometry and olfactometry using odour intensity (OI) and aroma extraction dilution analysis (AEDA). Ninety-nine volatile organic compounds (VOC) were identified in these raw GRS and TMR milk samples; 33 of which were also present in the feed and rumen samples from these diets. Only the abundance of 13 VOC varied significantly based on diet. However, the odours of both raw milks were quite distinct as aroma perception is not influenced by abundance alone but also by the odour activity of each VOC. Approximately, 30% of the VOC influenced the aroma perception of these raw milks. This study clearly highlighted the significant impact of VOC transferring from the diet that influenced the aroma perception of both raw GRS and TMR milk. The aroma of the raw TMR milk was more complex than that of the raw GRS milk, and many of the key dietary-derived-odour-active VOC likely arose during the production of the TMR feed as most were either derived from Maillard reactions or impacted by heat. Seventeen of the 44 odour activities detected differed between both sample types. This study has clearly demonstrated the impact of diet on the aroma perception of raw bovine milk.

The Potential Role of Creatine in Vascular Health.

Creatine is an organic compound, consumed exogenously in the diet and synthesized endogenously via an intricate inter-organ process. Functioning in conjunction with creatine kinase, creatine has long been known for its pivotal role in cellular energy provision and energy shuttling. In addition to the abundance of evidence supporting the ergogenic benefits of creatine supplementation, recent evidence suggests a far broader application for creatine within various myopathies, neurodegenerative diseases, and other pathologies. Furthermore, creatine has been found to exhibit non-energy related properties, contributing as a possible direct and in-direct antioxidant and eliciting anti-inflammatory effects. In spite of the new clinical success of supplemental creatine, there is little scientific insight into the potential effects of creatine on cardiovascular disease (CVD), the leading cause of mortality. Taking into consideration the non-energy related actions of creatine, highlighted in this review, it can be speculated that creatine supplementation may serve as an adjuvant therapy for the management of vascular health in at-risk populations. This review, therefore, not only aims to summarize the current literature surrounding creatine and vascular health, but to also shed light onto the potential mechanisms in which creatine may be able to serve as a beneficial supplement capable of imparting vascular-protective properties and promoting vascular health.

Oxidative Quality of Dairy Powders: Influencing Factors and Analysis.

Lipid oxidation (LO) is a primary cause of quality deterioration in fat-containing dairy powders and is often used as an estimation of a products shelf-life and consumer acceptability. The LO process produces numerous volatile organic compounds (VOC) including aldehydes, ketones and alcohols, which are known to contribute to the development of off-flavours in dairy powders. The main factors influencing the oxidative state of dairy powders and the various analytical techniques used to detect VOC as indicators of LO in dairy powders are outlined. As the ability to identify and quantify specific VOC associated with LO improves this review highlights how these techniques can be used in conjunction with olfactory and sensory analysis to better understand product specific LO processes with the aim of maximizing shelf-life without compromising quality.

Fenebrutinib in H1 antihistamine-refractory chronic spontaneous urticaria: a randomized phase 2 trial.

Bruton's tyrosine kinase (BTK) is crucial for FcεRI-mediated mast cell activation and essential for autoantibody production by B cells in chronic spontaneous urticaria (CSU). Fenebrutinib, an orally administered, potent, highly selective, reversible BTK inhibitor, may be effective in CSU. This double-blind, placebo-controlled, phase 2 trial (EudraCT ID 2016-004624-35 ) randomized 93 adults with antihistamine-refractory CSU to 50 mg daily, 150 mg daily and 200 mg twice daily of fenebrutinib or placebo for 8 weeks. The primary end point was change from baseline in urticaria activity score over 7 d (UAS7) at week 8. Secondary end points were the change from baseline in UAS7 at week 4 and the proportion of patients well-controlled (UAS7 ≤ 6) at week 8. Fenebrutinib efficacy in patients with type IIb autoimmunity and effects on IgG-anti-FcεRI were exploratory end points. Safety was also evaluated. The primary end point was met, with dose-dependent improvements in UAS7 at week 8 occurring at 200 mg twice daily and 150 mg daily, but not at 50 mg daily of fenebrutinib versus placebo. Asymptomatic, reversible grade 2 and 3 liver transaminase elevations occurred in the fenebrutinib 150 mg daily and 200 mg twice daily groups (2 patients each). Fenebrutinib diminished disease activity in patients with antihistamine-refractory CSU, including more patients with refractory type IIb autoimmunity. These results support the potential use of BTK inhibition in antihistamine-refractory CSU.