Intradental mechano-nociceptors serve as sentinels that prevent tooth damage.

Pain is the anticipated output of the trigeminal sensory neurons that innervate the tooth's vital interior 1,2 ; however, the contribution of intradental neurons to healthy tooth sensation has yet to be defined. Here, we employ in vivo Ca 2+ imaging to identify and define a population of myelinated high-threshold mechanoreceptors (intradental HTMRs) that detect superficial structural damage of the tooth and initiate jaw opening to protect teeth from damage. Intradental HTMRs remain inactive when direct forces are applied to the intact tooth but become responsive to forces when the structural integrity of the tooth is compromised, and the dentin or pulp is exposed. Their terminals collectively innervate the inner dentin through overlapping receptive fields, allowing them to monitor the superficial structures of the tooth. Indeed, intradental HTMRs detect superficial enamel damage and encode its degree, and their responses persist in the absence of either PIEZO2 or Na v 1.8 3,4 . Optogenetic activation of intradental HTMRs triggers a rapid, jaw opening reflex via contraction of the digastric muscle. Taken together, our data indicate that intradental HTMRs serve as sentinels that guard against mechanical threats to the tooth, and their activation results in physical tooth separation to minimize irreversible structural damage. Our work provides a new perspective on the role of intradental neurons as protective rather than exclusively pain-inducing and illustrates additional diversity in the functions of interoreceptors.

Exploring the Combined Effect of Exercise and Apigenin on Aluminium-Induced Neurotoxicity in Zebrafish.

Aluminium (AL) is a strong environmental neurotoxin linked to neurodegenerative disorders. Widespread industrial use leads to its presence in water systems, causing bioaccumulation in organisms. This, in turn, results in the bioaccumulation of AL in various organisms. Several studies have highlighted the benefits of enhanced physical activity in combating neurodegenerative diseases. Meanwhile widespread presence of apigenin in aquatic environment has been largely overlooked, in terms of its potential to counter AL-induced neurotoxicity. The combined impact of exercise and apigenin in mitigating the effects of AL-induced neurotoxicity in aquatic animals remains unexplored. Hence, the objective of this study is to determine whether the combined treatment of exercise and apigenin can effectively alleviate the chronic neurotoxicity induced by AL. Zebrafish that were exposed to AL showed behaviours resembling anxiety, increased aggression, unusual swimming pattern, and memory impairment, which are typical features observed in Alzheimer's disease (AD)-like syndrome. Combined treatment of exercise and apigenin protects zebrafish from AL-induced neurotoxicity, which was measured by improvements in memory, reduced anxiety and aggression, and increased levels of antioxidant enzymes and acetylcholinesterase (AChE) activity. Furthermore, AL exposure is associated with increased expression of genes related to neuroinflammation and AD. However, synergistic effect of exercise and apigenin counteract this effect in AL-treated zebrafish. These findings suggest that AL is involved in neurodegenerative diseases in fish, which could affect the integrity of aquatic ecosystem. Hence, there is a strong correlation between enhanced physical activity, apigenin, and the well-being of the ecosystem.

Ethnic differences in prostate cancer presentation: a time for testing advocacy.

PURPOSE: It is recognised that there are ethnic variations in prostate cancer (PCa) epidemiology, affecting outcomes. South Asians (SA) are less likely to be diagnosed with PCa than others, although recent evidence shows PCa is rising amongst SA. This study examines the differences between ethnicities in PCa presentation, progression risk and prostate-specific antigen (PSA) testing use. METHODS: This retrospective study is on biopsy-diagnosed PCa patients from a multi-ethnic area in London. We grouped ethnicities as SA, White, Black and others, compared presenting symptoms, PSA, Gleason score (GS), and clinical stage, and estimated the D'Amico risk across ethnicities. We also evaluated if the presentation was due to symptoms or an elevated PSA. RESULTS: We studied 1176 patients with biopsy-proven PCa. Black patients were diagnosed about 3 years before others (65 ± 8.8 years, p = < 0.001). There was no significant difference between ethnicities in presenting PSAs. At presentation, 65-71% were in the high-risk D'Amico category across all ethnicities. SA were least likely to have PSA test-detected cancers (38%, p = 0.001) and had the highest proportion with advanced GS (30.6%). There was no significant difference in the risk of disease progression between groups. CONCLUSION: Black men were diagnosed youngest. SA had the highest proportion with advanced GS. Most ethnicities had a high risk of progression. SA had the least PSA test-detected cases. The significance of the study lies in understanding ethnic variations in PCa, which could direct targeted prevention and management. We recommend further ethnicity studies and interventions encouraging SA men to embrace PSA testing.

Combined effects of a high-fat diet and polyethylene microplastic exposure induce impaired lipid metabolism and locomotor behavior in larvae and adult zebrafish.

Microplastics (MP), tiny plastic particles, can be ingested by fish through their habitat or contaminated food sources. When combined with a high-fat diet (HFD), MP exposure may lead to increased MP accumulation in fish and negative impacts on their health. However, the underlying mechanisms of how MP and HFD interact to promote fat accumulation in fish remain poorly understood. In this study, we aimed to evaluate the combined effect of HFD and polyethylene MP (PE-MP) in the zebrafish model (Danio rerio) and decipher its molecular mechanisms. Adult zebrafish exposed to the combined HFD and PE-MP showed elevated lipid accumulation, total cholesterol, triglycerides, and abnormal swimming behavior compared to HFD-fed fish. Histological and gene expression analysis revealed severe hepatic inflammation and injury, resembling nonalcoholic fatty liver disease (NAFLD) in the HFD + PE-MP exposed zebrafish. Moreover, HFD and PE-MP exposure upregulated genes related to lipogenesis (SREBP1, FAS, and C/EBPα) and inflammation (tnfα, il1ß, and il-6) in the liver. These findings underscore the interactive effect of environmental pollutants and fish diet, emphasizing the importance of improving fish culture practices to safeguard fish health and human consumers from microplastic contamination through the food chain. This research sheds light on the complex interactions between microplastics and diet, providing valuable insights into the potential risks of microplastic pollution in aquatic ecosystems and the implications for human health. Understanding the underlying molecular mechanisms will contribute to international research efforts to mitigate the adverse effects of microplastics on both environmental and public health.

Thirty-day morbidity and mortality of elective urological surgery in patients aged 80 years and over in a UK district general hospital.

PURPOSE: An ageing population has led to many people aged 80 and over requiring urological surgery. There are concerns that operating on octogenarians may be fraught with higher morbidity and mortality risk. Therefore, the purpose was to study postoperative outcomes in people aged 80 years and over undergoing elective urological surgery. MATERIALS AND METHODS: We retrospectively reviewed the 30-day readmissions and deaths in patients aged 80 years and over who had elective urological surgery over a seven and half year period from February 2011 to July 2018 in a district general hospital. Surgeries were stratified into minor, intermediate and major. Our data did not include supra-major surgeries like radical cystectomy as these are done in tertiary centres. We used logistic regression to examine factors associated with readmissions and death. RESULTS: A total of 1239 patients had 2201 operations. The median age was 84.1 years. Procedures on the bladder were the most common, followed by prostate surgery. A 17.9% of operations resulted in an adverse outcome (death or readmission attributable to surgery) within 30 days. There were 21 deaths, equating to 1% of all surgeries undertaken. There was a significant difference in both readmissions and deaths by American Society of Anaesthesiologists (ASA) grade. The median time to readmission from surgery was 18 (IQR 13-23) days. The highest number of readmissions occurred in the third week after surgery. A 94% of the readmissions were for a minor complication (grade I Clavien Dindo), with haematuria and urinary retention being most common. CONCLUSIONS: This study informs hospitals, surgeons, patient advocacy groups and insurance, that the morbidity and mortality risks of non-supra major elective urological surgery in patients aged 80 and over are not disproportionately high.

Acute urinary retention.

Acute urinary retention is a common clinical presentation in emergency departments in the UK and is responsible for over 30 000 hospital admissions annually. Awareness of the latest advice and guidelines regarding its presentation, investigation and management is paramount to improve patient outcomes and reduce morbidity. Immediate management of acute urinary retention relies on timely bladder decompression by catheterisation. Knowledge of the routes and types of catheterisation, including the associated risks, complications and contraindications, is essential to allow rapid and early intervention, thus preventing further complications. Differences in the presentation of patients with acute urinary retention reflect varying aetiologies, the knowledge of which determines long-term management and prognosis.

Widespread gaps in the quality of care for primary biliary cholangitis in UK.

OBJECTIVE: Primary biliary cholangitis (PBC) is a progressive, autoimmune, cholestatic liver disease affecting approximately 15 000 individuals in the UK. Updated guidelines for the management of PBC were published by The European Association for the Study of the Liver (EASL) in 2017. We report on the first national, pilot audit that assesses the quality of care and adherence to guidelines. DESIGN: Data were collected from 11 National Health Service hospitals in England, Wales and Scotland between 2017 and 2020. Data on patient demographics, ursodeoxycholic acid (UDCA) dosing and key guideline recommendations were captured from medical records. Results from each hospital were evaluated for target achievement and underwent χ2 analysis for variation in performance between trusts. RESULTS: 790 patients' medical records were reviewed. The data demonstrated that the majority of hospitals did not meet all of the recommended EASL standards. Standards with the lowest likelihood of being met were identified as optimal UDCA dosing, assessment of bone density and assessment of clinical symptoms (pruritus and fatigue). Significant variations in meeting these three standards were observed across UK, in addition to assessment of biochemical response to UDCA (all p<0.0001) and assessment of transplant eligibility in high-risk patients (p=0.0297). CONCLUSION: Our findings identify a broad-based deficiency in 'real-world' PBC care, suggesting the need for an intervention to improve guideline adherence, ultimately improving patient outcomes. We developed the PBC Review tool and recommend its incorporation into clinical practice. As the first audit of its kind, it will be used to inform a future wide-scale reaudit.

Effects of booster sessions on self-management interventions for chronic musculoskeletal pain: a systematic review and meta-analysis of randomised controlled trials.

ABSTRACT: Our objective was to investigate the effectiveness of booster sessions after self-management interventions as a means of maintaining self-management behaviours in the treatment of chronic musculoskeletal pain. We searched MEDLINE, EMBASE, Science Citation Index, Cochrane Central Register of Controlled Trials, and PsychINFO. Two authors independently identified eligible trials and collected data. We calculated the odds ratio for the analyses of dichotomous data and standardised mean differences (SMDs) with 95% confidence interval (CI) for continuous variables. Our search identified 14 studies with a total of 1695 patients. All studies were at high risk of bias and provided very low quality evidence. For the primary outcomes, booster sessions had no evidence of an effect on improving patient-reported outcomes on physical function (SMD -0.13, 95% CI -0.32 to -0.06; P = 0.18), pain-related disability (SMD -0.16, 95% CI -0.36 to 0.03; P = 0.11), and pain self-efficacy (SMD 0.15, 95% CI -0.07 to 0.36; P = 0.18). For the secondary outcomes, booster sessions caused a significant reduction in patient-reported pain catastrophising (SMD -0.42, 95% CI -0.64 to -0.19; P = 0.0004) and no evidence of an effect on patient-reported pain intensity, depression, coping, or treatment adherence. There is currently little evidence that booster sessions are an effective way to prolong positive treatment effects or improve symptoms of long-term musculoskeletal conditions after self-management interventions. However, the studies were few with high heterogeneity, high risk of bias, and overall low quality of evidence. Our review argues against including booster sessions routinely to self-management interventions for the purpose of behaviour maintenance.

Stratification of Patients With Sjögren's Syndrome and Patients With Systemic Lupus Erythematosus According to Two Shared Immune Cell Signatures, With Potential Therapeutic Implications.

OBJECTIVE: Similarities in the clinical and laboratory features of primary Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE) have led to attempts to treat patients with primary SS or SLE with similar biologic therapeutics. However, the results of many clinical trials are disappointing, and no biologic treatments are licensed for use in primary SS, while only a few biologic agents are available to treat SLE patients whose disease has remained refractory to other treatments. With the aim of improving treatment selections, this study was undertaken to identify distinct immunologic signatures in patients with primary SS and patients with SLE, using a stratification approach based on immune cell endotypes. METHODS: Immunophentyping of 29 immune cell subsets was performed using flow cytometry in peripheral blood from patients with primary SS (n = 45), patients with SLE (n = 29), and patients with secondary SS associated with SLE (SLE/SS) (n = 14), all of whom were considered to have low disease activity or be in clinical remission, and sex-matched healthy controls (n = 31). Data were analyzed using supervised machine learning (balanced random forest, sparse partial least squares discriminant analysis), logistic regression, and multiple t-tests. Patients were stratified by K-means clustering and clinical trajectory analysis. RESULTS: Patients with primary SS and patients with SLE had a similar immunologic architecture despite having different clinical presentations and prognoses. Stratification of the combined primary SS, SLE, and SLE/SS patient cohorts by K-means cluster analysis revealed 2 endotypes, characterized by distinct immune cell profiles spanning the diagnoses. A signature of 8 T cell subsets that distinctly differentiated the 2 endotypes with high accuracy (area under the curve 0.9979) was identified in logistic regression and machine learning models. In clinical trajectory analyses, the change in damage scores and disease activity levels from baseline to 5 years differed between the 2 endotypes. CONCLUSION: These findings identify an immune cell toolkit that may be useful for differentiating, with high accuracy, the immunologic profiles of patients with primary SS and patients with SLE as a way to achieve targeted therapeutic approaches.

Non-invasive diagnostic tests for Helicobacter pylori infection.

BACKGROUND: Helicobacter pylori (H pylori) infection has been implicated in a number of malignancies and non-malignant conditions including peptic ulcers, non-ulcer dyspepsia, recurrent peptic ulcer bleeding, unexplained iron deficiency anaemia, idiopathic thrombocytopaenia purpura, and colorectal adenomas. The confirmatory diagnosis of H pylori is by endoscopic biopsy, followed by histopathological examination using haemotoxylin and eosin (H & E) stain or special stains such as Giemsa stain and Warthin-Starry stain. Special stains are more accurate than H & E stain. There is significant uncertainty about the diagnostic accuracy of non-invasive tests for diagnosis of H pylori. OBJECTIVES: To compare the diagnostic accuracy of urea breath test, serology, and stool antigen test, used alone or in combination, for diagnosis of H pylori infection in symptomatic and asymptomatic people, so that eradication therapy for H pylori can be started. SEARCH METHODS: We searched MEDLINE, Embase, the Science Citation Index and the National Institute for Health Research Health Technology Assessment Database on 4 March 2016. We screened references in the included studies to identify additional studies. We also conducted citation searches of relevant studies, most recently on 4 December 2016. We did not restrict studies by language or publication status, or whether data were collected prospectively or retrospectively. SELECTION CRITERIA: We included diagnostic accuracy studies that evaluated at least one of the index tests (urea breath test using isotopes such as 13C or 14C, serology and stool antigen test) against the reference standard (histopathological examination using H & E stain, special stains or immunohistochemical stain) in people suspected of having H pylori infection. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the references to identify relevant studies and independently extracted data. We assessed the methodological quality of studies using the QUADAS-2 tool. We performed meta-analysis by using the hierarchical summary receiver operating characteristic (HSROC) model to estimate and compare SROC curves. Where appropriate, we used bivariate or univariate logistic regression models to estimate summary sensitivities and specificities. MAIN RESULTS: We included 101 studies involving 11,003 participants, of which 5839 participants (53.1%) had H pylori infection. The prevalence of H pylori infection in the studies ranged from 15.2% to 94.7%, with a median prevalence of 53.7% (interquartile range 42.0% to 66.5%). Most of the studies (57%) included participants with dyspepsia and 53 studies excluded participants who recently had proton pump inhibitors or antibiotics.There was at least an unclear risk of bias or unclear applicability concern for each study.Of the 101 studies, 15 compared the accuracy of two index tests and two studies compared the accuracy of three index tests. Thirty-four studies (4242 participants) evaluated serology; 29 studies (2988 participants) evaluated stool antigen test; 34 studies (3139 participants) evaluated urea breath test-13C; 21 studies (1810 participants) evaluated urea breath test-14C; and two studies (127 participants) evaluated urea breath test but did not report the isotope used. The thresholds used to define test positivity and the staining techniques used for histopathological examination (reference standard) varied between studies. Due to sparse data for each threshold reported, it was not possible to identify the best threshold for each test.Using data from 99 studies in an indirect test comparison, there was statistical evidence of a difference in diagnostic accuracy between urea breath test-13C, urea breath test-14C, serology and stool antigen test (P = 0.024). The diagnostic odds ratios for urea breath test-13C, urea breath test-14C, serology, and stool antigen test were 153 (95% confidence interval (CI) 73.7 to 316), 105 (95% CI 74.0 to 150), 47.4 (95% CI 25.5 to 88.1) and 45.1 (95% CI 24.2 to 84.1). The sensitivity (95% CI) estimated at a fixed specificity of 0.90 (median from studies across the four tests), was 0.94 (95% CI 0.89 to 0.97) for urea breath test-13C, 0.92 (95% CI 0.89 to 0.94) for urea breath test-14C, 0.84 (95% CI 0.74 to 0.91) for serology, and 0.83 (95% CI 0.73 to 0.90) for stool antigen test. This implies that on average, given a specificity of 0.90 and prevalence of 53.7% (median specificity and prevalence in the studies), out of 1000 people tested for H pylori infection, there will be 46 false positives (people without H pylori infection who will be diagnosed as having H pylori infection). In this hypothetical cohort, urea breath test-13C, urea breath test-14C, serology, and stool antigen test will give 30 (95% CI 15 to 58), 42 (95% CI 30 to 58), 86 (95% CI 50 to 140), and 89 (95% CI 52 to 146) false negatives respectively (people with H pylori infection for whom the diagnosis of H pylori will be missed).Direct comparisons were based on few head-to-head studies. The ratios of diagnostic odds ratios (DORs) were 0.68 (95% CI 0.12 to 3.70; P = 0.56) for urea breath test-13C versus serology (seven studies), and 0.88 (95% CI 0.14 to 5.56; P = 0.84) for urea breath test-13C versus stool antigen test (seven studies). The 95% CIs of these estimates overlap with those of the ratios of DORs from the indirect comparison. Data were limited or unavailable for meta-analysis of other direct comparisons. AUTHORS' CONCLUSIONS: In people without a history of gastrectomy and those who have not recently had antibiotics or proton ,pump inhibitors, urea breath tests had high diagnostic accuracy while serology and stool antigen tests were less accurate for diagnosis of Helicobacter pylori infection.This is based on an indirect test comparison (with potential for bias due to confounding), as evidence from direct comparisons was limited or unavailable. The thresholds used for these tests were highly variable and we were unable to identify specific thresholds that might be useful in clinical practice.We need further comparative studies of high methodological quality to obtain more reliable evidence of relative accuracy between the tests. Such studies should be conducted prospectively in a representative spectrum of participants and clearly reported to ensure low risk of bias. Most importantly, studies should prespecify and clearly report thresholds used, and should avoid inappropriate exclusions.