Bacterial findings in patients referred to hospital for the treatment of acute tonsillitis with or without peritonsillar phlegmon.

BACKGROUND: The vast majority of patients with acute tonsillitis (AT) are managed in general practice. However, occasionally patients are referred to hospital for specialized management because of aggravated symptoms and/or findings suggestive of peritonsillar involvement. No prospective studies have been conducted aiming to investigate the prevalent and significant microorganisms in this highly selected group of patients. We aimed to describe the microbiological findings of acute tonsillitis with or without peritonsillar phlegmon (PP) in patients referred for hospital treatment and to point out potential pathogens using the following principles to suggest pathogenic significance: (1) higher prevalence in patients compared to healthy controls, (2) higher abundance in patients compared to controls, and (3) higher prevalence at time of infection compared to time of follow up. METHODS: Meticulous and comprehensive cultures were performed on tonsillar swabs from 64 patients with AT with (n = 25) or without (n = 39) PP and 55 healthy controls, who were prospectively enrolled at two Danish Ear-Nose-Throat Departments between June 2016 and December 2019. RESULTS: Streptococcus pyogenes was significantly more prevalent in patients (27%) compared to controls (4%) (p < 0.001). Higher abundance was found in patients compared to controls for Fusobacterium necrophorum (mean 2.4 vs. 1.4, p = 0.017) and S. pyogenes (mean 3.1 vs. 2.0, p = 0.045) in semi-quantitative cultures. S. pyogenes, Streptococcus dysgalactiae, and Prevotella species were significantly more prevalent at time of infection compared to follow up (p = 0.016, p = 0.016, and p = 0.039, respectively). A number of species were detected significantly less frequently in patients compared to controls and the mean number of species was significantly lower in patients compared to controls (6.5 vs. 8.3, p < 0.001). CONCLUSIONS: Disregarding Prevotella spp. because of the prevalence in healthy controls (100%), our findings suggest that S. pyogenes, F. necrophorum, and S. dysgalactiae are significant pathogens in severe AT with or without PP. In addition, infections were associated with reduced diversity (dysbacteriosis). TRIAL REGISTRATION: The study is registered in the ClinicalTrials.gov protocol database (# 52,683). The study was approved by the Ethical Committee at Aarhus County (# 1-10-72-71-16) and by the Danish Data Protection Agency (# 1-16-02-65-16).

Secretin-Stimulated Magnetic Resonance Imaging Reveals Variable Diagnostic Accuracy According to Etiology in Pancreatic Disease.

OBJECTIVES: Secretin-stimulated magnetic resonance imaging (s-MRI) is the best validated radiological modality assessing pancreatic exocrine secretion. In this prospective observational study, we compare the diagnostic accuracy of s-MRI for exocrine pancreatic failure due to different pancreatic diseases and healthy controls. METHODS: We performed s-MRI in 21 cystic fibrosis (CF) patients, 78 patients with chronic pancreatitis (CP) and 20 healthy controls. Exocrine failure was defined by fecal elastase-1 of less than 200 µg/g or bicarbonate concentration from endoscopic secretin test of less than 80 mmol/L. RESULTS: Eleven CF and 61 CP patients were exocrine insufficient. Insufficient CF patients had lower s-MRI volume output compared with all other groups (P < 0.05). Insufficient CP patients had reduced volume output compared with controls and sufficient CF (P < 0.05). Secretin-stimulated MRI yielded overall accuracy of 0.78 (95% confidence interval [CI], 0.70-0.86) for exocrine failure. When divided according to etiology, the test yielded accuracy of 0.95 (95% CI, 0.90-1) in CF and 0.73 (95% CI, 0.64-0.82) in CP. CONCLUSIONS: The accuracy of s-MRI volume output measures to diagnose exocrine failure was higher in CF than in CP. Differences in s-MRI volume output in patients with exocrine failure may be due to different etiological and pathogenic mechanisms in CF and CP.

Quantification of parenchymal calcifications in chronic pancreatitis: relation to atrophy, ductal changes, fibrosis and clinical parameters.

OBJECTIVES: Parenchymal calcifications are considered a hallmark finding of chronic pancreatitis (CP), but little is known about its relation to the clinical presentation and other morphological features such as atrophy, fibrosis and ductal changes. The aim was to quantify the number and maximal size of parenchymal calcifications assessed on computed tomography (CT) and to explore the association with other CT and magnetic resonance imaging (MRI)-based pancreatic features and clinical parameters. METHODS: A well-characterised cohort of 54 CP patients was included. CT measurements included number and size of parenchymal calcifications, gland diameter and ductal diameter. MRI measurements included gland volume, ductal diameter, fibrosis (diffusion) and fatty infiltration (Dixon). Clinical parameters included body mass index (BMI), CP duration and aetiology, M-ANNHEIM clinical stage, tobacco use, alcohol consumption, the presence of diabetes, faecal elastase, clinical pain score and quality of life. RESULTS: There were no correlations between the number and size of parenchymal calcifications and any of the other morphological CT and MRI parameters (all p > .05), except for larger size of calcifications in patients with high number of calcifications (p < .001). The number of parenchymal calcifications was negatively correlated with BMI (r = -0.35, p = .0088). The number and size of parenchymal calcifications did not correlate with any of the other clinical parameters (all p > .2). CONCLUSION: Our findings could indicate the existence of parenchymal calcifications as an independent pathophysiological process involved in the development of CP. Translational impact: Quantifications of calcifications could, in combination with other imaging biomarkers, be a useful imaging marker relevant for characterising CP.

MRI assessed pancreatic morphology and exocrine function are associated with disease burden in chronic pancreatitis.

BACKGROUND AND AIM: The aim of this study was to explore the association between morphological and functional secretin-stimulated MRI parameters with hospitalization, quality of life (QOL), and pain in patients with chronic pancreatitis (CP). PATIENTS AND METHODS: This prospective cohort study included 82 patients with CP. Data were obtained from clinical information, QOL, and pain as assessed by questionnaires (The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and modified Brief Pain Inventory short form). Secretin-stimulated MRI morphological parameters included pancreatic gland volume, main pancreatic duct diameter, the modified Cambridge Classification of Duct Abnormality, apparent diffusion coefficient, fat signal fraction, and the pancreatic secretion volume as a functional parameter. The primary outcomes were time to first hospitalization related to the CP, as well as annual hospitalization frequency and duration. The secondary outcomes were pain severity, QOL, and pain interference scores. RESULTS: A main pancreatic duct diameter below 5 mm was associated with reduced time to first hospitalization (hazard ratio=2.06; 95% confidence interval: 1.02-4.17; P=0.043). Pancreatic secretion volume was correlated with QOL (r=0.31; P=0.0072) and pain interference score (r=-0.27; P=0.032), and fecal elastase was also correlated with QOL (r=0.28; P=0.017). However, functional and morphological findings were not related to pain intensity. CONCLUSION: Advanced pancreatic imaging techniques may be a highly sensitive tool for prognostication and monitoring of disease activity and its consequences.

Acute physiological and electrical accentuation of vagal tone has no effect on pain or gastrointestinal motility in chronic pancreatitis.

BACKGROUND: The effective management of pain in chronic pancreatitis (CP) remains a therapeutic challenge. Analgesic drugs, such as opioids, and the underlying pathology can impair gut function. The autonomic nervous system influences hormone secretion and gut motility. In healthy volunteers, electrical (using noninvasive transcutaneous vagal nerve stimulation [t-VNS]) and physiological (using deep slow breathing [DSB]) modulation of parasympathetic tone results in pain attenuation and enhanced gut motility. Thus, the aims were to investigate whether t-VNS and DSB could enhance the parasympathetic tone, decrease pain sensitivity and improve gut motility in CP. PATIENTS AND METHODS: A total of 20 patients (12 males, mean age=61 years, range: 50-78 years) with CP were randomized to short-term (60 minutes) t-VNS and DSB, or their placebo equivalent, in a crossover design. Cardiometrically derived parameters of autonomic tone, quantitative sensory testing of bone and muscle pain pressure, conditioned pain modulation (CPM) and assessments of gastroduodenal motility with ultrasound were performed. RESULTS: In comparison to sham, t-VNS and DSB increased cardiac vagal tone (CVT) (P<0.001). However, no changes in pain pressure thresholds for bone (P=0.95) or muscle (P=0.45) were seen. There was diminished CPM (P=0.04), and no changes in gastroduodenal motility were observed (P=0.3). CONCLUSION: This explorative study demonstrated that t-VNS and DSB increased CVT in patients with CP. However, this short-lasting increase did not affect pain sensitivity to musculoskeletal pain or gastroduodenal motility. The chronic pain in CP patients is complex, and future trials optimizing neuromodulation for pain relief and improved motility are needed.

Secretin-stimulated MRI characterization of pancreatic morphology and function in patients with chronic pancreatitis.

BACKGROUND/OBJECTIVES: Chronic pancreatitis (CP) is characterized by abnormal pancreatic morphology and impaired endocrine and exocrine function. However, little is known about the relationship between pancreatic morphology and function, and also the association with the etiology and clinical manifestations of CP. The aim was to explore pancreatic morphology and function with advanced MRI in patients with CP and healthy controls (HC) METHODS: Eighty-two patients with CP and 22 HC were enrolled in the study. Morphological imaging parameters included pancreatic main duct diameter, gland volume, fat signal fraction and apparent diffusion coefficient (ADC) values. Functional secretin-stimulated MRI (s-MRI) parameters included pancreatic secretion (bowel fluid volume) and changes in pancreatic ADC value before and after secretin stimulation. Patients were classified according to the modified Cambridge and M-ANNHEIM classification system and fecal elastase was collected. RESULTS: All imaging parameters differentiated CP patients from HC; however, correlations between morphological and functional parameters in CP were weak. Patients with alcoholic and non-alcoholic etiology had comparable s-MRI findings. Fecal elastase was positively correlated to pancreatic gland volume (r = 0.68, P = 0.0016) and negatively correlated to Cambridge classification (r = -0.35, P < 0.001). Additionally, gland volume was negatively correlated to the duration of CP (r = -0.39, P < 0.001) and baseline ADC (r = -0.35, P = 0.027). When stratified by clinical stage (M-ANNHEIM), the pancreatic gland volume was significantly decreased in the severe stages of CP (P = 0.001). CONCLUSIONS: S-MRI provides detailed information about pancreatic morphology and function and represents a promising non-invasive imaging method to characterize pancreatic pathophysiology and may enable monitoring of disease progression in patients with CP.

Secretin-stimulated MRI assessment of exocrine pancreatic function in patients with cystic fibrosis and healthy controls.

PURPOSE: Secretin-stimulated magnetic resonance imaging (s-MRI) and pancreatic diffusion weighted imaging (DWI) are novel non-invasive imaging techniques for assessment of exocrine pancreatic insufficiency (EPI). The aim was to validate s-MRI assessed pancreatic secreted volume using novel semi-automatic quantification software, and to assess the ability of s-MRI with DWI to diagnose EPI in patients with cystic fibrosis (CF). METHODS: s-MRI and DWI was performed in 19 patients with CF (median age 21 years; range 16-56; eight men) and in 10 healthy controls (HC) (median age 46 years; range 20-65; four men). Sequential coronal T2-weighted images covering the duodenum and small bowel and axial DWI were acquired before and 1, 5, 9, and 13 min after secretin stimulation. A short endoscopic secretin test was used as reference method for EPI. RESULTS: CF patients with EPI had lower apparent diffusion coefficient before secretin in the pancreatic head (P < 0.001) and lower secreted bowel fluid volumes (P = 0.035) compared to HC and CF patients without EPI. ROC curve analyses identified that secreted fluid volume after 13 min yielded the highest diagnostic accuracy for diagnosing EPI (AUC 0.93; 95% CI [0.80-1.00]). CONCLUSION: Pancreatic s-MRI is useful for the assessment of exocrine pancreatic function with high diagnostic accuracy for the diagnosis of EPI in CF.

Opioid treatment and hypoalbuminemia are associated with increased hospitalisation rates in chronic pancreatitis outpatients.

BACKGROUND/OBJECTIVES: Chronic pancreatitis (CP) is a complex and debilitating disease with high resource utilisation. Prospective data on hospital admission rates and associated risk factors are scarce. We investigated hospitalisation rates, causes of hospitalisations and associated risk factors in CP outpatients. METHODS: This was a prospective cohort study comprising 170 patients with CP. The primary outcome was time to first pancreatitis related hospitalisation and secondary outcomes were the annual hospitalisation frequency (hospitalisation burden) and causes of hospitalisations. A number of clinical and demographic parameters, including pain pattern and severity, opioid use and parameters related to the nutritional state, were analysed for their association with hospitalisation rates. RESULTS: Of the 170 patients, 57 (33.5%) were hospitalised during the follow-up period (median 11.4 months [IQR 3.8-26.4]). The cumulative hospitalisation incidence was 7.6% (95% CI; 4.5-12.2) after 30 days and 28.8% (95% CI; 22.2-35.7) after 1 year. Eighteen of the hospitalised patients (32%) had three or more admissions per year. High dose opioid treatment (>100 mg per day) (Hazard Ratio 3.1 [95% CI; 1.1-8.5]; P = 0.03) and hypoalbuminemia (<36 g/l) (Hazard Ratio 3.8 [95% CI; 2.0-7.8]; P < 0.001) were identified as independent risk factors for hospitalisation. The most frequent causes of hospitalisations were pain exacerbation (40%) and common bile duct stenosis (28%). CONCLUSIONS: One-third of CP outpatients account for the majority of hospital admissions and associated risk factors are high dose opioid treatment and hypoalbuminemia. This information should be implemented in outpatient monitoring strategies to identify risk patients and improve treatment.

Secretin-Stimulated Magnetic Resonance Imaging Assessment of the Benign Pancreatic Disorders: Systematic Review and Proposal for a Standardized Protocol.

This systemic review summarizes the current literature and general consensus on secretin-stimulated magnetic resonance imaging (s-MRI) of the benign pancreatic disorders and discusses important aspects on how s-MRI is optimally performed. The aim is to provide an overview, for clinicians and radiologist, of the s-MRI protocols and the range of clinical applications. Furthermore, the review will summarize the criteria for evaluation of pancreatic morphology and function based on s-MRI.The literature search indentified 69 original articles and 15 reviews. Chronic pancreatitis was the disease that was most frequently assessed by s-MRI (33%), followed by acute pancreatitis (9%). Dynamic thick-slab 2-dimensional magnetic resonance cholangiopancreatography was the most used imaging sequence (86%). The diameter of the main pancreatic duct (75%) and pancreatic exocrine function based on visual grading of duodenal filling (67%) were the most evaluated pancreatic features. Sufficient similarities between studies were identified to propose the most agreeable standardized s-MRI protocol for morphological and functional assessment of the pancreas. In the future, more research and increased collaboration between centers is necessary to achieve more consensus and optimization of s-MRI protocols.

Eccentric exercise slows in vivo microvascular reactivity during brief contractions in human skeletal muscle.

Unaccustomed exercise involving eccentric contractions results in muscle soreness and an overall decline in muscle function, however, little is known about the effects of eccentric exercise on microvascular reactivity in human skeletal muscle. Fourteen healthy men and women performed eccentric contractions of the dorsiflexor muscles in one leg, while the contralateral leg served as a control. At baseline, and 24 and 48 h after eccentric exercise, the following were acquired bilaterally in the tibialis anterior muscle: 1) transverse relaxation time (T2)-weighted magnetic resonance images to determine muscle cross-sectional area (mCSA) and T2; 2) blood oxygen level-dependent (BOLD) images during and following brief, maximal voluntary contractions (MVC) to monitor the hyperemic responses with participants positioned supine in a 3T magnet; 3) muscle strength; and 4) pain pressure threshold. Compared with the control leg, eccentric exercise resulted in soreness, decline in strength (∼20%), increased mCSA (∼7%), and prolonged T2 (∼7%) at 24 and 48 h (P < 0.05). The BOLD response to a brief MVC was altered 24 and 48 h after eccentric exercise, such that time-to-peak (∼35%, P < 0.05) and time-to-half-recovery (∼23%, P < 0.05) were prolonged. The altered contraction-induced hyperemic response suggests slowed microvascular reactivity and altered matching of O2 delivery to O2 utilization within muscle tissue showing signs of muscle damage. These changes in microvascular regulation after eccentric exercise may impede rapid adjustments in muscle blood flow at exercise onset and during activities involving brief bursts of muscle activation, which may impair O2 delivery and contribute to reduced muscle function after eccentric exercise.

Study protocol for a randomised, double-blinded, placebo-controlled, clinical trial of S-ketamine for pain treatment in patients with chronic pancreatitis (RESET trial).

INTRODUCTION: Chronic pancreatitis (CP) is an inflammatory disease that causes irreversible damage to pancreatic tissue. Pain is its most prominent symptom. In the absence of pathology suitable for endoscopic or surgical interventions, pain treatment usually includes opioids. However, opioids often have limited efficacy. Moreover, side effects are common and bothersome. Hence, novel approaches to control pain associated with CP are highly desirable. Sensitisation of the central nervous system is reported to play a key role in pain generation and chronification. Fundamental to the process of central sensitisation is abnormal activation of the N-methyl-D-aspartate receptor, which can be antagonised by S-ketamine. The RESET trial is investigating the analgaesic and antihyperalgesic effect of S-ketamine in patients with CP. METHODS AND ANALYSIS: 40 patients with CP will be enrolled. Patients are randomised to receive 8 h of intravenous S-ketamine followed by oral S-ketamine, or matching placebo, for 4 weeks. To improve blinding, 1 mg of midazolam will be added to active and placebo treatment. The primary end point is clinical pain relief as assessed by a daily pain diary. Secondary end points include changes in patient-reported outcome measures, opioid consumption and rates of side effects. The end points are registered through the 4-week medication period and for an additional follow-up period of 8 weeks to investigate long-term effects. In addition, experimental pain measures also serves as secondary end points, and neurophysiological imaging parameters are collected. Furthermore, experimental baseline recordings are compared to recordings from a group of healthy controls to evaluate general aspects of pain processing in CP. ETHICS AND DISSEMINATION: The protocol is approved by the North Denmark Region Committee on Health Research Ethics (N-20130040) and the Danish Health and Medicines Authorities (EudraCT number: 2013-003357-17). The results will be disseminated in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION NUMBER: The study is registered at http://www.clinicaltrialsregister.eu (EudraCT number 2013-003357-17).

Cardiovascular diseases are largely underreported in Danish centenarians.

BACKGROUND: the substantial decline in oldest old mortality has led to more people surviving to very old age. As morbidity and disability generally increases with age epidemiological research in ageing has focused on the health of oldest olds. However, most studies are based on self-reported or physician-reported information, not objective health information. OBJECTIVE: to estimate and compare the prevalence of cardiovascular diseases (CVDs) in Danish centenarians using three different sources of information: self-reported, physician-reported and objective data. DESIGN: the population-based clinical-epidemiological study of 100-year-old Danes. METHODS: all eligible participants were interviewed (self-report) in their domicile and offered a clinical examination, including an electrocardiogram (ECG) and blood pressure measurement. Further health information was retrieved from general practitioners' medical files and the Danish National Discharge Register (physician report). RESULTS: out of 276 eligible, 207 (75%) participated. Blood pressure and ECG were measured in 76 and 69%, respectively. There was poor agreement between self-reported and physician-reported CVDs, and between physician-reported CVDs and clinical objective CVD diagnoses. Only angina pectoris reached a Kappa value of 0.5. ECG revealed twice as many cases of myocardial infarction and ischaemia compared with physician-reported. Using both physician-reported and ECG 95 (46%) of the centenarians suffered from at least one of the diseases myocardial infarction, angina pectoris or atrial fibrillation. Adding physician-reported heart failure and hypertension increased the prevalence of CVD to 80%. CONCLUSION: self-reported information largely underestimates the CVD life-time prevalence in Danish centenarians. Objective clinical examinations are necessary to evaluate true disease prevalence in oldest old.