The burden of recurrence acute pancreatitis and annual event rates are underestimated because of high rates of home self-management.

BACKGROUND/OBJECTIVES: The event-rate of recurrent acute pancreatitis (RAP) in patient populations is critical for powering research studies. We hypothesize that some patients manage RAP attacks at home, reducing event rate estimations based on counting emergency department (ED) visits and hospitalizations only. The aim of this study was to determine the rates of home self-management of recurrent acute pancreatitis compared to ED visits and hospitalizations. METHODS: An anonymous 8-question survey was sent to 1825 individuals on an email list of individuals with a history of acute pancreatitis (AP) or chronic pancreatitis or interest in pancreatic diseases. Question were designed to identify subjects with RAP within the past 2 years and to subdivide patients based on having a chronic pain syndrome or not. RESULTS: After an initial email request and one reminder a total of 194 subjects responded with 98 RAP subjects suitable for analysis. Annual AP events included an average of 1.44 hospitalizations, 1.37 ED visits, 2.46 disrupted work/school/social engagements, and 3.95 pancreatitis-like pain attacks per year. Patients with RAP average 6.8 RAP events per year with 58.4 % managed at home. CONCLUSIONS: The burden of disease in patients with RAP is significantly underestimated, especially for patients with chronic pain. Future studies should include measures to capture RAP events managed at home and utilize methods of documenting RAP events.

Purinergic GPCR-integrin interactions drive pancreatic cancer cell invasion.

Pancreatic ductal adenocarcinoma (PDAC) continues to show no improvement in survival rates. One aspect of PDAC is elevated ATP levels, pointing to the purinergic axis as a potential attractive therapeutic target. Mediated in part by highly druggable extracellular proteins, this axis plays essential roles in fibrosis, inflammation response, and immune function. Analyzing the main members of the PDAC extracellular purinome using publicly available databases discerned which members may impact patient survival. P2RY2 presents as the purinergic gene with the strongest association with hypoxia, the highest cancer cell-specific expression, and the strongest impact on overall survival. Invasion assays using a 3D spheroid model revealed P2Y2 to be critical in facilitating invasion driven by extracellular ATP. Using genetic modification and pharmacological strategies, we demonstrate mechanistically that this ATP-driven invasion requires direct protein-protein interactions between P2Y2 and αV integrins. DNA-PAINT super-resolution fluorescence microscopy reveals that P2Y2 regulates the amount and distribution of integrin αV in the plasma membrane. Moreover, receptor-integrin interactions were required for effective downstream signaling, leading to cancer cell invasion. This work elucidates a novel GPCR-integrin interaction in cancer invasion, highlighting its potential for therapeutic targeting.

Food-Specific IgG4 Is Elevated Throughout the Upper Gastrointestinal Tract in Eosinophilic Esophagitis.

BACKGROUND: Food-specific immunoglobulin G4 (FS-IgG4) is associated with eosinophilic esophagitis (EoE); however, it is not clear whether production is limited to the esophagus. AIMS: To assess FS-IgG4 levels in the upper gastrointestinal tract and plasma and compare these with endoscopic disease severity, tissue eosinophil counts, and patient-reported symptoms. METHODS: We examined prospectively banked plasma, throat swabs, and upper gastrointestinal biopsies (esophagus, gastric antrum, and duodenum) from control (n = 15), active EoE (n = 24), and inactive EoE (n = 8) subjects undergoing upper endoscopy. Patient-reported symptoms were assessed using the EoE symptom activity index (EEsAI). Endoscopic findings were evaluated using the EoE endoscopic reference score (EREFS). Peak eosinophils per high-power field (eos/hpf) were assessed from esophageal biopsies. Biopsy homogenates and throat swabs were normalized for protein content and assessed for FS-IgG4 to milk, wheat, and egg. RESULTS: Median FS-IgG4 for milk and wheat was significantly increased in the plasma, throat swabs, esophagus, stomach, and duodenum of active EoE subjects compared to controls. No significant differences for milk- or wheat-IgG4 were observed between active and inactive EoE subjects. Among the gastrointestinal sites sampled, FS-IgG4 levels were highest in the esophagus. Esophageal FS-IgG4 for all foods correlated significantly across all sites sampled (r ≥ 0.59, p < 0.05). Among subjects with EoE, esophageal FS-IgG4 correlated significantly with peak eos/hpf (milk and wheat) and total EREFS (milk). EEsAI scores and esophageal FS-IgG4 levels did not correlate. CONCLUSIONS: Milk and wheat FS-IgG4 levels are elevated in plasma and throughout the upper gastrointestinal tract in EoE subjects and correlate with endoscopic findings and esophageal eosinophilia.

How long is too long: A retrospective study evaluating the impact of the duration of noninvasive oxygenation support strategies (high flow nasal cannula & BiPAP) on mortality in invasive mechanically ventilated patients with COVID-19.

BACKGROUND/AIM: We investigated the association of noninvasive oxygenation support [high flow nasal cannula (HFNC) and BiPAP], timing of invasive mechanical ventilation (IMV), and inpatient mortality among patients hospitalized with COVID-19. METHODS: Retrospective chart review study of patients hospitalized with COVID-19 (ICD-10 code U07.1) and received IMV from March 2020-October 2021. Charlson comorbidity index (CCI) was calculated; Obesity defined as body mass index (BMI) ≥ 30 kg/m2; morbid obesity was BMI ≥ 40 kg/m2. Clinical parameters/vital signs recorded at time of admission. RESULTS: 709 COVID-19 patients underwent IMV, predominantly admitted from March-May 2020 (45%), average age 62±15 years, 67% male, 37% Hispanic, and 9% from group living settings. 44% had obesity, 11% had morbid obesity, 55% had type II diabetes, 75% had hypertension, and average CCI was 3.65 (SD = 3.11). Crude mortality rate was 56%. Close linear association of age with inpatient-mortality risk was found [OR (95% CI) = 1.35 (1.27-1.44) per 5 years, p<0.0001)]. Patients who died after IMV received noninvasive oxygenation support significantly longer: 5.3 (8.0) vs. 2.7 (SD 4.6) days; longer use was also independently associated with a higher risk of inpatient-mortality: OR = 3.1 (1.8-5.4) for 3-7 days, 7.2 (3.8-13.7) for ≥8 days (reference: 1-2 days) (p<0.0001). The association magnitude varied between age groups: 3-7 days duration (ref: 1-2 days), OR = 4.8 (1.9-12.1) in ≥65 years old vs. 2.1 (1.0-4.6) in <65 years old. Higher mortality risk was associated with higher CCI in patients ≥65 (P = 0.0082); among younger patients, obesity (OR = 1.8 (1.0-3.2) or morbid obesity (OR = 2.8;1.4-5.9) (p<0.05) were associated. No mortality association was found for sex or race. CONCLUSION: Time spent on noninvasive oxygenation support [as defined by high flow nasal cannula (HFNC) and BiPAP] prior to IMV increased mortality risk. Research for the generalizability of our findings to other respiratory failure patient populations is needed.

Melatonin In Acute Mania Investigation (MIAMI-UK). A randomized controlled trial of add-on melatonin in bipolar disorder.

OBJECTIVES: Current options for treating emergent episodes of hypomania and mania in bipolar disorder are limited. Our objective was to compare the effectiveness and safety of add-on melatonin in hypomania or mania over 3 weeks as a well-tolerated therapy. METHODS: A randomized, double-blind, parallel-group, 3-week comparison of modified release melatonin (n = 21) vs placebo (n = 20) in adult bipolar patients aged 18-65 years. Permuted block randomization was used with participants and investigators masked to treatment allocation. Trial registration is ISRCTN28988273 and EUdraCT2008-000281-23. Approved by the South Central National Research Ethics Service (Oxford REC A) ref: 09/H0604/63. RESULTS: The trial was negative as there was no significant difference between melatonin and placebo on the primary outcome-mean Young Mania Rating Scale (YMRS) score at Day 21: (mean difference [MD] -1.77 ([95% CI: -6.39 to 2.85]; P = .447). Significantly fewer patients on melatonin scored 10 or more on the Altman Self Rating Mania Scale: (odds ratio [OR] 0.164 [95% CI: 0.0260-1.0002]; P = .05). Quick Inventory of Depression Symptomatology Clinician Version-16 (QIDS-C16) scores were not significantly different. (OR 1.77 [95% CI: 0.43-7.29]; P = .430). The proportion of patients scoring less than or equal to 5 on the self-report QIDS-SR16 at end-point was greater for the melatonin group (OR 8.35 [95% CI: 1.04-67.23]; P = .046). CONCLUSIONS: In this small trial, melatonin did not effectively treat emerging hypomania or mania as there was no significant difference on the primary outcome. The sample size limitation and secondary outcomes suggest further investigation of melatonin treatment in mood episodes is indicated.

Differential modulation of pressure pain threshold in response to transcutaneous spinal direct current stimulation with physical activity level.

This study investigated the interaction between physical activity level and responses to transcutaneous spinal direct current stimulation (tsDCS) as reflected in changes in pressure pain threshold (PPT) in the lower extremity. Participants (n = 35, 15 males) consisted of physically active young adults. PPTs were determined at three sites (thigh, leg and foot) on the dominant leg before and after 20-min of anodal tsDCS applied at mid-thoracic level. Based on a questionnaire, participants were assigned to either a low-moderately active (n = 21) or highly active group (n = 14). At baseline, participants in the two activity groups exhibited comparable PPTs. After the intervention, PPTs were significantly elevated at all sites at 5-min and 30-min post-tsDCS. An interaction was found between activity groups and tsDCS-induced changes at the thigh site owing to a larger elevation in PPTs in the highly active group. These results corroborate previous findings regarding antalgic effects of tsDCS and point to the role of physical activity level as a potential factor susceptible to modulate responses to tsDCS interventions.

When is an error not a prediction error? An electrophysiological investigation.

A recent theory holds that the anterior cingulate cortex (ACC) uses reinforcement learning signals conveyed by the midbrain dopamine system to facilitate flexible action selection. According to this position, the impact of reward prediction error signals on ACC modulates the amplitude of a component of the event-related brain potential called the error-related negativity (ERN). The theory predicts that ERN amplitude is monotonically related to the expectedness of the event: It is larger for unexpected outcomes than for expected outcomes. However, a recent failure to confirm this prediction has called the theory into question. In the present article, we investigated this discrepancy in three trial-and-error learning experiments. All three experiments provided support for the theory, but the effect sizes were largest when an optimal response strategy could actually be learned. This observation suggests that ACC utilizes dopamine reward prediction error signals for adaptive decision making when the optimal behavior is, in fact, learnable.

Feasibility assessment of telephone-administered behavioral treatment for adolescent migraine.

OBJECTIVES: To examine the feasibility of administering behavioral migraine management training by telephone (TAT) and the acceptability of TAT to adolescents with episodic migraine. METHODS: 34 adolescents (M = 14 years) with migraine (M = 3.6 migraines/month; M = 29.2 hours duration) were randomly assigned to a two-month telephone administered behavioral migraine management program (TAT) or to a standard Triptan Treatment (TT). Outcome was assessed at three- and eight-month evaluations. Participants completed a daily migraine diary that yielded information about number, duration and severity of migraines and migraine-related disability, as well as the Migraine Specific Quality of Life Questionnaire - Adolescent. In addition, TAT participants evaluated key aspects of the TAT program using 5-point Likert-like rating scales. Lastly, the ability of adolescents to demonstrate specific headache management skills following TAT was assessed. RESULTS: All fifteen adolescents who entered TAT successfully demonstrated either full or partial mastery of two or more skills and nearly half demonstrated at least partial mastery of all four skills evaluated. Ninety three percent of the TAT participants reported having a positive relationship with their phone counselor. They also reported a preference for the telephone-based treatment over in-clinic visits and rated the manual and tapes as helpful. Treatment effects (in terms of percent improvement) ranged from consistently large across both evaluations for improvement in number of migraines (54% and 71%), disability equivalent hours (80% and 63%) and quality of life (44% and 48%), to moderate or variable for migraine duration (35% and 23%) and severity (30% and 34%). The TT group also showed clinically meaningful reductions in headache parameters and improvements in quality of life. CONCLUSIONS: Completion rates for TAT were high; adolescents evaluated their experience with TAT positively and were able to exhibit key behavioral headache management skills following treatment. While clinically significant improvements in migraine and migraine-related disability/quality of life were observed with both TAT and treatment as usual (triptan therapy), the small study size and the absence of a control group do not permit conclusions about the effectiveness of either treatment. Nonetheless these results indicate TAT may be a promising treatment format for improving access to behavioral treatments for underserved adolescents and justifies further evaluation of TAT both alone and in combination with drug therapy.

Comorbidity of psychiatric and behavioral disorders in pediatric migraine.

OBJECTIVE: To determine whether behavioral and psychiatric disorders occur more frequently in school-age children with migraine headache. To also elucidate treatment response related to comorbid psychiatric or behavioral diagnosis. BACKGROUND: Recurrent migraine headaches are common in school-age children. Concurrent behavioral or psychiatric diagnoses could significantly impact headache frequency, severity, and response to treatment. METHODS: Healthy children from 6 to 17 years of age presenting to our headache clinic with migraine headache according to International Headache Society (IHS) criteria were identified. Parents/guardians were asked to complete the Child Symptom Inventory, 4th edition (CSI-4) after written informed consent. Children with positive rating scales underwent psychological interviews for confirmatory diagnosis. Results were compared to controls. Headache patients were assigned our usual treatment paradigm. Response regarding headache frequency was assessed at 3 months. RESULTS: A total of 47 patients were diagnosed with migraine headaches. The mean age was 10.55 years. Thirty controls were identified. After completing the CSI-4 and confirmatory psychological interview, 14 of 47 headache patients fulfilled Diagnostic and Statistical Manual (DSM-4) criteria for a psychiatric or behavioral disorder. Oppositional defiant disorder (ODD) was significantly represented among children with migraine compared to the control group of children. Headache patients improved significantly post-treatment regarding their headache frequencies regardless of comorbid psychiatric or behavioral disorder. No significant differences were noted between boys and girls regarding diagnoses or treatment outcome. CONCLUSION: ODD was a significant comorbidity in our headache population. Although families complained of significant behavioral symptomatology in their children, most of these symptoms did not qualify their children for a psychiatric diagnosis and may be related to the stressors of headache on social/school disruption.

Relationship between phenotypic and genotypic florfenicol resistance in Escherichia coli.

This study evaluated the relationship between florfenicol resistance and flo genotypes in 1,987 Escherichia coli isolates from cattle. The flo gene was detected in 164 isolates, all of which expressed resistance to florfenicol at MICs of >/=256 microg/ml. The florfenicol MICs for all isolates that lacked flo were

Factors associated with migraine-related quality of life and disability in adolescents: a preliminary investigation.

OBJECTIVES: This study examined factors associated with impaired quality of life and functioning in a sample of treatment-seeking adolescent migraineurs. Subjects.-The 37 participants were 51.4% female, and averaged 14.3 years of age and 4.1 migraines per month for the previous 36 months. PROCEDURE: The Migraine-Specific Quality of Life Questionnaire, questionnaire items inquiring about missed activities, and headache diary recordings of missed and impaired activity time served as dependent measures. Variables studied were age; gender; migraine frequency, duration, and severity; presence of nausea, photophobia, or phonophobia; and number of visits to an emergency department in the previous year. RESULTS: Three hierarchical forward regressions and one logistic regression, controlling for age and gender, revealed that the presence of nausea and at least one emergency department visit predicted poorer quality of life and a greater number of missed activities in these adolescent migraineurs. The presence of migraine-related missed activity hours from headache diaries was predicted by being male, having higher combined photophobia and phonophobia sensitivity scores, as well as more frequent and severe migraines. Greater impairment was predicted by having longer average duration attacks. CONCLUSIONS: These preliminary findings suggest that the continued development of effective treatment approaches to alleviate pain, suffering, and disability in adolescent migraineurs is required. In particular, evidence for the impact of nausea and sensitivities suggests that they may be important targets for treatment. As well, adolescent migraineurs with a history of a visit to an emergency department in the previous year likely experience greater individual and family distress, more disability, and poorer quality of life that require thoughtful, comprehensive treatment to prevent the development of more severe headache difficulties.

Recent advances and future directions in the biopsychosocial assessment and treatment of arthritis.

This article provides an overview of the emerging literature on biopsychosocial assessment and treatment for two of the most common forms of arthritis: osteoarthritis and rheumatoid arthritis. The article is divided into 3 parts. In the 1st part, the basic elements of the biopsychosocial approach to assessing and treating persons having arthritis is described. In the 2nd part, the authors evaluate studies of biopsychosocial approaches to the assessment of arthritis pain and disability. Six research areas are reviewed: learned helplessness, depression, stress, pain coping, self-efficacy, and the social context of arthritis. The 3rd part of the article reviews studies that testing the efficacy of biopsychosocial treatment approaches for persons having osteoarthritis and rheumatoid arthritis.