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Aims: To investigate the co-existence of diabetic peripheral neuropathy (DPN), painful diabetic peripheral neuropathy (PDPN), and cardiac autonomic neuropathy (CAN) and to establish a model to predict CAN based on peripheral measurements.Methods: Eighty participants (20 type 1 diabetes (T1DM) + PDPN, 20 T1DM + DPN, 20 T1DM-DPN (without DPN), and 20 healthy controls (HC)) underwent quantitative sensory testing, cardiac autonomic reflex tests (CARTs), and conventional nerve conduction. CAN was defined as ≥ 2 abnormal CARTs. After the initial analysis, the participants with diabetes were re-grouped based on the presence or absence of small (SFN) and large fibre neuropathy (LFN), respectively. A prediction model for CAN was made using logistic regression with backward elimination.Results: CAN was most prevalent in T1DM + PDPN (50%), followed by T1DM + DPN (25%) and T1DM-DPN and HC (0%). The differences in prevalence of CAN between T1DM + PDPN and T1DM-DPN/HC were significant (p < 0.001). When re-grouping, 58% had CAN in the SFN group and 55% in the LFN group, while no participants without either SFN or LFN had CAN. The prediction model had a sensitivity of 64%, a specificity of 67%, a positive predictive value of 30%, and a negative predictive value of 90%.Conclusion: This study suggests that CAN predominantly co-exists with concomitant DPN. Aims: To investigate the co-existence of diabetic peripheral neuropathy (DPN), painful diabetic peripheral neuropathy (PDPN), and cardiac autonomic neuropathy (CAN) and to establish a model to predict CAN based on peripheral measurements. Methods: Eighty participants (20 type 1 diabetes (T1DM) + PDPN, 20 T1DM + DPN, 20 T1DM-DPN (without DPN), and 20 healthy controls (HC)) underwent quantitative sensory testing, cardiac autonomic reflex tests (CARTs), and conventional nerve conduction. CAN was defined as ≥ 2 abnormal CARTs. After the initial analysis, the participants with diabetes were re-grouped based on the presence or absence of small (SFN) and large fibre neuropathy (LFN), respectively. A prediction model for CAN was made using logistic regression with backward elimination. Results: CAN was most prevalent in T1DM + PDPN (50%), followed by T1DM + DPN (25%) and T1DM-DPN and HC (0%). The differences in prevalence of CAN between T1DM + PDPN and T1DM-DPN/HC were significant (p < 0.001). When re-grouping, 58% had CAN in the SFN group and 55% in the LFN group, while no participants without either SFN or LFN had CAN. The prediction model had a sensitivity of 64%, a specificity of 67%, a positive predictive value of 30%, and a negative predictive value of 90%. Conclusion: This study suggests that CAN predominantly co-exists with concomitant DPN.

The purpose of this study was to assess the clinical outcomes of adults with invasive meningococcal disease (IMD) and to compare the outcomes of patients with IMD caused by a penicillin susceptible isolate (minimum inhibitory concentration (MIC) ≤ 0.06 mg/L) with patients with IMD caused by an isolate with reduced penicillin susceptibility (MIC 0.06 mg/L). We also assessed the outcomes of patients with IMD caused by an isolate with reduced penicillin susceptibility who were treated exclusively with intravenous (IV) benzylpenicillin.Retrospective study of all culture positive IMD in adult patients (age ≥ 15 years) in the Auckland region from 2004 to 2017.One hundred and thirty-nine patients were included; 94 had penicillin susceptible isolates (88 cured, 6 died), and 45 had an isolate with reduced penicillin susceptibility (41 cured, 1 possible relapse, 3 died). The median benzylpenicillin/ceftriaxone treatment duration was 3 days for both groups. There was no difference in the patient outcomes of both groups. Eighteen patients with IMD caused by an isolate with reduced penicillin susceptibility received benzylpenicillin alone and were cured.This study provides further support to existing data that has shown that short duration IV beta-lactam treatment is effective for IMD in adults. Only a small number of patients with meningitis caused by an isolate with reduced penicillin susceptibility received benzylpenicillin alone, limiting its evaluation. For Neisseria meningitidis meningitis, we recommend ceftriaxone as empiric treatment and as definitive treatment when this is caused by an isolate with reduced penicillin susceptibility.

Aims: The aim of this study was to investigate the effects of tapentadol and oxycodone using the nociceptive withdrawal reflex and sensory evoked potentials. Methods: Twenty-one healthy volunteers completed a cross-over trial with oxycodone (10 mg), tapentadol (50 mg) extended-release tablets, or placebo treatment administered orally BID for 14 days. Electrical stimulations were delivered on the plantar side of the foot to evoke a nociceptive withdrawal reflex at baseline and post-interventions. Electromyography, recorded at tibialis anterior, and electroencephalography were recorded for analysis of: number of reflexes, latencies, and area under the curve of the nociceptive withdrawal reflex as well as latencies, amplitudes and dipole sources of the sensory-evoked potential. Results: Tapentadol decreased the odds ratio of eliciting nociceptive withdrawal reflex by −0.89 (P =.001, 95% confidence interval [CI] −1.46, −0.32), whereas oxycodone increased the latency of the N1 component of the sensory-evoked potential at the vertex by 12.5 ms (P =.003, 95% CI 3.35, 21.69). Dipole sources revealed that the anterior cingulate component moved caudally for all three interventions (all P

Small nerve fibres are important when studying diabetic peripheral neuropathy (DPN) as they could be first affected. However, assessing their integrity and function adequately remains a major challenge. The aim of this study was to investigate the association between different degrees of DPN, the presence of neuropathic pain, and the intensity of the axon-reflex flare response provoked by epidermal histamine. Eighty adults were included and divided into 4 groups of 20 with type 1 diabetes and: painful DPN (T1DM+PDPN), non-painful DPN (T1DM+DPN), no DPN and no pain (T1DM-DPN), and 20 persons without diabetes or pain (HC). The vasomotor responses were captured by a Full-field Laser Speckle Perfusion Imager. The response was lowest in T1DM+DPN, followed by T1DM+PDPN, T1DM-DPN and HC. The response was significantly reduced in DPN (T1DM+DPN, T1DM+PDPN) compared with people without (T1DM-DPN, HC) (P < .001). The response was also attenuated in diabetes irrespective of the degree of DPN (T1DM+PDPN, T1DM+DPN, T1DM-DPN) (P < .001). There were no differences in the response between painful neuropathy (T1DM+PDPN) and painless DPN (T1DM+DPN) (P = .189). The method can distinguish between groups with and without diabetes and with and without DPN but cannot distinguish between groups with and without painful DPN. Perspective: This study describes how diabetes attenuates the axon-reflex response, and how it is affected by neuropathy and pain clarifying previous findings. Furthermore, the study is the first to utilize histamine when evoking the response, thus providing a new and fast alternative for future studies into the pathophysiology of neuropathic pain.

It remains unknown why some people with diabetes develop painful neuropathies while others experience no pain. This study aimed to validate a novel method for assessing the function of small sensory nerves in diabetes to further elucidate this phenomenon. The function of large and small nerves was assessed using a novel perception threshold tracking technique in 3 well-characterized groups (n = 60) with type 1 diabetes, namely, (1) painful diabetic peripheral neuropathy (T1DM + PDPN), (2) painless diabetic peripheral neuropathy (T1DM + DPN), and (3) no neuropathy (T1DM - DPN), and healthy controls (n = 20). Electrical currents with different shapes, duration, and intensities were applied by 2 different skin electrodes activating large and small fibers, respectively. The minimal current needed to activate the fibers were analyzed as the rheobase of the stimulus-response function. Nerve fiber selectivity was measured by accommodation properties of stimulated nerves. The rheobase of both fiber types were highest for T1DM + PDPN, followed by T1DM + DPN, T1DM - DPN, and healthy controls, indicating that the nerve properties are specific in individuals with diabetes and pain. There was an overall significant difference between the groups ( P < 0.01). The accommodation properties of stimulated fibers were different between the 2 electrodes ( P < 0.05) apart from in the group with T1DM + PDPN, where both electrodes stimulated nerves displaying properties similar to large fibers. Perception threshold tracking reveals differences in large and small nerve fiber function between the groups with and without diabetes, DPN, and pain. This indicates that the methods have potential applications in screening DPN and explore further the features differentiating painful from nonpainful DPN. It remains unknown why some people with diabetes develop painful neuropathies while others experience no pain. This study aimed to validate a novel method for assessing the function of small sensory nerves in diabetes to further elucidate this phenomenon. The function of large and small nerves was assessed using a novel perception threshold tracking technique in 3 well-characterized groups (n = 60) with type 1 diabetes, namely, (1) painful diabetic peripheral neuropathy (T1DM + PDPN), (2) painless diabetic peripheral neuropathy (T1DM + DPN), and (3) no neuropathy (T1DM - DPN), and healthy controls (n = 20). Electrical currents with different shapes, duration, and intensities were applied by 2 different skin electrodes activating large and small fibers, respectively. The minimal current needed to activate the fibers were analyzed as the rheobase of the stimulus-response function. Nerve fiber selectivity was measured by accommodation properties of stimulated nerves. The rheobase of both fiber types were highest for T1DM + PDPN, followed by T1DM + DPN, T1DM - DPN, and healthy controls, indicating that the nerve properties are specific in individuals with diabetes and pain. There was an overall significant difference between the groups ( P < 0.01). The accommodation properties of stimulated fibers were different between the 2 electrodes ( P < 0.05) apart from in the group with T1DM + PDPN, where both electrodes stimulated nerves displaying properties similar to large fibers. Perception threshold tracking reveals differences in large and small nerve fiber function between the groups with and without diabetes, DPN, and pain. This indicates that the methods have potential applications in screening DPN and explore further the features differentiating painful from nonpainful DPN.

Background Non-invasive modalities for assessing chronic pancreatitis (CP) are needed in clinical practice. Purpose To investigate the correlation between magnetic resonance elastography (MRE)-derived stiffness and T1 relaxation times (as proxies of fibrosis) and explore their relationships to gland volume and pancreatic functions in patients with CP and healthy controls (HCs). Material and Methods In 49 patients with CP and 35 HCs, pancreatic stiffness, T1 relaxation times, and gland volume were assessed. Fecal elastase and the presence of diabetes were used to evaluate pancreatic exocrine and endocrine functions. Uni- and multivariable linear regression models were used to analyze correlations between imaging parameters. Results There was a positive correlation between MRE-derived stiffness and T1 relaxation times in patients with CP (R2 = 0.42; P 2 = 0.14; P = 0.028). There was no correlation between MRE-derived stiffness and gland volume in patients (R2 = 0.007; P = 0.065) or HCs (R2 = 0.010; P = 0.57). T1 relaxation time was correlated to gland volume (R2 = 0.19; P = 0.002) in patients with CP but not in the HCs ( P = 0.056). Severity of pancreatic functional impairment was reflected by increased fibrosis-related parameters in patients without functional impairment, followed by a further increase in fibrosis-related parameters and reduction in gland volume in patients with pancreatic functional impairments. Conclusion Pancreatic MRE-derived stiffness and T1 relaxation times might reflect early pathophysiological changes in CP. The dynamic correlation with pancreatic function suggests that these parameters may be useful for the non-invasive and early identification of CP.

Aim: An objective assessment of small nerve fibers is key to the early detection of diabetic peripheral neuropathy (DPN). This study investigates the diagnostic accuracy of a novel perception threshold tracking technique in detecting small nerve fiber damage. Methods: Participants with type 1 diabetes (T1DM) without DPN (n = 20), with DPN (n = 20), with painful DPN (n = 20) and 20 healthy controls (HCs) underwent perception threshold tracking on the foot and corneal confocal microscopy. Diagnostic accuracy of perception threshold tracking compared to corneal confocal microscopy was analyzed using logistic regression. Results: The rheobase, corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and corneal nerve fiber length (CNFL) (all P < .001) differed between groups. The diagnostic accuracy of perception threshold tracking (rheobase) was excellent for identifying small nerve fiber damage, especially for CNFL with a sensitivity of 94%, specificity 94%, positive predictive value 97%, and negative predictive value 89%. There was a significant correlation between rheobase with CNFD, CNBD, CNFL, and Michigan Neuropathy Screening Instrument (all P < .001). Conclusion: Perception threshold tracking had a very high diagnostic agreement with corneal confocal microscopy for detecting small nerve fiber loss and may have clinical utility for assessing small nerve fiber damage and hence early DPN. Clinical Trials: NCT04078516

Aims: We aimed to quantify microstructural white matter abnormalities using magnetic resonance imaging and examine their associations with 1) brain metabolite and volumes and 2) clinical diabetes-specific characteristics and complications in adults with type 1 diabetes mellitus (T1DM) and distal symmetric peripheral neuropathy (DSPN). Methods: Diffusion tensor images (DTI) obtained from 46 adults with T1DM and DSPN and 28 healthy controls were analyzed using tract-based spatial statistics and were then associated with 1) brain metabolites and volumes and 2) diabetes-specific clinical characteristics (incl. HbA 1c, diabetes duration, level of retinopathy, nerve conduction assessment). Results: Adults with T1DM and DSPN had reduced whole-brain FA skeleton (P = 0.018), most prominently in the inferior longitudinal fasciculus and retrolenticular internal capsule (P < 0.001). Reduced fractional anisotropy (FA) was associated with lower parietal N-acetylaspartate/creatine metabolite ratio (r = 0.399, P = 0.006), brain volumes (P ≤ 0.002), diabetes duration (r = −0.495, P < 0.001) and sural nerve amplitude (r = 0.296, P = 0.046). Additionally, FA was reduced in the subgroup with concomitant proliferative retinopathy compared to non-proliferative retinopathy (P = 0.03). No association was observed between FA and HbA 1c. Conclusions: This hypothesis-generating study provided that altered white matter microstructural abnormalities in T1DM with DSPN were associated with reduced metabolites central for neuronal communications and diabetes complications, indicating that peripheral neuropathic complications are often accompanied by central neuropathy.

Objective: Alterations of the central nervous system are increasingly being recognized as a part of diabetes, especially in the thalamus and the default mode network (DMN). However, the functional involvement in diabetic peripheral neuropathy (DPN) is poorly understood. This study aimed to investigate functional connectivity of thalamus and DMN in individuals with DPN and the associations to clinical characteristics. Methods: Forty-seven type 1 diabetes mellitus (T1DM) individuals with DPN and 28 healthy controls underwent resting-state functional magnetic resonance imaging. Seed-to-voxel and ROI-to-ROI analyses were performed for thalamus and DMN. The connectivity for both thalamus and DMN were correlated to clinical parameters. Results: Alterations in the functional connectivity of the thalamus and DMN were observed in individuals with T1DM and DPN. Thalamus showed decreased connectivity to the middle frontal, superior frontal, and precentral cortex (all p FWE-correcteduncorrected

In milk and milk products, small membrane-enclosed vesicles can be found, commonly termed extracellular vesicles (EVs). Milk-derived EVs have previously been suggested to have immunoregulatory properties, especially important for infants without a fully functioning immune system. In the present study, EV fractions were isolated from human milk, mature and colostrum bovine milk, and two dairy fractions, and successively surveyed for their immunomodulating effects on lipopolysaccharide (LPS)-stimulated macrophages (RAW264.7). RAW264.7 cell material and supernatant were evaluated by monitoring degradation of IκBα in the NF-κB pathway, and IL-6 and IL-1β cytokine production, using Western blotting and enzyme-linked immunosorbent assaying, respectively. The results revealed that preincubation with EVs derived from raw human and bovine milk lowered the LPS-activated response of the NF-κB pathway. Additionally, it was found that preincubation with EVs, from human and bovine milk as well as dairy whey or skim milk-derived fractions, decreased secretion of proinflammatory cytokines from LPS-activated RAW264.7 cells. The findings that milk-derived EVs can change the inflammatory response in macrophages support the notion that milk EVs have an important role in mother-to-infant communication and protection of a newborn.

Individual, cultural and structural barriers exist in reporting rape to the police. Our study’s context is Norway, where reporting is more accepted than before and is even encouraged. Still, few who experience rape report the incident. Based on qualitative interviews we examine how women who refrain from reporting rapes give their choice meaning. We draw from Boltanski and Thévenot’s version of cultural sociology, especially the idea that meaning-making in concrete situations relates to wider ‘regimes of justification’: particular framings that render choices and interpretations intelligible. The aftermath of rape leaves women with having to balance their own and others’ needs and expectations. In talking about the rape and how they afterwards manoeuvre to reconcile conflicting norms and needs, the women activate two different regimes of justification; an instrumental and an ontological. They negotiate between expectations set out in an instrumental regime of justification, focusing on acts and actions, and a more ontological regime of justification, wherein focus lies on their sense of self and future identities. They position themselves as ‘evolving selves’, a position from where they are able to prevent further ruptures by deploying a developmental logic rather than answering the call to ‘do the right thing’ and report. This work was supported by the Norwegian Ministry of Justice and Public Security, Domestic Violence Research Program.

Objective Thalamus is essential in processing of sensory information. This study explored the associations between thalamic volume and intra-thalamic metabolites and associations to clinical and experimental characteristics of sensory function in adults with diabetic polyneuropathy. Methods 48 adults with type 1 diabetes and confirmed distal symmetric peripheral neuropathy (DPSN) and 28 healthy controls participated in a cross-sectional study and underwent a brain magnetic resonance imaging scan. Estimates for thalamic volume were extracted using voxel-based morphometry and intra-thalamic N-acetylaspartate/creatine (NAA/cre) levels were assessed by magnetic resonance spectroscopy. Associations between thalamic volume and clinical measures, quantitative sensory testing and neuropathic phenotype were explored. Results In diabetes, reduced gray matter volume was identified including bilateral thalamus (all p≤0.001) in comparison to healthy participants. Thalamic volume estimates were positively associated to intra-thalamic NAA/cre (r=0.4; p=0.006), however not to diabetes duration (p=0.5), severity of DSPN (p=0.7), or presence of pain (p=0.3). Individuals with the lowest thalamic volume had greatest loss of protective sensation (light touch using von Frey-like filaments, p=0.037) and highest pain tolerance to electric stimulation (tetanic stimulation, p=0.008) compared to individuals with the highest thalamic volume. Conclusions In this cohort with type 1 diabetes and severe DSPN, thalamic atrophy was present and associated with reduced NAA/cre, indicating thalamic structural loss and dysfunction. Thalamic atrophy was associated to reduced sensory function involving large fiber neuropathy and sensation to tetanic stimulation that may reflect synaptic transmission. This may ultimately contribute to the current understanding of the pathophysiology behind the perception changes evident in DSPN.

Next-generation sequencing (NGS) is an excellent methodology for measuring residual disease in acute myeloid leukemia and surveying several subclones simultaneously. There is little experience with interpretation of differential clonal responses to therapy. We hypothesized that differential clonal response could best be studied in patients with residual disease at the time of response evaluation. We performed targeted panel sequencing of paired diagnostic and first treatment evaluation samples in 69 patients with residual disease by morphology or measurable residual disease (MRD) level >0.02. Five patients had a rising clone at the time of evaluation. In a representative case, the rising clone was present only in the putative healthy stem cells (CD45lowCD34+CD38–CD123–CD7–) and not in the putative leukemic stem cells (CD34+CD38–CD123+CD7+) cells, thus indicating nonmalignant clonal hematopoiesis. In contrast, 17 of 43 evaluable patients exhibited a differential response in genes related to the leukemic clone. Twenty-six of 43 patients exhibited a clonal response that followed the overall treatment response. Patients with a differential response had better event-free survival (EFS) and overall survival (OS) than those in whom the clonal response followed the overall response (log-rank test, EFS: p = 0.045, OS: p = 0.050). This indicates that when following multiple leukemia-related clones, the less chemotherapy-responsive clone could, in some cases, have lower relapse potential, contrary to what is known when using standard mutation or fusion transcript-based disease surveillance. In conclusion, our results confirm the potential of refining MRD assessments by following multiple clones and warrants further studies on the precise interpretations of multiclone NGS–MRD assays.

In this study we investigated brain morphology in adults with diabetic neuropathy. We aimed to characterize gray matter volume (GMV) and cortical thickness, and to explore associations between whole brain morphology and clinical characteristics. 46 adults with type 1 diabetes and distal symmetric peripheral neuropathy (DSPN) and 28 healthy controls underwent magnetic resonance imaging scans. GMV and cortical thickness were estimated using voxel-/surface-based morphometry. Associations between total GMV and clinical characteristics were explored. Adults with DSPN had reduced total GMV compared with controls (627.4 ± 4.1 mL vs. 642.5 ± 5.2 mL, P = 0.026). GMV loss was more pronounced for participants with painful neuropathy compared with controls (619.1±8.9 mL vs. 642.4±5.2 mL, P = 0.026) and for those with proliferative vs. non-proliferative retinopathy (609.9 ± 6.8 mL vs. 636.0 ± 4.7 mL, P = 0.003). Characteristics such as severity of neuropathy and decreased parietal N-acetylaspartate/creatine metabolite concentration seem to be related to GMV loss in this cohort. Regional GMV loss was confined to bilateral thalamus/putamen/caudate, occipital and precentral regions, and decreased cortical thickness was identified in frontal areas. Since the observed total GMV loss influenced with clinical characteristics, brain imaging could be useful for supplementary characterization of diabetic neuropathy. The regional brain changes could suggest that some areas are more vulnerable in this cohort.

PURPOSE: This feasibility and validation study addresses the potential use of magnetic resonance imaging (MRI) texture analysis of the pancreas in patients with chronic pancreatitis (CP).METHODS: Extraction of 851 MRI texture features from diffusion weighted imaging (DWI) of the pancreas was performed in 77 CP patients and 22 healthy controls. Features were reduced to classify patients into subgroups, and a Bayes classifier was trained using a tenfold cross-validation forward selection procedure. The classifier was optimized to obtain the best average m-fold accuracy, sensitivity, specificity, and positive predictive value. Classifiers were: presence of disease (CP vs. healthy controls), etiological risk factors (alcoholic vs. nonalcoholic etiology of CP and tobacco use vs. no tobacco use), and complications to CP (presumed pancreatogenic diabetes vs. no diabetes and pancreatic exocrine insufficiency vs. normal pancreatic function).RESULTS: The best classification performance was obtained for the disease classifier selecting only five of the original features with 98% accuracy, 97% sensitivity, 100% specificity, and 100% positive predictive value. The risk factor classifiers obtained good performance using 9 (alcohol: 88% accuracy) and 10 features (tobacco: 86% accuracy). The two complication classifiers obtained similar accuracies with only 4 (diabetes: 83% accuracy) and 3 features (exocrine pancreatic function: 82% accuracy).CONCLUSION: Pancreatic texture analysis demonstrated to be feasible in patients with CP and discriminate clinically relevant subgroups based on etiological risk factors and complications. In future studies, the method may provide useful information on disease progression (monitoring) and detection of biomarkers characterizing early-stage CP.

Purpose: Non-invasive imaging methods to detect morphological changes of the pancreas in patients with mild chronic pancreatitis (CP) are needed. This study aimed to compare magnetic resonance imaging-based parameters, pancreatic volume, T1 mapping, magnetic resonance elastography (MRE), and proton density fat fraction between CP patients and controls, and determine the diagnostic performance for diagnosing different stages of CP. Methods: Nineteen patients with mild CP (Cambridge grade 2 or less or recurring acute pancreatitis; n = 19), 30 with moderate/severe CP (Cambridge grade 3 and 4), and 35 healthy controls underwent pancreatic magnetic resonance imaging to assess the above mentioned magnetic resonance imaging-based parameters. The diagnostic performance of each parameter for detecting any mild and moderate/severe CP was determined using receiver operating characteristic analysis. Results: Pancreatic volume, T1 relaxation times, MRE-derived stiffness, and proton density fat fraction differed significantly between patients with mild CP, moderate/severe CP, and healthy controls (all p < 0.05). T1 mapping and MRE showed a very high diagnostic performance for distinguishing the mild CP group from the control group (T1 mapping: receiver operating characteristic area under the curve (ROC-AUC): 0.94; sensitivity: 84%; specificity: 91%, MRE: ROC-AUC: 0.93; sensitivity: 89%; specificity: 94%). T1 mapping and MRE also had the highest performance for diagnosing the presence of any CP from the control group (ROC-AUCs of 0.98 and 0.97, respectively). Conclusion: Quantitative assessments of T1 relaxation time and MRE-derived stiffness had high performance in detecting mild CP and could probably reflect the early fibrotic changes in CP.

Background: Tapentadol is a combined opioid agonist and norepinephrine reuptake inhibitor with fewer gastrointestinal side effects at equianalgesic doses compared with classical strong opioids. Previous studies on tapentadol have included multi-morbid patients in whom confounders exclude detailed assessment of the mechanistic effects and strict comparison with other opioids or placebo. This study aimed at investigating the effects of tapentadol and oxycodone on gastrointestinal motility and gastrointestinal side effects. Methods: 21 healthy males participated in a randomized, double-blind, placebo-controlled, crossover study. Tapentadol (50 mg twice daily), oxycodone (10 mg twice daily), or placebo tablets were administered for 14 days. Segmental gastrointestinal transit times and colonic motility parameters were measured with electromagnetic capsules. Gastrointestinal side effects were assessed using questionnaires. Key Results: During dosing with tapentadol, gastrointestinal side effects and motility parameters were on placebo level. Compared with tapentadol, oxycodone increased whole gut transit time by 17.9 hours (p =.015) and rectosigmoid transit time by 6.5 hours (p =.005). Compared with tapentadol, oxycodone also reduced long, fast antegrade colonic movements (p =.001). In comparison with placebo, oxycodone prolonged whole gut transit time by 31.6 hours, (p

Objective: The present study investigated differences between opioids to experimental tonic pain in healthy men. Methods: Twenty-one males participated in this cross-over-trial. Interventions twice daily were oxycodone (10 mg), tapentadol (50 mg) and placebo for 14 days. Tonic pain was induced on day 1, 4 and 14 by immersing the hand in 2 °C water for 120 s. Electroencephalography was recorded during test pain at baseline and after 14 days. Spectral analysis and source localization were investigated in predefined frequency bands. Results: A decreased perception of pain on day 4 persisted throughout the 14 days compared to baseline (p < 0.006). Oxycodone decreased the electroencephalography spectral power in the delta and theta bands and increased power in the alpha1, alpha2 and beta1 bands (p < 0.03). Tapentadol increased spectral power in the alpha1 band (p < 0.001). Source localization revealed that oxycodone decreased activity of the temporal and limbic region in the delta band, and frontal lobe in the alpha2 and beta1 bands, whereas tapentadol decreased alpha1 band activity in the temporal lobe compared to placebo. Conclusion: Oxycodone and tapentadol reduced pain perception and changed the central processing of tonic pain. Significance: Different mechanisms of action were involved, where oxycodone affected cortical structures more than tapentadol.

Tapentadol and oxycodone are commonly used analgesics. Preclinical studies have shown that oxycodone modulates brain metabolites related to opioid pathways, whereas tapentadol also affects noradrenergic activity. However, knowledge about the function of the medications in the human brain is limited. The aim was to investigate effects of tapentadol and oxycodone on brain glutamate, the most important neurotransmitter in pain processing. Magnetic resonance spectroscopy was obtained in 21 healthy subjects from the anterior cingulate cortex, prefrontal cortex, and insula at baseline and after 14 days of treatment with either 50 mg tapentadol, 10 mg oxycodone (equipotent dose, both extended release) or placebo twice daily in a randomized double-blind cross-over study. Compared to baseline, decreased glutamate/creatine levels were identified in anterior cingulate cortex after tapentadol (1.26 ± 0.14 vs. 1.35 ± 0.18, P =.04) and oxycodone (1.26 ± 0.10 vs. 1.35 ± 0.12, P =.05) treatments, both with 7% reduction. This indicates that both analgesics modulate the glutamatergic system at the supraspinal level in humans.

CO2 capture by CaO in molten salts is a variant of calcium looping in which the active substances (CaO/CaCO3) are dissolved or in a slurry with inorganic molten salts. One of the main advantages is the nonexistence of degradation in the reactivity between the active material and CO2. Previous research has revealed good absorption and desorption characteristics with CaO contents up to 20 wt% in eutectic CaF2-CaCl2. The hypothesis is that the formed CaCO3 continuously dissolves in the melt, leaving highly reactive CaO readily available for the incoming CO2. In the present study, the CaO content is increased to 40 wt%, and the absorption characteristics is investigated with focus on the sorption capacity and CO2 removal rate. The chemical system is also evaluated experimentally with regards to viscosity and solubility of the formed CaCO3 during CO2 absorption, with the aim of determining chemical upscaling limitations. The results show that the practical CaO content limit is 30 wt%, in which a sorption capacity of 20 g CO2/100 g sorbent is observed, without any deterioration of the reaction kinetics. For 40 wt% CaO, the sorption capacity is higher, but on the expense of the CO2 removal rate and CaO conversion. This is attributed to a significant increase in viscosity and the solubility limit of CaCO3 being exceeded.

AIMS: This study aimed to investigate cortical source activity and identify source generators in people with type 1 diabetes during rest and tonic cold pain.METHODS: Forty-eight participants with type 1 diabetes and neuropathy, and 21 healthy controls were investigated with electroencephalography (EEG) during 5-minutes resting and 2-minutes tonic cold pain (immersing the hand into water at 2 °C). EEG power was assessed in eight frequency bands, and EEG source generators were analyzed using standardized low-resolution electromagnetic tomography (sLORETA).RESULTS: Compared to resting EEG, cold pain EEG power differed in all bands in the diabetes group (all p < 0.001) and six bands in the controls (all p < 0.05). Source generator activity in the diabetes group was increased in delta, beta2, beta3, and gamma bands and decreased in alpha1 (all p < 0.006) with changes mainly seen in the frontal and limbic lobe. Compared to controls, people with diabetes had decreased source generator activity during cold pain in the beta2 and beta3 bands (all p < 0.05), mainly in the frontal lobe.CONCLUSIONS: Participants with type 1 diabetes had altered EEG power and source generator activity predominantly in the frontal and limbic lobe during tonic cold pain. The results may indicate modulated central transmission and neuronal impairment.

BACKGROUND AND PURPOSE: The changes in functional brain connectivity induced by treatment with analgesics are poorly investigated. Unfortunately, results from clinical studies investigating treatments in patients with pain are often confounded by co-medication and comorbidity. Thalamus is central in sensory processing, and we hypothesized that functional connectivity between thalamus and other brain areas in healthy volunteers was different in treatment with oxycodone, representing a pure opioid, compared to treatment with tapentadol, which has a dual effect on the opioidergic and adrenergic systems.METHODS: Twenty-one healthy male volunteers were included in a randomized, double-blind, three-armed, placebo-controlled, cross-over study. All received tapentadol (50 mg extended release), oxycodone (10 mg extended release), or placebo twice daily for 14 days. Resting-state functional magnetic resonance imaging data were obtained before and after treatment. Seed-based functional connectivity analyses were performed between thalamus and other brain regions.RESULTS: Compared to placebo, tapentadol increased functional connectivity between left thalamus and precentral cortex (P = .048), whereas oxycodone decreased functional connectivity between bilateral thalamus and the anterior cingulate cortex (P ≤ .005).CONCLUSIONS: This study has shown that the functional connectivity between thalamus and other brain areas central in pain processing was different for the tapentadol and oxycodone treatments compared to placebo. This supports that the two treatments exert different mechanism of action. Further studies with larger sample sizes need to be carried out in order to validate this.

Extracellular RNAs are unstable and rapidly degraded unless protected. Bovine-milk extracellular vesicles (EVs) confer protection to dietary miRNAs, although it remains unclear whether this importantly improves their chances of reaching host target cells to exert biological effects. Caco-2, HT-29, Hep-G2 and FHs-74 cell lines were exposed to natural/labelled milk EVs to evaluate cellular uptake. Five frequently reported human milk miRNAs (miR-146b-5p, miR-148a-3p, miR-30a-5p, miR-26a-5p, and miR-22-3p) were loaded into EVs. The intracellular concentration of each miRNA in cells was determined. In addition, an animal study giving an oral dose of loaded EVs in C57BL6/ mice were performed. Gene expression regulation was assessed by microarray analysis. Digestive stability analysis showed high overall degradation of exogenous miRNAs, although EV-protected miRNAs better resisted gastrointestinal digestion compared to free miRNAs (tenfold higher levels). Importantly, orally delivered EV-loaded miRNAs reached host organs, including brain, in mice. However, no biological effect has been identified. Milk EVs protect miRNAs from degradation and facilitate cellular uptake. miRNA concentration in EVs from bovine milk might be insufficient to produce gene modulation. Nevertheless, sizable amounts of exogenous miRNAs may be loaded into EVs, and orally delivered EV-loaded miRNAs can reach tissues in vivo, increasing the possibility of exerting biological effects. Further investigation is justified as this could have an impact in the field of nutrition and health (i.e., infant formulas elaboration).

Introduction: In this single-center study of 268 acute myeloid leukemia (AML) patients, we have tested if a subset of 4 routinely employed immunophenotypic stem cell-associated markers correlated with the presence of recurrently mutated genes and if the markers were predictive for mutational status. Methods: Immunophenotypic data from 268 diagnostic AML samples obtained in 2009–2018 were analyzed retrospectively for the antigens CD34, CD117, CD123, and CLEC12A. Correlation between immunophenotypes and mutations was analyzed by Fischer’s exact test. Clinical applicability of the markers for predicting mutational status was evaluated by receiver operating characteristics analyses, where an area under the curve (AUC) of at least 0.85 was accepted as clinically relevant. Results: For a number of genes, the antigen expression differed significantly between mutated and wild-type gene expression. Despite low AUCs, CD123 and CLEC12A correlated with FLT3+NPM1− and FLT3+NPM1+. Three subsets met the AUC requirements (CD34+, CD34+CD117+, and CD34−CD117+) for predicting FLT3−NPM1+ or FLT3+NPM1+. Conclusion: The value of immunophenotypes as surrogate markers for mutational status in AML seems limited when employing CD123 and CLEC12A in combination with CD34 and CD117. Defining relevant cutoffs for given markers is challenging and hampered by variation between laboratories and patient groups.

Objectives Opioids are often used in treatment of severe pain, although many patients experience gastrointestinal side-effects like constipation. The aim of the current study was to investigate changes in colonic volume, as the result of both colonic motility and fluid transport, in healthy volunteers during opioid treatment with tapentadol as compared with oxycodone and placebo. Methods In a randomized, double-blind, cross-over study, 21 healthy male volunteers were administered equianalgesic dosages of oral tapentadol (50 mg bid), oxycodone (10 mg bid) or corresponding placebo for 14 days. Segmental colonic volumes were quantified using T2-weighted magnetic resonance images, and gastrointestinal side-effects were assessed with questionnaires. Results Total colonic volume increase during treatment was higher during tapentadol and oxycodone treatment (median 48 and 58 mL) compared to placebo (median −14 mL, both p≤0.003). Tapentadol (and placebo) treatment resulted in more bowel movements (both p Conclusions Tapentadol treatment increased colonic volume without leading to harder stools, likely as the opioid sparing effects result in less water absorption from the gut lumen. Oxycodone treatment also increased colonic volume, but with a simultaneous increase in stool dryness and gastrointestinal and central nervous system side-effects. The results confirm that tapentadol treatment may be advantageous to oxycodone regarding tolerability to pain treatment.

Overexpressed genes may be useful for monitoring of measurable residual disease (MRD) in patients with childhood acute myeloid leukemia (AML) without a leukemia-specific target. The normal expression of five leukemia-associated genes (SPAG6, ST18, MSLN, PRAME, XAGE1A) was defined in children without hematologic disease (n = 53) and children with suspected infection (n = 90). Gene expression at AML diagnosis (n=50) and during follow-up (n = 21) was compared with child-specific reference values. At diagnosis, 34/50 children (68%) had high expression of at least one of the five genes, and so did 16/31 children (52%) without a leukemia-specific target. Gene expression was quantified in 110 peripheral blood (PB) samples (median, five samples/patient; range, 1 to 10) during follow-up in 21 patients with high expression at diagnosis. All nine patients with PB sampling performed within 100 days of disease recurrence displayed overexpression of SPAG6, ST18, PRAME, or XAGE1A at a median of 2 months (range, 0.6 to 9.6 months) before hematologic relapse, whereas MSLN did not reach expression above normal prior to hematologic relapse. Only 1 of 130 (0.8%) follow-up analyses performed in 10 patients in continuous complete remission had transient expression above normal. SPAG6, ST18, PRAME, and XAGE1A expression in PB may predict relapse in childhood AML patients and facilitate MRD monitoring in most patients without a leukemia-specific target.

In this chapter, we present an outline of the information available on major indigenous phospholipid membrane-associated milk enzymes. Only enzymes the presence of which have firmly been documented are considered, except catalase. A large number of enzymes have previously been associated with milk phospholipid membranes, but many of these are omitted, because they are judged to have low abundance, to be contaminants, to be inactive, or to have limited significance in milk. Information about enzyme presence, activity measurement, structure, isolation, biological role and significance in milk is presented.

Background & aims Chronic abdominal pain is the primary symptom of chronic pancreatitis, but unfortunately it is difficult to treat. Vagal nerve stimulation studies have provided evidence of anti-nociceptive effect in several chronic pain conditions. We investigated the pain-relieving effects of transcutaneous vagal nerve stimulation in comparison to sham treatment in chronic pancreatitis patients. Methods We conducted a randomised double-blinded, sham-controlled, crossover trial in patients with chronic pancreatitis. Patients were randomly assigned to receive a two-week period of cervical transcutaneous vagal nerve stimulation using the gammaCore device followed by a two-week sham stimulation, or vice versa. We measured clinical and experimental endpoints before and after each treatment. The primary clinical endpoint was pain relief, documented in a pain diary using a visual analogue scale. Secondary clinical endpoints included Patients’ Global Impression of Change score, quality of life and Brief Pain Inventory questionnaire. Secondary experimental endpoints included cardiac vagal tone and heart rate. Results No differences in pain scores were seen in response to two weeks transcutaneous vagal nerve stimulation as compared to sham treatment (difference in average pain score (visual analogue scale): 0.17, 95%CI (-0.86;1.20), P = 0.7). Similarly, no differences were seen for secondary clinical endpoints, except from an increase in the appetite loss score (13.9, 95%CI (0.5:27.3), P = 0.04). However, improvements in maximum pain scores were seen for transcutaneous vagal nerve stimulation and sham treatments as compared to their respective baselines: vagal nerve stimulation (-1.3±1.7, 95%CI (-2.21:-0.42), P = 0.007), sham (-1.3±1.9, 95%CI (-2.28:-0.25), P = 0.018). Finally, heart rate was decreased after two weeks transcutaneous vagal nerve stimulation in comparison to sham treatment (-3.7 beats/min, 95%CI (-6.7:-0.6), P = 0.02). Conclusion In this sham-controlled crossover study, we found no evidence that two weeks transcutaneous vagal nerve stimulation induces pain relief in patients with chronic pancreatitis. Trial registration number The study is registered at NCT03357029; www.clinicaltrials.gov.

OBJECTIVES: Noninvasive vagus nerve stimulation (nVNS) has not only shown antinociceptive effects, but also demonstrated anti-inflammatory and antidepressant effects. These effects could be beneficial in chronic pancreatitis (CP) patients suffering from chronic abdominal pain, even though the underlying central mechanisms remain unclear. The aim was to investigate the effect of cervical nVNS in patients with painful CP on brain functional connectivity and cerebral metabolites.MATERIALS AND METHODS: In a randomized double-blind, sham-controlled crossover trial, we used resting-state functional magnetic resonance imaging to investigate functional connectivity changes of limbic structures (seed-based analysis) after two weeks cervical nVNS treatment (GammaCore) as compared with two weeks sham treatment. Similarly, magnetic resonance spectroscopy was performed in the anterior cingulate cortex (ACC) with assessment of glutamate/creatine (Glu/cre) and N-acetylaspartate/creatine (NAA/cre).RESULTS: Sixteen CP patients (mean age 56.6 ± 9.4 years) completed the trial. nVNS induced reduced functional connectivity compared to sham treatment between 1) bilateral thalamus and bilateral superior frontal gyrus, 2) ACC and putamen, and 3) posterior cingulate cortex and right thalamus (all p CONCLUSION: In our population of CP patients, cervical nVNS compared with sham treatment induced reduced functional connectivity of limbic structures, as also observed in other patient groups. The findings are relevant, since we have previously demonstrated an effect on pain scores in CP patients for both nVNS and sham treatment. Our results elucidate the effects in the central nervous system following nVNS treatment of CP patients, pointing at potential beneficial effects in this patient group.

Extracellular vesicles facilitate intercellular communication by transferring bioactive molecules with the potential to elicit host responses. Raw bovine milk contains functional extracellular vesicles that are taken up by humans. By comparing with extracellular vesicles from unprocessed bovine milk, the impact of pasteurisation, hydrodynamic cavitation treatment, or homogenisation on purity of milk extracellular vesicles isolated by a series of centrifugation steps followed by size-exclusion chromatography was assessed. Extracellular vesicles could be isolated from all four source materials, though to varying extents as evident from Western blots. In particular, homogenisation resulted in co-isolation of non-extracellular vesicle material such as β-casein, β-lactoglobulin, and triacylglycerol. RNA concentrations were highest in extracellular vesicles derived from the three processed source materials, thus indicating co-isolation of other RNA-containing detergent-labile particles in addition to native milk extracellular vesicles. Overall, this study shows that the history of milk processing impacts the purity of milk extracellular vesicles.

The presence of extracellular vesicles (EVs) in milk has gained interest due to their capacity to modulate the infant&rsquo, s intestinal and immune system. Studies suggest that milk EVs are enriched in immune-modulating proteins and miRNA, highlighting their possible health benefits to infants. To assess uptake of milk EVs by intestinal epithelial cells, a method was developed using labelling of isolated EVs with fluorophore-conjugated lactadherin. Lactadherin is a generic and validated EV marker, which enables an effective labelling of phosphatidylserine (PS) exposing EVs. Labelled EVs could effectively be used to describe a dose- and time-dependent uptake into the intestinal epithelial Caco-2 cell line. Additionally, fluorescence microscopy was employed to show that EVs colocalize with endosomal markers and lysosomes, indicating that EVs are taken up via general endocytotic mechanisms. Collectively, a method to specifically label isolated EVs is presented and employed to study the uptake of milk EVs by intestinal epithelial cells.

OBJECTIVES: Temporal information about the structural brain changes in chronic pancreatitis (CP) and its relation to the clinical manifestations is lacking. This study investigated changes in morphological brain parameters over 7 years in painful CP patients, compared with controls.METHODS: In this 7-year longitudinal magnetic resonance imaging study, we included 23 CP patients and 14 controls. Gray matter volume (GMV) and cortical thickness were examined using voxel-based and surface-based morphometry. In addition, patients completed pain questionnaires and diary.RESULTS: At baseline, patients had reduced GMV and cortical thickness in widespread brain areas compared with controls. After 7 years of follow-up, the GMV loss was more pronounced in patients compared with controls, particularly in precentral gyrus and putamen. Moreover, an increase in pain scores was associated with a less reduction of thalamic GMV (P = 0.046), whereas an increase in brief pain inventory score was associated with more reduction in cortical thickness of precentral (P = 0.005) and superior temporal gyri (P = 0.019), indicating that brain morphological alterations are associated with the pain.CONCLUSIONS: Chronic pancreatitis pain is associated with morphological brain changes over time in several areas, reflecting that brain plasticity may be a consequence of repeated long-term nociceptive signaling.

NCAM1 and NCAM2 have ectodomains consisting of 5 Ig domains followed by 2 membrane-proximal FnIII domains. In this study we investigate and compare the structures and functions of these FnIII domains. The NCAM1 and -2 FnIII2 domains both contain a Walker A motif. In NCAM1 binding of ATP to this motif interferes with NCAM1 binding to FGFR. We obtained a structural model of the NCAM2 FnIII2 domain by NMR spectroscopy, and by titration with an ATP analogue we show that the NCAM2 Walker A motif does not bind ATP. Small angle X-ray scattering (SAXS) data revealed that the NCAM2 FnIII1-2 double domain exhibits a very low degree of flexibility. Moreover, recombinant NCAM2 FnIII domains bind FGFR in vitro, and the FnIII1-2 double domain induces neurite outgrowth in a concentration-dependent manner through activation of FGFR. Several synthetic NCAM1-derived peptides induce neurite outgrowth via FGFR. Only 2 of 5 peptides derived from similar regions in NCAM2 induce neurite outgrowth, but the most potent of these peptides stimulates neurite outgrowth through FGFR-dependent activation of the Ras-MAPK pathway. These results reveal that the NCAM2 FnIII domains form a rigid structure that binds and activates FGFR in a manner related to, but different from NCAM1.

Background Standardized objective methods to assess the analgesic effects of opioids, enable identification of underlying mechanisms of drug actions in the central nervous system. Opioids may exert their effect on both cortical and spinal levels. In this study actions of morphine at both levels were investigated, followed by analysis of a possible correlation between the cortical processing and spinal transmission. Methods The study was conducted after a double-blinded, two-way crossover design in thirty-nine healthy participants. Each participant received 30 mg morphine or placebo as oral solution in randomized order. The electroencephalogram (EEG) was recorded during rest and during immersion of the hand into ice-water. Electrical stimulation of the sole of the foot was used to elicit the nociceptive withdrawal reflex and the reflex amplitude was recorded. Results Data from thirty subjects was included in the data analysis. There was no change in the activity in resting EEG (P > 0.05) after morphine administration as compared to placebo. During cold pressor stimulation, morphine significantly lowered the relative activity in the delta (1–4 Hz) band (P = 0.03) and increased the activity in the alpha (8–12 Hz) band (P = 0.001) as compared to placebo. The reflex amplitudes significantly decreased after morphine administration (P = 0.047) as compared to placebo. There was no correlation between individual EEG changes during cold pressor stimulation and the decrease in the reflex amplitude after morphine administration (P > 0.05). Conclusions Cold pressor EEG and the nociceptive reflex were more sensitive to morphine analgesia than resting EEG and can be used as standardized objective methods to assess opioid effects. However, no correlation between the analgesic effect of morphine on the spinal and cortical assessments could be demonstrated.

Calcium halide based molten salts have recently attracted interest for a number of applications such as direct reduction of oxides for metal production and as liquefying agent in cyclic sorption processes for CO2 by CaO from dilute flue gases (Ca-looping). A fundamental aspect of these melts is the possible hydrolysis reaction upon exposure to gaseous H2O forming corrosive and poisonous hydrogen halides. In this work experiments have been performed investigating the formation of HCl and HF from a molten salt consisting of a 13.8 wt% CaF2 in CaCl2 eutectic exposed to a flowing gas consisting of 10 vol% H2O in N2. Hydrolysis has been investigated as function of content of CaO and temperature. HCl and HF are shown to be formed at elevated temperatures; HCl forms to a substantially larger extent than HF. Addition of CaO has a marked, limiting effect on the hydrolysis. Thermodynamic modeling of the reaction indicates activity coefficients for CaO above unity in the system. For cyclic CO2-capture based on thermal swing, it is advisable to keep the temperature in the carbonation (absorption) reactor well below 850 ℃ while maintaining a high CaO content if molten CaCl2 is employed. Similar conclusions can be drawn with regards to CaF2.

Acute myeloid leukemia (AML) is a heterogeneous disease where selected subgroups of patients, linked by the presence of biological and clinical high-risk features, are candidates to receive allogenic hematopoietic stem cell transplantation HSCT) as post-remission consolidation treatment. The achievement of morphological complete remission (CR) before HSCT is an important pre-requisite to optimize the chance of successful post-transplant outcome. Minimal residual disease (MRD) assessment by quantitative polymerase chain reaction (q-PCR) has been shown to increase the ability to monitor therapy response in AML, improving prognostic accuracy and allowing to refine transplant strategies. Although MRD assessment was shown to have potential benefit when measured after induction and consolidation therapy courses, its role before HSCT remains to be fully elucidated. In order to contribute to better clarify this issue, we conducted a q-PCR I-BFM-AML collaborative study to measure MRD in bone marrow samples collected within 5 weeks prior to HSCT of 108 pediatric AML patients harboring one of the main recurrent AML aberrancies t(8;21)(q22;q22); RUNX1-RUNX1T1, inv(16)(p13.1q22)/t(16;16)(p13.1;q22); CBFB-MYH11, t(9;11)(p22;q23); KMT2A-MLLT3 or FLT3-ITD. Sixty patients underwent HSCT in first complete remission (CR1) with an overall survival (OS) of 84% versus 54% for the 48 transplanted in CR2 achieved after an initial relapse. Sixty patients showed q-MRD negativity (defined as a value lower than 2.1x10-4 calculated by ROC curve analysis with respect to diagnosis or relapse), whereas in 48 patients we detected q-MRD levels >2.1x10-4. Five-year OS after HSCT was 83% for patients with q-MRD negativity, while that of patients with q-MRD above the cutoff was 57% (p=0.012). As regards, cumulative incidence of relapse (CIR), q-MRD above the cutoff was associated with a high risk of recurrence (26% versus 10% for patients with q-MRD 2-log versus 73% for q-MRD2.1x10-4 and 2-log, HR). This combined stratification by q-MRD resulted into a better subdivision of the OS probability, which was 83%, 69% and 39% for LR, IR and HR respectively (p=0.004). Finally, a multivariate Cox regression model revealed that, together with CR status at time of the allograft (CR2, hazard ratio 4.4, p=0.001), q-MRD was an independent factor (hazard ratio 0.5, p=0.001) predicting HSCT outcome. In conclusion, this study supports the role of q-MRD pre-HSCT as a useful prognostic tool in childhood AML, able to provide information to tailor transplant strategies involving conditioning regimen intensity and graft-versus-host disease prophylaxis. Disclosures Reinhardt: AbbVie: Consultancy; Novartis: Consultancy, Other: Institutional Research Funding; Jazz: Consultancy, Other: Institutional Research Funding; Celgene: Consultancy, Other: Institutional Research Funding; bluebird bio: Consultancy; Roche: Consultancy, Other: Institutional Research Funding; Biotest: Other: Institutional Research Funding; Novo Nordisk: Other: Institutional Research Funding; Behring: Other: Institutional Research Funding. Merli:Bellicum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; SOBI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria; Sanofi-Genzyme: Honoraria; Atara Therapeutics: Honoraria.

OBJECTIVE: The functional connectivity of the brain in chronic pancreatitis (CP) remains unknown. This study aimed to investigate functional connectivity in CP patients using resting state functional magnetic resonance imaging (fMRI) and explore the associations to clinical parameters and altered cerebral metabolites.METHODS: Seed-based and ROI-to-ROI analyses were performed to assess connectivity within and between the default mode network (DMN) and salience network (SN). Additionally, functional connectivity in these networks were investigated in relation to clinical parameters (CP etiology, pain, medication, etc.) and cerebral glutamate/creatine level in the anterior cingulate cortex.RESULTS: Thirty CP patients and 23 healthy controls were analyzed. CP patients showed hyper-connectivity in DMN and SN as compared to healthy controls. Furthermore, CP patients had reduced anti-correlated functional connectivity between DMN and SN (all P ≤ 0.009). The altered DMN connectivity correlated to glutamate/creatine level (r = 0.503, P = 0.020) in patients with pain, but not to the clinical parameters.CONCLUSIONS: CP patients had altered functional connectivity within and between brain networks. Altered DMN functional connectivity had an association to cerebral metabolic changes.SIGNIFICANCE: Altered functional connectivity in CP share similarities with other chronic pain conditions, and support our understanding of altered brain circuitry associated with the CP disease.

IntroductionThe management of chronic pancreatitis (CP) is challenging and requires a personalised approach focused on the individual patient’s main symptoms. Abdominal pain is the most prominent symptom in CP, where central pain mechanisms, including sensitisation and impaired pain modulation, often are involved. Recent clinical studies suggest that vagal nerve stimulation (VNS) induces analgesic effects through the modulation of central pain pathways. This study aims to investigate the effect of 2 weeks transcutaneous VNS (t-VNS) on clinical pain in patients with CP, in comparison to the effect of sham treatment.Methods and analysisTwenty-one patients with CP will be enrolled in this randomised, double-blinded, single-centre, sham-controlled, cross-over study. The study has two treatment periods: A 2-week active t-VNS using GammaCore device and a 2-week treatment with a sham device. During both treatment periods, the patients are instructed to self-administer VNS bilaterally to the cervical vagal area, three times per day. Treatment periods will be separated by 2 weeks. During the study period, patients will record their daily pain experience in a diary (primary clinical endpoint). In addition, all subjects will undergo testing which will include MRI, quantitative sensory testing, cardiac vagal tone assessment and collecting blood samples, before and after the two treatments to investigate mechanisms underlying VNS effects. The data will be analysed using the principle of intention to treat.Ethics and disseminationThe regional ethics committee has approved the study: N-20170023. Results of the trial will be submitted for publication in peer-reviewed journals.Trial registration numberThe study is registered at www.clinicaltrials.gov:NCT03357029.

Relapse after hematopoietic stem cell transplantation in pediatric acute myeloid leukemia is a fatal event in the majority of cases. Immunotherapy may prevent an impending relapse if instituted at first molecular evidence of disease recurrence. Wilms tumor gene 1 (WT1) is overexpressed in the majority of children and may constitute a useful molecular marker of measurable residual disease applicable for disease monitoring in peripheral blood where the background amplification from healthy hematopoiesis is less prevalent compared with bone marrow. We report the measurable residual disease kinetics from a child with FLT3-internal tandem duplication acute myeloid leukemia where sequential WT1 monitoring in peripheral blood-guided withdrawal of immunosuppression.