Pain management in chronic pancreatitis.

Pain in chronic pancreatitis (CP) is difficult to manage. Many patients suffer from inadequate pain relief, completely incapacitating them in their daily activities. Historically, despite their well-known adverse effects, opioids have been the pillar of treatment regimens in painful CP. The management is now gradually evolving with a better understanding of the underlying pathophysiology of CP-related pain. Clinicians should follow a holistic approach to the management of CP-associated pain, which must involve lifestyle changes that are coupled with analgesic medications and other pain-relieving interventions. Furthermore, there is no easy cure for vanquishing CP-associated pain. Each patient must be evaluated on a case-by-case basis by a multidisciplinary team to decide which treatment option is best suited for that individual.

Do-It-Yourself Ultrasonography Phantom Model for Improving Hand Skills: A Technical Report.

This technical report focuses on developing a do-it-yourself (DIY) model of a water phantom for training in ultrasound-guided needle insertion techniques. Ultrasound technology is becoming more widely used in perioperative and intensive care settings. However, accurate needle placement using ultrasound guidance necessitates strong spatial reasoning and hand-eye coordination. To address this, the authors experimented with a water phantom model that is cost-effective, easily accessible, and efficient for training. The DIY water phantom was made using materials such as an examination glove, a used vial rubber cap, water, adhesive tape, sealing glue, and a target object. This technical report discusses the process of assembling the water phantom and the potential benefits it offers for ultrasound training.

Discovery of CVN417, a Novel Brain-Penetrant α6-Containing Nicotinic Receptor Antagonist for the Modulation of Motor Dysfunction.

Nicotinic acetylcholine receptor (nAChR) α6 subunit RNA expression is relatively restricted to midbrain regions and is located presynaptically on dopaminergic neurons projecting to the striatum. This subunit modulates dopamine neurotransmission and may have therapeutic potential in movement disorders. We aimed to develop potent and selective α6-containing nAChR antagonists to explore modulation of dopamine release and regulation of motor function in vivo. High-throughput screening (HTS) identified novel α6-containing nAChR antagonists and led to the development of CVN417. This molecule blocks α6-containing nAChR activity in recombinant cells and reduces firing frequency of noradrenergic neurons in the rodent locus coeruleus. CVN417 modulated phasic dopaminergic neurotransmission in an impulse-dependent manner. In a rodent model of resting tremor, CVN417 attenuated this behavioral phenotype. These data suggest that selective antagonism of α6-containing nAChR, with molecules such as CVN417, may have therapeutic utility in treating the movement dysfunctions observed in conditions such as Parkinson's disease.

Striatal Dopamine Transporter Function Is Facilitated by Converging Biology of α-Synuclein and Cholesterol.

Striatal dopamine transporters (DAT) powerfully regulate dopamine signaling, and can contribute risk to degeneration in Parkinson's disease (PD). DATs can interact with the neuronal protein α-synuclein, which is associated with the etiology and molecular pathology of idiopathic and familial PD. Here, we tested whether DAT function in governing dopamine (DA) uptake and release is modified in a human-α-synuclein-overexpressing (SNCA-OVX) transgenic mouse model of early PD. Using fast-scan cyclic voltammetry (FCV) in ex vivo acute striatal slices to detect DA release, and biochemical assays, we show that several aspects of DAT function are promoted in SNCA-OVX mice. Compared to background control α-synuclein-null mice (Snca-null), the SNCA-OVX mice have elevated DA uptake rates, and more pronounced effects of DAT inhibitors on evoked extracellular DA concentrations ([DA]o) and on short-term plasticity (STP) in DA release, indicating DATs play a greater role in limiting DA release and in driving STP. We found that DAT membrane levels and radioligand binding sites correlated with α-synuclein level. Furthermore, DAT function in Snca-null and SNCA-OVX mice could also be promoted by applying cholesterol, and using Tof-SIMS we found genotype-differences in striatal lipids, with lower striatal cholesterol in SNCA-OVX mice. An inhibitor of cholesterol efflux transporter ABCA1 or a cholesterol chelator in SNCA-OVX mice reduced the effects of DAT-inhibitors on evoked [DA]o. Together these data indicate that human α-synuclein in a mouse model of PD promotes striatal DAT function, in a manner supported by extracellular cholesterol, suggesting converging biology of α-synuclein and cholesterol that regulates DAT function and could impact DA function and PD pathophysiology.

Central sleep apnea and atrial fibrillation: A review on pathophysiological mechanisms and therapeutic implications.

Precipitating factors and chronic diseases associated with atrial fibrillation (AF) are detailed in the literature. Emerging evidence over the last several decades suggests a potential causal relationship between central sleep apnea (CSA) and AF. Mechanisms including apnea-induced hypoxia with intermittent arousal, fluctuating levels of carbon dioxide, enhanced sympathetic/neurohormonal activation and oxidative stress causing inflammation have been implicated as etiologic causes of AF within this subpopulation. CSA affects the efficacy of pharmacologic and catheter-based antiarrhythmic treatments, which is why treating CSA prior to these interventions may lead to lower rates of AF. Subsequently, a reduction in the AF burden with transvenous phrenic nerve stimulation (TPNS) has become a topic of interest. The present review describes the relationship between these conditions, pathophysiologic mechanisms implicating the role of CSA in development of AF, and emerging therapeutic interventions.

Diabetes Causes Dysfunctional Dopamine Neurotransmission Favoring Nigrostriatal Degeneration in Mice.

BACKGROUND: Numerous studies indicate an association between neurodegenerative and metabolic diseases. Although still a matter of debate, growing evidence from epidemiological and animal studies indicate that preexisting diabetes increases the risk to develop Parkinson's disease. However, the mechanisms of such an association are unknown. OBJECTIVES: We investigated whether diabetes alters striatal dopamine neurotransmission and assessed the vulnerability of nigrostriatal neurons to neurodegeneration. METHODS: We used streptozotocin-treated and genetically diabetic db/db mice. Expression of oxidative stress and nigrostriatal neuronal markers and levels of dopamine and its metabolites were monitored. Dopamine release and uptake were assessed using fast-scan cyclic voltammetry. 6-Hydroxydopamine was unilaterally injected into the striatum using stereotaxic surgery. Motor performance was scored using specific tests. RESULTS: Diabetes resulted in oxidative stress and decreased levels of dopamine and its metabolites in the striatum. Levels of proteins regulating dopamine release and uptake, including the dopamine transporter, the Girk2 potassium channel, the vesicular monoamine transporter 2, and the presynaptic vesicle protein synaptobrevin-2, were decreased in diabetic mice. Electrically evoked levels of extracellular dopamine in the striatum were enhanced, and altered dopamine uptake was observed. Striatal microinjections of a subthreshold dose of the neurotoxin 6-hydroxydopamine in diabetic mice, insufficient to cause motor alterations in nondiabetic animals, resulted in motor impairment, higher loss of striatal dopaminergic axons, and decreased neuronal cell bodies in the substantia nigra. CONCLUSIONS: Our results indicate that diabetes promotes striatal oxidative stress, alters dopamine neurotransmission, and increases vulnerability to neurodegenerative damage leading to motor impairment. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Resource utilization associated with hospital and office-based insertion of a miniaturized insertable cardiac monitor: results from the RIO 2 randomized US study.

Background: Previous studies support operational benefits when moving insertable cardiac monitor (ICM) insertions outside the cardiac catheterization/electrophysiology laboratories, but this has not been directly assessed in a randomized trial or when the procedure is specifically moved to the office setting. To gain insight, the RIO 2 US study collected resource utilization and procedure time intervals for ICM insertion in-office and in-hospital and these data were used to calculate costs associated with staff time and supply use in each setting.Methods and results: The Reveal LINQ In-Office 2 US study (randomized [1:1], multicenter, unblinded) included 482 patients to undergo insertion of the ICM in-hospital (in an operating room or CATH/EP laboratory) (n = 251) or in-office (n = 231). Detailed information on resource utilization was collected prospectively by the study and used to compare resource utilization and procedure time intervals during ICM insertion procedures performed in-office vs. in-hospital. In addition, costs associated with staff time and supply use in each setting were calculated retrospectively. Total visit duration (check-in to discharge) was 107 min shorter in-office vs. in-hospital (95% CI = 97-116 min; p < 0.001). Patient preparation and education in-office were more likely to occur in the same room as the procedure, compared with in-hospital (91.6% vs. 34.2%, p < 0.001 and 87.3% vs. 22.1%, p < 0.001, respectively). There was a reduction in registered nurse and cardiovascular/operating room technologist involvement in-office, accompanied by higher physician and medical assistant participation. Overall staff time spent per case was 75% higher in-hospital, leading to 50% higher staffing costs compared to in-office.Conclusions: ICM insertion in a physician's office vs. a hospital setting resulted in reduced patient visit time and reduced overall staff time, with a consequent reduction in staffing costs. Clinical trial registration: ClinicalTrials.gov NCT02395536.

Safety of in-hospital insertable cardiac monitor procedures performed outside the traditional settings: results from the Reveal LINQ in-office 2 international study.

BACKGROUND: Historically, the majority of insertable cardiac monitor (ICM) procedures were performed in the cardiac catheterization (cath) lab, electrophysiology (EP) lab, or operating room (OR). The miniaturization of ICMs allows the procedure to be relocated within the hospital without compromising patient safety. We sought to estimate the rate of untoward events associated with procedures performed within the hospital but outside the traditional settings and to characterize resource utilization, procedure time intervals, and physician experience. METHODS: The Reveal LINQ in-Office 2 (RIO 2) International study was a single arm, multicenter, prospective study. Patients indicated for an ICM and willing to undergo device insertion outside the cath/EP lab or OR were eligible and followed for 90 days after insertion. RESULTS: A total of 191 patients (45.5% female aged 63.8 ± 26.9 years) underwent successful Reveal LINQ ICM insertion at 17 centers in Europe, Canada and Australia. The median total visit duration was 106 min (interquartile range [IQR]: 55-61). Patient preparation and patient education accounted for 10 min (IQR: 5-20) and 10 min (IQR: 8-15) of total visit duration, respectively. Preparation and education occurred in the procedure room for 90.6 and 60.2% of patients, respectively. There were no untoward events (0.0, 95% CI: 0.0-2.1%) though four patients presented with procedure-related adverse events that did not require invasive intervention. Physicians rated procedure location as convenient or very convenient. CONCLUSIONS: The Reveal LINQ™ ICM insertion can be safely and efficiently performed in the hospital outside the cath/EP lab or OR. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02412488 ; registered on April 9, 2015.

GLP-1 neurons form a local synaptic circuit within the rodent nucleus of the solitary tract.

Glutamatergic neurons that express pre-proglucagon (PPG) and are immunopositive (+) for glucagon-like peptide-1 (i.e., GLP-1+ neurons) are located within the caudal nucleus of the solitary tract (cNTS) and medullary reticular formation in rats and mice. GLP-1 neurons give rise to an extensive central network in which GLP-1 receptor (GLP-1R) signaling suppresses food intake, attenuates rewarding, increases avoidance, and stimulates stress responses, partly via GLP-1R signaling within the cNTS. In mice, noradrenergic (A2) cNTS neurons express GLP-1R, whereas PPG neurons do not. In this study, confocal microscopy in rats confirmed that prolactin-releasing peptide (PrRP)+ A2 neurons are closely apposed by GLP-1+ axonal varicosities. Surprisingly, GLP-1+ appositions were also observed on dendrites of PPG/GLP-1+ neurons in both species, and electron microscopy in rats revealed that GLP-1+ boutons form asymmetric synaptic contacts with GLP-1+ dendrites. However, RNAscope confirmed that rat GLP-1 neurons do not express GLP-1R mRNA. Similarly, Ca2+ imaging of somatic and dendritic responses in mouse ex vivo slices confirmed that PPG neurons do not respond directly to GLP-1, and a mouse crossbreeding strategy revealed that <1% of PPG neurons co-express GLP-1R. Collectively, these data suggest that GLP-1R signaling pathways modulate the activity of PrRP+ A2 neurons, and also reveal a local "feed-forward" synaptic network among GLP-1 neurons that apparently does not use GLP-1R signaling. This local GLP-1 network may instead use glutamatergic signaling to facilitate dynamic and potentially selective recruitment of GLP-1 neural populations that shape behavioral and physiological responses to internal and external challenges.

Retrospective review of 65 atrioesophageal fistulas post atrial fibrillation ablation.

BACKGROUND: Although a rare complication of catheter based ablation for atrial fibrillation (AF), atrioesophageal fistula (AEF) is a serious and fatal event [1-5]. Most reports of AEF are single cases or small case series. OBJECTIVE: The purpose of this study was to perform a comprehensive literature search of all published atrioesophageal fistula following catheter ablation for AF in order to identify the mortality rates associated with therapeutic modalities and suggest the most definitive management in reducing mortality. METHODS: A comprehensive literature review of reported observational cases of atrioesophageal fistula post catheter based ablation for atrial fibrillation was performed. RESULTS: Sixty-five cases of AEF post atrial fibrillation ablation were reviewed. The mean age was 55 years old. 73.8% (48/65) of the identified cases occurred in males (p < 0.001). Of the 65 cases, 13 underwent surgical radiofrequency ablation (RFA) and 52 underwent percutaneous RFA. Mortality resulted in 53.8% of those who underwent surgical RFA and in 55.8% of those who underwent percutaneous RFA (p = .888). The time range interval from procedure to onset of symptoms was 1-60 days. The most prevalent symptom, fever, occurred in 52 of the 65 cases, followed by neurological symptoms (n = 44). CT of the chest (n = 37), transthoracic echocardiogram (n = 21), and CT of the head (n = 18) were the preferred diagnostic modalities. Patients who underwent surgical correction with esophageal repair for treatment were more likely to survive, in comparison to patients who were treated with non-surgical interventions, such as antibiotic therapy, anticoagulation therapy or esophageal stenting. Of the total 34 patients who were treated surgically, 27 survived (79.4%). Of the total 31 patients who were treated non-surgically, only 2 survived (6.5%), reflecting significantly lower mortality with surgical versus non-surgical therapy (p < 0.001). CONCLUSION: Atrioesophageal fistula is an uncommon but potentially fatal complication of atrial fibrillation ablation. Patients who underwent surgical repair were twelve times more likely to survive than those treated with stenting, antibiotic therapy or no intervention. Based on the observation that patients are 12 times more likely to survive an AEF with surgery than without, the authors believe that prompt surgical correction of AEF should be considered as standard of care when dealing with this dreaded complication.

Holding Area LINQ Trial (HALT).

BACKGROUND: Recent studies have shown that insertable cardiac monitors (ICMs) can be implanted out of the traditional hospital setting and efforts are being made to explore the feasibility of implanting these devices in a specific standardized location other than the operating room or a cardiac catherization/electrophysiology lab. METHODS: This was a prospective, non-randomized, single center post-market clinical trial designed to occur in the holding area of a hospital operating room or cardiac catheterization/electrophysiology laboratory. The Medtronic Reveal LINQ ICM was implanted and patients were followed for 90 days post implant. This study was designed to observe any procedure related adverse events stemming from the holding area implantation. RESULTS: Twenty patients were implanted at our hospital in a holding room not traditionally associated with the electrophysiology/cardiac/operatory labs. One patient was lost to the 90-day follow up. In one case, ICM implantation led to diagnosis requiring removal of ICM before the 90 day follow up and insertion of a biventricular implantable cardioverter defibrillator (ICD). In the remaining 18 patients, there were no serious complications such as minor skin infections, systemic infections or procedure-related adverse events requiring device explant. CONCLUSION: When following a standardized protocol with attention to sterile technique, it is feasible to implant ICMs in a holding area with no procedure related adverse events (AE).

Heart Rhythm Society: expert consensus statements-part 1.

One of the most important roles for professional societies in medicine is assembling multiple stakeholders and experts to develop documents that can help guide and define policies and strategies for best medical care. Each year the Heart Rhythm Society (HRS) develops several consensus documents that address critical clinical subjects that have been identified by input from HRS members and HRS committees. Over the past 5 years, HRS has produced documents with multiple professional societies from around the world, and although the topics chosen for exploration center around arrhythmia management, the reviews and recommendations made in the documents are important for clinical cardiologists and generalists who are not arrhythmia specialists. When an internist or other primary care provider identifies a patient who may be having symptoms from an arrhythmia, the referral first is made to the clinical cardiologist and only later, if necessary, does an arrhythmia specialist become involved. These expert consensus statements are developed for specific clinical questions regarding arrhythmia management where there is controversy or uncertainty, often with less data from randomized controlled trials to help guide recommendations, which must then be made by extrapolation of existing data, observational data, and expert opinion. In this 2-part review, the consensus statements developed by the HRS over the past 5 years that pertain to adults are discussed in part 1; part 2 focuses on consensus statements that HRS has developed in conjunction with the Pediatric and Congenital Electrophysiology Society that address arrhythmia issues in children and adults with congenital heart disease.

Heart Rhythm Society: expert consensus statements-part 2.

One of the most important roles for professional societies in medicine is assembling multiple stakeholders and experts to develop documents that can help guide and define policies and strategies for best medical care. Each year the Heart Rhythm Society (HRS) develops several consensus documents that address critical clinical subjects that have been identified by input from HRS members and HRS committees. Over the past 5 years, HRS has produced documents with multiple professional societies from around the world, and although the topics chosen for exploration center around arrhythmia management, the reviews and recommendations made in the documents are important for clinical cardiologists and generalists who are not arrhythmia specialists. When an internist or other primary care provider identifies a patient who may be having symptoms from an arrhythmia, the referral first is made to the clinical cardiologist and only later, if necessary, does an arrhythmia specialist become involved. These expert consensus statements are developed for specific clinical questions regarding arrhythmia management where there is controversy or uncertainty, often with less data from randomized controlled trials to help guide recommendations, which must then be made by extrapolation of existing data, observational data, and expert opinion. In this 2-part review, the consensus statements developed by the HRS over the past 5 years that pertain to adults are discussed in part 1; part 2 focuses on consensus statements that HRS has developed in conjunction with the Pediatric and Congenital Electrophysiology Society that address arrhythmia issues in children and adults with congenital heart disease.

In-office insertion of a miniaturized insertable cardiac monitor: Results from the Reveal LINQ In-Office 2 randomized study.

BACKGROUND: Recent miniaturization of an insertable cardiac monitor (ICM) may make it possible to move device insertion from a hospital to office setting. However, the safety of this strategy is unknown. OBJECTIVES: The primary objective was to compare the safety of inserting the Reveal LINQ ICM in an office vs a hospital environment. Ancillary objectives included summarizing device- and procedure-related adverse events and responses to a physician questionnaire. METHODS: Five hundred twenty-one patients indicated for an ICM were randomized (1:1 ratio) to undergo ICM insertion in a hospital or office environment at 26 centers in the United States in the Reveal LINQ In-Office 2 study (ClinicalTrials.gov identifier NCT02395536). Patients were followed for 90 days. RESULTS: ICM insertion was successful in all 482 attempted patients (office: 251; hospital: 231). The untoward event rate (composite of unsuccessful insertion and ICM- or insertion-related complications) was 0.8% (2 of 244) in the office and 0.9% (2 of 227) in the hospital (95% confidence interval, -3.0% to 2.9%; 5% noninferiority: P < .001). In addition, adverse events occurred during 2.5% (6 of 244) of office and 4.4% (10 of 227) of hospital insertions (95% confidence interval [office minus inhospital rates], -5.8% to 1.9%; 5% noninferiority: P < .001). Physicians indicated that for procedures performed in an office vs a hospital, there were fewer delays >15 minutes (16% vs 35%; P < .001) and patient response was more often "very positive." Physicians considered the office location "very convenient" more frequently than the hospital location (85% vs 27%; P < .001). CONCLUSION: The safety profile for the insertion of the Reveal LINQ ICM is excellent irrespective of insertion environment. These results may expand site of service options for LINQ insertion.

Prospective randomized comparison of rotational angiography with three-dimensional reconstruction and computed tomography merged with electro-anatomical mapping: a two center atrial fibrillation ablation study.

PURPOSE: To compare the efficacy and accuracy of rotational angiography with three-dimensional reconstruction (3DATG) image merged with electro-anatomical mapping (EAM) vs. CT-EAM. METHODS: A prospective, randomized, parallel, two-center study conducted in 36 patients (25 men, age 65 ± 10 years) undergoing AF ablation (33 % paroxysmal, 67 % persistent) guided by 3DATG (group 1) vs. CT (group 2) image fusion with EAM. 3DATG was performed on the Philips Allura Xper FD 10 system. Procedural characteristics including time, radiation exposure, outcome, and navigation accuracy were compared between two groups. RESULTS: There was no significant difference between the groups in total procedure duration or time spent for various procedural steps. Minor differences in procedural characteristics were present between two centers. Segmentation and fusion time for 3DATG or CT-EAM was short and similar between both centers. Accuracy of navigation guided by either method was high and did not depend on left atrial size. Maintenance of sinus rhythm between the two groups was no different up to 24 months of follow-up. CONCLUSION: This study did not find superiority of 3DATG-EAM image merge to guide AF ablation when compared to CT-EAM fusion. Both merging techniques result in similar navigation accuracy.

Asymptomatic Pulmonary Vein Stenosis: Hemodynamic Adaptation and Successful Ablation.

Pulmonary vein stenosis is a well-established possible complication following an atrial fibrillation ablation of pulmonary veins. Symptoms of pulmonary vein stenosis range from asymptomatic to severe exertional dyspnea. The number of asymptomatic patients with pulmonary vein stenosis is greater than originally estimated; moreover, only about 22% of severe pulmonary vein stenosis requires intervention. We present a patient with severe postatrial fibrillation (AF) ablation pulmonary vein (PV) stenosis, which was seen on multiple imaging modalities including cardiac computed tomography (CT) angiogram, lung perfusion scan, and pulmonary angiogram. This patient did not have any pulmonary symptoms. Hemodynamic changes within a stenosed pulmonary vein might not reflect the clinical severity of the obstruction if redistribution of pulmonary artery flow occurs. Our patient had an abnormal lung perfusion and ventilation (V/Q) scan, suggesting pulmonary artery blood flow redistribution. The patient ultimately underwent safe repeat atrial fibrillation ablation with successful elimination of arrhythmia.

Growth hormone and the cardiovascular system.

Growth hormone (GH) exerts its effects through insulin-like growth factor-1, and although ubiquitous in human tissues, it has a significant role in cardiovascular function. In recent years, there has been a great deal of interest in GH as an etiologic factor in many cardiovascular disease states. Acromegaly, a state of endogenous GH excess, results in myocardial hypertrophy and decreased cardiac performance with increased cardiovascular mortality. Additional insight into the role of excess GH on the cardiovascular system has been gained from data collected in athletes doping with GH. Likewise, GH deficiency is associated with increased mortality, possibly from the associated increase in atherosclerosis, lipid abnormalities, and endothelial dysfunction. However, further research is required to clarify the benefit of GH treatment in both deficient states and in heart failure patients.

Left-sided atrial flutter originating in the coronary sinus after radiofrequency ablation of atrial fibrillation.

We describe a case of atypical atrial flutter presenting 1 year after radiofrequency ablation for atrial fibrillation (AF). Electrophysiologic study showed a reentry circuit involving the inferolateral aspect of the mitral annulus and the coronary sinus (CS); however, a mitral isthmus line did not terminate the arrhythmia. Participation of the proximal CS musculature in the circuit suggested a possible target for ablation. Radiofrequency energy applications from within the CS terminated the tachycardia. Mapping and ablation within the CS should be considered in patients with post-AF ablation arrhythmias, particularly when the mitral annulus appears to be involved in the tachycardia circuit.