Islet Isolation Outcomes in Patients Undergoing Total Pancreatectomy With Islet Autotransplantation in the POST Consortium.

BACKGROUND: In total pancreatectomy with islet autotransplantation (TPIAT), a greater number of islets transplanted produces more favorable outcomes. We aimed to determine predictors of islet isolation outcomes. METHODS: We investigated factors associated with islet isolation outcomes expressed as islet number (IN), islet equivalents (IEQ; standardized to an islet with 150 µm diameter), IN/kg, or IEQ/kg using data from the multicenter Prospective Observational Study of TPIAT. Single-predictor linear regression was used to estimate the association of individual patient and disease characteristics with islet isolation outcomes, and augmented backward elimination was used to select variables to include in multivariable analyses. RESULTS: In multivariable analyses, only elevated hemoglobin A1c was associated with worse outcomes for all measures (P < 0.001 for all). Total IEQ obtained for transplant was higher for participants with Hispanic ethnicity (P = 0.002) or overweight status pre-TPIAT (P < 0.001) and lower with non-White race (P = 0.03), genetic pancreatitis (P = 0.02), history of lateral pancreaticojejunostomy (P = 0.03), and presence of atrophy (P = 0.006) or ductal changes (P = 0.014) on imaging. IEQ/kg was higher in females (P = 0.01) and Hispanic participants (P = 0.046) and generally lower with older age (nonlinear association, P < 0.001) and pancreatic atrophy (P < 0.001) on imaging. Total IN and IN/kg showed trends similar, but not identical, to IEQ and IEQ/kg, respectively. CONCLUSIONS: Patient demographics and certain pancreatic disease features were associated with outcomes from islet isolation. Hemoglobin A1c before TPIAT was the metabolic testing measure most strongly associated with islet isolation results.

American College of Gastroenterology Guidelines: Management of Acute Pancreatitis.

Acute pancreatitis (AP), defined as acute inflammation of the pancreas, is one of the most common diseases of the gastrointestinal tract leading to hospital admission in the United States. It is important for clinicians to appreciate that AP is heterogenous, progressing differently among patients and is often unpredictable. While most patients experience symptoms lasting a few days, almost one-fifth of patients will go on to experience complications, including pancreatic necrosis and/or organ failure, at times requiring prolonged hospitalization, intensive care, and radiologic, surgical, and/or endoscopic intervention. Early management is essential to identify and treat patients with AP to prevent complications. Patients with biliary pancreatitis typically will require surgery to prevent recurrent disease and may need early endoscopic retrograde cholangiopancreatography if the disease is complicated by cholangitis. Nutrition plays an important role in treating patients with AP. The safety of early refeeding and importance in preventing complications from AP are addressed. This guideline will provide an evidence-based practical approach to the management of patients with AP.

Quality of Life Following TPIAT: A Patient Experience Survey.

OBJECTIVES: Total pancreatectomy with islet autotransplantation (TPIAT) is performed to improve the quality of life (QOL) of patients with chronic pancreatitis. Few reports have documented QOL following TPIAT, with none using the pancreatitis-specific Pancreatitis Quality of Life Instrument (PANQOLI). We surveyed patients at our center who underwent TPIAT to document postoperative QOL. METHODS: We collected survey data from 18 adult patients who underwent TPIAT at our medical center from 2012 to 2020. Patients were asked questions assessing QOL following TPIAT and completed the Short Form (SF)-12 and PANQOLI instruments. RESULTS: Forty-three patients who underwent TPIAT were mailed surveys, and 18 were returned. The mean age was 45 years, and 67% of respondents were female. Almost half (44%) had hereditary pancreatitis. Sixty-seven percent believed their overall QOL had improved after surgery. The mean post-operative SF-12 physical score was 38.9 and mean mental score was 44. The mean PANQOLI score was 66 (physical function 20, role function 16, emotional function 14, self-worth 15). Following surgery, 33% were using opiate medications and 67% were using anti-hyperglycemic medications. CONCLUSIONS: TPIAT resulted in improved self-reported QOL in most patients, although post-operative physical and mental QOL are less compared to the average healthy United States adult.

Diagnosis and Management of Pancreatic Cysts.

As pancreatic cyst incidence rises, likely due to the ubiquitous increase in cross-sectional imaging, their management presents multiple challenges for both the practitioner and patient. It is critical that all pancreatic cysts are appropriately characterized, as treatment decisions depend on an accurate diagnosis. Diagnostic modalities such as cytology, biopsy, and cyst fluid biomarkers allow for definitive diagnosis of virtually all lesions. Some cysts, such as intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, and cystic pancreatic endocrine neoplasms, have malignant potential and must be surveyed. Other cysts, such as serous cystadenomas and pancreatic fluid collections, do not have malignant potential. Surveillance strategies vary widely depending on cyst type and size and while multiple medical societies advocate surveillance, their published surveillance guidelines are heterogenous. Cysts with high-risk stigmata or worrisome features are usually resected, depending on the patient's surgical fitness. In patients unfit for resection, newer endoscopic ablative techniques are advocated. Controversial aspects regarding cyst management include whether surveillance can be stopped, how surveillance should be performed, and the extensive financial burden cyst management places on the health care system. Further study into the natural history of cystic lesions, including definitive determination of the rate of malignant transformation for each cyst type, is essential.

In vivo imaging in transgenic songbirds reveals superdiffusive neuron migration in the adult brain.

Neuron migration is a key phase of neurogenesis, critical for the assembly and function of neuronal circuits. In songbirds, this process continues throughout life, but how these newborn neurons disperse through the adult brain is unclear. We address this question using in vivo two-photon imaging in transgenic zebra finches that express GFP in young neurons and other cell types. In juvenile and adult birds, migratory cells are present at a high density, travel in all directions, and make frequent course changes. Notably, these dynamic migration patterns are well fit by a superdiffusive model. Simulations reveal that these superdiffusive dynamics are sufficient to disperse new neurons throughout the song nucleus HVC. These results suggest that superdiffusive migration may underlie the formation and maintenance of nuclear brain structures in the postnatal brain and indicate that transgenic songbirds are a useful resource for future studies into the mechanisms of adult neurogenesis.

An in vitro medium for modeling gut dysbiosis associated with cystic fibrosis.

The gut physiology of pediatric and adult persons with cystic fibrosis (pwCF) is altered relative to healthy persons. The CF gut is characterized, in part, as having excess mucus, increased fat content, acidic pH, increased inflammation, increased antibiotic perturbation, and the potential for increased oxygen availability. These physiological differences shift nutritional availability and the local environment for intestinal microbes, thus likely driving significant changes in microbial metabolism, colonization, and competition with other microbes. The impact of any specific change in this physiological landscape is difficult to parse using human or animal studies. Thus, we have developed a novel culture medium representative of the CF gut environment, inclusive of all the aforementioned features. This medium, called CF-MiPro, maintains CF gut microbiome communities, while significantly shifting nonCF gut microbiome communities toward a CF-like microbial profile, characterized by low Bacteroidetes and high Proteobacteria abundance. This medium is able to maintain this culture composition for up to 5 days of passage. Additionally, microbial communities passaged in CF-MiPro produce significantly less immunomodulatory short-chain fatty acids (SCFA), including propionate and butyrate, than communities passaged in MiPro, a culture medium representative of healthy gut physiology, confirming not only a shift in microbial composition but also altered community function. Our results support the potential for this in vitro culture medium as a new tool for the study of CF gut dysbiosis. IMPORTANCE Cystic fibrosis is an autosomal recessive disease that disrupts ion transport at mucosal surfaces, leading to mucus accumulation and altered physiology of both the lungs and the intestines, among other organs, with the resulting altered environment contributing to an imbalance of microbial communities. Culture media representative of the CF airway have been developed and validated; however, no such medium exists for modeling the CF intestine. Here, we develop and validate a first-generation culture medium inclusive of features that are altered in the CF colon. Our findings suggest this novel medium, called CF-MiPro, as a maintenance medium for CF gut microbiome samples and a flexible tool for studying key drivers of CF-associated gut dysbiosis.

Indomethacin with or without prophylactic pancreatic stent placement to prevent pancreatitis after ERCP: a randomised non-inferiority trial.

BACKGROUND: The combination of rectally administered indomethacin and placement of a prophylactic pancreatic stent is recommended to prevent pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk patients. Preliminary evidence suggests that the use of indomethacin might eliminate or substantially reduce the need for stent placement, a technically complex, costly, and potentially harmful intervention. METHODS: In this randomised, non-inferiority trial conducted at 20 referral centres in the USA and Canada, patients (aged ≥18 years) at high risk for post-ERCP pancreatitis were randomly assigned (1:1) to receive rectal indomethacin alone or the combination of indomethacin plus a prophylactic pancreatic stent. Patients, treating clinicians, and outcomes assessors were masked to study group assignment. The primary outcome was post-ERCP pancreatitis. To declare non-inferiority, the upper bound of the two-sided 95% CI for the difference in post-ERCP pancreatitis (indomethacin alone minus indomethacin plus stent) would have to be less than 5% (non-inferiority margin) in both the intention-to-treat and per-protocol populations. This trial is registered with ClinicalTrials.gov (NCT02476279), and is complete. FINDINGS: Between Sept 17, 2015, and Jan 25, 2023, a total of 1950 patients were randomly assigned. Post-ERCP pancreatitis occurred in 145 (14·9%) of 975 patients in the indomethacin alone group and in 110 (11·3%) of 975 in the indomethacin plus stent group (risk difference 3·6%; 95% CI 0·6-6·6; p=0·18 for non-inferiority). A post-hoc intention-to-treat analysis of the risk difference between groups showed that indomethacin alone was inferior to the combination of indomethacin plus prophylactic stent (p=0·011). The relative benefit of stent placement was generally consistent across study subgroups but appeared more prominent among patients at highest risk for pancreatitis. Safety outcomes (serious adverse events, intensive care unit admission, and hospital length of stay) did not differ between groups. INTERPRETATION: For preventing post-ERCP pancreatitis in high-risk patients, a strategy of indomethacin alone was not as effective as a strategy of indomethacin plus prophylactic pancreatic stent placement. These results support prophylactic pancreatic stent placement in addition to rectal indomethacin administration in high-risk patients, in accordance with clinical practice guidelines. FUNDING: US National Institutes of Health.

A Randomized Controlled Phase 2 Dose-Finding Trial to Evaluate the Efficacy and Safety of Camostat in the Treatment of Painful Chronic Pancreatitis: The TACTIC Study.

BACKGROUND & AIMS: Chronic pancreatitis (CP) causes an abdominal pain syndrome associated with poor quality of life. We conducted a clinical trial to further investigate the efficacy and safety of camostat, an oral serine protease inhibitor that has been used to alleviate pain in CP. METHODS: This was a double-blind randomized controlled trial that enrolled adults with CP with a baseline average daily worst pain score ≥4 on a numeric rating system. Participants were randomized (1:1:1:1) to receive camostat at 100, 200, or 300 mg 3 times daily or placebo. The primary end point was a 4-week change from baseline in the mean daily worst pain intensity score (0-10 on a numeric rating system) using a mixed model repeated measure analysis. Secondary end points included changes in alternate pain end points, quality of life, and safety. RESULTS: A total of 264 participants with CP were randomized. Changes in pain from baseline were similar between the camostat groups and placebo, with differences of least squares means of -0.11 (95% CI, -0.90 to 0.68), -0.04 (95% CI, -0.85 to 0.78), and -0.11 (95% CI, -0.94 to 0.73) for the 100 mg, 200 mg, and 300 mg groups, respectively. Multiple subgroup analyses were similar for the primary end point, and no differences were observed in any of the secondary end points. Treatment-emergent adverse events attributed to the study drug were identified in 42 participants (16.0%). CONCLUSION: We were not able to reject the null hypothesis of no difference in improvements in pain or quality of life outcomes in participants with painful CP who received camostat compared with placebo. Studies are needed to further define mechanisms of pain in CP to guide future clinical trials, including minimizing placebo responses and selecting targeted therapies. CLINICALTRIALS: gov, Number: NCT02693093.

An In Vitro Medium for Modeling Gut Dysbiosis Associated with Cystic Fibrosis.

The gut physiology of pediatric and adult persons with cystic fibrosis (pwCF) is altered relative to healthy persons. The CF gut is characterized, in part, as having excess mucus, increased fat content, acidic pH, increased inflammation, increased antibiotic perturbation and the potential for increased oxygen availability. These physiological differences shift nutritional availability and the local environment for intestinal microbes, thus likely driving significant changes in microbial metabolism, colonization and competition with other microbes. The impact of any specific change in this physiological landscape is difficult to parse using human or animal studies. Thus, we have developed a novel culture medium representative of the CF gut environment, inclusive of all the aforementioned features. This medium, called CF-MiPro, maintains CF gut microbiome communities, while significantly shifting non-CF gut microbiome communities toward a CF-like microbial profile, characterized by low Bacteroidetes and high Proteobacteria abundance. This medium is able to maintain this culture composition for up to 5 days of passage. Additionally, microbial communities passaged in CF-MiPro produce significantly less immunomodulatory short chain fatty acids (SCFA), including propionate and butyrate, than communities passaged in MiPro, a culture medium representative of healthy gut physiology, confirming not only a shift in microbial composition but altered community function. Our results support the potential for this in vitro culture medium as a new tool for the study of gut dysbiosis in CF.

Nutritional Risks in Patients Undergoing Total Pancreatectomy Islet AutoTransplantation in the POST Consortium.

BACKGROUND AND AIMS: Total pancreatectomy with islet autotransplantation (TPIAT) can relieve pain for individuals with acute recurrent or chronic pancreatitis. However, TPIAT may increase the risk of poor nutritional status with complete exocrine pancreatic insufficiency, partial duodenectomy, and intestinal reconstruction. Our study's objective was to evaluate nutritional status, anthropometrics, and vitamin levels before and after TPIAT. METHODS: The multicenter Prospective Observational Study of TPIAT (POST) collects measures including vitamins A, D, and E levels, pancreatic enzyme dose, and multivitamin (MVI) administration before and 1-year after TPIAT. Using these data, we studied nutritional and vitamin status before and after TPIAT. RESULTS: 348 TPIAT recipients were included (68% adult, 37% male, 93% Caucasian). In paired analyses at 1-year follow-up, vitamin A was low in 23% (vs 9% pre-TPIAT, p < 0.001); vitamin E was low in 11% (vs 5% pre-TPIAT, p = 0.066), and 19% had vitamin D deficiency (vs 12% pre-TPIAT, p = 0.035). Taking a fat-soluble multivitamin (pancreatic MVI) was associated with lower risk for vitamin D deficiency (p = 0.002). Adults were less likely to be on a pancreatic MVI at follow-up (34% vs 66% respectively, p < 0.001). Enzyme dosing was adequate. More adults versus children were overweight or underweight pre- and post-TPIAT. Underweight status was associated with vitamin A (p = 0.014) and E (p = 0.02) deficiency at follow-up. CONCLUSIONS: Prevalence of fat-soluble vitamin deficiencies increased after TPIAT, especially if underweight. We strongly advocate that all TPIAT recipients have close post-operative nutritional monitoring, including vitamin levels. Pancreatic MVIs should be given to minimize risk of developing deficiencies.

Direct laser writing of 3D electrodes on flexible substrates.

This report describes a 3D microelectrode array integrated on a thin-film flexible cable for neural recording in small animals. The fabrication process combines traditional silicon thin-film processing techniques and direct laser writing of 3D structures at micron resolution via two-photon lithography. Direct laser-writing of 3D-printed electrodes has been described before, but this report is the first to provide a method for producing high-aspect-ratio structures. One prototype, a 16-channel array with 300 µm pitch, demonstrates successful electrophysiological signal capture from bird and mouse brains. Additional devices include 90 µm pitch arrays, biomimetic mosquito needles that penetrate through the dura of birds, and porous electrodes with enhanced surface area. The rapid 3D printing and wafer-scale methods described here will enable efficient device fabrication and new studies examining the relationship between electrode geometry and electrode performance. Applications include small animal models, nerve interfaces, retinal implants, and other devices requiring compact, high-density 3D electrodes.

Lessons from a COVID-19 outbreak in the disability support sector, Australian Capital Territory, August 2021.

Abstract: People with disability are at higher risk of severe outcomes from SARS-CoV-2 infection. Due to complex client needs and available staffing, disability support providers (DSP) were limited in their ability to mitigate the introduction of SARS-CoV-2 into disability support settings. This report describes the characteristics of a Delta variant outbreak associated with a single DSP in Canberra, Australian Capital Territory (ACT), in August 2021. We calculated attack rates for workplace exposure sites and households, using the number of people present at workplaces and households as the denominator. Thirty confirmed cases were identified, comprised of 13 support workers, six clients, and 11 household and other contacts. The median age of cases was 30.5 years (range 1 to 80 years) and 5 cases (17%) were hospitalised. No cases were admitted to an intensive care unit (ICU) or died. Twenty-two percent of people in close contact with confirmed SARS-CoV-2 cases in this cluster (23/103) subsequently tested positive to SARS-CoV-2. Investigations identified multiple primary cases, with one primary case the likely infection source for at least 17 other cases. Despite the majority being eligible for vaccination, only two cases were fully vaccinated (two doses > 14 days before exposure). The mean secondary attack rate at workplace sites (15% or 12/80 close contacts infected) was lower than the tertiary attack rate (47.8% or 11/23 close contacts infected). The overall risk of contracting SARS-CoV-2 in DSP-related work sites was lower than for household settings (relative risk: 0.42; 95% confidence interval: 0.21-0.82). These findings demonstrate the importance of ongoing collaboration between governments and the disability support sector. Development and delivery of targeted health messaging to people with disability and to disability support workers, regarding infection control in the home setting, and identification of enablers for vaccination, should be the highest priorities from this collaboration.

Public health interventions successfully mitigated multiple incursions of SARS-CoV-2 Delta variant in the Australian Capital Territory.

The COVID-19 pandemic has presented a unique opportunity to understand how real-time pathogen genomics can be used for large-scale outbreak investigations. On 12 August 2021, the Australian Capital Territory (ACT) detected an incursion of the SARS-CoV-2 Delta (B.1.617.2) variant. Prior to this date, SARS-CoV-2 had been eliminated locally since 7 July 2020. Several public health interventions were rapidly implemented in response to the incursion, including a territory-wide lockdown and comprehensive contact tracing. The ACT has not previously used pathogen genomics at a population level in an outbreak response; therefore, this incursion also presented an opportunity to investigate the utility of genomic sequencing to support contact tracing efforts in the ACT. Sequencing of >75% of the 1793 laboratory-confirmed cases during the 3 months following the initial notification identified at least 13 independent incursions with onwards spread in the community. Stratification of cases by genomic cluster revealed that distinct cohorts were affected by the different incursions. Two incursions resulted in most of the community transmission during the study period, with persistent transmission in vulnerable sections of the community. Ultimately, both major incursions were successfully mitigated through public health interventions, including COVID-19 vaccines. The high rates of SARS-CoV-2 sequencing in the ACT and the relatively small population size facilitated detailed investigations of the patterns of virus transmission, revealing insights beyond those gathered from traditional contact tracing alone. Genomic sequencing was critical to disentangling complex transmission chains to target interventions appropriately.

Nanoparticles Targeted to Fibroblast Activation Protein Outperform PSMA for MRI Delineation of Primary Prostate Tumors.

Accurate delineation of gross tumor volumes remains a barrier to radiotherapy dose escalation and boost dosing in the treatment of solid tumors, such as prostate cancer. Magnetic resonance imaging (MRI) of tumor targets has the power to enable focal dose boosting, particularly when combined with technological advances such as MRI-linear accelerator. Fibroblast activation protein (FAP) is overexpressed in stromal components of >90% of epithelial carcinomas. Herein, the authors compare targeted MRI of prostate specific membrane antigen (PSMA) with FAP in the delineation of orthotopic prostate tumors. Control, FAP, and PSMA-targeting iron oxide nanoparticles were prepared with modification of a lymphotropic MRI agent (FerroTrace, Ferronova). Mice with orthotopic LNCaP tumors underwent MRI 24 h after intravenous injection of nanoparticles. FAP and PSMA nanoparticles produced contrast enhancement on MRI when compared to control nanoparticles. FAP-targeted MRI increased the proportion of tumor contrast-enhancing black pixels by 13%, compared to PSMA. Analysis of changes in R2 values between healthy prostates and LNCaP tumors indicated an increase in contrast-enhancing pixels in the tumor border of 15% when targeting FAP, compared to PSMA. This study demonstrates the preclinical feasibility of PSMA and FAP-targeted MRI which can enable targeted image-guided focal therapy of localized prostate cancer.

Racial and Gender Disparities Among Obese Patients With Pancreatic Cancer: A Trend Analysis in the United States.

BACKGROUND: Pancreatic cancer (PC) is the third leading cause of cancer death. Obesity can increase the risk of PC by up to 50%. Studies have shown racial and gender disparities in PC, however, there is a paucity of such information in obese PC patients. AIM: The aim of this study was to: (1) evaluate the incidence and prevalence of obesity among PC patients in the United States over the last 15 years, and (2) determine if variation exists in the demographic of obese PC patients over the last 15 years. It is hoped that this information could be used to assist in primary prevention and early detection of PC. METHODS: A population-based retrospective analysis in IBM Explorys, a pooled, national, deidentified database of 63 million patients from 300 hospitals in the United States. Patient populations were identified using SNOMED and ICD codes. Cochrane-Armitage testing was performed to analyze trends in obesity among PC. Subgroup analysis for gender, age, race, and mortality rate were assessed. RESULTS: The percentage of obese patients with PC increased over the 15-year period (2.5% to 8.5%, P <0.0001). Rates of obesity among PC patients increased among females ( P =0.0004), individuals under age 65 years ( P =0.0002), and all races, but especially for African Americans ( P =0.0007) and those in minority groups. CONCLUSION: Awareness of disparities in PC and applying targeted care to those at increased risk are essential to improve future outcomes, including increased health care access and recruitment in research studies for minority groups.

Characterisation of internal oxygen concentration of strawberry (Fragaria × ananassa) and blueberry (Vaccinium corymbosum).

Gas exchange mechanisms play crucial roles in maintaining fruit post-harvest quality in perishable fruit such as strawberry (Fragaria×ananassa Duch.) and blueberry (Vaccinium corymbosum L.). The internal oxygen concentration ([O2 ]) of strawberry and blueberry were measured using Clark-type oxygen sensing electrodes. The volume of intercellular voids in strawberry was obtained by micro-computed tomography (micro-CT). In both berries, internal [O2 ] was consistent and relatively high across measured tissues. The overall [O2 ] was well above the Michaelis constant (K m ) for cytochrome c oxidase in both fruit and different from previously examined grape (Vitis vinifera L.) berry mesocarp with near zero minimum [O2 ]. In strawberry and blueberry, cell vitality was also maintained at full maturity in the mesocarp. Higher storage temperature (i.e. 20 vs 4°C) reduced internal [O2 ] of strawberry. Pedicel detachment in blueberry was associated with greater fruit dehydration and lower internal [O2 ] after short-term storage of 12h. The results suggest that the intercellular voids of the fruit's mesocarp provide an efficient gas exchange route for maintaining high fruit internal [O2 ] post-harvest.

Acute pancreatitis precedes chronic pancreatitis in the majority of patients: Results from the NAPS2 consortium.

INTRODUCTION: The mechanistic definition of chronic pancreatitis (CP) identifies acute pancreatitis (AP) as a precursor stage. We hypothesized that clinical AP frequently precedes the diagnosis of CP and is associated with patient- and disease-related factors. We describe the prevalence, temporal relationship and associations of AP in a well-defined North American cohort. METHODS: We evaluated data from 883 patients with CP prospectively enrolled in the North American Pancreatitis Studies across 27 US centers between 2000 and 2014. We determined how often patients had one or more episodes of AP and its occurrence in relationship to the diagnosis of CP. We used multivariable logistic regression to determine associations for prior AP. RESULTS: There were 624/883 (70.7%) patients with prior AP, among whom 161 (25.8%) had AP within 2 years, 115 (18.4%) within 3-5 years, and 348 (55.8%) >5 years prior to CP diagnosis. Among 504 AP patients with available information, 436 (86.5%) had >1 episode. On multivariable analyses, factors associated with increased odds of having prior AP were a younger age at CP diagnosis, white race, abdominal pain, pseudocyst(s) and pancreatic duct dilatation/stricture, while factors associated with a lower odds of having prior AP were exocrine insufficiency and pancreatic atrophy. When compared with patients with 1 episode, those with >1 AP episode were diagnosed with CP an average of 5 years earlier. CONCLUSIONS: Nearly three-quarters of patients were diagnosed with AP prior to CP diagnosis. Identifying which AP patients are at-risk for future progression to CP may provide opportunities for primary and secondary prevention.