Search

Mark E Lowe, Wednesday A SevillaDivision of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USAAbstract: Pancreatitis is inflammation of the pancreas that can be acute and self-limiting or, in a small percentage of patients, recurrent. Patients with recurrent episodes of acute pancreatitis (RAP) often progress to chronic pancreatitis. Pancreatitis in all forms causes significant economic and social burdens. Prevention of RAP may decrease those burdens and halt progression to chronic disease. Unfortunately, no therapy has proven effective at altering the course of RAP. While enteral nutritional therapy plays an important role in the treatment of acute pancreatitis during episodes, nutritional advice provided to patients in an attempt to prevent recurrent episodes has not proven effective in most cases. Discontinuing alcohol consumption and treating dyslipidemia with diet and medication can help patients with these issues. In patients whose pancreatitis is associated with celiac disease or eosinophilic gastroenteritis, a gluten-free diet and avoidance of food allergens can be effective in stopping RAP. Advice to take pancreatic enzyme replacement therapy, lose weight, control diabetes, decrease dietary sucrose, decrease dietary fat or avoid monosodium glutamate has little to no evidence of efficacy. Some studies suggest that an antioxidant cocktail may decrease the frequency of RAP and the intensity of chronic pain, but the evidence is weak. Nutritional therapy may have a role in the treatment of patients with RAP. At present, there are no clear guidelines for nutritional advice to give these patients. More studies are needed to identify nutritional interventions that will benefit patients with RAP.Keywords: pancreatitis, nutrition, pancreatic enzyme replacement therapy, antioxidants, herbal supplements

Children in poverty must contend with systems that do not meet their needs. We explored what, at a neural level, helps explain children's resilience in these contexts. Lower coupling between lateral frontoparietal network (LFPN) and default mode network (DMN)-linked, respectively, to externally- and internally-directed thought-has previously been associated with better cognitive performance. However, we recently found the opposite pattern for children in poverty. Here, we probed ecologically-valid assessments of performance. In a pre-registered study, we investigated trajectories of network coupling over ages 9-13 and their relation to school grades and attention problems. We analyzed longitudinal data from ABCD Study (N = 8366 children at baseline; 1303 below poverty). The link between cognitive performance and grades was weaker for children in poverty, highlighting the importance of ecologically-valid measures. As predicted, higher LFPN-DMN connectivity was linked to worse grades and attentional problems for children living above poverty, while children below poverty showed opposite tendencies. This interaction between LFPN-DMN connectivity and poverty related to children's grades two years later; however, it was attenuated when controlling for baseline grades and was not related to attention longitudinally. Together, these findings suggest network connectivity is differentially related to performance in real-world settings for children above and below poverty.

Introduction: Among children who suffer from acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP), acute pancreatitis (AP) episodes are painful, often require hospitalization, and contribute to disease complications and progression. Despite this recognition, there are currently no interventions to prevent AP episodes. In this retrospective cohort study, we assessed the impact of pancreatic enzyme therapy (PERT) use on clinical outcomes among children with pancreatic-sufficient ARP or CP., Methods: Children with pancreatic-sufficient ARP or CP in the INSPPIRE-2 cohort were included. Clinical outcomes were compared for those receiving vs not receiving PERT, as well as frequency of AP before and after PERT. Logistic regression was used to study the association between development of AP episodes after starting PERT and response predictors., Results: Among 356 pancreatic-sufficient participants, 270 (76%) had ARP, and 60 (17%) received PERT. Among those on PERT, 42% did not have a subsequent AP episode, during a mean 2.1 years of follow-up. Children with a SPINK1 mutation ( P = 0.005) and those with ARP (compared with CP, P = 0.008) were less likely to have an AP episode after starting PERT. After initiation of PERT, the mean AP annual incidence rate decreased from 3.14 down to 0.71 ( P < 0.001)., Discussion: In a retrospective analysis, use of PERT was associated with a reduction in the incidence rate of AP among children with pancreatic-sufficient ARP or CP. These results support the need for a clinical trial to evaluate the efficacy of PERT to improve clinical outcomes among children with ARP or CP., (Copyright © 2024 by The American College of Gastroenterology.)

Objective: To determine if mild-moderate hypertriglyceridemia (HTG) is associated with increased development of chronic pancreatitis (CP) or pancreatitis-associated complications in children with acute recurrent or CP., Study Design: Longitudinal data from the INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2) cohort of children with acute recurrent or CP (n = 559) were analyzed. Subjects were divided into normal triglycerides (<150 mg/dL; 1.7 mmol/L), any HTG (≥150 mg/dL; ≥1.7 mmol/L), mild-moderate HTG (150-499 mg/dL; 1.7-5.6 mmol/L), moderate HTG (500-999 mg/dL; 5.6-11.3 mmol/L), and severe HTG groups (≥1000 mg/dL; ≥11.3 mmol/L), based on highest serum triglyceride value. Laboratory, imaging, pancreatitis and hospital events, complications, and quality of life data were analyzed., Results: In children with acute recurrent or CP and HTG, there was no increase in the number of pancreatitis attacks per person-years, nor an increase in CP prevalence. However, HTG severity was associated with increased pancreatic inflammation, pancreatic cysts, pain, hospital days, number of hospitalizations, intensive care, and missed school days., Conclusions: Mild-moderate HTG in children with acute recurrent or CP was not associated with increased pancreatitis frequency, nor increased development of CP, but was associated with increased pancreatitis complications and disease burden. As a treatable condition, treatment of mild-moderate HTG may be considered to reduce pancreatitis-associated complications and medical burden in children with acute recurrent or CP., Competing Interests: Declaration of Competing Interest Z.M.S. is currently an employee of 4D Molecular Therapeutics Inc and a consultant for BridgeBio Pharma and Renexxion. M.A.H. is the president of CAPER, a board member of CAPER, and a board member of the National Pancreas Foundation. T.G. received a research grant from Vertex Pharmaceuticals, and she is a consultant for Cystic Fibrosis Foundation (CFF). C.Y.O. is a consultant for and has received research grant from Vertex Pharmaceuticals. E.R.P. is a consultant for BridgeBio and Ultragenyx. S.J.S. is a consultant for UpToDate, Nestle, Abbvie, Renexxion, and the CFF. A.J.F. is a consultant for Takeda and AbbVie, CFF, and is a member of the CAPER board. V.D.M. is an Associate Editor for JPGN Reports. D.M.T. is an Associate Editor for JPGN. M.W. is a consultant for and has received research grants from Vertex Pharmaceuticals. M.E.L. receives royalties from Millipore Inc and UpToDate and consults for CFF. A.U. is a consultant for CFF and Abbvie Inc. The other authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to determine patient reported burdensome experiences and research interests in children with acute recurrent pancreatitis or chronic pancreatitis and their families., Methods: Children with pancreatitis and their families completed a web-based survey. Subject prioritized rankings of symptoms or quality of life issues and topics for future research were assessed. Data are presented as family and children scores., Results: Among 80 participants, 18 were children with pancreatitis and 62 were family members. Top 5 ranked symptoms or quality of life issues were:1) pain, 2) fatigue, 3) missing school, 4) upset stomach, and 5) not knowing when an attack will occur. Top 5 ranked future research topics were:1) how to prevent a pancreatitis attack, 2) how pancreatitis affects other parts of the body, 3) ways to treat or handle pain, 4) what is the cause of pancreatitis, and 5) teach doctors about pancreatitis., Conclusions: This study highlights the importance of patient and family input in caring for children with pancreatitis. The most bothersome symptoms were pain, fatigue and upset stomach. Children with pancreatitis and families would like future research to primarily focus on prevention of pancreatitis attacks, pain therapy, and complications of pancreatitis., Competing Interests: Conflicts of Interest and Source of Funding: Conflicts of Interest: M. Lowe is a consultant for the Cystic Fibrosis Foundation and receives royalties from Millipore Inc. and UpToDate. A. Uc is a consultant for the Cystic Fibrosis Foundation and Abbvie Inc. The remaining authors declare that they have no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background & Aims: Protease-sensitive PNLIP variants were recently associated with chronic pancreatitis (CP) in European populations. The pathological mechanism yet remains elusive. Herein, we performed a comprehensive genetic and functional analysis of PNLIP variants found in a large Chinese cohort, aiming to further unravel the enigmatic association of PNLIP variants with CP., Methods: All coding and flanking intronic regions of the PNLIP gene were analyzed for rare variants by targeted next-generation sequencing in 1082 Chinese CP patients and 1196 controls. All novel missense variants were subject to analysis of secretion, lipase activity, and proteolytic degradation. One variant was further analyzed for its potential to misfold and induce endoplasmic reticulum (ER) stress. p.F300L, the most common PNLIP variant associated with CP, was used as a control., Results: We identified 12 rare heterozygous PNLIP variants, with 10 being novel. The variant carrier frequency did not differ between the groups. Of them, only the variant p.A433T found in a single patient was considered pathologically relevant. p.A433T exhibited increased susceptibility to proteolytic degradation, which was much milder than p.F300L. Interestingly, both variants exhibited an increased tendency to misfold, leading to intracellular retention as insoluble aggregates, reduced secretion, and elevated ER stress., Conclusions: Our genetic and functional analysis of PNLIP variants identified in a Chinese CP cohort suggests that the p.A433T variant and the previously identified p.F300L variant are not only protease-sensitive but also may be potentially proteotoxic. Mouse studies of the PNLIP p.F300L and p.A433T variants are needed to clarify their role in CP., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Decisions about how to divide resources have profound social and practical consequences. Do explanations regarding the source of existing inequalities influence how children and adults allocate new resources? When 3- to 6-year-old children (N = 201) learned that inequalities were caused by structural forces (stable external constraints affecting access to resources) as opposed to internal forces (effort), they rectified inequalities, overriding previously documented tendencies to perpetuate inequality or divide resources equally. Adults (N = 201) were more likely than children to rectify inequality spontaneously; this was further strengthened by a structural explanation but reversed by an effort-based explanation. Allocation behaviors were mirrored in judgments of which allocation choices by others were appropriate. These findings reveal how explanations powerfully guide social reasoning and action from childhood through adulthood., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The CEL gene encodes carboxyl ester lipase, a pancreatic digestive enzyme. CEL is extremely polymorphic due to a variable number tandem repeat (VNTR) located in the last exon. Single-base deletions within this VNTR cause the inherited disorder MODY8, whereas little is known about VNTR single-base insertions in pancreatic disease. We therefore mapped CEL insertion variants (CEL-INS) in 200 Norwegian patients with pancreatic neoplastic disorders. Twenty-eight samples (14.0%) carried CEL-INS alleles. Most common were insertions in repeat 9 (9.5%), which always associated with a VNTR length of 13 repeats. The combined INS allele frequency (0.078) was similar to that observed in a control material of 416 subjects (0.075). We performed functional testing in HEK293T cells of a set of CEL-INS variants, in which the insertion site varied from the first to the 12th VNTR repeat. Lipase activity showed little difference among the variants. However, CEL-INS variants with insertions occurring in the most proximal repeats led to protein aggregation and endoplasmic reticulum stress, which upregulated the unfolded protein response. Moreover, by using a CEL-INS-specific antibody, we observed patchy signals in pancreatic tissue from humans without any CEL-INS variant in the germline. Similar pancreatic staining was seen in knock-in mice expressing the most common human CEL VNTR with 16 repeats. CEL-INS proteins may therefore be constantly produced from somatic events in the normal pancreatic parenchyma. This observation along with the high population frequency of CEL-INS alleles strongly suggests that these variants are benign, with a possible exception for insertions in VNTR repeats 1-4., (© The Author(s) 2024. Published by Oxford University Press.)

There has been significant progress in understanding the effects of childhood poverty on neurocognitive development. This progress has captured the attention of policymakers and promoted progressive policy reform. However, the prevailing emphasis on the harms associated with childhood poverty may have inadvertently perpetuated a deficit-based narrative, focused on the presumed shortcomings of children and families in poverty. This focus can have unintended consequences for policy (e.g., overlooking strengths) as well as public discourse (e.g., focusing on individual rather than systemic factors). Here, we join scientists across disciplines in arguing for a more well-rounded, "strength-based" approach, which incorporates the positive and/or adaptive developmental responses to experiences of social disadvantage. Specifically, we first show the value of this approach in understanding normative brain development across diverse human environments. We then highlight its application to educational and social policy, explore pitfalls and ethical considerations, and offer practical solutions to conducting strength-based research responsibly. Our paper re-ignites old and recent calls for a strength-based paradigm shift, with a focus on its application to developmental cognitive neuroscience. We also offer a unique perspective from a new generation of early-career researchers engaged in this work, several of whom themselves have grown up in conditions of poverty. Ultimately, we argue that a balanced strength-based scientific approach will be essential to building more effective policies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Rationale: The identification of early chronic obstructive pulmonary disease (COPD) is essential to appropriately counsel patients regarding smoking cessation, provide symptomatic treatment, and eventually develop disease-modifying treatments. Disease severity in COPD is defined using race-specific spirometry equations. These may disadvantage non-White individuals in diagnosis and care. Objectives: Determine the impact of race-specific equations on African American (AA) versus non-Hispanic White individuals. Methods: Cross-sectional analyses of the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort were conducted, comparing non-Hispanic White ( n  = 6,766) and AA ( n  = 3,366) participants for COPD manifestations. Measurements and Main Results: Spirometric classifications using race-specific, multiethnic, and "race-reversed" prediction equations (NHANES [National Health and Nutrition Examination Survey] and Global Lung Function Initiative "Other" and "Global") were compared, as were respiratory symptoms, 6-minute-walk distance, computed tomography imaging, respiratory exacerbations, and St. George's Respiratory Questionnaire. Application of different prediction equations to the cohort resulted in different classifications by stage, with NHANES and Global Lung Function Initiative race-specific equations being minimally different, but race-reversed equations moving AA participants to more severe stages and especially between the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0 and preserved ratio impaired spirometry groups. Classification using the established NHANES race-specific equations demonstrated that for each of GOLD stages 1-4, AA participants were younger, had fewer pack-years and more current smoking, but had more exacerbations, shorter 6-minute-walk distance, greater dyspnea, and worse BODE (body mass index, airway obstruction, dyspnea, and exercise capacity) scores and St. George's Respiratory Questionnaire scores. Differences were greatest in GOLD stages 1 and 2. Race-reversed equations reclassified 774 AA participants (43%) from GOLD stage 0 to preserved ratio impaired spirometry. Conclusions: Race-specific equations underestimated disease severity among AA participants. These effects were particularly evident in early disease and may result in late detection of COPD.

Background/objectives: Studies of a rare homozygous missense mutation identified in two brothers diagnosed with congenital pancreatic lipase deficiency (CPLD) provided the first definitive evidence linking CPLD with missense mutations in the gene of PNLIP. Herein, we investigated the molecular basis for the loss-of-function in the three novel PNLIP variants (c.305G > A, p.(W102∗); c.562C > T, p.(R188C); and c.1257G > A, p.(W419∗)) associated with CPLD., Methods: We characterized three novel PNLIP variants in transfected cells by assessing their secretion, intracellular distribution, and markers of endoplasmic reticulum (ER) stress., Results: All three variants had secretion defects. Notably, the p.R188C and p.W419∗ variants induced misfolding of PNLIP and accumulated as detergent-insoluble aggregates resulting in elevated BiP at both protein and mRNA levels indicating increased ER stress., Conclusions: All three novel PNLIP variants cause a loss-of-function through impaired secretion. Additionally, the p.R188C and p.W419∗ variants may induce proteotoxicity through misfolding and potentially increase the risk for pancreatic acinar cell injury., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Evaluation for activating mutations in KRAS , NRAS , and BRAF in colorectal cancer (CRC) and in KRAS in pancreatic ductal adenocarcinoma (PDAC) is essential for clinical care. Plasma cell-free DNA (cfDNA) next-generation sequencing (NGS) allows convenient assessment of a tumor's molecular profile, however low tumor DNA shedding limits sensitivity. We investigated mutant allele frequency (MAF) of other oncogenic dominant genes to identify a threshold for accurate detection of KRAS, NRAS, and BRAF (RAS/RAF) mutations in cfDNA., Methods: Molecular and clinical data were obtained from the Duke Molecular Registry of Tumors and the SCRUM-Japan GOZILA study. Patients with CRC or PDAC and a KRAS , NRAS , or BRAF activating single nucleotide variant (SNV) present on tissue NGS and with available cfDNA assays were included. Recursive partitioning and Wilcoxon-rank statistics methods identified potential cut-points for discriminative MAF values., Results: One hundred and thirty-five CRC and 30 PDAC cases with 198 total cfDNA assays met criteria. Greatest non- RAS/RAF dominant gene MAF of 0.34% provided maximum discrimination for predicting RAS/RAF SNV detection. Sensitivity for RAS/RAF SNVs increased with dominant gene MAF, with MAF ≥1% predicting sensitivity >98%, MAF between 0.34 and 1% predicting sensitivity of 84.0%, and MAF £0.34% predicting sensitivity of 50%. For 43 cfDNA assays that did not detect RAS/RAF SNVs, 18 assays detected 34 other oncogenic variants, of which 80.6% were not also detected on tissue., Conclusions: Non- RAS/RAF dominant oncogenic mutation MAF ≥1% on cfDNA NGS predicts high sensitivity to detect RAS/RAF oncogenic SNVs in CRC and PDAC. MAF £0.34% indicates an assay may not reliably detect RAS/RAF SNVs, despite detection on tissue testing. Most variants from assays that did not detect RAS/RAF had MAF <1% and were not detected on tissue, suggesting potential confounding. These data suggest a practical approach to determining cfDNA assay adequacy, with implications for guiding clinical decisions in CRC and PDAC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-114/coif). KU reports honoraria from Chugai Pharmaceutical, Taiho Pharmaceutical and Yakult Honsha. MG reports royalties from SciMed Solutions as part of a software licensing agreement. MI reports grants/research funding from Eisai, Merck biopharma, Eli Lilly Japan, Yakult, Ono, ASLAN, J-Pharma, AstraZeneca, Pfizer, Merus N.V., Nihon Servier, Delta-Fly Pharma, Chiome Bioscience, Bristol-Myers Squibb, Chugai Pharmaceutical, Novartis, Bayer, Takeda, MSD, Syneos Health, as well as honoraria from Eisai, MSD, Eli Lilly Japan, Yakult, Teijin Pharma, Astellas, Sumitomo Dainippon, Otsuka, Nihon Servier, Taiho, Chugai Pharmaceutical, Bristol-Myers Squibb, Novartis, Bayer, Takeda, EA Pharma, AstraZeneca, AbbVie, Abbott Japan, Fujifilm Toyama Chemical, and Incyte Biosciences Japan. MU reports grants/research fundings from Taiho Pharmaceutical, AstraZeneca, Merck, MSD, Astellas Pharma, Eisai, Ono Pharmaceutical, Incyte, Chugai Pharmaceutical, DFP, Daiichi Sankyo, Novartis, Boehringer Ingelheim, and J-pharma, and also honoraria from Taiho Pharmaceutical, AstraZeneca, Yakult Honsha, MSD, Nihon Servier, Ono Pharmaceutical, Uncyte, Chugai Pharmaceutical, Boehringer Ingelheim, and J-Pharma. HT reports grants/research funding from Daiichi Sankyo and Takeda, and also honoraria from Guardant Health AMEA, Chugai Pharmaceutical, Ono, Eli Lilly, Takeda, and Merck. YK reports scholarly/research support or grant funding from Ono, Chugai Pharmaceutical, Taiho, Shionogi, Nippon Zoki, Asahi Kasei, Nippon Kayaku, Daiichi Sankyo, IQVIA Services Japan, MSD, Astellas Pharma, Incyte, Eisai, National Cancer Center Japan, Syneos Health, ShiftZero, Parexel International, Japan Clinical Cancer Research Organization, EPS, Sysemx Corporation, and the Public Health Research Foundation; and also honoraria from Ono, Taiho, Astellas Pharma, EA Pharma, Daiichi Sankyo, Nippon Kayaku, Pfizer, Nippon Zoki, Sanofi, Nipro, Asahi, Chugai Pharmaceutical, MSD, Zeria, Eli Lilly, Bayer, Yakult, Sumitomo Dainippon Pharma, Incyte, and Merck. TE reports research grants and honoraria from MSD, Daiichi Sankyo, and, Chugai, grants from Pfizer, Astellas, Quintiles, Syneos Health, Amgen, Ono, Novartis, Astellas, Amgen Biopharma, Asahi Kasei Pharma, and IQVIA, and honoraria from Taiho, Eli Lilly, and Bristol Myers Squib, outside the submitted work. TD reports research funds from MSD, Amgen and Ono Pharmaceutical, and honoraria from Sysmex, Ono Pharmaceutical, SAWAI Pharmaceutical Co and Daiichi Sankyo, outside the submitted work. HB reports research funding from Ono Pharmaceutical and honoraria from Ono Pharmaceutical, Taiho, and Eli Lilly. TBS reports research funding/grants from Agio, Arys, Arcua, Atreca, Boston Biomedical, Bayer, Eisai, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Genentech, Novartic, Mirati, Merus, Abgenomics, Incyte, Pfizer, and BMS; consulting fees from Ipsen, Arcus, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, Eisai, Merus, Merck, Stemline, Abbvie, Boehringer Ingelheim, Janssen, Daiichi Sankyo, Natera, TreosBio, Celularity, Caladrius Biosciences, Exact Science, Sobi, Beigene, Kapaph, AstraZeneca, Deciphera, Zai Labs, Exelixis, MJH Life Sciences, Aptitude Health, Illumina, Foundation Medicine, and Sanofi; patents currently licensed to Imugene and Recursionl; and participation in DSMB or Scientific Advistory Boards for The Valley Hospital, Fibrogen, Suzhou Kintor, AstraZeneca, Exelixis, Merck, Eisai, PanCan, 1GLOBE, Imugene, Immuneering, Xilis, Replimune, Artiva, and Sun Biopharma. TY reports research support/grants from Amgen, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, FALCO, Genomedia, Molecular Health GmbH, MSD, Boehringer Ingelheim, Ono, Pfizer, Roche Diagnostics, Sanofi, Sysmex Corporation, and Taiho as well as consulting fees from Sumitomo Corporation and honoraria from Bayer, Chugai Pharmaceutical, Merck, MSD, Ono, and Takeda. JS reports grant/research support from Abbvie, Amgen, AStar D3, Bayer, Beigene, Curegenix, Daiichi-Sankyo, Eli Lilly, Erasca, Gossamer Bio, Leap Therapeutics, Nektar, Roche/Genentech, Seagen, and Silverback Therapeutics; and consulting fees from or serving in an advisory role to Abbvie, Amgen, AstraZeneca, Bayer, Beigene, Daiichi-Sankyo, Eli Lilly, G3 Therapeutics, GSK, Natera, Pfizer, Pionyr Immunotherapeutics, Roche/Genentech, Seagen, Silverback Therapeutics, Takeda, and Viatris. YN reports grants and honoraria from Chugai, grants from Taiho, Guardant Health, Genomedia, Daiichi-Sankyo, Seagen, and Roche Diagnostics, and honoraria from Guardant Health AMEA and Merck. The other authors have no conflicts of interest to declare., (2023 Journal of Gastrointestinal Oncology. All rights reserved.)

Background: COPD diagnosis is tightly linked to the fixed-ratio spirometry criteria of FEV 1 /FVC < 0.7. African-Americans are less often diagnosed with COPD., Objective: Compare COPD diagnosis by fixed-ratio with findings and outcomes by race., Design: Genetic Epidemiology of COPD (COPDGene) (2007-present), cross-sectional comparing non-Hispanic white (NHW) and African-American (AA) participants for COPD diagnosis, manifestations, and outcomes., Setting: Multicenter, longitudinal US cohort study., Participants: Current or former smokers with ≥ 10-pack-year smoking history enrolled at 21 clinical centers including over-sampling of participants with known COPD and AA. Exclusions were pre-existing non-COPD lung disease, except for a history of asthma., Measurements: Subject diagnosis by conventional criteria. Mortality, imaging, respiratory symptoms, function, and socioeconomic characteristics, including area deprivation index (ADI). Matched analysis (age, sex, and smoking status) of AA vs. NHW within participants without diagnosed COPD (GOLD 0; FEV 1  ≥ 80% predicted and FEV 1 /FVC ≥ 0.7)., Results: Using the fixed ratio, 70% of AA (n = 3366) were classified as non-COPD, versus 49% of NHW (n = 6766). AA smokers were younger (55 vs. 62 years), more often current smoking (80% vs. 39%), with fewer pack-years but similar 12-year mortality. Density distribution plots for FEV 1 and FVC raw spirometry values showed disproportionate reductions in FVC relative to FEV 1 in AA that systematically led to higher ratios. The matched analysis demonstrated GOLD 0 AA had greater symptoms, worse D L CO, spirometry, BODE scores (1.03 vs 0.54, p < 0.0001), and greater deprivation than NHW., Limitations: Lack of an alternative diagnostic metric for comparison., Conclusions: The fixed-ratio spirometric criteria for COPD underdiagnosed potential COPD in AA participants when compared to broader diagnostic criteria. Disproportionate reductions in FVC relative to FEV 1 leading to higher FEV 1 /FVC were identified in these participants and associated with deprivation. Broader diagnostic criteria for COPD are needed to identify the disease across all populations., (© 2023. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Objective: Increasing evidence implicates mutation-induced protein misfolding and endoplasm reticulum (ER) stress in the pathophysiology of chronic pancreatitis (CP). The paucity of animal models harbouring genetic risk variants has hampered our understanding of how misfolded proteins trigger CP. We previously showed that pancreatic triglyceride lipase (PNLIP) p.T221M, a variant associated with steatorrhoea and possibly CP in humans, misfolds and elicits ER stress in vitro suggesting proteotoxicity as a potential disease mechanism. Our objective was to create a mouse model to determine if PNLIP p.T221M causes CP and to define the mechanism., Design: We created a mouse model of Pnlip p.T221M and characterised the structural and biochemical changes in the pancreas aged 1-12 months. We used multiple methods including histochemistry, immunostaining, transmission electron microscopy, biochemical assays, immunoblotting and qPCR., Results: We demonstrated the hallmarks of human CP in Pnlip p.T221M homozygous mice including progressive pancreatic atrophy, acinar cell loss, fibrosis, fatty change, immune cell infiltration and reduced exocrine function. Heterozygotes also developed CP although at a slower rate. Immunoblot showed that pancreatic PNLIP T221M misfolded as insoluble aggregates. The level of aggregates in homozygotes declined with age and was much lower in heterozygotes at all ages. The Pnlip p.T221M pancreas had increased ER stress evidenced by dilated ER, increased Hspa5 (BiP) mRNA abundance and a maladaptive unfolded protein response leading to upregulation of Ddit3 (CHOP), nuclear factor-κB and cell death., Conclusion: Expression of PNLIP p.T221M in a preclinical mouse model results in CP caused by ER stress and proteotoxicity of misfolded mutant PNLIP., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Autoimmune (AI) diseases appear to be a product of genetic predisposition and environmental triggers. Disruption of the skin barrier causes exacerbation of psoriasis/eczema. Oxidative stress is a mechanistic pathway for pathogenesis of the disease and is also a primary mechanism for the detrimental effects of air pollution., Methods: We evaluated the association between autoimmune skin diseases (psoriasis or eczema) and air pollutant mixtures in 9060 subjects from the Personalized Environment and Genes Study (PEGS) cohort. Pollutant exposure data on six criteria air pollutants are publicly available from the Center for Air, Climate, and Energy Solutions and the Atmospheric Composition Analysis Group. For increased spatial resolution, we included spatially cumulative exposure to volatile organic compounds from sites in the United States Environmental Protection Agency Toxic Release Inventory and the density of major roads within a 5 km radius of a participant's address from the United States Geological Survey. We applied logistic regression with quantile g-computation, adjusting for age, sex, diagnosis with an autoimmune disease in family or self, and smoking history to evaluate the relationship between self-reported diagnosis of an AI skin condition and air pollution mixtures., Results: Only one air pollution variable, sulfate, was significant individually (OR = 1.06, p = 3.99E-2); however, the conditional odds ratio for the combined mixture components of PM 2.5 (black carbon, sulfate, sea salt, and soil), CO, SO 2 , benzene, toluene, and ethylbenzene is 1.10 (p-value = 5.4E-3)., Significance: While the etiology of autoimmune skin disorders is not clear, this study provides evidence that air pollutants are associated with an increased prevalence of these disorders. The results provide further evidence of potential health impacts of air pollution exposures on life-altering diseases., Significance and Impact Statement: The impact of air pollution on non-pulmonary and cardiovascular diseases is understudied and under-reported. We find that air pollution significantly increased the odds of psoriasis or eczema in our cohort and the magnitude is comparable to the risk associated with smoking exposure. Autoimmune diseases like psoriasis and eczema are likely impacted by air pollution, particularly complex mixtures and our study underscores the importance of quantifying air pollution-associated risks in autoimmune disease., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Young children often endorse stereotypes-such as "girls are bad at math." We explore one mechanism through which these beliefs may be transmitted: via pragmatic inference. Specifically, we ask whether preschoolers and adults can learn about an unmentioned social group from what is said about another group, and if this inferential process is sensitive to the context of the utterance. Sixty-three- to five-year-old children and fifty-five adults were introduced to two novel social groups-Stripeys and Dotties-and witnessed a speaker praising abilities of one group (e.g., "the Stripeys are good at building chairs"). To examine the effect of context, we compared situations where the speaker was knowledgeable about the abilities of both groups, and had been queried about the performance of both groups (broad context), versus situations where the speaker was only knowledgeable about one group and was only asked about that group (narrow context). Both preschoolers and adults were sensitive to context: they were more likely to infer that the group not mentioned by the speaker was relatively unskilled, and were more confident about it, in the broad context condition. Our work integrates research in language development and social cognitive development and demonstrates that even young children can "read between the lines," utilizing subtle contextual cues to pick up negative evaluative messages about social groups even from statements that ostensibly do not mention them at all. HIGHLIGHTS: After hearing a speaker praise one group's skill, preschoolers and adults infer that an unmentioned group is relatively less skilled across a range of measures. These inferences are context-sensitive and are stronger when the speaker is knowledgeable of and asked about both groups' skill level. These results shed light on how children may indirectly learn negative stereotypes, especially ones that adults are unlikely to state explicitly. This work extends previous research on children's developing pragmatic ability, as well as their ability to learn about the social world from language., (© 2022 John Wiley & Sons Ltd.)

Background: The United Nations calculates there were 703 million adults 65 years and older globally as of 2019 with this number projected to double by 2050. A significant number of older adults live with comorbid health conditions, making the role of a nurse in long-term care (LTC) complex. Our objective was to identify the challenges, facilitators, workload, professional development and clinical environment issues that influence nurses and nursing students to seek work and continue to work in LTC settings., Methods: Eligibility criteria included being a nurse in a LTC setting and research with a substantial qualitative component. Multiple databases (including Medline and CINAHL) were searched between 2013 and 2019 along with grey literature. Covidence was used to organise a team of 10 into a paired review of titles and abstracts to the final full text screening, extraction and appraisal with the CASP Qualitative Studies Checklist. Analysis involved a thematic synthesis approach. The Enhancing Transparency in Reporting the Synthesis of Qualitative Research (ENTREQ) checklist informed the writing of the review., Results: The search resulted in 18 articles and dissertations. Areas investigated included recruitment, resilience, employment and retention, how nurses perceived their professional work, rewards and difficulties, supervision, student preceptorship and career aspiration, nurses' perceptions of occupational status, along with leadership, education and development needs, and intentions to manage resident deteriorating health. The five themes were (1) perspectives of nursing influenced by the organisation, (2) pride in, and capacity to build relationships, (3) stretching beyond the technical skills, (4) autonomy, and (5) taking on the challenge of societal perceptions., Discussion: This review revealed what is required to recruit nursing students to careers in LTC and retain nurses. To be explored is how staff can work to their full scope of practice and the resultant impact on resident care, including how to maximise a meaningful life for residents and their families., Registration: National Institute for Health Research UK (Prospero ID: CRD42019125214)., (© 2021 John Wiley & Sons Ltd.)

Background: Despite institutional perioperative bundles and national infection prevention guidelines, surgical site infection (SSI) after a major abdominal operation remains a significant source of morbidity. Negative pressure therapy (NPT) has revolutionized care for open wounds but the role of closed incision NPT (ciNPT) remains unclear., Study Design: We conducted a multi-institutional randomized controlled trial evaluating SSI after major elective colorectal or hepatopancreatobiliary surgery (Clinical Trial Registration: NCT01905397). Patients were randomized to receive conventional wound care vs ciNPT (Prevena Incision Management System, 3M Health Care, San Antonio, TX). The primary endpoint was postoperative incisional SSI. SSI incidence was evaluated at inpatient days 4 or 5 and again at postoperative day 30. With 144 patients studied, the estimated power was 85% for detecting a difference in SSIs between 17% and 5% (conventional vs ciNPT; 1-sided α = 0.1). Secondary endpoints included SSI type, length of stay, 30-day readmission, and mortality. T-tests were used to compare continuous variables between treatments; similarly, chi-square tests were used to compare categorical variables. A p value of <0.05 was considered significant, except in the primary comparison of incisional and organ SSIs., Results: During the 2013 to 2021 time period, 164 patients were randomized, and of those, 138 were evaluable (ciNPT n = 63; conventional n = 75). Incisional SSIs occurred in 9 (14%) patients in the ciNPT group and 13 (17%) patients in the conventional group (p = 0.31). Organ or space SSIs occurred in 7 (11%) patients in the ciNPT group and 10 (13%) in the conventional therapy group (p = 0.35)., Conclusions: In this multi-institutional, randomized controlled trial of patients undergoing colorectal or hepatopancreatobiliary surgery, incidence of incisional SSIs between ciNPT and conventional wound therapy was not statistically significant. Future trials should focus on patient populations undergoing specific procedures types that have the highest risk for SSI., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background & Aims: The CEL gene encodes the digestive enzyme carboxyl ester lipase. CEL-HYB1, a hybrid allele of CEL and its adjacent pseudogene CELP, is a genetic variant suggested to increase the risk of chronic pancreatitis (CP). Our aim was to develop a mouse model for CEL-HYB1 that enables studies of pancreatic disease mechanisms., Methods: We established a knock-in mouse strain where the variable number of tandem repeat (VNTR) region of the endogenous mouse Cel gene was substituted with the mutated VNTR of the human CEL-HYB1 allele. Heterozygous and homozygous Cel-HYB1 mice and littermate wildtype controls were characterized with respect to pancreatic pathology and function., Results: We successfully constructed a mouse model with pancreatic expression of a humanized CEL-HYB1 protein. The Cel-HYB1 mice spontaneously developed features of CP including inflammation, acinar atrophy and fatty replacement, and the phenotype became more pronounced as the animals aged. Moreover, Cel-HYB1 mice were normoglycemic at age 6 months, whereas at 12 months they exhibited impaired glucose tolerance. Immunostaining of pancreatic tissue indicated the formation of CEL protein aggregates, and electron microscopy showed dilated endoplasmic reticulum. Upregulation of the stress marker BiP/GRP78 was seen in pancreatic parenchyma obtained both from Cel-HYB1 animals and from a human CEL-HYB1 carrier., Conclusions: We have developed a new mouse model for CP that confirms the pathogenicity of the human CEL-HYB1 variant. Our findings place CEL-HYB1 in the group of genes that increase CP risk through protein misfolding-dependent pathways., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: The objective of this study is to investigate risk factors and disease burden in pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP)., Methods: Data were obtained from INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2), the largest multi-center prospective cohort study in pediatric patients with ARP or CP., Results: Of 689 children, 365 had ARP (53%), 324 had CP (47%). CP was more commonly associated with female sex, younger age at first acute pancreatitis (AP) attack, Asian race, family history of CP, lower BMI%, genetic and obstructive factors, PRSS1 mutations and pancreas divisum. CFTR mutations, toxic-metabolic factors, medication use, hypertriglyceridemia, Crohn disease were more common in children with ARP. Constant or frequent abdominal pain, emergency room (ER) visits, hospitalizations, medical, endoscopic or surgical therapies were significantly more common in CP, episodic pain in ARP. A total of 33.1% of children with CP had exocrine pancreatic insufficiency (EPI), 8.7% had diabetes mellitus. Compared to boys, girls were more likely to report pain impacting socialization and school, medical therapies, cholecystectomy, but no increased opioid use. There was no difference in race, ethnicity, age at first AP episode, age at CP diagnosis, duration of disease, risk factors, prevalence of EPI or diabetes between boys and girls. Multivariate analysis revealed that family history of CP, constant pain, obstructive risk factors were predictors of CP., Conclusions: Children with family history of CP, constant pain, or obstructive risk factors should raise suspicion for CP., Competing Interests: M.E.L. is on the Board of Directors of the National Pancreas Association and receives royalties from Millipore Inc and UpToDate. T.G. received a research grant from Vertex Pharmaceuticals, and she is a consultant for Cystic Fibrosis Foundation (CFF). A.U. is a member of American Board of Pediatrics, Subboard of Pediatric Gastroenterology, Associate Editor of Pancreatology, and consultant for CFF. S.J.S. is a consultant for UpToDate, Nestle, Abbvie, and the Cystic Fibrosis Foundation, and she has a grant from Gilead. V.D.M. is an Associate Editor for JPGN Reports. The remaining authors report no conflicts of interest., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

BACKGROUND. Imaging findings represent key criteria for diagnosing chronic pancreatitis in children. Understanding radiologists' agreement for imaging findings is critical to standardizing and optimizing diagnostic criteria. OBJECTIVE. The purpose of this study is to evaluate the interobserver agreement among experienced pediatric radiologists for subjective, quantitative, and semiquantitative imaging findings of chronic pancreatitis in children. METHODS. In this retrospective study, CT or MRI examinations performed in children with chronic pancreatitis were submitted by six sites participating in the INSPPIRE (International Study Group of Pediatric Pancreatitis: In Search for a Cure) Consortium. One pediatric radiologist from each of the six sites reviewed examinations; three of the radiologists independently reviewed all CT examinations, and the other three radiologists independently reviewed all MRI examinations. Reviewers recorded 13 categoric imaging findings of chronic pancreatitis and measured pancreas thickness and pancreatic duct diameter. Agreement was assessed using kappa coefficients for the categoric variables and intraclass correlation coefficients (ICCs) for the continuous variables. RESULTS. A total of 76 CT and 80 MRI examinations performed in 110 children (65 girls and 45 boys; mean age, 11.3 ± 4.6 [SD] years) were reviewed. For CT, kappa coefficients for categoric findings ranged from -0.01 to 0.81, with relatively high kappa coefficients noted for parenchymal calcifications (κ = 0.81), main pancreatic duct dilatation (κ = 0.63), and atrophy (κ = 0.52). ICCs for parenchymal thickness measurements ranged from 0.57 in the pancreas head to 0.80 in the body and tail. The ICC for duct diameter was 0.85. For MRI, kappa coefficients for categoric findings ranged from -0.01 to 0.74, with relatively high kappa coefficients noted for main duct irregularity (κ = 0.74), side branch dilatation (κ = 0.70), number of dilated side branches (κ = 0.65), and main duct dilatation (κ = 0.64); kappa coefficient for atrophy was 0.52. ICCs for parenchymal thickness measurements ranged from 0.53 for the neck and body individually to 0.68 in the tail. ICC for duct diameter was 0.77. CONCLUSION. Interobserver agreement was fair to moderate for most CT and MRI findings of chronic pancreatitis in children. CLINICAL IMPACT. This study highlights challenges for the imaging diagnosis of pediatric chronic pancreatitis. Standardized and/or objective criteria are needed given the importance of imaging in diagnosis.

Objectives: Abdominal pain, emergency department visits, and hospitalizations impact lives of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). Data on health-related quality of life (HRQOL) in this population, however, remains limited. We aimed to evaluate HRQOL in children with ARP or CP; and test biopsychosocial risk factors associated with low HRQOL., Methods: Data were acquired from the INternational Study Group of Pediatric Pancreatitis: In search for a cuRE registry. Baseline demographic and clinical questionnaires, the Child Health Questionnaire (measures HRQOL) and Child Behavior Checklist (measures emotional and behavioral functioning) were completed at enrollment., Results: The sample included 368 children (54.3% girls, mean age = 12.7years, standard deviation [SD] = 3.3); 65.2% had ARP and 34.8% with CP. Low physical HRQOL (M = 38.5, SD = 16.0) was demonstrated while psychosocial HRQOL (M = 49.5, SD = 10.2) was in the normative range. Multivariate regression analysis revealed that clinical levels of emotional and behavioral problems (B = -10.28, P  < 0.001), episodic and constant abdominal pain (B = 04.66, P = 0.03; B = -13.25, P < 0.001) were associated with low physical HRQOL, after accounting for ARP/CP status, age, sex, exocrine, and endocrine disease (F [9, 271] = 8.34, P < 0.001). Borderline and clinical levels of emotional and behavioral problems (B = -10.18, P < 0.001; B = -15.98, P < 0.001), and constant pain (B = -4.46, P < 0.001) were associated with low psychosocial HRQOL (F [9, 271] = 17.18, P < 0.001)., Conclusions: Findings highlight the importance of assessing HRQOL and treating pain and psychosocial problems in this vulnerable group of children., Competing Interests: M.L. is on the Board of Directors of the National Pancreas Association; receives royalties from Millipore Inc and UpToDate. T.G. received a research grant from Vertex Pharmaceuticals and she is a consultant for Cystic Fibrosis Foundation. M.B. is a consultant for AbbVie Inc and ARIEL Precision Medicine. C.Y.O. is a consultant for Vertex Pharmaceuticals. A.U. is a member of American Board of Pediatrics, Subboard of Pediatric Gastroenterology and a consultant for Cystic Fibrosis Foundation. The other authors declare no conflicts of interest., (Copyright © 2022 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Children in poverty must contend with systems that do not meet their needs. We explored what, at a neural level, helps explain children's resilience in these contexts. Lower coupling between lateral frontoparietal network (LFPN) and default mode network (DMN)-linked, respectively, to externally- and internally-directed thought-has previously been associated with better cognitive performance. However, we recently found the opposite pattern for children in poverty. Here, we probed ecologically-valid assessments of performance. In a pre-registered study, we investigated trajectories of network coupling over ages 9-13 and their relation to school grades and attention problems. We analyzed longitudinal data from ABCD Study (N = 8366 children at baseline; 1303 below poverty). The link between cognitive performance and grades was weaker for children in poverty, highlighting the importance of ecologically-valid measures. As predicted, higher LFPN-DMN connectivity was linked to worse grades and attentional problems for children living above poverty, while children below poverty showed opposite tendencies. This interaction between LFPN-DMN connectivity and poverty related to children's grades two years later; however, it was attenuated when controlling for baseline grades and was not related to attention longitudinally. Together, these findings suggest network connectivity is differentially related to performance in real-world settings for children above and below poverty., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Parents with fewer educational and economic resources (low socioeconomic-status, SES) tend to speak less to their children, with consequences for children's later life outcomes. Despite this well-established and highly popularized link, less research addresses why the SES "word gap" exists. Moreover, while research has assessed individual-level contributors to the word gap-like differences in parenting knowledge-we know little about how structural constraints that vary according to SES might affect caregivers' speech. In two pre-registered studies, we test whether experiencing financial scarcity can suppress caregivers' speech to their children. Study 1 suggests that higher-SES caregivers who are prompted to reflect on scarcity-particularly those who reflect on financial scarcity-speak less to their 3-year-olds in a subsequent play session, relative to a control group. Study 2 suggests that mid- to higher-SES caregivers engage in fewer back-and-forth exchanges with their children at the end of the month-when they are more likely to be experiencing financial hardship-than the rest of the month. These studies provide preliminary evidence that-above and beyond caregivers' individual characteristics-structural constraints may affect how much parents speak to their children., (© 2021 John Wiley & Sons Ltd.)

Prior research indicates that lower resting-state functional coupling between two brain networks, lateral frontoparietal network (LFPN) and default mode network (DMN), relates to cognitive test performance, for children and adults. However, most of the research that led to this conclusion has been conducted with non-representative samples of individuals from higher-income backgrounds, and so further studies including participants from a broader range of socioeconomic backgrounds are required. Here, in a pre-registered study, we analyzed resting-state fMRI from 6839 children ages 9-10 years from the ABCD dataset. For children from households defined as being above poverty (family of 4 with income > $25,000, or family of 5+ with income > $35,000), we replicated prior findings; that is, we found that better performance on cognitive tests correlated with weaker LFPN-DMN coupling. For children from households defined as being in poverty, the direction of association was reversed, on average: better performance was instead directionally related to stronger LFPN-DMN connectivity, though there was considerable variability. Among children in households below poverty, the direction of this association was predicted in part by features of their environments, such as school type and parent-reported neighborhood safety. These results highlight the importance of including representative samples in studies of child cognitive development., (© 2021. The Author(s).)

Empirical audit and review is an approach to assessing the evidentiary value of a research area. It involves identifying a topic and selecting a cross-section of studies for replication. We apply the method to research on the psychological consequences of scarcity. Starting with the papers citing a seminal publication in the field, we conducted replications of 20 studies that evaluate the role of scarcity priming in pain sensitivity, resource allocation, materialism, and many other domains. There was considerable variability in the replicability, with some strong successes and other undeniable failures. Empirical audit and review does not attempt to assign an overall replication rate for a heterogeneous field, but rather facilitates researchers seeking to incorporate strength of evidence as they refine theories and plan new investigations in the research area. This method allows for an integration of qualitative and quantitative approaches to review and enables the growth of a cumulative science., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Abstract: We reviewed INSPPIRE (International Study Group of Pediatric Pancreatitis: In Search for a Cure) database for splanchnic venous thrombosis or arterial pseudoaneurysms to determine the incidence, risk factors and outcomes of peripancreatic vascular complications in children with acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP). Of 410 children with diagnostic imaging studies, vascular complications were reported in five (1.2%); two had ARP, three CP. The vascular events were reported during moderately severe or severe acute pancreatitis (AP) in four, mild AP in one. Venous thrombosis occurred in four, arterial pseudoaneurysm (left gastric artery) in one. Two patients with venous thrombosis were treated with anticoagulant, one achieved recanalization (splenic vein). In two patients who did not receive anticoagulants, one re-canalized. No adverse effects were observed with anticoagulants. The child with pseudoaneurysm underwent aneurysmal coiling. Anti-coagulants appear to be safe in children with acute pancreatitis, their long-term benefit needs to be further investigated., Competing Interests: Dr Mark Lowe is on the Board of Directors of the National Pancreas Association and receives royalties from Millipore Inc and UpToDate. Dr Tanja Gonska received a research grant from Vertex Pharmaceuticals, and she is a consultant for Cystic Fibrosis Foundation. Dr Aliye Uc is a member of American Board of Pediatrics, Subboard of Pediatric Gastroenterology, Associate Editor of Pancreatology and Consultant for Cystic Fibrosis Foundation. The remaining authors report no conflicts of interest., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Nontuberculous mycobacteria (NTM) are environmental organisms that can cause opportunistic pulmonary disease with species diversity showing significant regional variation. In the United States, Hawai'i shows the highest rate of NTM pulmonary disease. The need for improved understanding of NTM reservoirs led us to identify NTM from patient respiratory specimens and compare NTM diversity between outdoor and indoor locations in Hawai'i. A total of 545 water biofilm samples were collected from 357 unique locations across Kaua'i ( n = 51), O'ahu ( n = 202), Maui ( n = 159), and Hawai'i Island ( n = 133) and divided into outdoor ( n = 179) or indoor ( n = 366) categories. rpoB sequence analysis was used to determine NTM species and predictive modeling applied to develop NTM risk maps based on geographic characteristics between environments. M. chimaera was frequently identified from respiratory and environmental samples followed by M. chelonae and M. abscessus; yet significantly less NTM were consistently recovered from outdoor compared to indoor biofilms, as exemplified by showerhead biofilm samples. While the frequency of M. chimaera recovery was comparable between outdoor and indoor showerhead biofilms, phylogenetic analyses demonstrate similar rpoB gene sequences between all showerhead and respiratory M. chimaera isolates, supporting outdoor and indoor environments as possible sources for pulmonary M. chimaera infections.

Variable number of tandem repeat (VNTR) sequences in the genome can have functional consequences that contribute to human disease. This is the case for the CEL gene, which is specifically expressed in pancreatic acinar cells and encodes the digestive enzyme carboxyl ester lipase. Rare single-base deletions (DELs) within the first (DEL1) or fourth (DEL4) VNTR segment of CEL cause maturity-onset diabetes of the young, type 8 (MODY8), an inherited disorder characterized by exocrine pancreatic dysfunction and diabetes. Studies on the DEL1 variant have suggested that MODY8 is initiated by CEL protein misfolding and aggregation. However, it is unclear how the position of single-base deletions within the CEL VNTR affects pathogenic properties of the protein. Here, we investigated four naturally occurring CEL variants, arising from single-base deletions in different VNTR segments (DEL1, DEL4, DEL9, and DEL13). When the four variants were expressed in human embryonic kidney 293 cells, only DEL1 and DEL4 led to significantly reduced secretion, increased intracellular aggregation, and increased endoplasmic reticulum stress compared with normal CEL protein. The level of O-glycosylation was affected in all DEL variants. Moreover, all variants had enzymatic activity comparable with that of normal CEL. We conclude that the longest aberrant protein tails, resulting from single-base deletions in the proximal VNTR segments, have highest pathogenic potential, explaining why DEL1 and DEL4 but not DEL9 and DEL13 have been observed in patients with MODY8. These findings further support the view that CEL mutations cause pancreatic disease through protein misfolding and proteotoxicity, leading to endoplasmic reticulum stress and activation of the unfolded protein response., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Genetic variants contribute to the risk of chronic pancreatitis (CP) in adults and children. The risk variant CEL-HYB1, a recombinant hybrid allele of CEL and its neighboring pseudogene (CELP), encodes a pathogenic variant of the pancreatic digestive enzyme carboxyl ester lipase (CEL). We previously identified combinations of two non-synonymous SNPs, c.1463T>C (p. Ile488Thr) and c.1643C>T (p. Thr548Ile), in the break point region of CEL-HYB1. Herein, we tested whether these missense variants alter CP risk and their impact on functional properties of the CEL-HYB1 protein. Examination of CEL-HYB1 haplotypes in European patients and controls revealed that the combinationThr488-Ile548 was present only in cases (p ≤ .001). The lipase activity of purified recombinant CEL-HYB1 variants showed normal or near normal activity. CEL-HYB variants expressed in HEK293T cells all had decreased secretion compared with CEL, formed intracellular protein aggregates, and triggered endoplasmic reticulum stress. Thus, we propose that the presence of missense variants in CEL-HYB increases the pathogenicity of CEL-HYB1 through misfolding and gain-of-function proteotoxicity. Interestingly, Thr488-Ile548 and Thr488-Thr548 were equally pathogenic in the functional assays even though only the Thr488-Ile548 haplotype was significantly enriched in cases. The explanation for the mismatch between genetic and functional data requires further investigation., (© 2020 Wiley Periodicals LLC.)

Three-dimensional (3D) representations of the environment are often critical for selecting actions that achieve desired goals. The success of these goal-directed actions relies on 3D sensorimotor transformations that are experience-dependent. Here we investigated the relationships between the robustness of 3D visual representations, choice-related activity, and motor-related activity in parietal cortex. Macaque monkeys performed an eight-alternative 3D orientation discrimination task and a visually guided saccade task while we recorded from the caudal intraparietal area using laminar probes. We found that neurons with more robust 3D visual representations preferentially carried choice-related activity. Following the onset of choice-related activity, the robustness of the 3D representations further increased for those neurons. We additionally found that 3D orientation and saccade direction preferences aligned, particularly for neurons with choice-related activity, reflecting an experience-dependent sensorimotor association. These findings reveal previously unrecognized links between the fidelity of ecologically relevant object representations, choice-related activity, and motor-related activity., Competing Interests: TC, RD, BK, AS, LT, ML, AR No competing interests declared, (© 2020, Chang et al.)

Objective: The aim of the study was to determine whether clinical characteristics and management of pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) differ across INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In Search for a cuRE) sites., Study Design: Data were collected from INSPPIRE and analyzed per US regions and "non-US" sites. Between-group differences were compared by Pearson chi-square test. Differences in disease burden were compared by Kruskal-Wallis test., Results: Out of the 479 subjects, 121 (25%) were enrolled in West, 151 (32%) Midwest, 45 Northeast (9%), 78 (16%) South, and 84 (18%) at non-US sites. Hispanic ethnicity was more common in South (P < 0.0001); white race in Northeast (P = 0.009). CP was less common and time from diagnosis of first acute pancreatitis to CP was longer in children at non-US sites (P = 0.0002 and P = 0.011, respectively). Genetic mutations were most common among all groups; PRSS1 variants predominated in Midwest (P = 0.002). Gallstones were more frequent in South (P = 0.002). Endoscopic retrograde cholangiopancreatography (ERCP) and computed tomography (CT) imaging were more commonly utilized in United States compared with non-United States (P < 0.0001), but there were no differences in the use of MRI/MRCP. Disease burden was highest in the West and Midwest, possibly as total pancreatectomy and islet autotransplantation (TPIAT) referral sites were located in these regions. All therapies were less commonly administered in non-US sites (P < 0.0001)., Conclusions: This is the first study to describe geographical variations in the INSPPIRE cohort, which possibly reflect variations in practice and referral patterns. The underlying reason behind the lower frequency of CP and fewer treatments in non-United States sites need to be further explored.

Many political movements across the world today define citizenship in exclusionary ethnic or religious terms. This study extends research on ethnic-national associations in adults to children, adding to the relatively sparse literature on the development of national associations in children and in nonwestern contexts. Explicit and implicit religious-national associations were examined in a sample of 160 nine- to sixteen-year-olds (79 Hindu; 81 Muslim) in Gujarat, India. Results suggest that while Hindu children show a strong Indian = Hindu association by age 9, Muslim children appear to be buffered from this association. Furthermore, this association uniquely predicts variance in children's attitudes about social policy and their concept of nationality, above and beyond their age, religion, and intergroup attitudes., (© 2019 Society for Research in Child Development.)

Visceral adipose tissue plays a critical role in numerous diseases. Although imaging studies often show adipose involvement in abdominal diseases, their outcomes may vary from being a mild self-limited illness to one with systemic inflammation and organ failure. We therefore compared the pattern of visceral adipose injury during acute pancreatitis and acute diverticulitis to determine its role in organ failure. Acute pancreatitis-associated adipose tissue had ongoing lipolysis in the absence of adipocyte triglyceride lipase (ATGL). Pancreatic lipase injected into mouse visceral adipose tissue hydrolyzed adipose triglyceride and generated excess nonesterified fatty acids (NEFAs), which caused organ failure in the absence of acute pancreatitis. Pancreatic triglyceride lipase (PNLIP) increased in adipose tissue during pancreatitis and entered adipocytes by multiple mechanisms, hydrolyzing adipose triglyceride and generating excess NEFAs. During pancreatitis, obese PNLIP-knockout mice, unlike obese adipocyte-specific ATGL knockouts, had lower visceral adipose tissue lipolysis, milder inflammation, less severe organ failure, and improved survival. PNLIP-knockout mice, unlike ATGL knockouts, were protected from adipocyte-induced pancreatic acinar injury without affecting NEFA signaling or acute pancreatitis induction. Therefore, during pancreatitis, unlike diverticulitis, PNLIP leaking into visceral adipose tissue can cause excessive visceral adipose tissue lipolysis independently of adipocyte-autonomous ATGL, and thereby worsen organ failure.

Objective: Functional pancreatic sphincter dysfunction (FPSD), previously characterized as pancreatic sphincter of Oddi dysfunction, is a rarely described cause of pancreatitis. Most studies are reported in adults with alcohol or smoking as confounders, which are uncommon risk factors in children. There are no tests to reliably diagnose FPSD in pediatrics and it is unclear to what degree this disorder contributes to childhood pancreatitis., Methods: We conducted a literature review of the diagnostic and treatment approaches for FPSD, including unique challenges applicable to pediatrics. We identified best practices in the management of children with suspected FPSD and formed a consensus expert opinion., Results: In children with acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP), we recommend that other risk factors, specifically obstructive factors, be ruled out before considering FPSD as the underlying etiology. In children with ARP/CP, FPSD may be the etiology behind a persistently dilated pancreatic duct in the absence of an alternative obstructive process. Endoscopic retrograde cholangiopancreatography with sphincterotomy should be considered in a select group of children with ARP/CP when FPSD is highly suspected and other etiologies have been effectively ruled out. The family and patient should be thoroughly counseled regarding the risks and advantages of endoscopic intervention. Endoscopic retrograde cholangiopancreatography for suspected FPSD should be considered with caution in children with ARP/CP when pancreatic ductal dilatation is absent., Conclusions: Our consensus expert guidelines provide a uniform approach to the diagnosis and treatment of pediatric FPSD. Further research is necessary to determine the full contribution of FPSD to pediatric pancreatitis.

A workshop on research gaps and opportunities for Precision Medicine in Pancreatic Disease was sponsored by the National Institute of Diabetes and Digestive Kidney Diseases on July 24, 2019, in Pittsburgh. The workshop included an overview lecture on precision medicine in cancer and 4 sessions: (1) general considerations for the application of bioinformatics and artificial intelligence; (2) omics, the combination of risk factors and biomarkers; (3) precision imaging; and (4) gaps, barriers, and needs to move from precision to personalized medicine for pancreatic disease. Current precision medicine approaches and tools were reviewed, and participants identified knowledge gaps and research needs that hinder bringing precision medicine to pancreatic diseases. Most critical were (a) multicenter efforts to collect large-scale patient data sets from multiple data streams in the context of environmental and social factors; (b) new information systems that can collect, annotate, and quantify data to inform disease mechanisms; (c) novel prospective clinical trial designs to test and improve therapies; and (d) a framework for measuring and assessing the value of proposed approaches to the health care system. With these advances, precision medicine can identify patients early in the course of their pancreatic disease and prevent progression to chronic or fatal illness.

Objective: The aim of the study was to determine the rate of progression from acute recurrent pancreatitis (ARP) to chronic pancreatitis (CP) in children and assess risk factors., Study Design: Data were collected from the INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE) cohort. Kaplan-Meier curves were constructed to calculate duration of progression from initial attack of acute pancreatitis (AP) to CP. Log-rank test was used to compare survival (nonprogression) probability distribution between groups. Cox proportional hazard regression models were fitted to obtain hazard ratio (with 95% confidence interval [CI]) of progression for each risk variable., Results: Of 442 children, 251 had ARP and 191 had CP. The median time of progression from initial attack of AP to CP was 3.79 years. The progression was faster in those ages 6 years or older at the first episode of AP compared to those younger than 6 years (median time to CP: 2.91 vs 4.92 years; P = 0.01). Children with pathogenic PRSS1 variants progressed more rapidly to CP compared to children without PRSS1 variants (median time to CP: 2.52 vs 4.48 years; P = 0.003). Within 6 years after the initial AP attack, cumulative proportion with exocrine pancreatic insufficiency was 18.0% (95% CI: 12.4%, 25.6%); diabetes mellitus was 7.7% (95% CI: 4.2%, 14.1%)., Conclusions: Children with ARP rapidly progress to CP, exocrine pancreatic insufficiency, and diabetes. The progression to CP is faster in children who were 6 years or older at the first episode of AP or with pathogenic PRSS1 variants. The factors that affect the aggressive disease course in childhood warrant further investigation.

Introduction: The significance of pancreas divisum (PD) as a risk factor for pancreatitis is controversial. We analyzed the characteristics of children with PD associated with acute recurrent or chronic pancreatitis to better understand its impact., Patients and Methods: We compared children with or without PD in the well-phenotyped INSPPIRE (INternational Study group of Pediatric Pancreatitis: In search for a cuRE) cohort. Differences were analyzed using 2-sample t test or Wilcoxon rank sum test for continuous variables, Pearson χ or Fisher exact test for categorical variables., Results: PD was found in 52 of 359 (14.5%) subjects, a higher prevalence than the general population (∼7%). Females more commonly had PD (71% vs. 55%; P=0.02). Children with PD did not have a higher incidence of mutations in SPINK1, CFTR, CTRC compared with children with no PD. Children with PD were less likely to have PRSS1 mutations (10% vs. 34%; P<0.01) or a family history of pancreatitis (P<0.05), and more likely to have hypertriglyceridemia (11% vs. 3%; P=0.03). Children with PD underwent significantly more endoscopic procedures and pancreatic sphincterotomy. Patients with PD had fewer attacks of acute pancreatitis (P=0.03) and were less likely to develop exocrine pancreatic insufficiency (P=0.01). Therapeutic endoscopic retrograde cholangiopancreatography was considered most helpful if pancreatic duct was impacted with stones (83% helpful)., Conclusions: PD is likely a risk factor for acute recurrent pancreatitis and chronic pancreatitis in children that appears to act independently of genetic risk factors. Patients with PD and stones obstructing the pancreatic duct benefit most from therapeutic endoscopic retrograde cholangiopancreatography.

Objectives: Premature activation of the digestive protease trypsin within the pancreatic parenchyma is a critical factor in the pathogenesis of pancreatitis. Alterations in genes that affect intrapancreatic trypsin activity are associated with chronic pancreatitis (CP). Recently, carboxyl ester lipase emerged as a trypsin-independent risk gene. Here, we evaluated pancreatic lipase (PNLIP) as a potential novel susceptibility gene for CP., Methods: We analyzed all 13 PNLIP exons in 429 nonalcoholic patients with CP and 600 control subjects from Germany, in 632 patients and 957 controls from France, and in 223 patients and 1,070 controls from Japan by DNA sequencing. Additionally, we analyzed selected exons in further 545 patients with CP and 1,849 controls originating from Germany, United States, and India. We assessed the cellular secretion, lipase activity, and proteolytic stability of recombinant PNLIP variants., Results: In the German discovery cohort, 8/429 (1.9%) patients and 2/600 (0.3%) controls carried a PNLIP missense variant (P = 0.02, odds ratio [OR] = 5.7, 95% confidence interval [CI] = 1.1-38.9). Variants detected in patients were prone to proteolytic degradation by trypsin and chymotrypsin. In the French replication cohort, protease-sensitive variants were also enriched in patients with early-onset CP (5/632 [0.8%]) vs controls (1/957 [0.1%]) (P = 0.04, OR = 7.6, 95% CI = 0.9-172.9). In contrast, we detected no protease-sensitive variants in the non-European populations. In the combined European data, protease-sensitive variants were found in 13/1,163 cases (1.1%) and in 3/3,000 controls (0.1%) (OR = 11.3, 95% CI = 3.0-49.9, P < 0.0001)., Conclusions: Our data indicate that protease-sensitive PNLIP variants are novel genetic risk factors for the development of CP.

Objectives: The aim of the present study was to investigate the natural history of chronic pancreatitis (CP); patients in the North American Pancreatitis Study2 (NAPS2, adults) and INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE, pediatric) were compared., Methods: Demographics, risk factors, disease duration, management and outcomes of 224 children and 1063 adults were compared using appropriate statistical tests for categorical and continuous variables., Results: Alcohol was a risk in 53% of adults and 1% of children (P < 0.0001); tobacco in 50% of adults and 7% of children (P < 0.0001). Obstructive factors were more common in children (29% vs 19% in adults, P = 0.001). Genetic risk factors were found more often in children. Exocrine pancreatic insufficiency was similar (children 26% vs adult 33%, P = 0.107). Diabetes was more common in adults than children (36% vs 4% respectively, P < 0.0001). Median emergency room visits, hospitalizations, and missed days of work/school were similar across the cohorts. As a secondary analysis, NAPS2 subjects with childhood onset (NAPS2-CO) were compared with INSPPIRE subjects. These 2 cohorts were more similar than the total INSPPIRE and NAPS2 cohorts, including for genetic risk factors. The only risk factor significantly more common in the NAPS2-CO cohort compared with the INSPPIRE cohort was alcohol (9% NAPS2-CO vs 1% INSPPIRE cohorts, P = 0.011)., Conclusions: Despite disparity in age of onset, children and adults with CP exhibit similarity in demographics, CP treatment, and pain. Differences between groups in radiographic findings and diabetes prevalence may be related to differences in risk factors associated with disease and length of time of CP.

Background: Dysfunctional reward processing is a core feature of major depressive disorder. While there is growing knowledge of reward processing in adolescent depression, researchers have ignored neural mechanisms of resilience to depression. Here, we examine neural correlates of reward processing that characterize resilience and risk in adolescents at risk for depression, facilitating the development of effective intervention approaches that strengthen resilience to psychopathology in at-risk youth., Methods: 50 adolescent females were followed through age 18: 32 at-risk adolescents who either did (remitted-depressed; n = 15) or did not (resilient; n = 17) experience a depressive episode, and 18 low-risk healthy controls. Participants completed clinical assessments at 18-month intervals and an fMRI reward-processing task in late adolescence. We conducted predictive modeling with a priori reward regions of interest (ROIs)., Results: At-risk resilient and remitted-depressed adolescents exhibited less striatal activation than did controls during anticipation of reward. Resilient adolescents exhibited greater activation than did remitted-depressed adolescents in the middle frontal gyrus during reward anticipation, and less activation in the superior frontal gyrus and cuneus during processing of reward outcome. Using predictive modeling, ventral anterior cingulate cortex and putamen activation during reward processing distinguished resilient from remitted-depressed adolescents with 83% accuracy., Limitations: The relatively small sample size of only females and the fact that fMRI data were obtained at one time point in late adolescence are limitations., Conclusions: Distinct patterns of neural activation in reward circuitry appear to be markers of risk and resilience that may be targets for prevention and treatment approaches aimed at strengthening adaptive reward processing in at-risk adolescents., (Copyright © 2018 Elsevier B.V. All rights reserved.)