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Katarzyna Sznurkowska,1 Justyna Luty,2 Ewa Bryl,2 Jacek M Witkowski,3 Blanka Hermann-Okoniewska,4 Piotr Landowski,1 Marta Kosek,1 Agnieszka Szlagatys-Sidorkiewicz1 1Department of Pediatrics, Pediatric Gastroenterology, Allergology and Nutrition, Medical University of Gdańsk, Gdańsk, Poland; 2Department of Pathology and Experimental Rheumatology, Medical University of Gdańsk, Gdańsk, Poland; 3Department of Pathophysiology, Medical University of Gdańsk, Gdańsk, Poland; 4Department of Pathology and Neuropathology, Medical University of Gdańsk, Gdańsk, PolandCorrespondence: Katarzyna SznurkowskaDepartment of Pediatrics, Pediatric Gastroenterology, Hepatology and Nutrition, Medical University of Gdańsk, Nowe Ogrody 1-6, Gdańsk 80-803, PolandTel +58 663625861Fax +48 58 764 04 40Email k.sznurkowska@gumed.edu.plBackground/Aims: The proportions of intestinal and peripheral regulatory T cells (Tregs) in pediatric inflammatory bowel disease (IBD) were poorly investigated, as well as different subsets of these cells. Helios and Neuropilin-1 were proposed as markers differentiating between thymic and peripheral Tregs. Therefore, the aim of current work was to investigate the proportions of Tregs and expression of Helios and Neuropilin-1 in Tregs in peripheral blood and intestinal mucosa of children with inflammatory bowel disease.Materials and methods: Fifteen patients newly diagnosed with inflammatory bowel disease: ulcerative colitis (n=7) and Crohn’s disease (n=8) were included in the study. Nine children who presented with no abnormalities in colonoscopy served as a control group. Quantification of regulatory T cells of the CD4+CD25highFOXP3+ phenotype, as well as Helios+ and Neuropilin-1+ in peripheral blood and bowel mucosa was based on multicolor flow cytometry.Results: The rates of circulating and intestinal Tregs were significantly higher in the studied group than in the control group. The rate of intestinal T regulatory lymphocytes was significantly higher than circulating Tregs in patients with IBD, but not in the control group. The median proportion of circulating FOXP3+Helios+ cells amounted to 24.83% in IBD patients and 15.93% in the controls. The median proportion of circulating FOXP3+Nrp-1+ cells was 34.23% in IBD and 21.01% in the control group. No statistically significant differences were noted for the circulating FOXP3+Helios+ cells and FOXP3+Nrp-1+ cells between the studied and the control group.Conclusion: The rates of circulating and intestinal T regulatory cells are increased in naïve pediatric patients with IBD. The rate of Tregs is higher in intestinal mucosa than in peripheral blood in patients with IBD. Flow cytometry is a valuable method assessing the composition of infiltrates in inflamed tissue. Helios and Neuropilin-1 likely cannot serve as markers to differentiate between natural and adaptive Tregs.Keywords: T regulatory cells, circulating Tregs, intestinal Tregs, Helios, Neuropilin-1, IBD, inflammatory bowel disease, children

Background. Placental Plasmodium falciparum infection modulates neonatal cell-mediated immune responses and is associated with increased susceptibility of infants to malaria. Methods. By flow-cytometric analysis of maternal peripheral and cord blood samples collected at delivery, we measured and compared the activation status and proinflammatory cytokine activity of T cells from women segregated into groups according to malaria status. Results. Stimulation with phorbol myristate acetate/ionomycin resulted in the highest percentages of tumor necrosis factor-α- and interferon-γ-positive γδ T cells in peripheral blood samples and in corresponding cord blood samples from those treated for malaria during pregnancy. Cord blood samples from this group also contained significantly higher percentages of CD69+ and CD25+ γδ T cells and CD3+ T cells, compared with samples from either the group with active placental P. falciparum infection at delivery or the group with no infection. Proinflammatory cytokine activity of cells from the group with placental P. falciparum infection at delivery was either similar to or lower than that of cells from the group with no infection. Conclusions. The findings imply that treatment of P. falciparum malaria during pregnancy leads to enhanced innate immune T cell activation and proinflammatory cytokine responses in both maternal and fetal compartments. Ongoing placental P. falciparum infection, conversely, is associated with an absence of such activity. [ABSTRACT FROM AUTHOR]

Background: Serious substance misuse and dependence is widely seen as damaging to an individual and to society in general. Whereas the medical and society effects of substance misuse are widely described, some commentators suggest substance misuse may be an "alternative lifestyle".Aim: To assess general life satisfaction amongst treatment-seeking people with substance dependence.Methods: The Satisfaction With Life Scale (SWLS) was administered to a sample of opioid-dependent people receiving substitute medication.Results: 105 subjects and 105 age-sex matched subjects in a comparison group completed the questionnaire. The mean SWLS score was 7.12 (SD = 10.6; median = 6) for patients compared to 22.6 (SD = 6.8) in the comparison group. (Two sided p < 0.0001; Median difference = -13.5; Wilcoxon signed rank test.)Conclusion: The study used a validated instrument and objective reports to confirm significantly higher rates of dissatisfaction with life among opioid dependent people in treatment when compared to members of the general population. [ABSTRACT FROM AUTHOR]

Acromegaly is a rare disorder of unregulated hypersecretion of growth hormone that causes cardiovascular, metabolic and respiratory complications. Herein, we describe the case of a middle-aged man admitted to the hospital with severe COVID-19 found to have clinical and biochemical evidence of acromegaly. His respiratory status declined despite initiation of standard treatments, prompting initiation of subcutaneous octreotide. Following initiation of this therapy, he rapidly improved and was discharged from the hospital 2 days later. Subsequent workup revealed a pituitary macroadenoma that was surgically removed, with improvement in his acromegaly symptoms. COVID-19 disease severity is increased by pre-existing diabetes, lung disease and immunosuppression. Although this patient had obstructive sleep apnoea and pre-diabetes, we hypothesise that our patient's acromegaly contributed to his severe course, as reflected by his rapid improvement after starting treatment with subcutaneous octreotide. Acromegaly may predispose to more severe outcomes in patients with COVID-19., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Root cause analysis (RCA) is a widely utilized tool for investigating systems issues that lead to patient safety events and near misses, yet only 38% of learners participate in an interdisciplinary patient safety investigation during training. Common barriers to RCA education and participation include faculty time and materials, trainee time constraints, and learner engagement., Methods: We developed a simulated RCA workshop to be taught to a mix of medical and surgical specialties from over 11 GME programs and to third-year medical students. The workshop was a single 90-minute session formatted as a gamified mystery dinner including characters and sequentially revealed clues to promote engagement. Participant satisfaction and subjective knowledge, skills, and attitudes were assessed with a pre/post survey., Results: The workshop was completed by 134 learners between October 2018 and October 2019. The short workshop duration and premade simulation allowed a small number of faculty to train a wide variety of learners in various educational settings. Participants' presurvey (124 out of 134, 92%) versus postsurvey (113 out of 134, 84%) responses showed that attitudes about RCA were statistically improved across all domains queried, with an average effect size of 0.6 (moderate effect); 91% of participants would recommend this course to a colleague., Discussion: A 90-minute, gamified, simulated RCA workshop was taught to medical students and multiple GME specialties with subjective improvements in patient safety attitudes and knowledge while alleviating faculty time constraints in case development., (© 2021 Smeraglio et al.)

Background: Identification of surrogate decision makers (SDMs) is an important part of advance care planning for hospitalized patients. Despite its importance, the best methods for engaging residents to sustainably improve SDM documentation have not been identified., Objective: We implemented a hospital-wide quality improvement initiative to increase identification and documentation of SDMs in the electronic health record (EHR) for hospitalized patients, utilizing a Housestaff Quality and Safety Council (HQSC)., Methods: EHR documentation of SDMs for all adult patients admitted to a tertiary academic hospital, excluding psychiatry, were tracked and grouped by specialty in a weekly run chart during the intervention period (July 2015 through April 2016). This also continued postintervention. Interventions included educational outreach for residents, monthly plan-do-study-act cycles based on performance feedback, and a financial incentive of a one-time payment of 0.75% of a resident's salary put into the retirement account of each resident, contingent on meeting an SDM documentation target. Comparisons were made using statistical process control and chi-square tests., Results: At baseline, SDMs were documented for 11.1% of hospitalized adults. The intervention period included 9146 eligible admissions. Hospital-wide SDM documentation increased significantly and peaked near the financial incentive deadline at 48% (196 of 407 admissions, P < 001). Postintervention, hospital-wide SDM documentation declined to 30% (134 of 446 admissions, P < .001), but remained stable., Conclusions: This resident-led intervention sustainably increased documentation of SDMs, despite a decline from peak rates after the financial incentive period and notable differences in performance patterns by specialty admitting service., Competing Interests: Conflict of interest: The authors declare they have no competing interests.

Autoimmune thyroid disease (ATD) is a chronic autoimmune thyroiditis with a complex pathogenesis including environmental factors, genetic background and immune system actions. Despite the large-scale research and discovery of new subpopulations of lymphocytes, cytokines, chemokines and their functions in the human body, the ethiology of ATD in many aspects remains a mystery. This article tries to summarize mostly the immunological aspects of this disease, including the roles of different cells types (dendritic cells, B cells, CD4 + and CD8 + T cells, NK cells and regulatory T cells) and of different cytokines (secreted by Th1/Th2/Th17/Th22 lymphocyte subpopulations and other, including the IL-23 and CXCL10). We describe the role of immunological abnormalities in the ATD pathogenesis and show that for some cells and cytokines their respective roles are not clear, and bi-directional action is possible. Finally, we propose a network of interactions between the immune cells and thyrocytes in the course of ATD., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Iron is one of the nutrients that require special consideration in a plant-based diet. The widespread belief is that meat is the best source of iron and a vegetarian diet increases the risk of its deficiency. This conviction has been the subject of analysis in a growing number of scientific reports., Objectives: The aim of this study was to assess the iron intake and iron metabolism in vegetarians and vegans compared to a control group., Material and Methods: A total of 55 vegetarians and 36 healthy volunteers were studied. The following parameters were measured in serum: iron, ferritin, transferrin, transferrin receptor, and hepcidin-25, using the enzyme-linked immunosorbent assay (ELISA) method. The dietary iron intake was assessed by a 24-h dietary recall., Results: The mean daily intake (DI) of iron was significantly higher in the female vegan group compared to the control group. Iron, hepcidin-25, ferritin and transferrin receptor in serum remained within their normal ranges. The ferritin concentration was significantly decreased and that of transferrin significantly higher in both female groups and in the male vegan group., Conclusions: The obtained results show that the studied parameters, excluding transferrin, remained within normal ranges. However, the ferritin concentration was significantly decreased in the female vegetarian group and also in both vegan groups. This may indicate low iron storage.

Cathepsin D (CD) up-regulation has been associated with human malignancy and poor prognosis. Thrombin up-regulated CD mRNA and protein in eight tumor cell lines as well as in human umbilical vascular endothelial cells (HUVEC). Thrombin increased the secretion of CD by 3- to 8-fold and enhanced chemotaxis ( approximately 2-fold) in 4T1 murine mammary CA cells, which was completely inhibited with the knockdown of CD. Secreted 4T1 CD induced neoangiogenesis by 2.4-fold on a chick chorioallantoic membrane, which was blocked in CD-KD cells. The addition of pure CD (2 ng) to the chick chorioallantoic membrane increased angiogenesis by 2.1-fold, which was completely inhibited by Pepstatin A (Pep A). CD enhanced human HUVEC chemotaxis and Matrigel tube formation by 2-fold, which was then blocked by Pep A. CD enhanced HUVEC matrix metalloproteinase 9 (MMP-9) activity by approximately 2-fold, which was completely inhibited by Pep A as well as a generic MMP inhibitor, GM6001. The injection of CD-KD 4T1 cells into syngeneic mice inhibited tumor growth by 3- to 4-fold compared with empty vector (EV) cells. Hirudin, a specific thrombin inhibitor, inhibited the growth of wild-type and EV cells by 2- to 3-fold, compatible with thrombin up-regulation of CD. CD and thrombin also contributed to spontaneous pulmonary metastasis; 4-fold nodule inhibition with CD versus EV and 4.6-fold inhibition with hirudin versus EV (P < 0.02). Thus, thrombin-induced CD contributes to the malignant phenotype by inducing tumor cell migration, nodule growth, metastasis, and angiogenesis. CD-induced angiogenesis requires the proteolytic activation of MMP-9.

Is alcoholism an illness or merely a self-inflicted indulgence? Can we afford specialist alcohol treatment services? Do they even work? Should the tax payer foot the bill? Is the lack of such services 'perverse'? In this lively debate Drs. Carnwath and Luty weigh up the pros and cons of controlling the effects of 'our favourite drug'.

Cigarette consumption and smoking cessation are influenced in part by genes. Personality traits have also been implicated in the aetiology of smoking. Neuroticism, a personality trait with a heritable component, correlates well with anxiety and depression, increasing the risk of being a smoker and decreasing the chance of smoking cessation. Several prior studies in non-British populations have given conflicting results as to whether some genetic polymorphisms affect the relationship between smoking and neuroticism. This study investigated the influence of serotonin transporter (5HTTLPR) genotypes on a composite measure of neuroticism and cigarette consumption/smoking cessation in a British population. Although neuroticism was significantly associated with cigarette consumption and smoking cessation, genotype did not affect this relationship. Our results do not support initial interest in utilising 5HTTLPR genotypes in combination with neuroticism ratings for predicting outcome in smoking cessation clinical settings.

A postal survey of a representative sample of UK adults was conducted. Subjects were asked "What do you understand by the term 'schizophrenia'?".Four hundred four completed questionnaires were received (81% response rate). Forty-two percent of respondents mentionedat least one first rank symptom of schizophrenia or gave a description that reasonably approximated to any diagnostic feature as stated inICD-10. Forty percent mentioned "split" or "multiple" personality. Thirty-eight percent described auditory hallucinations or "hearing voices".Fifteen percent mentioned "delusions" or described passivity experiences. Only 6% of subjects mentioned violence in their descriptions.

The CA repeat microsatellite DXS456, with a heterozygosity of 77%, has been localized by multipoint linkage analysis in relation to 20 other genetic markers. DXS456 mapped to a 4.2-cM interval defined by the flanking markers DXS178 and DXS287. The maximum likelihood order of markers, cen-(DXYS1X/DXYS13X/DXYS2X/DXYS12X)-DXS366 -DXS178-DXS456-DXS287-DXS358-DXS267- qter, is favored by odds greater than 1000:1 over the subset of most likely alternative orders. Linkage of DXS456 can be inferred for at least six disease genes that are known to be linked to markers in the region Xq21.31-Xq25 and the marker will serve as an important index point for orienting these and other disease and marker loci in the region.

The human genome contains approximately 50,000 copies of an interspersed repeat with the sequence (dT.dG/dA.dC)n, where n = approximately 10-60. We and others have found that several of these repeats have variable lengths in different individuals, with allelic fragments varying in size by multiples of 2 bp. These "microsatellite" variable number of tandem repeats (VNTRs) may be scored by PCR, using unique flanking primers to amplify the repeat-containing regions and resolving the products on DNA sequencing gels. Since few VNTRs have been found on the X chromosome, we screened a flow-sorted X chromosome-specific genomic library for microsatellites. Approximately 25% of the phage clones hybridized to a poly (dT-dG).poly(dA-dC) probe. Of seven X-linked microsatellites present in positive phages, five are polymorphic and three have both eight or more alleles and heterozygosities exceeding 75%. Using PCR to amplify genomic DNAs from hybrid cell panels, we confirmed the X localization of these VNTRs and regionally mapped four of them. The fifth VNTR was regionally mapped by virtue of its tight linkage to DXS87 in Centre du Polymorphisme Humain families. We conclude that whatever factors limit the occurrence of "classical" VNTRs and RFLPs on the X chromosome do not appear to operate in the case of microsatellite VNTRs.

The human genome contains approximately 50,000 copies of an interspersed repeat with the sequence (dT-dG)n, where n = approximately 10-60. In humans, (TG)n repeats have been found in several sequenced regions. Since minisatellite regions with larger repeat elements often display extensive length polymorphisms, we suspected that (TG)n repeats ("microsatellites") might also be polymorphic. Using the polymerase chain reaction to amplify a (TG)n microsatellite in the human cardiac actin gene, we detected 12 different allelic fragments in 37 unrelated individuals, 32 of whom were heterozygous. Codominant Mendelian inheritance of fragments was observed in three families with a total of 24 children. Because of the widespread distribution of (TG)n microsatellites, polymorphisms of this type may be generally abundant and present in regions where minisatellites are rare, making such microsatellite loci very useful for linkage studies in humans.