Remote assessment of ADHD in children and adolescents: recommendations from the European ADHD Guidelines Group following the clinical experience during the COVID-19 pandemic.

The COVID-19 pandemic led ADHD services to modify the clinical practice to reduce in-person contact as much as possible to minimise viral spread. This had far-reaching effects on day-to-day clinical practice as remote assessments were widely adopted. Despite the attenuation of the acute threat from COVID, many clinical services are retaining some remote practices. The lack of clear evidence-based guidance about the most appropriate way to conduct remote assessments meant that these changes were typically implemented in a localised, ad hoc, and un-coordinated way. Here, the European ADHD Guidelines Group (EAGG) discusses the strengths and weaknesses of remote assessment methods of children and adolescents with ADHD in a narrative review based on available data and expert opinions to highlight key recommendations for future studies and clinical practice. We conclude that going forward, despite remote working in clinical services functioning adequately during the pandemic, all required components of ADHD assessment should still be completed following national/international guidelines; however, the process may need adaptation. Social restrictions, including changes in education provision, can either mask or exacerbate features associated with ADHD and therefore assessment should carefully chart symptom profile and impairment prior to, as well as during an ongoing pandemic. While remote assessments are valuable in allowing clinical services to continue despite restrictions and may have benefits for routine care in the post-pandemic world, particular attention must be paid to those who may be at high risk but not be able to use/access remote technologies and prioritize these groups for conventional face-to-face assessments.

Long-term methylphenidate exposure and 24-hours blood pressure and left ventricular mass in adolescents and young adults with attention deficit hyperactivity disorder.

Young people with attention deficit hyperactivity disorder (ADHD) are now being treated with psychostimulant medication for longer than was previously the case and are increasingly likely to remain on methylphenidate into adolescence and adulthood. This study was designed to determine whether the long-term use of methylphenidate (MPH, immediate release or extended release) increases blood pressure and left ventricular mass (LVM) identified by echocardiography in adolescents and young adults with ADHD aged 12-25 years. In a five-site cross-sectional design two groups were compared for 24- hour blood pressure and heart rate (HR) registrations and LVM: 1) adolescents and young adults with ADHD who had been treated with MPH for > 2 years (N=162, age mean (SD) 15.6 (3.0)), and 2) adolescents and young adults with ADHD who had never been treated with methylphenidate (N=71, age mean 17.4 (4.2)). The analyses were controlled for propensity scores derived from age, sex, height, weight, and 19 relevant background variables. A blood pressure indicative of hypertension (>95th percentile) was observed in 12.2% (95% confidence interval 7.3 - 18.9%) of the participants in the MPH treated group and in 9.6% (95%CI 3.2 - 21.0%) of the MPH naïve group, with overlapping intervals. The 24-hour recorded systolic blood pressure (SBP) and HR were significantly higher during daytime in medicated individuals with ADHD than in those with unmedicated ADHD, but were similar in both groups during the night. 24-hour diastolic blood pressure (DBP) did not differ between both groups during either daytime or at night. LVM, corrected for body-surface area (LVMBSA), also did not differ between the two groups (p=0.20, controlling for confounders). Further, MPH daily dose and duration of treatment were unrelated to LVMBSA, SBP, and DBP. Long-term MPH use in adolescents and young adults with ADHD is associated with small but significant increases of SBP and HR during daytime. Given the current sample size, the proportions of hypertension do not differ significantly between MPH treated and MPH-naïve individuals with ADHD. Future studies with larger samples, longer treatment duration, and/or with within-subject designs are necessary. The results do, however, further support recommendations that highlight the importance of monitoring blood pressure and HR during MPH treatment.

High cysteine diet reduces insulin resistance in SHR-CRP rats.

Increased plasma total cysteine (tCys) has been associated with obesity and metabolic syndrome in human and some animal studies but the underlying mechanisms remain unclear. In this study, we aimed at evaluating the effects of high cysteine diet administered to SHR-CRP transgenic rats, a model of metabolic syndrome and inflammation. SHR-CRP rats were fed either standard (3.2 g cystine/kg diet) or high cysteine diet (HCD, enriched with additional 4 g L-cysteine/kg diet). After 4 weeks, urine, plasma and tissue samples were collected and parameters of metabolic syndrome, sulfur metabolites and hepatic gene expression were evaluated. Rats on HCD exhibited similar body weights and weights of fat depots, reduced levels of serum insulin, and reduced oxidative stress in the liver. The HCD did not change concentrations of tCys in tissues and body fluids while taurine in tissues and body fluids, and urinary sulfate were significantly increased. In contrast, betaine levels were significantly reduced possibly compensating for taurine elevation. In summary, increased Cys intake did not induce obesity while it ameliorated insulin resistance in the SHR-CRP rats, possibly due to beneficial effects of accumulating taurine.

Control of protein function through oxidation and reduction of persulfidated states.

Irreversible oxidation of Cys residues to sulfinic/sulfonic forms typically impairs protein function. We found that persulfidation (CysSSH) protects Cys from irreversible oxidative loss of function by the formation of CysSSO1-3H derivatives that can subsequently be reduced back to native thiols. Reductive reactivation of oxidized persulfides by the thioredoxin system was demonstrated in albumin, Prx2, and PTP1B. In cells, this mechanism protects and regulates key proteins of signaling pathways, including Prx2, PTEN, PTP1B, HSP90, and KEAP1. Using quantitative mass spectrometry, we show that (i) CysSSH and CysSSO3H species are abundant in mouse liver and enzymatically regulated by the glutathione and thioredoxin systems and (ii) deletion of the thioredoxin-related protein TRP14 in mice altered CysSSH levels on a subset of proteins, predicting a role for TRP14 in persulfide signaling. Furthermore, selenium supplementation, polysulfide treatment, or knockdown of TRP14 mediated cellular responses to EGF, suggesting a role for TrxR1/TRP14-regulated oxidative persulfidation in growth factor responsiveness.

Imaging Informatics Fellowship Curriculum: a Survey to Identify Core Topics and Potential Inter-Program Areas of Collaboration.

New consumer technologies and interoperability standards have dated the first standardized curriculum for imaging informatics fellowships suggested by the Society for Computer Applications in Radiology (SCAR) in 2004 (Journal of digital imaging 17(4):244-248, 2004). Last year, analysis from this institution characterized current state fellowship graduation requirements and broad curriculum topics for the first time in over a decade (SIIM Strategic Plan 2017-2020). However, an updated "core" curriculum has not yet been developed. Using the recent current state analysis as a baseline, we aimed to perform a focused assessment and propose that this would work towards an updated consensus "core" curriculum as outlined by the Society for Imaging Informatics in Medicine (SIIM, previously SCAR) strategic plan. A secondary aim was to identify individual program strengths and weaknesses to foster inter-program collaboration. Using sub-topics from the National Imaging Informatics Curriculum (NIIC), a week-long introductory course for residents, we expanded the original 29 broad curriculum categories identified in last year's current state analysis into 114 sub-topics. We surveyed imaging informatics fellowship directors to identify sub-topic prioritization on a 5-item Likert scale, teaching methods for each sub-topic, cross-departmental partnerships, and individual program strengths and weaknesses. Only 8% of sub-topics (10/114) received a "definitely" rating with 100% agreement while the majority of sub-topics 77% (88/114) had mixed grading defined by two or fewer "definitely" ratings. These sub-topics mapped to only 4 of the original 29 broad fellowship curriculum categories including Standards, Programming/Development/Software, Infrastructure, and PACS/RIS/Reporting. Our plan is to use consensus topics to build a "core" informatics fellowship curriculum and initiate discussion surrounding mixed grading topics. Knowledge of individual program strengths and weaknesses can be used to foster inter-program collaboration.

A Survey of Imaging Informatics Fellowships and Their Curricula: Current State Assessment.

In a 2016 survey of imaging informatics ("II") fellowship graduates, the surveyed fellowship graduates expressed the "opinion that II fellowships needed further formalization and standardization" Liao et al. (J Digit Imaging, 2016). This, coupled with the fact that the original published "standardized" curriculum is about 15 years out of date in our rapidly changing systems, suggests an opportunity for curriculum improvement. Before agreeing on improved structural and content suggestions for fellowships, we completed a current-state assessment of how each fellowship organizes its education and what requirements each have for fellowship completion. In this work, we aimed to collect existing information about imaging informatics fellowship curricula by contacting institutions across the country. A survey was completed by phone with the fellowship directors of existing imaging informatics fellowships across the country. Additionally, we collected existing documentation that outlines the curricula currently in use at institutions. We reviewed both the interview responses and documentation to assess overlapping trends and institutional differences in curriculum structure and content. All fellowships had suggested reading lists, didactic lectures, and a required project for each fellow. There were required practicum activities or teaching experience each in two fellowships, and one fellowship had a mandatory certification requirement for graduation. Curriculum topics in Technical Informatics or Business and Management were covered by a majority of institutions, while Quality and Safety and Research topics had inconsistent coverage across fellowships. Our plan is to reengage II fellowship directors to develop a core curriculum, which is part of the Society of Imaging Informatics in Medicine strategic plan.

Magnetic Stress Monitoring Using a Directional Potential Drop Technique.

An alternating current potential drop technique is presented that exploits anisotropic magnetostriction to monitor changes in applied stress in steel. The background to the technique is provided together with an ad hoc approximation that describes the sensitivity of the sensor to the underlying properties. A uniaxial loading experiment has been conducted on duplex and mild steel specimens showing that changes in stress are measureable. Saturation and hysteresis afflict the measurement, which, in addition to sensitivity to temperature and magnetisation, may undermine inversion. With the capabilities and limitations of the proposed technique introduced, guidance on possible suitable applications are given, concluding that use for monitoring the number and relative size of fatigue stress cycles may be a suitable and attractive opportunity.

Effect of genetic and nongenetic factors on chemical composition of individual milk samples from dromedary camels (Camelus dromedarius) under intensive management.

The aims of the present study were to monitor the changes in gross chemical composition of individual dromedary camel milk over a 5-yr period, to provide reference values, and to determine the effect of genetic and nongenetic factors influencing camel milk composition under intensive management. A total of 1,528 lactating dromedary camels were included in the study. Animals were fed a constant diet and were milked twice a day in a herringbone parlor. Milk samples were collected at monthly intervals using a sampling device and then fat, protein, lactose, total solids (TS), and solids-nonfat (SNF) concentrations of raw camel milk were determined with an automatic milk analyzer. For each milk sample, production parameters were recorded and quantities (grams) of milk constituents were calculated. The overall mean quantity and fat, protein, lactose, SNF, and TS concentrations of the morning milk were 4.0 kg, 2.58%, 2.95%, 4.19%, 8.08%, and 10.46%, respectively. Milk quantity showed a positive correlation with lactose and a negative correlation with all other components. Parity exerted a strong effect on all milk parameters. Primiparous dromedaries (n = 60) produced less milk with higher concentrations of components than did multiparous animals (n = 1,468). Milk composition varied among the 7 breeds tested, but none of the genotypes was found to be superior to the others in this respect. We detected a significant, yet small calf sex-biased difference in milk yield and composition. Stage of lactation and season strongly influenced milk yield and all milk components. We also found a significant interaction between month postpartum (mPP) and month of the year. The concentration of all milk components decreased from 1 to 5 mPP. Later, lactose concentration and quantity continued to decrease parallel with decreasing milk production. The concentration of other components showed a temporary increase in mid lactation, from 6 to 11 mPP, and in late lactation, from 18 to 23 mPP. Mean fat, protein, SNF, and TS concentrations showed a high seasonal variation (9.5 to 28.7%), with the lowest and highest values being measured during summer and winter, respectively. This seasonal variation was independent of nutrition and may reflect an endogenous circannual rhythm. We observed a noticeable variation among years. Dromedary camels could provide a useful in vivo model to study the homeorhetic regulation of mammary cell function by endogenous and environmental factors.

Utilization and safety of proton-pump inhibitors and histamine-2 receptor antagonists in children and adolescents: an observational cohort study.

BACKGROUND: Little is known about the use of acid-suppressing treatments and related safety events in children. OBJECTIVE: This study compared patient characteristics and safety outcomes among children prescribed acid-suppressing drugs for the first time. METHODS: The Health Improvement Network was used to determine the characteristics of children prescribed a proton pump inhibitor (PPI; esomeprazole or another PPI) or a histamine-2 receptor antagonist (H2RA) by UK primary care physicians between October 2009 and September 2012. Pre-defined safety outcomes were compared among the treatment groups in up to 18 months of follow-up. RESULTS: The cohorts comprised 8,172 patients on PPIs (including 24 patients on esomeprazole) and 7,905 on H2RAs. The baseline characteristics were similar between cohorts, although the children in the PPI cohorts tended to be older. No safety outcomes occurred in the esomeprazole cohort. In the other-PPIs cohort, 92 safety outcomes occurred, most commonly gastroenteritis (n = 36; 39.1%). In the H2RAs cohort, 193 safety outcomes occurred, most commonly gastroenteritis (n = 62; 32.1%). The incidence of most safety outcomes was higher in the H2RAs cohort than in the other-PPIs cohort, including failure to thrive (3.11 [95% confidence interval (CI) = 2.25-4.28] vs 0.49 per 1,000 person-years [95% CI = 0.22-1.07]) and gastroenteritis (5.27 [95% CI = 4.11-6.75] vs 3.04 per 1,000 person-years [95% CI = 2.20-4.20]). CONCLUSION: Esomeprazole is rarely prescribed to children when they first require acid-suppressing medication, compared with other PPIs/H2RAs. Overall, more safety outcomes occurred in the H2RAs cohort than in the PPI cohorts.

Microarchitectural study of the augmented bone following ridge preservation with a porcine xenograft and a collagen membrane: preliminary report of a prospective clinical, histological, and micro-computed tomography analysis.

Socket preservation using a combination of porcine xenograft and collagen membrane maintains the vertical and horizontal dimensions of the ridge. The aim of this study was to evaluate the microarchitecture of the grafted area by histological analysis and micro-computed tomography. Patients in the test group (group 1; nine patients) underwent socket preservation, while the sockets in the control group (group 2; eight patients) were allowed to heal without preservation. After a 6-month healing period, bone core biopsy samples were obtained and implants were placed in the augmented sites in the test group (12 biopsy samples) and the non-augmented sockets of the control group (12 biopsy samples). Analysis of the biopsy samples obtained from group 1 revealed that particles of the graft were surrounded by newly formed bone in eight cases and by granulation tissue in four cases. Micromorphometric data showed statistically significant differences in several parameters between the microarchitecture of the native bone and the newly formed bone within the augmented sites, which suggests that the xenograft particles interfere with the bony healing of the alveoli.

Comparing Preliminary and Final Neuroradiology Reports: What Factors Determine the Differences?

BACKGROUND AND PURPOSE: Trainees' interpretations of neuroradiologic studies are finalized by faculty neuroradiologists. We aimed to identify the factors that determine the degree to which the preliminary reports are modified. MATERIALS AND METHODS: The character length of the preliminary and final reports and the percentage character change between the 2 reports were determined for neuroradiology reports composed during November 2012 to October 2013. Examination time, critical finding flag, missed critical finding flag, trainee level, faculty experience, imaging technique, and native-versus-non-native speaker status of the reader were collected. Multivariable linear regression models were used to evaluate the association between mean percentage character change and the various factors. RESULTS: Of 34,661 reports, 2322 (6.7%) were read by radiology residents year 1; 4429 (12.8%), by radiology residents year 2; 3663 (10.6%), by radiology residents year 3; 2249 (6.5%), by radiology residents year 4; and 21,998 (63.5%), by fellows. The overall mean percentage character change was 14.8% (range, 0%-701.8%; median, 6.6%). Mean percentage character change increased for a missed critical finding (+41.6%, P < .0001), critical finding flag (+1.8%, P < .001), MR imaging studies (+3.6%, P < .001), and non-native trainees (+4.2%, P = .018). Compared with radiology residents year 1, radiology residents year 2 (-5.4%, P = .002), radiology residents year 3 (-5.9%, P = .002), radiology residents year 4 (-8.2%, P < .001), and fellows (-8.7%; P < .001) had a decreased mean percentage character change. Senior faculty had a lower mean percentage character change (-6.88%, P < .001). Examination time and non-native faculty did not affect mean percentage character change. CONCLUSIONS: A missed critical finding, critical finding flag, MR imaging technique, trainee level, faculty experience level, and non-native-trainee status are associated with a higher degree of modification of a preliminary report. Understanding the factors that influence the extent of report revisions could improve the quality of report generation and trainee education.

Structural and Morphometric Comparison of Lower Incisors in PACAP-Deficient and Wild-Type Mice.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with widespread distribution. PACAP plays an important role in the development of the nervous system, it has a trophic and protective effect, and it is also implicated in the regulation of various physiological functions. Teeth are originated from the mesenchyme of the neural crest and the ectoderm of the first branchial arch, suggesting similarities with the development of the nervous system. Earlier PACAP-immunoreactive fibers have been found in the odontoblastic and subodontoblastic layers of the dental pulp. Our previous examinations have shown that PACAP deficiency causes alterations in the morphology and structure of the developing molars of 7-day-old mice. In our present study, morphometric and structural comparison was performed on the incisors of 1-year-old wild-type and PACAP-deficient mice. Hard tissue density measurements and morphometric comparison were carried out on the mandibles and the lower incisors with micro-CT. For structural examination, Raman microscopy was applied on frontal thin sections of the mandible. With micro-CT morphometrical measurements, the size of the incisors and the relative volume of the pulp to dentin were significantly smaller in the PACAP-deficient group compared to the wild-type animals. The density of calcium hydroxyapatite in the dentin was reduced in the PACAP-deficient mice. No structural differences could be observed in the enamel with Raman microscopy. Significant differences were found in the dentin of PACAP-deficient mice with Raman microscopy, where increased carbonate/phosphate ratio indicates higher intracrystalline disordering. The evaluation of amide III bands in the dentin revealed higher structural diversity in wild-type mice. Based upon our present and previous results, it is obvious that PACAP plays an important role in tooth development with the regulation of morphogenesis, dentin, and enamel mineralization. Further studies are required to clarify the molecular background of the effects of PACAP on tooth development.

Efficacy of neck circumference to identify metabolic syndrome in 3-10 year-old European children: Results from IDEFICS study.

BACKGROUND AND AIMS: Several studies demonstrated that larger neck circumference (NC) in children and adolescents may help to identify obesity and cardio-metabolic abnormalities. We aimed to evaluate the correlation between NC and metabolic syndrome (MetS) risk factors and to determine the utility of this anthropometric index to identify MetS in European children. METHODS AND RESULTS: The present cross-sectional analysis includes 15,673 children (3-10 years) participating in the IDEFICS study. A continuous MetS (cMetS) score was calculated summing age and sex standardized z-scores of specific MetS risk factors. Receiver Operating Characteristic analysis, stratified by one-year age groups, was used to determine the ability of NC to identify children with unfavorable metabolic profile, corresponding to cMetS score ≥ 90th percentile. The areas under the curve values for NC associated with cMetS score values ≥ 90th percentile were significantly greater in girls than in boys (p < 0.001), except for 5 < 6 years group. For boys, optimal NC cut-off values ranged from 26.2 cm for the lowest age group (3 < 4 years), up to 30.9 cm for the highest age group (9 < 10 years). In girls, corresponding values varied from 24.9 cm to 29.6 cm. CONCLUSION: The study demonstrated the efficacy of NC in identifying European children with an unfavorable metabolic profile.

Prospective observational study protocol to investigate long-term adverse effects of methylphenidate in children and adolescents with ADHD: the Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study.

INTRODUCTION: Methylphenidate is the most frequently used medication for the treatment of attention-deficit/hyperactivity disorder (ADHD) in Europe. Following concerns about its safety, the European Commission called for research into the long-term effects of methylphenidate on children and adolescents with ADHD. The Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) research programme was designed to address this call. At the heart of this programme is a 2-year longitudinal naturalistic pharmacovigilance study being conducted in 27 European sites. METHODS AND ANALYSIS: 3 cohorts of children and adolescents (aged 6-17) living in the UK, Germany, Italy and Hungary are being recruited:Group 1 (Medicated ADHD): 800 ADHD medication-naive children and adolescents with a clinical diagnosis of ADHD about to start methylphenidate treatment for the first time.Group 2 (Unmedicated ADHD): 400 children and adolescents with a clinical diagnosis of ADHD who have never been treated with ADHD medication and have no intention of beginning medication.Group 3 (Non-ADHD): 400 children and adolescents without ADHD who are siblings of individuals in either group 1 or 2.All participants will be assessed 5 times during their 2-year follow-up period for growth and development, psychiatric, neurological and cardiovascular health. The primary outcome measure will be the height velocity SD score. ETHICS AND DISSEMINATION: Ethical approval for the study has been granted by the East of Scotland Research Ethics Service. Following this approval, patient information leaflets and consent forms were translated as necessary and submissions made by lead sites in each of the other 3 countries to their own ethics committees. Following ethical approval in each country, local ethical permissions at each site were sought and obtained as needed. The study's website (http://www.adhd-adduce.org/page/view/2/Home) provides information for researchers, participants and the general public. TRIAL REGISTRATION NUMBER: NCT01470261.

Exposure to acid-suppressing drugs during pregnancy and the risk of asthma in childhood: an observational cohort study.

BACKGROUND: Some research has suggested a potential link between prenatal exposure to proton pump inhibitors (PPIs) or H2 -receptor antagonists (H2 RAs) and the development of childhood asthma. AIM: To quantify the relative risk of asthma in children who experienced pre-natal exposure to PPIs and/or H2 RAs, adjusting for potential confounders. METHODS: In this observational cohort study (NCT01787435), women aged 18-45 years with completed pregnancies between January 1996 and December 2010 were identified from The Health Improvement Network in the United Kingdom, and were linked to infants. Hazard ratios (HRs) were estimated using Cox proportional hazard models. RESULTS: Our analysis identified 2371 prenatally exposed and 7745 unexposed infants. The incidence of asthma (per 1000 person-years) was 19.52 in the unexposed cohort, 23.88 in the PPI cohort and 32.16 in the H2 RA cohort. After adjusting for maternal healthcare utilisation during the year before pregnancy, the HR for asthma in infants whose mothers received prescriptions at any time during pregnancy was 1.12 (95% confidence interval: 0.88-1.44) for PPIs and 1.43 (1.20-1.70) for H2 RAs, when compared with unexposed infants. With further adjustment for maternal comorbidities and other medications, the HR for asthma was 1.03 (0.76-1.40) for PPIs and 1.32 (1.05-1.64) for H2 RAs. CONCLUSIONS: Our analysis showed no association between prenatal exposure to PPIs and asthma in childhood after adjusting for confounders. The association found for H2 RAs may be explained largely by underlying environmental or genetic factors, as suggested by reductions in hazard ratio estimates following adjustment for maternal comorbidities.

Fat, sugar and water intakes among families from the IDEFICS intervention and control groups: first observations from I.Family.

BACKGROUND: The objective of this paper is to investigate differences in diets of families in intervention versus control communities 5 years after the Identification and Prevention of Dietary- and Lifestyle-Induced Health Effects in Children and Infants intervention ended. METHODS: Altogether, 4,691 families from the I.Family study with at least one participating parent and one child are included in this analysis. Diet quality indicators, defined as propensities to consume fat, sugar, water and fruit and vegetables, are calculated from a 59-item food frequency questionnaire. Multilevel linear models with random intercepts for study centre are used to determine whether mean diet indicators, calculated at the family level, differed as a function of previous exposure to the intervention. RESULTS: Families in the intervention communities reported a significantly lower sugar propensity (19.8% vs. 20.7% of total food items, p < 0.01) and a higher water propensity (47.3% vs. 46.0% of total beverages, p < 0.05) compared with families in the control communities, while fat and fruit and vegetables propensities were similar. No significant diet differences between intervention and control children were present at the Identification and Prevention of Dietary- and Lifestyle-Induced Health Effects in Children and Infants baseline. DISCUSSION: This result indicates better diet quality in intervention families, which was not present in children when their diets were assessed before the intervention, and gives some cause for optimism regarding the sustainability of some aspects of the diet intervention.

Systematic review: the effects of long-term proton pump inhibitor use on serum gastrin levels and gastric histology.

BACKGROUND: Proton pump inhibitors (PPIs) have a well-established safety profile. However, concerns have been raised about a potential relationship between PPI-induced hypergastrinaemia and the development of enterochromaffin-like (ECL) cell hyperplasia, neuroendocrine tumours and gastric cancer during long-term therapy. AIM: To review the effects of long-term PPI use on serum gastrin levels and gastric histopathology. METHODS: A systematic literature search was conducted in PubMed on 21 April 2015 to identify studies reporting the effects of long-term (defined as >3 years) PPI use on gastrin levels and gastric histopathology. RESULTS: A total of 16 studies (1920 patients) met the inclusion criteria. During long-term PPI therapy, mean gastrin levels rose to one to three times the upper limit of the normal range (~100 pg/mL), and an increased prevalence of ECL cell hyperplasia was observed (+7.8-52.0%). Helicobacter pylori-positive patients had a significantly increased risk of developing ECL linear/micronodular hyperplasia compared with H. pylori-negative patients [OR: 2.45 (95% CI: 1.47-4.10), P = 0.0006]; however, no evidence of neoplastic changes was found. The risk of corpus atrophy was markedly higher in H. pylori-positive patients than in H. pylori-negative patients [OR: 11.45 (95% CI: 6.25-20.99), P < 0.00001]. Not a single case of gastric adenocarcinoma was found. CONCLUSIONS: Long-term PPI therapy induced moderate hypergastrinaemia in most patients and an increased prevalence of ECL cell hyperplasia. H. pylori-positive patients receiving long-term PPI therapy were exposed to a higher risk of corpus atrophy than H. pylori-negative patients. No neuroendocrine tumours or gastric cancers were found.

Tree Tensor Network State with Variable Tensor Order: An Efficient Multireference Method for Strongly Correlated Systems.

We study the tree-tensor-network-state (TTNS) method with variable tensor orders for quantum chemistry. TTNS is a variational method to efficiently approximate complete active space (CAS) configuration interaction (CI) wave functions in a tensor product form. TTNS can be considered as a higher order generalization of the matrix product state (MPS) method. The MPS wave function is formulated as products of matrices in a multiparticle basis spanning a truncated Hilbert space of the original CAS-CI problem. These matrices belong to active orbitals organized in a one-dimensional array, while tensors in TTNS are defined upon a tree-like arrangement of the same orbitals. The tree-structure is advantageous since the distance between two arbitrary orbitals in the tree scales only logarithmically with the number of orbitals N, whereas the scaling is linear in the MPS array. It is found to be beneficial from the computational costs point of view to keep strongly correlated orbitals in close vicinity in both arrangements; therefore, the TTNS ansatz is better suited for multireference problems with numerous highly correlated orbitals. To exploit the advantages of TTNS a novel algorithm is designed to optimize the tree tensor network topology based on quantum information theory and entanglement. The superior performance of the TTNS method is illustrated on the ionic-neutral avoided crossing of LiF. It is also shown that the avoided crossing of LiF can be localized using only ground state properties, namely one-orbital entanglement.

The conserved Trp114 residue of thioredoxin reductase 1 has a redox sensor-like function triggering oligomerization and crosslinking upon oxidative stress related to cell death.

The selenoprotein thioredoxin reductase 1 (TrxR1) has several key roles in cellular redox systems and reductive pathways. Here we discovered that an evolutionarily conserved and surface-exposed tryptophan residue of the enzyme (Trp114) is excessively reactive to oxidation and exerts regulatory functions. The results indicate that it serves as an electron relay communicating with the FAD moiety of the enzyme, and, when oxidized, it facilitates oligomerization of TrxR1 into tetramers and higher multimers of dimers. A covalent link can also be formed between two oxidized Trp114 residues of two subunits from two separate TrxR1 dimers, as found both in cell extracts and in a crystal structure of tetrameric TrxR1. Formation of covalently linked TrxR1 subunits became exaggerated in cells on treatment with the pro-oxidant p53-reactivating anticancer compound RITA, in direct correlation with triggering of a cell death that could be prevented by antioxidant treatment. These results collectively suggest that Trp114 of TrxR1 serves a function reminiscent of an irreversible sensor for excessive oxidation, thereby presenting a previously unrecognized level of regulation of TrxR1 function in relation to cellular redox state and cell death induction.