HERG mutation predicts short QT based on channel kinetics but causes long QT by heterotetrameric trafficking deficiency.
Mutations in the KCNH2 (hERG, human ether-à-go-go related gene) gene may cause a reduction of the delayed rectifier current I(Kr), thereby leading to the long QT syndrome (LQTS). The reduced I(Kr) delays the repolarisation of cardiac cells and renders patients vulnerable to ventricular arrhythmias and sudden death. We identified a novel mutation in a LQTS family and investigated its functional consequences using molecular and microscopic techniques. Genetic screening in the LQTS family revealed a heterozygous frameshift mutation p.Pro872fs located in the C-terminus of the KCNH2 gene. The mutation leads to a premature truncation of the C-terminus of the hERG protein. p.Pro872fs channels lack 282 amino acids at the C-terminus and possess an extra 4-amino acid tail. Both the kinetic and biochemical properties of the p.Pro872fs and p.Pro872fs/WT channels were studied in HEK293 cells and resulted in a novel proof of concept for heterozygous LQTS mutations: homotetrameric p.Pro872fs channels displayed near-normal expression, trafficking, and channel kinetics. Unexpectedly, upon co-expression of p.Pro872fs and WT channels, the repolarising power (the proportion of hERG current contributing to the action potential as the percentage of the total current available) was substantially higher during action potential clamp experiments as compared to WT channels alone. This would lead to a shorter rather than a prolonged QT interval. However, at the same time, heterotetramerisation of p.Pro872fs and WT channels also caused a dominant negative effect on trafficking by an increase in ER retention of these heterotetrameric channels, which surpassed the former gain in repolarising power. The LQTS phenotype in the studied family is caused by a mutation with novel properties. We demonstrate that a KCNH2 mutation that clinically leads to long QT syndrome causes at the cellular level both a "gain" and a "loss" of HERG channel function due to a kinetic increase in repolarising power and a decrease in trafficking efficiency of heteromultimeric channels.


[Effect of immobilization stress on the course of experimental influenza infection and the process of interferon formation].
The experimental data on the peculiar features of interferon production in C57BL/6 mice, infected with the lethal dose of influenza virus and simultaneously subjected to the action of a stress factor, are presented. Immobilization stress was found to exert pronounced influence on the interferon-producing system of the body, which was manifested by the appearance of alpha interferon in a titer of up to 1:80 in the blood of intact animals. 6-hour immobilization preceding infection did not accelerate the development of the lethal from of influenza infection, but sharply suppressed the viral induction of the synthesis of interferon.


Repetition frequency tunability and stability of BH InAs/InP QD and InGaAsP/InP QW two-section mode-locked laser diodes.
Ultra-high repetition rate (UHRR) mode-locked laser diodes (MLLD) have shown promising results for applications based on optical sampling such as asynchronous optical sampling (ASOPS), optical sampling by repetition-rate tuning (OSBERT), and optical ranging. Important metrics to consider are the repetition frequency (RF) and the RF linewidth. Here, we compare two monolithically integrated MLLDs. A quantum dot (QD) MLLD with an RF of approx. 50.1 GHz and a quantum well (QW) MLLD with an RF of approx. 51.4 GHz. The tunability of the RF is characterized by sweeping the lasers pump current, temperature, and saturable absorber (SA) reverse voltage. The QW MLLD has a tuning range of 31 MHz with an average RF linewidth of 53 kHz, while the QD MLLD has a smaller tuning range of 26 MHz with a higher average RF linewidth of 172 kHz.


Comparing Different Statistical Models and Multiple Testing Corrections for Association Mapping in Soybean and Maize.
Association mapping (AM) is a powerful tool for fine mapping complex trait variation down to nucleotide sequences by exploiting historical recombination events. A major problem in AM is controlling false positives that can arise from population structure and family relatedness. False positives are often controlled by incorporating covariates for structure and kinship in mixed linear models (MLM). These MLM-based methods are single locus models and can introduce false negatives due to over fitting of the model. In this study, eight different statistical models, ranging from single-locus to multilocus, were compared for AM for three traits differing in heritability in two crop species: soybean (Glycine max L.) and maize (Zea mays L.). Soybean and maize were chosen, in part, due to their highly differentiated rate of linkage disequilibrium (LD) decay, which can influence false positive and false negative rates. The fixed and random model circulating probability unification (FarmCPU) performed better than other models based on an analysis of Q-Q plots and on the identification of the known number of quantitative trait loci (QTLs) in a simulated data set. These results indicate that the FarmCPU controls both false positives and false negatives. Six qualitative traits in soybean with known published genomic positions were also used to compare these models, and results indicated that the FarmCPU consistently identified a single highly significant SNP closest to these known published genes. Multiple comparison adjustments (Bonferroni, false discovery rate, and positive false discovery rate) were compared for these models using a simulated trait having 60% heritability and 20 QTLs. Multiple comparison adjustments were overly conservative for MLM, CMLM, ECMLM, and MLMM and did not find any significant markers; in contrast, ANOVA, GLM, and SUPER models found an excessive number of markers, far more than 20 QTLs. The FarmCPU model, using less conservative methods (false discovery rate, and positive false discovery rate) identified 10 QTLs, which was closer to the simulated number of QTLs than the number found by other models.


Fully Decentralized Semi-supervised Learning via Privacy-preserving Matrix Completion.
Distributed learning refers to the problem of inferring a function when the training data are distributed among different nodes. While significant work has been done in the contexts of supervised and unsupervised learning, the intermediate case of Semi-supervised learning in the distributed setting has received less attention. In this paper, we propose an algorithm for this class of problems, by extending the framework of manifold regularization. The main component of the proposed algorithm consists of a fully distributed computation of the adjacency matrix of the training patterns. To this end, we propose a novel algorithm for low-rank distributed matrix completion, based on the framework of diffusion adaptation. Overall, the distributed Semi-supervised algorithm is efficient and scalable, and it can preserve privacy by the inclusion of flexible privacy-preserving mechanisms for similarity computation. The experimental results and comparison on a wide range of standard Semi-supervised benchmarks validate our proposal.


Switching the redox mechanism: models for proton-coupled electron transfer from tyrosine and tryptophan.
The coupling of electron and proton transfer is an important controlling factor in radical proteins, such as photosystem II, ribinucleotide reductase, cytochrome oxidases, and DNA photolyase. This was investigated in model complexes in which a tyrosine or tryptophan residue was oxidized by a laser-flash generated trisbipyridine-Ru(III) moiety in an intramolecular, proton-coupled electron transfer (PCET) reaction. The PCET was found to proceed in a competition between a stepwise reaction, in which electron transfer is followed by deprotonation of the amino acid radical (ETPT), and a concerted reaction, in which both the electron and proton are transferred in a single reaction step (CEP). Moreover, we found that we could analyze the kinetic data for PCET by Marcus' theory for electron transfer. By altering the solution pH, the strength of the Ru(III) oxidant, or the identity of the amino acid, we could induce a switch between the two mechanisms and obtain quantitative data for the parameters that control which one will dominate. The characteristic pH-dependence of the CEP rate (M. Sjodin et al. J. Am. Chem. Soc. 2000, 122, 3932) reflects the pH-dependence of the driving force caused by proton release to the bulk. For the pH-independent ETPT on the other hand, the driving force of the rate-determining ET step is pH-independent and smaller. On the other hand, temperature-dependent data showed that the reorganization energy was higher for CEP, while the pre-exponential factors showed no significant difference between the mechanisms. Thus, the opposing effect of the differences in driving force and reorganization energy determines which of the mechanisms will dominate. Our results show that a concerted mechanism is in general quite likely and provides a low-barrier reaction pathway for weakly exoergonic reactions. In addition, the kinetic isotope effect was much higher for CEP (kH/kD > 10) than for ETPT (kH/kD = 2), consistent with significant changes along the proton reaction coordinate in the rate-determining step of CEP.


White matter in temporal lobe epilepsy: clinico-pathological correlates of water diffusion abnormalities.
Using magnetic resonance imaging, it is possible to measure the behavior of diffusing water molecules, and the metrics derived can be used as indirect markers of tissue micro-architectural properties. Numerous reports have demonstrated that patients with temporal lobe epilepsy (TLE) have water diffusion abnormalities in several white matter structures located within and beyond the epileptogenic temporal lobe, showing that TLE is not a focal disorder, but rather a brain network disease. Differences in severity and spatial extent between patients with or without mesial temporal sclerosis (MTS), as well as differences related to hemispheric seizure onset, are suggestive of different pathophysiological mechanisms behind different forms of TLE, which in turn result in specific cognitive disabilities. The biological interpretation of diffusion abnormalities is based on a wealth of information from animal models of white matter damage, and is supported by recent reports that directly correlate diffusion metrics with histological characteristics of surgical specimens of TLE patients. Thus, there is now more evidence showing that the increased mean diffusivity (MD) and concomitant reductions of diffusion anisotropy that are frequently observed in several white matter bundles in TLE patients reflect reduced axonal density (increased extra-axonal space) due to smaller-caliber axons, and abnormalities in the myelin sheaths of the remaining axons. Whether these histological and diffusion features are a predisposing factor for epilepsy or secondary to seizures is still uncertain; some reports suggest the latter. This article summarizes recent findings in this field and provides a synopsis of the histological features seen most frequently in post-surgical specimens of TLE patients in an effort to aid the interpretation of white matter diffusion abnormalities.


Peritoneal Dialysis during the COVID-19 Pandemic Is an Effective Treatment in Developing Countries: A Report from Mexico.
During the height of the coronavirus disease-19 (COVID-19) pandemic, some renal replacement therapy (RRT) modalities were insufficient, forcing medical centers to diversify the RRT modalities offered. In this study, we reported the outcomes of chronic peritoneal dialysis (PD) patients and acute PD in critically ill patients during COVID-19 pandemic in a tertiary care medical center in Mexico. This descriptive, longitudinal, observational, retrospective study included 47 adult patients with atypical pneumonia in a tertiary care medical center in Mexico during the first and second waves of the COVID-19 pandemic. Chronic PD patients and PD incident patients due to acute kidney injury (AKI) were included. Forty-seven patients were studied (29 chronic PD patients and 18 incident PD patients due to AKI); median age was 59 (48-68) years; 63.8% were men. The ultrafiltrate volume per day was 815 (596.1-1,193.2) mL. Overall mortality was 61.7%, 55.2% in chronic PD patients, and 72.2% in PD incident patients due to AKI. A higher Sequential Organ Failure Assessment (SOFA) score, the need for mechanical ventilation at admission, and the requirement for vasopressors were predictors for mortality (p < 0.01). In low- and lower-middle-income countries, PD was a valid alternative for RRT during the COVID-19 pandemic. In AKI patients, PD can correct hyperkalemia, acidosis, uremia, and volume overload; however, there was higher mortality in PD incident patients due to AKI. The main risk factors for mortality were a high SOFA score at admission, the need for invasive mechanical ventilation, and the requirement for vasopressors.


Neither gastric topological distribution nor principle virulence genes of Helicobacter pylori contributes to clinical outcomes.
Studies on Helicobacter pylori (H pylori) and gastroduodenal diseases have focused mainly on the distal sites of the stomach, but relationship with the gastric cardia is lacking. The aim of this study is to determine if the gastric topology and genotypic distribution of H pylori were associated with different upper gastrointestinal pathologies in a multiethnic Asian population. Gastric biopsies from the cardia, body/corpus and antrum were endoscoped from a total of 155 patients with dyspepsia and/or reflux symptoms, with informed consent. H pylori isolates obtained were tested for the presence of 26 kDa, ureC, cagA, vacA, iceA1, iceA2 and babA2 genes using PCR while DNA fingerprints were generated using random amplification polymorphic DNA (RAPD). H pylori was present in 51/155 (33%) of patients studied. Of these, 16, 15 and 20 were isolated from patients with peptic ulcer diseases, gastroesophageal reflux diseases and non-ulcer dyspepsia, respectively. Of the H pylori positive patients, 75% (38/51) had H pylori in all three gastric sites. The prevalence of various genes in the H pylori isolates was shown to be similar irrespective of their colonization sites as well as among the same site of different patients. The RAPD profiles of H pylori isolates from different gastric sites were highly similar among intra-patients but varied greatly between different patients. Topographic colonization of H pylori and the virulence genes harboured by these isolates have no direct bearing to the clinical state of the patients. In multi-ethnic Singapore, the stomach of each patient is colonized by a predominant strain of H pylori, irrespective of the clinical diagnosis.


Evaluation of anterior versus posterior component separation for hernia repair in a cadaveric model.
Component separation remains an integral step during ventral hernia repair. Although a multitude of techniques are described, anterior component separation (ACS) via external oblique release (EOR) and posterior component separation (PCS) via transversus abdominis muscle release (TAR) are commonly utilized. The extent of myofascial medialization after ACS or PCS has not been well elucidated. We conducted a comparative analysis of ACS versus PCS in an established cadaveric model. Fifteen cadavers underwent both ACS via EOR and PCS via TAR. Following midline laparotomy (MLL), baseline myofascial elasticity was measured. Steps for ACS included creation of subcutaneous flaps (SQF), external oblique release (EOR), and retrorectus dissection (RRD). For PCS, steps included retrorectus dissection (RRD), transversus abdominis muscle division (TAD), and retromuscular dissection (RMD). Maximal advancement of anterior rectus fascia (ARF) was measured following application of tension to the fascia as a whole, and separately at upper, middle, and lower segments. Statistical analysis was performed with Mann-Whitney U test. Values are represented as average myofascial medialization in centimeters. Following MLL an average of 5.0 ± 0.9 cm (range 3.4-6.0 cm) of baseline medialization was obtained. Complete ACS provided 8.8 ± 1.2 cm (range 6.3-10.7 cm) of ARF advancement compared to 10.2 ± 1.7 cm (range 7.6-12.7 cm) with PCS, p = 0.046. In the upper and mid-abdomen, we noted increased ARF advancement with PCS versus ACS (8.1 ± 1.4 cm vs. 6.7 ± 1.2 cm and 11.4 ± 1.5 vs. 9.6 ± 1.4 cm, respectively, p = 0.01). Similar levels of ARF advancement were observed in the lower abdomen, 9.1 ± 1.7 cm versus 8.7 ± 1.8 cm, p = 0.535. Component separation via both anterior and posterior approaches provide substantial myofascial advancement. In our model, we noted statistically greater anterior fascial medialization after PCS versus ACS as a whole, and especially in the upper and mid-abdomen. We advocate PCS as a reliable and possibly superior alternative for linea alba restoration for reconstructive repairs, especially for large defects in the upper and mid-abdomen.


Oxytocin and cortisol in the hypnotic interaction.
Changes in oxytocin and cortisol levels were tested in healthy volunteers during hypnotic interactions in standardized laboratory sessions. Pre- to posthypnosis changes of oxytocin and cortisol were related to the hypnotic susceptibility of subjects and the relational experiences reposted by subjects and hypnotists on several paper-and-pencil tests. Results show that the changes in oxytocin are not related to hypnotic susceptibility but to relational experiences. After the hypnotic interaction, the subject's oxytocin level increased if perceived harmony with the hypnotist was high, whereas it increased in the hypnotist if the subject had memories of less warm emotional relationships with his or her parents. The results are interpreted within the social-psychobiological model of hypnosis.


Are serial brain imaging scans required for children who have suffered acute intracranial injury secondary to blunt head trauma?
In most instances, infants and children with moderate to severe head trauma undergo a head computed tomography (CT) scan as part of their initial evaluation. Several authors have advocated a routine second head CT after traumatic brain injury (TBI) to identify progressive lesions that may require surgical intervention. However, recent studies have challenged the need for a routine second brain imaging study after TBI. In addition, recent reports have raised concerns about the potential for malignancy following CT scanning, especially in pediatric patients. The authors performed a retrospective case series of all patients, aged 0 to 21 years, who presented to their 2 emergency departments (EDs) and received an International Classification of Disease-9th revision code related to intracranial injury. Out of 47 children, 5 (11%) underwent neurosurgical intervention following their second imaging study, and 1 of these interventions was unplanned after the first study. Compared with children who did not require an intervention following their second scan, children who received an intervention were more likely to have been subjected to nonaccidental trauma and to have presented to the ED more than 4 hours after the injury. Most children with intracranial injury following blunt trauma who did not require immediate neurosurgical intervention but instead underwent a follow-up brain imaging study did not require subsequent unplanned neurosurgical intervention. Serial brain imaging may not be required for all children with intracranial injury.


Comparison of placental α microglobulin-1 protein assay (Amnisure) with speculum examination for the diagnosis of premature preterm rupture of membranes (PPROM): a clinical evaluation.
In this study, we aimed to compare the clinical outcomes of Premature Preterm Rupture of Membranes (PPROM) cases diagnosed by classical speculum examination and by placental alpha microglobulin-1 protein (PAMG-1) assay. The medical records of all patients with singleton pregnancies that were diagnosed with PPROM were retrospectively reviewed. Singleton pregnancies with PPROM diagnosis that was confirmed either by direct visualisation of amniotic fluid leaking through the cervix or by placental alpha microglobulin-1 protein (PAMG-1) assay if no amniotic fluid leakage was documented were included in the study. Demographics, prenatal and postnatal characteristics were reviewed from the medical charts and were recorded. The study included 138 pregnancies with PPROM; 111 patients in clinical speculum examination group and 27 in PAMG-1 assay group. There were no significant differences in maternal and pregnancy characteristics between the clinical speculum examination and PAMG-1 assay groups. Foetal outcomes were comparable between clinical speculum examination and PAMG-1 assay groups. In the clinical speculum examination group, there were nine (8.1%) chorioamnionitis cases, however, there were no chorioamnionitis cases in the PAMG-1 assay group during the latency period (p = .21).Impact statementWhat is already known on this subject? Placental alpha microglobulin-1 protein assay uses immunochromatography method to detect trace amount of placental alpha microglobulin-1 protein in vaginal fluids and has high sensitivity and specificity for ROM diagnosis. However, to the best of our knowledge, the clinical outcome of ROM cases detected by classical speculum examination and by placental alpha microglobulin-1 protein assay has not been compared in the literature previously.What do the results of this study add? Although statistically insignificant, cases diagnosed by PAMG-1 assay had lower risk of chorioamnionitis during latency period.What are the implications of these findings for clinical practice and/or further research? Whether cases diagnosed by PAMG-1 assay represent a milder form of rupture of membranes than cases diagnosed by classical speculum examination group warrants further research.


Over-Expression of Rice CBS Domain Containing Protein, OsCBSX3, Confers Rice Resistance to Magnaporthe oryzae Inoculation.
Cystathionine β-synthase (CBS) domain containing proteins (CDCPs) constitute a big family in plants and some members in this family have been implicated in a variety of biological processes, but the precise functions and the underlying mechanism of the majority of this family in plant immunity remain to be elucidated. In the present study, a CBS domain containing protein gene, OsCBSX3, is functionally characterized in rice resistance against Magnaporthe oryzae (M. oryzae). By quantitative real-time PCR, transcripts of OsCBSX3 are up-regulated significantly by inoculation of M. oryzae and the exogenously applied salicylic acid (SA) and methyl jasmonate (MeJA). OsCBSX3 is exclusively localized to the plasma membrane by transient expression of OsCBSX3 fused to green fluorescent protein (GFP) through approach of Agrobacterium infiltration in Nicotiana benthamiana leaves. The plants of homozygous T3 transgenic rice lines of over-expressing OsCBSX3 exhibit significant enhanced resistance to M. oryzae inoculation, manifested by decreased disease symptoms, and inhibition of pathogen growth detected in DNA. Consistently, the over-expression of OsCBSX3 enhances the transcript levels of immunity associated marker genes including PR1a, PR1b, PR5, AOS2, PAL, NH1, and OsWRKY13 in plants inoculated with M. oryzae. These results suggest that OsCBSX3 acts as a positive regulator in resistance of rice to M. oryzae regulated by SA and JA-mediated signaling pathways synergistically.


Functional status, heart rate, and rhythm abnormalities in 521 Fontan patients 6 to 18 years of age.
Our objective was to determine the relationship between functional outcome and abnormalities of heart rate and rhythm after the Fontan operation. The National Heart, Lung, and Blood Institute Pediatric Heart Network conducted a cross-sectional analysis of patients who had undergone a Fontan procedure at the 7 network centers. Analysis was based on 521 patients with an electrocardiogram (n = 509) and/or bicycle exercise test (n = 404). The Child Health Questionnaire parent report and the oxygen consumption at the anaerobic threshold were used as markers of functional outcome. Various Fontan procedures had been performed: intracardiac lateral tunnel (59%), atriopulmonary connection (14%), extracardiac later tunnel (13%), and extracardiac conduit (11%). Prior volume unloading surgery was performed in 389 patients: bidirectional Glenn (70%) and hemi-Fontan (26%). A history of atrial tachycardia was noted in 9.6% of patients and 13.1% of patients had a pacemaker. Lower resting heart rate and higher peak heart rate were each weakly associated with better functional status, as defined by higher anaerobic threshold (R = -0.18, P = .004, and R = 0.16, P = .007, respectively) and higher Child Health scores for physical functioning (R = -0.18, P < .001, and R = 0.17, P = .002, respectively). Higher anaerobic threshold was also independently associated with younger age and an abnormal P-axis. Resting bradycardia was not associated with anaerobic threshold or Child Health scores. In pediatric patients (6-18 years) after the Fontan procedure, a lower resting heart rate and a higher peak heart rate are each independently associated with better physical function as measured by anaerobic threshold and Child Health scores. However, these correlations are weak, suggesting that other, nonrhythm and nonrate, factors may have a greater impact on the functional outcome of pediatric patients after the Fontan operation.


Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency in Greek newborns: the Mediterranean C563T mutation screening.
Glucose-6-Phosphate Dehydrogenase (G6PD) gene is located at the X-chromosome at Xq28 and the disease is recessively inherited predominantly in males. More than 400 variants have been proposed based on clinical and enzymatic studies. The aim of the current study was to identify C563T mutation in G6PD-deficient newborns and to correlate the enzyme residual activity with the presence of the mutation. Some 1189 full-term neonates aged 3-5 days old were tested for G6PD activity in dried blood spots from Guthrie cards using a commercial kit. DNA extraction from Guthrie cards and mutation identification among the deficient samples were performed with current techniques. A total of 92 (7.7%) newborns were G6PD-deficient. In 46 (50%), the mutation C563T was identified. The residual activity in C563T hemizygote males (n = 28) was statistically significantly lower (1.23 ± 0.93 U/g Hb) than that in non-C563T G6PD-deficient males (n = 25) (4.01 ± 1.20 U/g Hb, p < 0.0001) and in controls (13.6 ± 2.9 U/g Hb, p < 0.0001). In C563T heterozygote females, the estimated enzyme activity was lower than that determined in non-C563T females. Male C563T hemizygotes suffer from G6PD deficiency and severe neonatal jaundice. G6PD activity showed statistically significant correlation with total bilirubin blood levels.


[Intralipid for treatment of local anaesthetic-induced toxicity].
Regional anaesthesia can be associated with severe complications, which may be due to overdose or accidental intravascular injection of local anaesthetics. The clinical picture varies and depends on the pharmacodynamics of specific drugs, the total dose used, and the route of injection. Among the most common side effects are: excitation, seizures, loss of consciousness, cardiac dysrhythmias, severe shock and cardiac arrest. Cardiovascular resuscitation in such cases may be prolonged and very difficult, mostly because local anaesthetics are lipid soluble and require a long time for redistribution. The majority of cases with lidocaine-induced cardiovascular complications can be successfully resuscitated due to the relatively short duration of action of the drug. Bupivacaine-induced cardiac arrest is probably the most dangerous, with resuscitations in such cases being usually very long and frequently unsuccessful. Recently, intravenous fat emulsion (Intralipid) has been used during resuscitation. This review focuses on the role of intravenous fat emulsions in the treatment of toxicity due to local anaesthetics. The possible antidotal mechanisms are discussed.


EANM procedure guidelines for radionuclide therapy with 177Lu-labelled PSMA-ligands (177Lu-PSMA-RLT).
Prostate-specific membrane antigen (PSMA) is expressed in most prostate cancers and can be identified by PSMA-ligand imaging, which has already become clinically accepted in several countries in- and outside Europe. PSMA-directed radioligand therapy (PSMA-RLT) with Lutetium-177 (177Lu-PSMA) is currently undergoing clinical validation. Retrospective observational data have documented favourable safety and striking clinical responses. Recent results from a prospective clinical trial (phase II) have been published confirming high response rates, low toxicity and reduction of pain in metastatic castration-resistant prostate cancer (mCRPC) patients who had progressed after conventional treatments. Such patients typically survive for periods less than 1.5 years. This has led some facilities to adopt compassionate or unproven use of this therapy, even in the absence of validation within a randomised-controlled trial. As a result, a consistent body of evidence exists to support efficacy and safety data of this treatment. The purpose of this guideline is to assist nuclear medicine specialists to deliver PSMA-RLT as an "unproven intervention in clinical practice", in accordance with the best currently available knowledge.


Postnatal neurobehavioral development in rats exposed in utero to caffeine.
Potential behavioral and teratogenic effects of caffeine were studied in Charles River CD albino rats. Caffeine in distilled water was given by gavage to pregnant rats (dams) at doses of 5, 25, 50 or 75 mg/kg on Days 3-19 of gestation. Concurrent controls received distilled water gavage (10 ml/kg) on the same days. Dams were allowed to deliver normally. Physical and behavioral observations were made on dams during gestation and lactation and on F1 offspring through 9 weeks of age. Caffeine decreased body weights and food intake and increased water intake in gestating dams but these effects dissipated during lactation. Spontaneous locomotor activity (PAC) and open field (OF) were increased immediately after caffeine gavage but not before. Parturition was slightly delayed. With analyses of data based on individual pups the following effects were noted. Pre- and post-weaning offspring body weights were decreased in females at 50 and 75 mg/kg and in males at 75 mg/kg. Incisor eruption was delayed in females at 5, 50 and 75 mg/kg and in males at all doses. Auditory startle developed earlier in the 5 mg/kg dose group but was delayed at 75 mg/kg for males only. Eye opening was delayed in both sexes at 25, 50 and 75 mg/kg. In females, vaginal opening was delayed at 5, 25 and 75 mg/kg and 9-week ovary weights were increased at 75 mg/kg. In postweaning males, food intake was decreased and water intake was increased with increasing dose. In males, PAC was decreased at 75 mg/kg only on Day 12. At 7 weeks of age, step-down passive avoidance was decreased at 5 and 25 mg/kg but increased at 50 and 75 mg/kg, and at 8 weeks of age, shuttlebox active avoidance was decreased with increasing dose. Maternal and offspring behaviors were only weakly correlated. Correction for litter effect in developmental data yielded fewer significant results and only at 50 and 75 mg/kg. The issue of whether it is always appropriate to correct for "litter effect" is discussed.


Use of the Escape nitinol stone retrieval basket facilitates fragmentation and extraction of ureteral and renal calculi: a pilot study.
Advances in ureteroscope and stone basket design have catapulted ureteroscopy to the forefront of surgical stone management; however, persistent problems such as stone migration continue to challenge urologists. The Escape nitinol stone retrieval basket (Boston Scientific, Natick, MA) is a stone basket designed to capture calculi and facilitate simultaneous laser lithotripsy in situ. We report our initial experience with the Escape basket for the management of urinary calculi and compare the use of this device with other methods of optimizing ureteroscopic stone management. A prospective evaluation of 23 patients undergoing ureteroscopic holmium:yttrium-aluminum-garnet laser lithotripsy of urinary calculi was performed at two institutions by two surgeons (R.M. and G.M.P). The Escape basket was used to prevent retrograde ureteral stone migration or to facilitate fragmentation and extraction of large renal calculi. Patient demographics and perioperative parameters were assessed. Twenty-three patients (16 men, 7 women), with a mean age of 55.5 years (range 33-74 yrs) were treated for renal (n = 9) or ureteral (n = 14) calculi. The mean stone diameter was 1.4 cm (range 0.4-2.5 cm), mean fragmentation time was 44.1 minutes (range 10-75 min), and mean energy used was 3.1 kJ (range 0.4-10.6 kJ). No complications were encountered. Eighty-seven percent (20/23) of patients were rendered completely stone free after ureteroscopic laser lithotripsy using the Escape basket. Of the three patients with residual calculi, one patient with a 2.5-cm renal calculus had residual fragments larger than 3 mm, and two patients with large renal calculi had residual fragments smaller than 3 mm. The Escape basket appears to be safe and effective in preventing stone migration and facilitating ureteroscopic laser lithotripsy and stone extraction.


Intestinal fatty acid binding protein gene expression reveals the cephalocaudal patterning during zebrafish gut morphogenesis.
Intracellular fatty acid-binding proteins (FABPs) are small and highly conserved cytoplasmic proteins that bind long-chain fatty acids and other hydrophobic ligands. We have examined, as a model for studying intestinal epithelial cell differentiation, the cell-specific and spatio-temporal expression of intestinal fatty acid-binding protein (i-fabp) gene during zebrafish larval development. After molecular cloning of zebrafish I-FABP cDNA, whole-mount in situ hybridization analysis revealed that i-fabp is expressed in the intestinal tube around day 3 postfertilization. By day 4, highest level of i-fabp transcript is encountered in the proximal columnar epithelium. From day 5 onwards, i-fabp is strongly expressed in the anterior intestine and its rostral expansion, slightly expressed in the esophagus mucosa and rectum, while no mRNA could be detected in the posterior intestine. Therefore, the regional differentiation of the intestine precedes first feeding and complete yolk resorption. I-fabp expression in the anterior intestine of the fed larvae is correlated with an intracellular storage of lipid droplets in the enterocytes and the massive synthesis of very low-density lipoprotein particles. In conclusion, the cephalocaudal expression pattern of i-fabp demarcates early during zebrafish gut morphogenesis the anterior fat absorbing to posterior cells of the intestine. This gene could be used as a marker for screening for mutations that affect the events of intestinal epithelial differentiation, cephalocaudal patterning, and asymmetric gut looping morphogenesis.


Velocity-space sensitivities of neutron emission spectrometers at the tokamaks JET and ASDEX Upgrade in deuterium plasmas.
Future fusion reactors are foreseen to be heated by the energetic alpha particles produced in fusion reactions. For this to happen, it is important that the energetic ions are sufficiently confined. In present day fusion experiments, energetic ions are primarily produced using external heating systems such as neutral beam injection and ion cyclotron resonance heating. In order to diagnose these fast ions, several different fast-ion diagnostics have been developed and implemented in the various experiments around the world. The velocity-space sensitivities of fast-ion diagnostics are given by so-called weight functions. Here instrument-specific weight functions are derived for neutron emission spectrometry detectors at the tokamaks JET and ASDEX Upgrade for the 2.45 MeV neutrons produced in deuterium-deuterium reactions in deuterium plasmas. Using these, it is possible to directly determine which part of velocity space each detector observes.


Specific targeting to CD4+ cells of recombinant vesicular stomatitis viruses encoding human immunodeficiency virus envelope proteins.
We generated replication-competent, recombinant vesicular stomatitis viruses (VSVs) expressing the human immunodeficiency virus (HIV) envelope protein or an HIV-VSV chimeric envelope protein in which the cytoplasmic domain of the HIV envelope protein was replaced with that from the VSV glycoprotein (G). These recombinants were generated with HIV type 1 (HIV-1) envelopes from both laboratory and primary isolates of HIV-1. The replication-competent recombinant viruses were stable and expressed the foreign proteins at high levels from extra transcription units in VSV. The foreign proteins were processed appropriately and transported to the cell surface. The incorporation of HIV gp120 into VSV particles was demonstrated biochemically only for the construct expressing the chimeric envelopes containing the VSV G cytoplasmic domain. The incorporation of the chimeric HIV envelope protein into the membrane of the recombinant VSV was also demonstrated by electron microscopy with gold-conjugated antibodies. To determine whether specific infection of CD4-positive cells could be demonstrated for these recombinants, we neutralized VSV infectivity due to VSV glycoprotein with anti-VSV serum. The neutralized recombinants expressing the chimeric envelope were able to infect only HeLa cells expressing CD4, and this CD4-specific infectivity was neutralized with anti-HIV serum. This assay also detected a 100-fold-lower titer of CD4-specific infectivity for the VSV recombinant expressing the wild-type HIV envelope. Our results illustrate that it is possible to express functional HIV envelopes from the VSV genome and target the recombinant virus to an alternative receptor. The recombinants may also prove useful as HIV vaccines.


The mating brain: early maturing sneaker males maintain investment into the brain also under fast body growth in Atlantic salmon (Salmo salar).
It has been suggested that mating behaviours require high levels of cognitive ability. However, since investment into mating and the brain both are costly features, their relationship is likely characterized by energetic trade-offs. Empirical data on the subject remains equivocal. We investigated if early sexual maturation was associated with brain development in Atlantic salmon (Salmo salar), in which males can either stay in the river and sexually mature at a small size (sneaker males) or migrate to the sea and delay sexual maturation until they have grown much larger (anadromous males). Specifically, we tested how sexual maturation may induce plastic changes in brain development by rearing juveniles on either natural or ad libitum feeding levels. After their first season we compared brain size and brain region volumes across both types of male mating tactics and females. Body growth increased greatly across both male mating tactics and females during ad libitum feeding as compared to natural feeding levels. However, despite similar relative increases in body size, early maturing sneaker males maintained larger relative brain size during ad libitum feeding levels as compared to anadromous males and females. We also detected several differences in the relative size of separate brain regions across feeding treatments, sexes and mating strategies. For instance, the relative size of the cognitive centre of the brain, the telencephalon, was largest in sneaker males. Our data support that a large relative brain size is maintained in individuals that start reproduction early also during fast body growth. We propose that the cognitive demands during complex mating behaviours maintain a high level of investment into brain development in reproducing individuals.


Signaling pathways and structural domains required for phosphorylation of EMS1/cortactin.
The structural characteristics of EMS1 (human cortactin) suggest that it may link signaling events to reorganization of the actin cytoskeleton. Interestingly, the EMS1 gene is commonly amplified and overexpressed in several human cancers, which may alter their invasive or metastatic properties. An 80 to 85-kDa mobility shift of EMS1 correlates with an alteration in subcellular distribution and is likely to represent an important regulatory event. In HEK 293 cells, epidermal growth factor treatment or cell detachment induced this shift, and this was blocked by the mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor PD98059. Furthermore, expression of a constitutively active form of MEK induced the shift, indicating that MEK activation was both sufficient and necessary for this modification. The epidermal growth factor-induced shift correlated with increased phosphorylation on serine and threonine residues of the same tryptic phosphopeptides detected under basal conditions. Deletion of the helical-proline-rich region of the protein blocked the mobility shift and EMS1 phosphorylation. In vitro kinase assays demonstrated that the extracellular signal-regulated kinases represent candidate kinases for this region, although other MEK-regulated enzymes must also participate. These data identify MEK as an important intermediate involved in EMS1 phosphorylation and highlight the helical-proline-rich region as a key regulatory domain.


Appropriateness of the indication for colonoscopy: is the endoscopist the 'gold standard'?
The appropriate selection of patients for colonoscopy is crucial for an efficient use of endoscopy. The role of endoscopist in filtering out inappropriate referrals is largely unknown. A multicentre, prospective study was performed in which consecutive patients referred for colonoscopy during a 1-month period were enrolled. Before colonoscopy, the endoscopist assessed appropriateness of the endoscopic referral without directly consulting official guidelines, also collecting clinical and demographic variables. Appropriateness of the indication was eventually assessed by a group of experts based on the American Society for Gastrointestinal Endoscopy guidelines, representing the gold standard. Outcomes of the study were the inappropriateness rate and the main related causes, as well as the concordance rate between the endoscopists and the experts. A multivariate analysis was performed to identify predictors of inappropriateness. One thousand seven hundred ninety-nine patients were enrolled in 20 centres, of which 1489 outpatients were included in the final analysis. According to the American Society for Gastrointestinal Endoscopy guidelines, 432 referrals were inappropriate, corresponding to an inappropriateness rate of 29%. At multivariate analysis, prescription of a repeated colonoscopy (≥2 colonoscopies in the same patient) was strongly associated with the inappropriateness of the indication (odds ratio: 8.8; 95% confidence interval: 6.2, 12.7). Postpolypectomy or post-colorectal cancer surveillance accounted for 77% of the inappropriate control procedures. A 79% concordance rate between endoscopist and expert assessment was found. Among the 317 discordant cases, postpolypectomy or post-colorectal cancer surveillance accounted for 51% of the cases, the endoscopists mistakenly classifying it as appropriate in 55% to 61% of the inappropriate cases. Inappropriateness in outpatient colonoscopy referrals remains high, surveillance procedures representing the most frequent source of inappropriateness.


A new eudesmanolide from Tanacetum balsamita L. and biological activities of extracts.
The ethyl acetate and methanol extracts from aerial parts of Tanacetum balsamita yielded a new derivative of 1-acetyl-erivanin, namely 1-acetyl-3-epi-erivanin (17), some known compounds, namely seventeen sesquiterpene lactones, five flavonoids, four coumarins, and a steroid. All extracts displayed antibacterial activity against test microorganisms except for Escherichia coli. The methanol (TBM) extract with an IC50 value of 0.180 mg/mL exhibited good antioxidant activity against DPPH radical while all extracts showed significant anti-inflammatory activity against lipoxygenase enzyme. The ethyl acetate (TBEA) extract presented moderate activity against α-glucosidase enzyme with an IC50 of 0.808 mg/mL. The highest total phenol content with 91.050 mg GAE/g extract was found in TBM. It is the first study on the isolation of secondary metabolites as well as 5-lipoxygenase and α-glucosidase inhibitory activity of T. balsamita growing in Turkey.


The use of mass defect plots for the identification of (novel) halogenated contaminants in the environment.
Mass defect is the difference between the nominal and exact mass of a chemical element or compound. An intrinsic property of polyhalogenated molecules is a uniquely negative mass defect, which readily distinguishes halogenated from non-halogenated compounds in a complex mass spectrum and can be visualized by constructing a mass defect plot. This study demonstrates the utility of the mass defect plot as a powerful tool to screen gas-chromatography (ultra)high-resolution mass spectrometry data for potentially toxic and bioaccumulative halogenated compounds in a Lake Ontario lake trout, an apex species in the Great Lakes environment. Our results indicate that the sample is contaminated with polychlorinated biphenyls, terphenyls, diphenylethers, as well as other chlorinated pesticides and flame retardants that are regulated and routinely analyzed by traditional target analyses. However, the mass defect plot also displays peaks which could be traced to the presence of as yet undiscovered contaminants. These include chlorinated polycyclic aromatic hydrocarbons as well as mixed halogenated analogues of the flame retardant Dechlorane 604. The identity of the latter class of compounds is supported by experiments with genuine standards.


Pathways through organizational socialization: A longitudinal qualitative study based on the psychological contract.
In this study, we explore different pathways during organizational socialization through the lens of the psychological contract using in-depth longitudinal qualitative methods. Analysis of 112 critical incident interviews with 27 newcomers across their first year of work reveals five distinct psychological contract pathways through socialization, within which fulfilment and breach influence adjustment by facilitating or restricting opportunities to learn and integrate, as well as influencing attitudes and behaviour. The analysis reveals that whilst perceived psychological contract fulfilment facilitates newcomer adjustment, perceived breach can disrupt the process. We provide a detailed account of the way socialization and the psychological contract unfold for newcomers over time, and show that psychological contract events can significantly alter the course of adjustment. Delivery of perceived promises that are of particular importance to newcomers during early tenure can accelerate adjustment. Managers should therefore attempt to find out which promised contributions are important to employees and prioritize their delivery.The negative effects of perceptions of broken promises on newcomer adjustment may be reversed by later delivery. Managers should explain the reasons for any broken promises and seek to fulfil them in the future.Ongoing support from managers can help newcomers to negotiate the difficult period after organizational entry, even where promises are perceived to have been broken.Direct managers should be made aware of information provided and promises made to newcomers by those responsible for recruitment.


In vivo nerve-macrophage interactions following peripheral nerve injury.
In vertebrates, the peripheral nervous system has retained its regenerative capacity, enabling severed axons to reconnect with their original synaptic targets. While it is well documented that a favorable environment is critical for nerve regeneration, the complex cellular interactions between injured nerves with cells in their environment, as well as the functional significance of these interactions, have not been determined in vivo and in real time. Here we provide the first minute-by-minute account of cellular interactions between laser transected motor nerves and macrophages in live intact zebrafish. We show that macrophages arrive at the lesion site long before axon fragmentation, much earlier than previously thought. Moreover, we find that axon fragmentation triggers macrophage invasion into the nerve to engulf axonal debris, and that delaying nerve fragmentation in a Wld(s) model does not alter macrophage recruitment but induces a previously unknown 'nerve scanning' behavior, suggesting that macrophage recruitment and subsequent nerve invasion are controlled by separate mechanisms. Finally, we demonstrate that macrophage recruitment, thought to be dependent on Schwann cell-derived signals, occurs independently of Schwann cells. Thus, live cell imaging defines novel cellular and functional interactions between injured nerves and immune cells.


A(1) or A(3) adenosine receptors induce late preconditioning against infarction in conscious rabbits by different mechanisms.
We investigated whether activation of A(1) or A(3) adenosine receptors (ARs) induces late preconditioning (PC) against infarction in conscious rabbits using the selective AR agonists 2-chloro-N(6)-cyclopentyladenosine (CCPA) and N(6)-3-iodobenzyladenosine-5'-N-methylcarboxamide (IB-MECA). In vitro radioligand binding and cAMP assays demonstrated CCPA to be approximately 200- to 400-fold selective for the rabbit A(1)AR and IB-MECA to be approximately 20-fold selective for the rabbit A(3)AR. We observed that (1) pretreatment of rabbits 24 hours earlier with CCPA (100 microgram/kg IV bolus) or IB-MECA (100 or 300 microgram/kg) resulted in an approximately 35% to 40% reduction in the size of the infarct induced by 30 minutes of coronary artery occlusion and 72 hours of reperfusion compared with vehicle-treated rabbits, whereas pretreatment with the selective A(2A)AR agonist CGS 21680 (100 microgram/kg) had no effect; (2) the delayed cardioprotective effect of CCPA, but not that of IB-MECA, was completely blocked by coadministration of the highly selective A(1)AR antagonist N-0861; (3) inhibition of nitric oxide synthase (NOS) with N(omega)-nitro-L-arginine during the 30-minute occlusion abrogated the infarct-sparing action of CCPA but not that of IB-MECA; and (4) inhibition of ATP-sensitive potassium (K(ATP)) channels with sodium 5-hydroxydecanoate during the 30-minute occlusion blocked the cardioprotective effects of both CCPA and IB-MECA. Taken together, these results indicate that activation of either A(1)ARs or A(3)ARs (but not A(2A)ARs) elicits delayed protection against infarction in conscious rabbits and that both A(1)AR- and A(3)AR-induced cardioprotection involves opening of K(ATP) channels. However, A(1)AR-induced late PC uses an NOS-dependent pathway whereas A(3)AR-induced late PC is mediated by an NOS-independent pathway.


A knowledge graph approach to predict and interpret disease-causing gene interactions.
Understanding the impact of gene interactions on disease phenotypes is increasingly recognised as a crucial aspect of genetic disease research. This trend is reflected by the growing amount of clinical research on oligogenic diseases, where disease manifestations are influenced by combinations of variants on a few specific genes. Although statistical machine-learning methods have been developed to identify relevant genetic variant or gene combinations associated with oligogenic diseases, they rely on abstract features and black-box models, posing challenges to interpretability for medical experts and impeding their ability to comprehend and validate predictions. In this work, we present a novel, interpretable predictive approach based on a knowledge graph that not only provides accurate predictions of disease-causing gene interactions but also offers explanations for these results. We introduce BOCK, a knowledge graph constructed to explore disease-causing genetic interactions, integrating curated information on oligogenic diseases from clinical cases with relevant biomedical networks and ontologies. Using this graph, we developed a novel predictive framework based on heterogenous paths connecting gene pairs. This method trains an interpretable decision set model that not only accurately predicts pathogenic gene interactions, but also unveils the patterns associated with these diseases. A unique aspect of our approach is its ability to offer, along with each positive prediction, explanations in the form of subgraphs, revealing the specific entities and relationships that led to each pathogenic prediction. Our method, built with interpretability in mind, leverages heterogenous path information in knowledge graphs to predict pathogenic gene interactions and generate meaningful explanations. This not only broadens our understanding of the molecular mechanisms underlying oligogenic diseases, but also presents a novel application of knowledge graphs in creating more transparent and insightful predictors for genetic research.


Biotransformation of silybin and its congeners.
Silybin and its congeners belong to a group of flavonolignans with strong biological activities. These compounds are potentially applicable in human medicine, e. g. due to their cytoprotective activity. As a part of herbal preparations available on the open market, they face the risk of potential negative drug-drug interactions. This review aims to evaluate current knowledge on the metabolism of these compounds by biotransformation enzymes, interactions with other drugs, their pharmacokinetics, and bioavailability. While silybin and its derivatives interact with cytochrome P450s, only metabolism of silybin by cytochrome P450 2C8 poses a risk of adverse effects. The main biotransformation route of silybin and derivatives was identified as conjugation, which is stereospecific in case of silybin. Studies of the metabolism, pharmacokinetics, potentional drug--drug interactions and increasing bioavailability of these flavonolignans play an important facet of possible therapeutical use of these compounds. The goal of our review is to aid future developments in the area of silybin research.


Achieving higher performing primary care through patient registration: A review of twelve high-income countries.
Patient registration with a primary care providers supports continuity in the patient-provider relationship. This paper develops a framework for analysing the characteristics of patient registration across countries; applies this framework to a selection of countries; and identifies challenges and ongoing reform efforts. 12 jurisdictions (Denmark, France, Germany, Ireland, Israel, Italy, Netherlands, Norway, Ontario [Canada], Sweden, Switzerland, United Kingdom) were selected for analysis. Information was collected by national researchers who reviewed relevant literature and policy documents to report on the establishment and evolution of patient registration, the requirements and benefits for patients, providers and payers, and its connection to primary care reforms. Patient registration emerged as part of major macro-level health reforms linked to the introduction of universal health coverage. Recent reforms introduced registration with the aim of improving quality through better coordination and efficiency through reductions in unnecessary referrals. Patient registration is mandatory only in three countries. Several countries achieve high levels of registration by using strong incentives for patients and physicians (capitation payments). Patient registration means different things in different countries and policy-makers and researchers need to take into consideration: the history and characteristics of the registration system; the use of incentives for patients and providers; and the potential for more explicit use of patient-provider agreements as a policy to achieve more timely, appropriate, continuous and integrated care.


Epidemiological Situation of Necrotizing Fasciitis and Factors in Thailand and Factors Associated with Its Morbidity and Mortality, 2014-2018.
Necrotizing fasciitis (NF) is a rare skin and soft-tissue bacterial infection with high morbidity and mortality. Knowledge about the prevalence and incidence of NF in Thailand is quite sparse. The objective of this study was to determine the prevalence of NF in Thailand and factors that may be potentially associated with NF morbidity and mortality. A cross-sectional study using secondary data from Thailand's national health databases between 2014 and 2018 was conducted. Descriptive statistics using median and percentage formats were used. This was complemented by multivariable logistic regression to determine the association between various factors (such as age and underlying diseases) with NF morbidity and mortality. Univariate spatial data analysis was exercised to identify the geographical hot spots in which the disease appeared. During 2014-2018, we found 90,683 NF cases. About 4.86% of the cases died. The median age for all cases was 59.39 years old. The annual incidence of NF demonstrated an upward trend (from 26.08 per 100,000 population in 2014 to 32.64 per 100,000 population in 2018). The monthly incidence was highest between May and August. A high incidence cluster (as indicated by local Moran's I) was found in the north-eastern region of Thailand. The most infected sites were on the ankles and feet (43.18%) with an amputation rate of 7.99% in all cases. Multivariable logistic regression indicated that the significant risk factor for amputation was a presence of underlying diseases, namely diabetes (OR 7.94, 95% CI 7.34-8.61). Risk factors for mortality included being elderly (OR 1.82, 95% CI 1.68-1.98) and a presence of underlying hypertension (OR 1.16, 95% CI 1.07-1.27), cirrhosis (OR 4.67, 95% CI 4.17-5.21), and malignancy (OR 1.88, 95% CI 1.55-2.26). As the elderly and those with chronic underlying diseases are likely to face non-preferable health outcomes from NF, healthcare providers should pay great attention to these groups of patients. Early and intensive treatment might be considered in these groups of patients. Further studies that aim to validate the volume of actual NF cases and reported NF cases are recommended.


Empowering Health care Systems and Communities for Snakebite Envenoming Control in India.
Snakebite envenoming (SBE) is a global health challenge, predominantly affecting economically disadvantaged regions. India contributes significantly to global snakebite mortality. Since 2013, the Indian Council of Medical Research (ICMR) has spearheaded efforts to combat SBE. A multi-sectoral engagement in the snakebite research projects and inputs from communities, traditional healers, and the health system have led to the creation of an Information Education and Communication (IEC) material suite, including management flowchart, information booklets, posters, and brochures, all available in local languages. These resources were broadly disseminated in high-burden regions in Maharashtra and Odisha, resulting in an approximately 10% increase in case reporting within a year. This holistic approach, engaging diverse stakeholders and addressing multiple facets of SBE, offers promise for alleviating the snakebite burden, not only in India but also in other low- and middle-income countries across South Asia, Africa, and South America, holding potential for broader positive global impact.


Psychosocial Factors in Children and Youth With Special Health Care Needs and Their Families.
Children and youth with special health care needs (CYSHCN) and their families may experience a variety of internal (ie, emotional and behavioral) and external (ie, interpersonal, financial, housing, and educational) psychosocial factors that can influence their health and wellness. Many CYSHCN and their families are resilient and thrive. Medical home teams can partner with CYSHCN and their families to screen for, evaluate, and promote psychosocial health to increase protective factors and ameliorate risk factors. Medical home teams can promote protective psychosocial factors as part of coordinated, comprehensive chronic care for CYSHCN and their families. A team-based care approach may entail collaboration across the care spectrum, including youth, families, behavioral health providers, specialists, child care providers, schools, social services, and other community agencies. The purpose of this clinical report is to raise awareness of the impact of psychosocial factors on the health and wellness of CYSHCN and their families. This clinical report provides guidance for pediatric providers to facilitate and coordinate care that can have a positive influence on the overall health, wellness, and quality of life of CYSHCN and their families.


(Mis)understanding Safety Culture and Its Relationship to Safety Management.
Although the concept of safety culture was coined in relation to major accidents like Chernobyl and Piper Alpha, it has been embraced by the safety community at large as a cause for unsafe practice. In this article, three approaches to safety culture are discussed in terms of their underlying concepts of culture and organizational culture. Culture is an intangible, fuzzy concept encompassing acquired assumptions that is shared among the members of a group and that provides meaning to their perceptions and actions and those of others. The basic assumptions that form the essence of a culture are shared, yet tacit, convictions, which manifest themselves subtly in the visible world. As applied by safety researchers, the culture concept is deprived of much of its depth and subtlety, and is morphed into a grab bag of behavioral and other visible characteristics, without reference to the meaning these characteristics might actually have, and often infused with normative overtones. By combining the three approaches, we can resurrect the notion of safety culture and strengthen its analytical potential in understanding the development and implementation of safety management systems.


Increased circulating blood cell counts in combat-related PTSD: Associations with inflammation and PTSD severity.
Inflammation is reported in post-traumatic stress disorder (PTSD). Few studies have investigated circulating blood cells that may contribute to inflammation. We assessed circulating platelets, white blood cells (WBC) and red blood cells (RBC) in PTSD and assessed their relationship to inflammation and symptom severity. One-hundred and sixty-three male combat-exposed veterans (82 PTSD, 81 non-PTSD) had blood assessed for platelets, WBC, and RBC. Data were correlated with symptom severity and inflammation. All cell counts were significantly elevated in PTSD. There were small mediation effects of BMI and smoking on these relationships. After adjusting for these, the differences in WBC and RBC remained significant, while platelet count was at trend level. In all subjects, all of the cell counts correlated significantly with inflammation. Platelet count correlated with inflammation only in the PTSD subjects. Platelet count, but none of the other cell counts, was directly correlated with PTSD severity ratings in the PTSD group. Combat PTSD is associated with elevations in RBC, WBC, and platelets. Dysregulation of all three major lineages of hematopoietic cells in PTSD, as well as their significant correlation with inflammation, suggest clinical significance of these changes.


Contemporary Demographic Reconstruction Methods Are Robust to Genome Assembly Quality: A Case Study in Tasmanian Devils.
Reconstructing species' demographic histories is a central focus of molecular ecology and evolution. Recently, an expanding suite of methods leveraging either the sequentially Markovian coalescent (SMC) or the site-frequency spectrum has been developed to reconstruct population size histories from genomic sequence data. However, few studies have investigated the robustness of these methods to genome assemblies of varying quality. In this study, we first present an improved genome assembly for the Tasmanian devil using the Chicago library method. Compared with the original reference genome, our new assembly reduces the number of scaffolds (from 35,975 to 10,010) and increases the scaffold N90 (from 0.101 to 2.164 Mb). Second, we assess the performance of four contemporary genomic methods for inferring population size history (PSMC, MSMC, SMC++, Stairway Plot), using the two devil genome assemblies as well as simulated, artificially fragmented genomes that approximate the hypothesized demographic history of Tasmanian devils. We demonstrate that each method is robust to assembly quality, producing similar estimates of Ne when simulated genomes were fragmented into up to 5,000 scaffolds. Overall, methods reliant on the SMC are most reliable between ∼300 generations before present (gbp) and 100 kgbp, whereas methods exclusively reliant on the site-frequency spectrum are most reliable between the present and 30 gbp. Our results suggest that when used in concert, genomic methods for reconstructing species' effective population size histories 1) can be applied to nonmodel organisms without highly contiguous reference genomes, and 2) are capable of detecting independently documented effects of historical geological events.


A Bounded Integer Model for Rating and Composite Scale Data.
Rating and composite scales are commonly used to assess treatment efficacy. The two main strategies for modelling such endpoints are to treat them as a continuous or an ordered categorical variable (CV or OC). Both strategies have disadvantages, including making assumptions that violate the integer nature of the data (CV) and requiring many parameters for scales with many response categories (OC). We present a method, called the bounded integer (BI) model, which utilises the probit function with fixed cut-offs to estimate the probability of a certain score through a latent variable. This method was successfully implemented to describe six data sets from four different therapeutic areas: Parkinson's disease, Alzheimer's disease, schizophrenia, and neuropathic pain. Five scales were investigated, ranging from 11 to 181 categories. The fit (likelihood) was better for the BI model than for corresponding OC or CV models (ΔAIC range 11-1555) in all cases but one (∆AIC - 63), while the number of parameters was the same or lower. Markovian elements were successfully implemented within the method. The performance in external validation, assessed through cross-validation, was also in favour of the new model (ΔOFV range 22-1694) except in one case (∆OFV - 70). A residual for diagnostic purposes is discussed. This study shows that the BI model respects the integer nature of data and is parsimonious in terms of number of estimated parameters.


H2 storage in isostructural UiO-67 and UiO-66 MOFs.
The recently discovered UiO-66/67/68 class of isostructural metallorganic frameworks (MOFs) [J. H. Cavka et al. J. Am. Chem. Soc., 2008, 130, 13850] has attracted great interest because of its remarkable stability at high temperatures, high pressures and in the presence of different solvents, acids and bases [L. Valenzano et al. Chem. Mater., 2011, 23, 1700]. UiO-66 is obtained by connecting Zr(6)O(4)(OH)(4) inorganic cornerstones with 1,4-benzene-dicarboxylate (BDC) as linker resulting in a cubic MOF, which has already been successfully reproduced in several laboratories. Here we report the first complete structural, vibrational and electronic characterization of the isostructural UiO-67 material, obtained using the longer 4,4'-biphenyl-dicarboxylate (BPDC) linker, by combining laboratory XRPD, Zr K-edge EXAFS, TGA, FTIR, and UV-Vis studies. Comparison between experimental and periodic calculations performed at the B3LYP level of theory allows a full understanding of the structural, vibrational and electronic properties of the material. Both materials have been tested for molecular hydrogen storage at high pressures and at liquid nitrogen temperature. In this regard, the use of a longer ligand has a double benefit: (i) it reduces the density of the material and (ii) it increases the Langmuir surface area from 1281 to 2483 m(2) g(-1) and the micropore volume from 0.43 to 0.85 cm(3) g(-1). As a consequence, the H(2) uptake at 38 bar and 77 K increases from 2.4 mass% for UiO-66 up to 4.6 mass% for the new UiO-67 material. This value is among the highest values reported so far but is lower than those reported for MIL-101, IRMOF-20 and MOF-177 under similar pressure and temperature conditions (6.1, 6.2 and 7.0 mass%, respectively) [A. G. Wong-Foy et al. J. Am. Chem. Soc., 2006, 128, 3494; M. Dinca and J. R. Long. Angew. Chem., Int. Ed., 2008, 47, 6766]. Nevertheless the remarkable chemical and thermal stability of UiO-67 and the absence of Cr in its structure would make this material competitive.


Usefulness of cone-beam CT in the evaluation of a spontaneously healed root fracture case.
Horizontal root fractures (HRF) usually affect anterior teeth of male patients as a result of trauma. The consequences can be complex because of combined damage to different tissues, but it has been reported that root fractures undergo healing in majority cases. Diagnosis of HRF must be based on clinical findings, sensibility tests, and radiographic examination. The cone-beam computed tomography (CBCT) has already been proven to be superior among other radiographic modalities for diagnostic imaging of root fractures. However, CBCT in these cases needs to be used in a careful manner, and only when the radiation exposure should be justified by the potential diagnostic benefits and improvement of the treatment results. This case report describes a case of spontaneously healed horizontal root fracture with displacement of the fragments and discusses the usefulness of CBCT in the follow-up of root fractures cases.


[ORL manifestations reported in AIDS. Apropos of 54 cases].
A review of 54 cases of AIDS established the ORL manifestations of this constantly fatal disease. Simple infections such as sinusitis, otitis and tonsillitis were frequent and quite typical, but buccopharyngeal herpes and particularly buccopharyngo-esophageal candidosis were widespread affections. The onset of candidosis in a subject at risk is a valid diagnostic factor for AIDS. A buccopharyngeal Kaposi tumor is specific and is usually associated with lesions in other, particularly cutaneous localizations. Marked emphasis is placed on the role of specialists in the detection of this disease, currently increasing at a high rate. In the USA, where AIDS is very prevalent and doctors very clearly informed, 40% of cases are detected from cervicofacial manifestations.


[Daily physical activity during the nine compulsory school years improves academic school results in boys but not girls - a prospective controlled intervention study].
One aim of the Bunkeflo project is to evaluate if daily school physical activity (PA) is associated with higher final school grades and improved eligibility for upper secondary school. One elementary school extended PA throughout elementary school to 200 minutes/week while control schools continued with in mean 60 minutes/week. We then registered final school grades and eligibility for upper secondary school in children who began first grade in the intervention school during the years before the intervention (1994-1997) and in the children who started 1998-2003 (that is, who had daily PA during the 9 compulsory school years). We also registered final school grades and eligibility for upper secondary school in all Swedish children who started school 1998-2003. We found that boys in the intervention group had higher eligibility rates and higher grade scores than boys who finished the same school before the intervention was implemented as well as higher in all Swedish boys. These differences in were not seen in girls. Daily school PA through elementary school is associated with higher final grade scores and higher eligibility rates for upper secondary school in boys.


Multiparametric MRI in Patients With Nonalcoholic Fatty Liver Disease.
Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease in the world, affecting more than 25% of the adult population. NAFLD covers a spectrum including simple steatosis, in which lipid accumulation in hepatocytes is the predominant histological characteristic, and nonalcoholic steatohepatitis (NASH), which is characterized by additional hepatic inflammation with or without fibrosis. Liver biopsy is currently the reference standard to discriminate between hepatic steatosis and steatohepatitis. Since liver biopsy has several disadvantages, noninvasive diagnostic methods with high sensitivity and specificity are desirable for the analysis of NAFLD. Improvements in magnetic resonance imaging (MRI) technology are continuously being implemented in clinical practice, specifically multiparametric MRI methods such as proton density fat-fraction (PDFF), T2 *, and T1 mapping, along with MR elastography. Multiparametric imaging of the liver has a promising role in the clinical management of NAFLD with quantification of fat content, iron load, and fibrosis, which are features in NAFLD. In the present article, we review the utility and limitations of multiparametric quantitative imaging of the liver for diagnosis and management of patients with NAFLD. LEVEL OF EVIDENCE: 5. TECHNICAL EFFICACY STAGE: 3.


Evolutionary conservation of chromosome territory arrangements in cell nuclei from higher primates.
We demonstrate that the nuclear topological arrangement of chromosome territories (CTs) has been conserved during primate evolution over a period of about 30 million years. Recent evidence shows that the positioning of chromatin in human lymphocyte nuclei is correlated with gene density. For example, human chromosome 19 territories, which contain mainly gene-dense and early replicating chromatin, are located toward the nuclear center, whereas chromosome 18 territories, which consist mainly of gene-poor and later replicating chromatin, is located close to the nuclear border. In this study, we subjected seven different primate species to comparative analysis of the radial distribution pattern of human chromosome 18- and 19-homologous chromatin by three-dimensional fluorescence in situ hybridization. Our data demonstrate that gene-density-correlated radial chromatin arrangements were conserved during higher-primate genome evolution, irrespective of the major karyotypic rearrangements that occurred in different phylogenetic lineages. The evolutionarily conserved positioning of homologous chromosomes or chromosome segments in related species supports evidence for a functionally relevant higher-order chromatin arrangement that is correlated with gene-density.


[Medical-biological approach to development of feeding ration for sportswomen--members of Russia weight lifting team].
Physical status of 12 sportswomen - member of Russia weight lifting team during training period was analiysed. Anthropometric, bioimpedance methods with analyzer ABC-01 "Medass" in observation [body weight Index (index Ketle-2), waist circle/hip circle index] and body compositions were used (adipose, bone and muscle tissues masse). Data obtained when bioimpedance method was used indicated: normal body weight and relative adipose mass to body weight - in 92%, surplus - in 8% of cases; body weight Index and normal level of adipose mass - in 75%, surplus - in 25%; active cellular mass and bone mass and general body liquid were found to be normal. 14-day feeding ration for sportswomen were analysed and 3 times per day food intakes was found to be not optimal. Data obtained let to recommend set of daily food products to compose optimal ration for present sportswomen group when energetic value of 4500 kKal and high nutritional value would be provided.


Role of A2B adenosine receptors in regulation of paracrine functions of stem cell antigen 1-positive cardiac stromal cells.
The existence of multipotent cardiac stromal cells expressing stem cell antigen (Sca)-1 has been reported, and their proangiogenic properties have been demonstrated in myocardial infarction models. In this study, we tested the hypothesis that stimulation of adenosine receptors on cardiac Sca-1(+) cells up-regulates their secretion of proangiogenic factors. We found that Sca-1 is expressed in subsets of mouse cardiac stromal CD31(-) and endothelial CD31(+) cells. The population of Sca-1(+)CD31(+) endothelial cells was significantly reduced, whereas the population of Sca-1(+)CD31(-) stromal cells was increased 1 week after myocardial infarction, indicating their relative functional importance in this pathophysiological process. An increase in adenosine levels in adenosine deaminase-deficient mice in vivo significantly augmented vascular endothelial growth factor (VEGF) production in cardiac Sca-1(+)CD31(-) stromal cells but not in Sca-1(+)CD31(+) endothelial cells. We found that mouse cardiac Sca-1(+)CD31(-) stromal cells predominantly express mRNA encoding A(2B) adenosine receptors. Stimulation of adenosine receptors significantly increased interleukin (IL)-6, CXCL1 (a mouse ortholog of human IL-8), and VEGF release from these cells. Using conditionally immortalized Sca-1(+)CD31(-) stromal cells obtained from wild-type and A(2B) receptor knockout mouse hearts, we demonstrated that A(2B) receptors are essential for adenosine-dependent up-regulation of their paracrine functions. We found that the human heart also harbors a population of stromal cells similar to the mouse cardiac Sca-1(+)CD31(-) stromal cells that increase release of IL-6, IL-8, and VEGF in response to A(2B) receptor stimulation. Thus, our study identified A(2B) adenosine receptors on cardiac stromal cells as potential targets for up-regulation of proangiogenic factors in the ischemic heart.


Interfering with nucleotide excision by the coronavirus 3'-to-5' exoribonuclease.
Some of the most efficacious antiviral therapeutics are ribonucleos(t)ide analogs. The presence of a 3'-to-5' proofreading exoribonuclease (ExoN) in coronaviruses diminishes the potency of many ribonucleotide analogs. The ability to interfere with ExoN activity will create new possibilities for control of SARS-CoV-2 infection. ExoN is formed by a 1:1 complex of nsp14 and nsp10 proteins. We have purified and characterized ExoN using a robust, quantitative system that reveals determinants of specificity and efficiency of hydrolysis. Double-stranded RNA is preferred over single-stranded RNA. Nucleotide excision is distributive, with only one or two nucleotides hydrolyzed in a single binding event. The composition of the terminal basepair modulates excision. A stalled SARS-CoV-2 replicase in complex with either correctly or incorrectly terminated products prevents excision, suggesting that a mispaired end is insufficient to displace the replicase. Finally, we have discovered several modifications to the 3'-RNA terminus that interfere with or block ExoN-catalyzed excision. While a 3'-OH facilitates hydrolysis of a nucleotide with a normal ribose configuration, this substituent is not required for a nucleotide with a planar ribose configuration such as that present in the antiviral nucleotide produced by viperin. Design of ExoN-resistant, antiviral ribonucleotides should be feasible.


Videometric analysis of regional left ventricular function before and after aortocoronary artery bypass surgery: correlation of peak rate of myocardial wall thickening with late postoperative graft flows.
The peak rate of systolic wall thickening (pdTw/dt) in regions of the left ventricle was determined by biplane roentgen videometry in 60 patients before and a median of 14 mo after aorto-coronary bypass graft surgery. The left ventricular ejection fraction, stroke volume, and end-diastolic volume and pressure did not change significantly after surgery in the presence of patent or occluded grafts (P greater than 0.05). Statistically significant increases occurred in the peak rate of systolic wall thickening regions supplied by patent bypass grafts, and significant decreases occurred in regions with occluded grafts (P less than 0.01). Of 42 preoperatively hypokinetic regions (pdTw/dt greater than 0 less than 5.0 cm/s) supplied by a patent graft, 30 improved by an average of 2.6 cm/s after operation; 18 returned to normal. Failure of 24 hypokinetic regions to improve to normal was associated with myocardial infarction in 11 or with late postoperative graft blood flows of less than 60 ml/min measured by videodensitometry, in 10. All seven preoperatively akinetic (pdTw/dt=0) or dyskinetic (pdTw/dt less than 0) regions did not improve after the operation despite the fact that, in five of the seven, coronary bypass flows were over 60 ml/min. All eight preoperatively hypokinetic regions supplied by coronary artery graft flows of less than or equal 40 ml/min failed to improve to normal after operation. All nine preoperatively hypokinetic regions supplied by coronary artery graft flows of over 60 ml/min improved to normal after surgery. Late postoperative coronary artery bypass graft flows, the functional status of the myocardium, the status and distribution of the native coronary circulation, and decreased regional function elsewhere in the ventricle must all be considered when regional left ventricular function is interpreted.


Effect of leukotriene D4 on nasal mucosal blood flow, nasal airway resistance and nasal secretion in humans.
The possible role of leukotriene D4 (LTD4) in nasal allergy was investigated in healthy volunteers. Nasal blood flow, nasal airway resistance, nasal discharge and nasal itching and sneezing were examined. LTD4 was found to induce a dose-response related increase in nasal mucosal blood flow as measured by laser-Doppler flowmetry. Histamine exhibited similar effects on blood flow in the same concentration range. Nasal airway resistance as recorded by rhinomanometry, increased in a dose-related manner after topical LTD4. Nasal secretion was obtained by nasal lavage and estimated from a dilution principle. Topical LTD4 did not increase the amount of nasal secretion, whereas a dose-related increase was found after topical histamine. LTD4 did not cause itching, sneezing or other irritative symptoms. In conclusion, LTD4 may play a role in nasal allergy by increasing blood flow and nasal airway resistance. Itching, sneezing and discharge, however, are apparently not caused by LTD4 but can be accounted for by the release of histamine or other mediators.


[Social and familial characteristics of pregnant adolescents seen at a high-risk care module].
Our aim was to identify social and familial characteristics in the pregnant adolescents. We conducted a cross-sectional survey in 74 pregnant adolescents referred to the Mexican Institute of Social Security's (IMSS) Vicente Guerrero Regional General Hospital High-Risk Module in Acapulco, Guerrero, Mexico from September to November, 2003. An opinion-descriptive questionnaire was formulated by a Committee of Experts and was applied to pregnant adolescents. Variables studied included personal data, obstetrics, and family characteristics. With regard to personal characteristics, average participant age was 17 years, 21 (28%) participants had a high-school academic level, 66 (89%) entertained an interest in continuing their academic studies, 49 (66%) were married, 66 (89%)were homemakers, 35 (47%) mentioned that the reason they got pregnant was to get married, while (36%) got married to leave their original home situation, 54 (73%) accepted the pregnancy, and 71 (96%) of participants reported feelings of responsibility with regard to caring for their infants. Obstetrical characteristics included sexual activity beginning at an average age of 15 years, 63 (85%) of participants' mothers had a pregnancy during adolescence, and 63 (85%) received information on contraceptives but 51 (69%) did not use these. Family characteristics showed 48 cases (65%) had parents who were married, 58 (62%) of participants lived with their spouses' family, 26 (35%) reported more confidence with their mothers, and 68 (92%) had support from their spouse during the pregnancy. It is essential to develop and organize a strategy to improve integral care for pregnant adolescents individually, in the family, and socially that includes active participation in the health education process, needs identification, and deciding on the best choices.


A hypothesis of thyroid-catecholamine-receptor interaction. Its relevance to affective illness.
Recent prospective studies suggest that thyroid state plays a role in affective disorders. A lack of thyroid hormones can lower the threshold for depression; an excess can contribute to a state of tense dysphoria. Thyroid function in some persons also appears to influence the course of affective disorders. Adequate mobilization of thyroid hormones favors recovery from depression; excess mobilization increases the risk of mania in vulnerable individuals. Although other mechanisms may be involved, evidence suggests that the modulation by thyroid hormones of the beta-adrenergic receptor response to catecholamines may contribute to these effects. Norepinephrine stimulates such receptors; thyroid hormones increase their ability to receive stimulation. The plausibility of such interactions between catecholamines and thyroid hormones occurring in the CNS is strengthened by their common origin in the amino acid tyrosine and by their synergism in many metabolic processes.


Synchronous timing of abrupt climate changes during the last glacial period.
Abrupt climate changes during the last glacial period have been detected in a global array of palaeoclimate records, but our understanding of their absolute timing and regional synchrony is incomplete. Our compilation of 63 published, independently dated speleothem records shows that abrupt warmings in Greenland were associated with synchronous climate changes across the Asian Monsoon, South American Monsoon, and European-Mediterranean regions that occurred within decades. Together with the demonstration of bipolar synchrony in atmospheric response, this provides independent evidence of synchronous high-latitude-to-tropical coupling of climate changes during these abrupt warmings. Our results provide a globally coherent framework with which to validate model simulations of abrupt climate change and to constrain ice-core chronologies.


89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer.
Programmed cell death protein-1/ligand-1 (PD-1/PD-L1) blockade is effective in a subset of patients with several tumor types, but predicting patient benefit using approved diagnostics is inexact, as some patients with PD-L1-negative tumors also show clinical benefit1,2. Moreover, all biopsy-based tests are subject to the errors and limitations of invasive tissue collection3-11. Preclinical studies of positron-emission tomography (PET) imaging with antibodies to PD-L1 suggested that this imaging method might be an approach to selecting patients12,13. Such a technique, however, requires substantial clinical development and validation. Here we present the initial results from a first-in-human study to assess the feasibility of imaging with zirconium-89-labeled atezolizumab (anti-PD-L1), including biodistribution, and secondly test its potential to predict response to PD-L1 blockade (ClinicalTrials.gov identifiers NCT02453984 and NCT02478099). We imaged 22 patients across three tumor types before the start of atezolizumab therapy. The PET signal, a function of tracer exposure and target expression, was high in lymphoid tissues and at sites of inflammation. In tumors, uptake was generally high but heterogeneous, varying within and among lesions, patients, and tumor types. Intriguingly, clinical responses in our patients were better correlated with pretreatment PET signal than with immunohistochemistry- or RNA-sequencing-based predictive biomarkers, encouraging further development of molecular PET imaging for assessment of PD-L1 status and clinical response prediction.


Endometriosis and Cannabis Consumption During the COVID-19 Pandemic: An International Cross-Sectional Survey.
Introduction: Endometriosis affects 1 in 10 women worldwide, with most experiencing difficulties achieving adequate symptom control. These difficulties have been compounded by the onset of the COVID-19 pandemic due to worldwide shifts in health care resource allocation. As cannabis is a relatively common form of self-management in endometriosis, this study aims to explore the impact of the COVID-19 pandemic on cannabis consumption in those with endometriosis. Methods: An anonymous, cross-sectional online international survey was developed and promoted by endometriosis advocacy/support organizations worldwide. Respondents needed to have a diagnosis of endometriosis and be aged between 18 and 55. Results: A total of 1634 responses were received from 46 different countries. The average age of respondents was 30, with a mean diagnosis age of 25. Eight hundred forty-six respondents (51%) reported consuming cannabis in the past 3 months, with 55% of these reporting use for symptom management only. One in five respondents (20%) reported having consumed cannabis previously, the most common reason for discontinuation (65%) was access difficulties during COVID. Those who had legal access were more likely to consume cannabis than those without (p<0.0001) and were more likely to disclose usage to health care professionals (p<0.0001). The most common reasons for consuming cannabis during COVID was increased stress/anxiety (59%) and lack of access to normal medical care (48%). Pre-pandemic, cannabis was mostly consumed at least once a day (61%) and in inhaled forms (51.6%). Consumption increased for most people (57%) during the pandemic. During the pandemic just under a quarter (23%) of respondents changed their mode of consumption, with a reduction in inhaled forms (39.5%) and an increase in consumption of edibles (40%) or oil (25.2%). Conclusions: Cannabis consumption, especially for symptom relief, was relatively common among those with endometriosis, with some people starting their consumption of cannabis due to health care restrictions that occurred due to the COVID-19 pandemic. Difficulties accessing cannabis and unpleasant/unwanted side effects were the most common reasons for lack of current cannabis consumption in those who had previously consumed it. Cannabis consumption may form an important part of endometriosis management especially when access to routine medical care is restricted.


Sleep disturbance in dementia with Lewy bodies and Alzheimer's disease: a multicenter analysis.
Evidence suggests that patients with dementia with Lewy bodies (DLB) may have more nocturnal sleep disturbance than patients with Alzheimer's disease (AD). We sought to confirm such observations using a large, prospectively collected, standardized, multicenter-derived database, i.e. the National Alzheimer's Coordinating Center Uniform Data Set. Nocturnal sleep disturbance (NSD) data, as characterized by the Neuropsychiatric Inventory Questionnaire (NPI-Q), were derived from 4,531 patients collected between September 2005 and November 2008 from 32 National Institute on Aging participating AD centers. Patient and informant characteristics were compared between those with and without NSD by dementia diagnosis (DLB and probable AD). Finally, a logistic regression model was created to quantify the association between NSD status and diagnosis while adjusting for these patient/informant characteristics, as well as center. NSD was more frequent in clinically diagnosed DLB relative to clinically diagnosed AD (odds ratio = 2.93, 95% confidence interval = 2.22-3.86). These results were independent from the gender of the patient or informant, whether the informant lived with the patient, and other patient characteristics, such as dementia severity, depressive symptoms, and NPI-Q-derived measures of hallucinations, delusions, agitation and apathy. In AD, but not DLB, patients, NSD was associated with more advanced disease. Comorbidity of NSD with hallucinations, agitation and apathy was higher in DLB than in AD. There was also evidence that the percentage of DLB cases with NSD showed wide variation across centers. As defined by the NPI-Q, endorsement of the nocturnal behavior item by informants is more likely in patients with DLB when compared to AD, even after the adjustment of key patient/informant characteristics.


The AMPK inhibitor compound C is a potent AMPK-independent antiglioma agent.
AMP-activated protein kinase (AMPK) is an evolutionarily conserved energy sensor important for cell growth, proliferation, survival, and metabolic regulation. Active AMPK inhibits biosynthetic enzymes like mTOR and acetyl CoA carboxylase (required for protein and lipid synthesis, respectively) to ensure that cells maintain essential nutrients and energy during metabolic crisis. Despite our knowledge about this incredibly important kinase, no specific chemical inhibitors are available to examine its function. However, one small molecule known as compound C (also called dorsomorphin) has been widely used in cell-based, biochemical, and in vivo assays as a selective AMPK inhibitor. In nearly all these reports including a recent study in glioma, the biochemical and cellular effects of compound C have been attributed to its inhibitory action toward AMPK. While examining the status of AMPK activation in human gliomas, we observed that glioblastomas express copious amount of active AMPK. Compound C effectively reduced glioma viability in vitro both by inhibiting proliferation and inducing cell death. As expected, compound C inhibited AMPK; however, all the antiproliferative effects of this compound were AMPK independent. Instead, compound C killed glioma cells by multiple mechanisms, including activation of the calpain/cathepsin pathway, inhibition of AKT, mTORC1/C2, cell-cycle block at G2-M, and induction of necroptosis and autophagy. Importantly, normal astrocytes were significantly less susceptible to compound C. In summary, compound C is an extremely potent antiglioma agent but we suggest that caution should be taken in interpreting results when this compound is used as an AMPK inhibitor.


Histone H2A.Z and homologues of components of the SWR1 complex are required to control immunity in Arabidopsis.
One of the mechanisms involved in chromatin remodelling is so-called 'histone replacement'. An example of such a mechanism is the substitution of canonical H2A histone by the histone variant H2A.Z. The ATP-dependent chromatin remodelling complex SWR1 is responsible for this action in yeast. We have previously proposed the existence of an SWR1-like complex in Arabidopsis by demonstrating genetic and physical interaction of the components SEF, ARP6 and PIE1, which are homologues of the yeast Swc6 and Arp6 proteins and the core ATPase Swr1, respectively. Here we show that histone variant H2A.Z, but not canonical H2A histone, interacts with PIE1. Plants mutated at loci HTA9 and HTA11 (two of the three Arabidopsis H2A.Z-coding genes) displayed developmental abnormalities similar to those found in pie1, sef and arp6 plants, exemplified by an early-flowering phenotype. Comparison of gene expression profiles revealed that 65% of the genes differentially regulated in hta9 hta11 plants were also mis-regulated in pie1 plants. Detailed examination of the expression data indicated that the majority of mis-regulated genes were related to salicylic acid-dependent immunity. RT-PCR and immunoblotting experiments confirmed constitutive expression of systemic acquired resistance (SAR) marker genes in pie1, hta9 hta11 and sef plants. Variations observed at the molecular level resulted in phenotypic alterations such as spontaneous cell death and enhanced resistance to the phytopathogenic bacteria Pseudomonas syringae pv. tomato. Thus, our results support the existence in Arabidopsis of an SWR1-like chromatin remodelling complex that is functionally related to that described in yeast and human, and attribute to this complex a role in maintaining a repressive state of the SAR response.