MRI biomarkers for Alzheimer's disease: the impact of functional connectivity in the default mode network and structural connectivity between lobes on diagnostic accuracy.
At present, clinical use of MRI in Alzheimer's disease (AD) is mostly focused on the assessment of brain atrophy, namely in the hippocampal region. Despite this, multiple biomarkers reflecting structural and functional brain connectivity changes have shown promising results in the assessment of AD. To help identify the most relevant ones that may stand a chance of being used in clinical practice, we compared multiple biomarker in terms of their value to discriminate AD from healthy controls and analyzed their age dependency. 20 AD patients and 20 matched controls underwent MRI-scanning (3T GE), including T1-weighted, diffusion-MRI, and resting-state-fMRI (rsfMRI). Whole brain, white matter, gray matter, cortical gray matter and hippocampi volumes were measured using icobrain. rsfMRI between regions of the default-mode-network (DMN) was assessed using group independent-component-analysis. Median diffusivity and kurtosis were determined in gray and white-matter. DTI data was used to evaluate pairwise structural connectivity between lobar regions and the hippocampi.Logistic-Regression and Random-Forest models were trained to classify AD-status based on, respectively different isolated features and age, and feature-groups combined with age. Hippocampal features, features reflecting the functional connectivity between the medial-Pre-Frontal-Cortex (mPFC) and the posterior regions of the DMN, and structural interhemispheric frontal connectivity showed the strongest differences between AD-patients and controls. Structural interhemispheric parietal connectivity, structural connectivity between the parietal lobe and hippocampus in the right hemisphere, and mPFC-DMN-features, showed only an association with AD-status (p < 0.05) but not with age. Hippocampi volumes showed an association both with age and AD-status (p < 0.05).Smallest-hippocampus-volume was the most discriminative feature. The best performance (accuracy:0.74, sensitivity:0.74, specificity:0.74) was obtained with an RF-model combining the best feature from each feature-group (smallest hippocampus volume, WM volume, median GM MD, lTPJ-mPFC connectivity and structural interhemispheric frontal connectivity) and age. Brain connectivity changes caused by AD are reflected in multiple MRI-biomarkers. Decline in both the functional DMN-connectivity and the parietal interhemispheric structural connectivity may assist sepparating healthy-aging driven changes from AD, complementing hippocampal volumes which are affected by both aging and AD.


Factors predicting relapse and treatment discontinuation with paliperidone 3-monthly long-acting injection: A 2-year naturalistic follow-up study.
Paliperidone 3-monthly (PP3M) long-acting injection has proven efficacy and effectiveness in schizophrenia. Little is known of its effectiveness in other diagnoses. All patients starting PP3M were followed up for 2 years. Main outcome measures were relapse and discontinuation from PP3M. Post hoc we examined outcomes in those switched back to one monthly paliperidone (PP1M) long-acting injection. Overall, 186 patients were followed-up. At the 2-year end point, 110 patients (59%) were still receiving PP3M, and 129 (70%) were receiving some form of paliperidone long-acting injection. Discontinuation from paliperidone long-acting injections (PPLAIs) was more likely with a nonschizophrenia diagnosis (hazard ratio [HR] for continuation 0.429 [95% confidence intervals (CI) - 0.21, 0.87 p = 0.018)), and prior clozapine use [in PP3M patients; HR for discontinuation 1.87 [95% CI - 1.05, 3.30 p = 0.032]). Relapse occurred in 20 (11%) of those receiving PP3M. Relapse on PP3M and PPLAIs was more likely in nonschizophrenia diagnosis (HR 0.17 for remaining relapse-free [95% CI - 0.06, 0.50; p = 0.001]; HR 0.21 [95% CI - 0.08, 0.58 p = 0.002], respectively), polypharmacy in PP3M patients (HR for relapse 7.91 [95% CI - 3.73, 22.9; p < 0.001]) and PPLAI patients (HR for relapse 6.45 [95% CI - 2.49, 16.5; p < 0.001]), and prior clozapine use in PP3M patients (HR for relapse 6.11 [95% CI - 1.82, 20.5; p = 0.003]) and PPLAI patients (HR for relapse 4.52 (95% CI - 1.51, 13.5; p = 0.007). Outcomes with PP3M are excellent in practice, even when used outside its formal license. PP3M was relatively more effective in those with an F20 schizophrenia diagnosis and in those never before considered for or prescribed clozapine.


Expectant Treatment of Mild Endometriosis Selectively Favors Survival of Female Fetuses
In this prospective cohort study, 30 women diagnosed at laparoscopy with mild endometriosis were treated expectantly and followed for 10 years. Eleven women had primary infertility and 19 secondary infertility. Before the diagnosis of endometriosis, 19 women had a total of 32 pregnancies: the female live birth rate was 25%, male live birth rate 28%, spontaneous abortion rate 44%, and ectopic pregnancy rate 3%. After expectant treatment of mild endometriosis, 25 women had a total of 51 pregnancies: the female live birth rate was 52.9%, male live birth rate 27.4%, spontaneous abortion rate 19.6%, and ectopic pregnancy rate zero. Expectant treatment of mild endometriosis in 30 infertile women resulted in 41 live-born infants: 66% females and 34% males. We conclude that expectant treatment of mild endometriosis selectively favors the survival of female infants.


Nonadiabatic reaction dynamics to silicon monosulfide (SiS): A key molecular building block to sulfur-rich interstellar grains.
Sulfur- and silicon-containing molecules are omnipresent in interstellar and circumstellar environments, but their elementary formation mechanisms have been obscure. These routes are of vital significance in starting a chain of chemical reactions ultimately forming (organo) sulfur molecules-among them precursors to sulfur-bearing amino acids and grains. Here, we expose via laboratory experiments, computations, and astrochemical modeling that the silicon-sulfur chemistry can be initiated through the gas-phase reaction of atomic silicon with hydrogen sulfide leading to silicon monosulfide (SiS) via nonadiabatic reaction dynamics. The facile pathway to the simplest silicon and sulfur diatomic provides compelling evidence for the origin of silicon monosulfide in star-forming regions and aids our understanding of the nonadiabatic reaction dynamics, which control the outcome of the gas-phase formation in deep space, thus expanding our view about the life cycle of sulfur in the galaxy.


Determining the optimal cholecalciferol dosing regimen in children with CKD: a randomized controlled trial.
The optimal treatment regimen for correcting 25-hydroxyvitamin D (25OHD) deficiency in children with chronic kidney disease (CKD) is not known. We compared cholecalciferol dosing regimens for achieving and maintaining 25OHD concentrations ≥30 ng/mL in children with CKD stages 2-4. An open-label, multicentre randomized controlled trial randomized children with 25OHD concentrations <30 ng/mL in 1:1:1 to oral cholecalciferol 3000 IU daily, 25 000 IU weekly or 100 000 IU monthly for 3 months (maximum three intensive courses). In those with 25OHD ≥30 ng/mL, 1000 IU cholecalciferol daily (maintenance course) was given for up to 9 months. Primary outcome was achieving 25OHD ≥30 ng/mL at the end of intensive phase treatment. Ninety children were randomized to daily (n = 30), weekly (n = 29) or monthly (n = 31) treatment groups. At the end of intensive phase, 70/90 (77.8%) achieved 25OHD ≥30 ng/mL; 25OHD concentrations were comparable between groups (median 44.3, 39.4 and 39.3 ng/mL for daily, weekly and monthly groups, respectively; P = 0.24) with no difference between groups for time to achieve 25OHD ≥30 ng/mL (P = 0.28). There was no change in calcium, phosphorus and parathyroid hormone, but fibroblast growth factor 23 (P = 0.002) and klotho (P = 0.001) concentrations significantly increased and were comparable in all treatment groups. Irrespective of dosing regimen, children with glomerular disease had 25OHD concentrations lower than non-glomerular disease (25.8 versus 41.8 ng/mL; P = 0.007). One child had a 25OHD concentration of 134 ng/mL, and 5.5% had hypercalcemia without symptoms of toxicity. Intensive treatment with oral cholecalciferol as daily, weekly or monthly regimens achieved similar 25OHD concentrations between treatment groups, without toxicity. Children with glomerular disease required higher doses of cholecalciferol compared with those with non-glomerular disease.


Suppressive effect of monocytes in vitro in patients with carcinoma of the uterine cervix.
The adherent cell fraction (AdC) of human peripheral blood mononuclear cells (PBM) contains two cell types of opposing function in vitro. Dendritic cells (DC) act as antigen-presenting cells (APC) in vitro, while monocytes (Mo) have a suppressive effect on antigen activation of T cells. In this report we show that patients with cervical carcinoma have a significantly increased number of suppressive Mo compared with healthy controls. The T cell response to Herpes Simplex Virus (HSV-1) and PPD was about the same in the two groups, but after removal of Mo by adherence a significantly higher T cell response was seen among the patients with advanced stage (Figo stage IIb-IVa) compared with patients in early stage (Figo stage Ia-IIa) and healthy controls. These observations indicate that patients with cervical carcinoma have an increased number of T cells reactive with HSV, and normal DC function. The relative suppression expressed on a per Mo basis was the same in all groups, which indicates that the increased suppression in the patients was caused by an increased number of Mo, and not by changes in their activation state.


Brief commentary: Under-recognition of underuse of clozapine in treating psychotic symptoms in Parkinson's disease.
Clozapine is an important drug in the treatment of Parkinson's disease (PD). It has proven efficacy in treating PD psychosis without worsening motor function, as well as in treating tremor refractory to L-Dopa, yet it is severely underused in the United States. Unlike the situation of treatment resistant schizophrenia, this underuse is underrecognized.


Differential functional ontogeny of dopamine presynaptic receptor regulation.
The ontogeny of dopamine (DA) presynaptic receptor regulation was examined neuropharmacologically in 7-, 14-, 21-, 28- and 35-day-old and adult rats. In striatum, gamma-butyrolactone (GBL) significantly increased DA levels as early as 7 days postnatally; apomorphine attenuated this increase beginning at 14 days postnatally. However, in olfactory tubercles, no increase in DA was observed after GBL until 21 days postnatally, and not until 35 days postnatally was apomorphine consistently able to attenuate this increase. Thus, DA presynaptic receptors in mesolimbic regions may mature several weeks later than in striatum.


Second messenger Ap4A polymerizes target protein HINT1 to transduce signals in FcεRI-activated mast cells.
Signal transduction systems enable organisms to monitor their external environments and accordingly adjust the cellular processes. In mast cells, the second messenger Ap4A binds to the histidine triad nucleotide-binding protein 1 (HINT1), disrupts its interaction with the microphthalmia-associated transcription factor (MITF), and eventually activates the transcription of genes downstream of MITF in response to immunostimulation. How the HINT1 protein recognizes and is regulated by Ap4A remain unclear. Here, using eight crystal structures, biochemical experiments, negative stain electron microscopy, and cellular experiments, we report that Ap4A specifically polymerizes HINT1 in solution and in activated rat basophilic leukemia cells. The polymerization interface overlaps with the area on HINT1 for MITF interaction, suggesting a possible competitive mechanism to release MITF for transcriptional activation. The mechanism depends precisely on the length of the phosphodiester linkage of Ap4A. These results highlight a direct polymerization signaling mechanism by the second messenger.


The social experience of participation in a COVID-19 vaccine trial: Subjects' motivations, others' concerns, and insights for vaccine promotion.
Vaccine hesitancy could undermine the effectiveness of COVID-19 vaccination programs. Knowledge about people's lived experiences regarding COVID-19 vaccination can enhance vaccine promotion and increase uptake. To use COVID-19 vaccine trial participants' experiences to identify key themes in the lived experience of vaccination early in the vaccine approval and distribution process. We interviewed 31 participants in the Iowa City, Iowa US site of the Pfizer/BioNTech COVID-19 vaccine phase 3 clinical trial. While trial participation differs from clinical receipt of an approved vaccine in key ways, it offers the first view of people's lived experiences of potentially receiving a COVID-19 vaccine. The trial context is also useful since decision-making about vaccination and medical research participation often involve similar hopes and concerns, and because the public appears to view even approved COVID-19 vaccines as experimental given their novelty. Semi-structured interviews addressed subjects' experiences, including decision-making and telling others about their trial participation. We analyzed verbatim transcripts of these interviews thematically and identified common themes relevant for vaccination decision-making. Participants across demographic groups, including age, sex/gender, race/ethnicity, and political affiliation, described largely similar experiences. Key motivations for participation included ending the pandemic/restoring normalcy, protecting oneself and others, doing one's duty, promoting/modeling vaccination, and expressing aspects of identity like being a helper, career-related motivations, and support of science/vaccines. Participants often felt uniquely qualified to help via trial participation due to personal attributes like health, sex/gender or race/ethnicity. They reported hearing concerns about side effects and the speed and politicization of vaccine development. Participants responded by normalizing and contextualizing side effects, de-politicizing vaccine development, and explaining how the rapid development process was nevertheless safe. These findings regarding participants' reported motivations for trial participation and interactions with concerned others can be incorporated into COVID-19 vaccine promotion messaging aimed at similar populations.


Development and evaluation of three real-time immuno-PCR assemblages for quantification of PSA.
Real-time PCR is a very sensitive technique to measure DNA concentrations. In real-time immuno-PCR, it is used as the detection system for quantification of proteins. Many ways to perform and assemble real-time immuno-PCR are possible. We have tested three different approaches for the detection of prostate specific antigen (PSA) and compared them with each other and with ELISA. We also demonstrate the applicability of real-time immuno-PCR to classify clinical PSA samples. Assemblage I is performed stepwise attaching the capture antibody to the vessel surface by adsorption and having the DNA-label linked to the detection antibody through biotin and streptavidin. In assemblage II, capture antibody is also adsorbed to the vessel surface but the detection antibody is pre-conjugated to the DNA-label. Assemblage III uses the pre-conjugated detection antibody/DNA-label but binds the capture antibody through biotin to surface immobilized streptavidin. We found assemblage II to be the most sensitive, with a detection limit of 4.8 x 10(5) PSA molecules. This can be compared to the detection limit of the ELISA, which is 5.7 x 10(7) molecules. Assemblage III was the most reproducible with a standard deviation (SD) of 0.21 cycles, while assemblage I was the least reproducible (SD=0.45 cycles). The SD of assemblage II was 0.25 cycles. We conclude that using pre-conjugated detection antibody/DNA-label enhances both the sensitivity and the reproducibility of real-time immuno-PCR. Measurements of PSA in serum samples using real-time immuno-PCR correlated well with measurements performed with ELISA. The real-time immuno-PCR measurements were more sensitive and the dynamic range was larger than with the ELISA.


Predictors of stroke favorable functional outcome in Guinea, results from the Conakry stroke registry.
Low- to middle-income countries (LMICs) now bear most of the stroke burden. In LMICs, stroke epidemiology and health care systems are different from HICs. Therefore, a high-income country (HIC)-based predictive model may not correspond to the LMIC stroke context. Identify the impact of modifiable variables in acute stroke management in Conakry, Guinea as potential predictors of favorable stroke outcome. Data were extracted from the Conakry stroke registry that includes 1018 patients. A logistic regression model was built to predict favorable stroke outcomes, defined as mRS 0-2. Age, admission NIHSS score, mean arterial blood pressure and capillary glycemia were chosen as covariates. Delay to brain CT imaging under 24 h from symptom onset, fever, presence of sores and abnormal lung auscultation were included as factors. NIHSS score on admission, age and ischemic stroke were included in the null model as nuisance parameters to determine the contribution of modifiable variables to predict stroke favorable outcome. Lower admission NIHSS, brain CT imaging within 24 h of symptoms onset and lower mean arterial blood pressure emerged as a significant positive predictors of favorable stroke outcome with respective odd ratios (OR) of 1.35 [1.28-1.43], 2.1 [1.16-3.8] and 1.01 [1.01-1.04]. The presence of fever or sores impacted negatively stroke favorable outcomes with OR of 0.3 [0.1-0.85] and 0.25 [0.14-0.45]. The area under receiver operating characteristic curves (AUC) of the model was 0.86. This model explained 44.5% of the variability of the favorable stroke outcome with 10.2% of the variability explained by the modifiable variables when admission NIHSS, and ischemic stroke were included in the null model as nuisance parameter. In the Conakry stroke registry, using a logistic regression to predict stroke favorable outcome, five variables that led to an AUC of 0.86: admission NIHSS, early brain CT imaging, fever, sores and mean blood pressure. This paves the way for future public health interventions to test whether modulating amendable variables leads to increased favorable stroke outcomes in LMICs.


Radioprotective effect of extract from Spirulina platensis in mouse bone marrow cells studied by using the micronucleus test.
The radioprotective effect of an extract of Spirulina platensis has been studied using the micronucleus test in polychromatic erythrocytes of bone marrow of mice. In this system the extract caused a significant reduction of the micronucleus frequencies induced by gamma-radiation.


Steroids from the roots of Cynanchum stauntonii.
A chemical investigation of the roots of Cynanchum stauntonii has resulted in the characterization of a new hydroperoxide with a 13,14 : 14,15-disecopregnane-type skeleton, named stauntonine (1), together with three related compounds, anhydrohirundigenin (2), anhydrohirundigenin monothevetoside (3), and glaucogenin-C mono- D-thevetoside (4). Their structures were established by spectroscopic methods, including X-ray crystallographic diffraction analysis of stauntonine that confirmed its relative stereochemistry. The compound 1 showed dose-dependent relaxation on aortic rings with endothelium contracted by phenylepherine or KCl.


Mechanical evaluation of different techniques for symphysis fracture fixation--an in vitro polyurethane mandible study.
The aim of this study was to make a comparative evaluation of the mechanical behavior of 4 different internal fixation systems for mandibular symphysis fractures. Forty polyurethane mandible replicas (Nacional, Jaú, SP, Brazil) were used. These were divided into 4 groups of different fixation methods: group 1P, 1 2.0-mm miniplate; group 2PLL, 2 2.0-mm parallel miniplates; group 2PERP, 2 2.0-mm perpendicular miniplates; and group LST, 2 2.0-mm lag screws. Each group was subjected to linear vertical loading in the molar region in an Instron 4411 servohydraulic mechanical testing unit (Instron Corporation, Norwood, MA). The load resistance values were measured at load application displacements of 1, 3, 5, and 10 mm. Means and standard deviations were compared with respect to statistical significance using analysis of variance (P < .05) and compared by the Tukey test. Group 1P showed the lowest peak load scores compared with other fixation methods. Group LST showed a statistically significant higher resistance than group 2PLL for all displacements. Group 2PERP showed lower resistance than group LST when displacements were 1 and 3 mm and statically significant similarity at displacements of 5 and 10 mm. However, group 2PERP showed no statistically significant differences compared with group 2PLL. The LST showed better mechanical behavior for symphysis fracture fixation than the other systems when the fixation methods were subjected to linear vertical loading in the molar region.


Rosette morphology in zona glomerulosa formation and function.
How morphology informs function is a fundamental biological question. Here, we review the morphological features of the adrenal zona glomerulosa (zG), highlighting recent cellular and molecular discoveries that govern its formation. The zG consists of glomeruli enwrapped in a Laminin-β1-enriched basement membrane (BM). Within each glomerulus, zG cells are organized as rosettes, a multicellular structure widely used throughout development to mediate epithelial remodeling, but not often found in healthy adult tissues. Rosettes arise by constriction at a common cellular contact point mediated/facilitated by adherens junctions (AJs). In mice, small, dispersed AJs first appear postnatally and enrich along the entire cell-cell contact around 10 days after birth. Subsequently, these AJ-rich contacts contract, allowing rosettes to form. Concurrently, flat sheet-like domains in the nascent zG, undergo invagination and folding, gradually giving rise to the compact round glomeruli that comprise the adult zG. How these structures impact adrenal function is discussed.


A longitudinal epigenome-wide association study of preeclamptic and normotensive pregnancy.
While preeclampsia (PE) is a leading cause of pregnancy-related morbidity/mortality, its underlying mechanisms are not fully understood. DNA methylation (DNAm) is a dynamic regulator of gene expression that may offer insight into PE pathophysiology and/or serve as a biomarker (e.g., risk, subtype, a therapeutic response). This study's purpose was to evaluate for differences in blood-based DNAm across all trimesters between individuals eventually diagnosed with PE (cases) and individuals who remained normotensive throughout pregnancy, did not develop proteinuria, and birthed a normally grown infant (controls). In the discovery phase, longitudinal, genome-wide DNAm data were generated across three trimesters of pregnancy in 56 participants (n=28 cases, n=28 controls) individually matched on self-identified race, pre-pregnancy body mass index, smoking, and gestational age at sample collection. An epigenome-wide association study (EWAS) was conducted, using surrogate variable analysis to account for unwanted sources of variation. No CpGs met the genome-wide significance p value threshold of 9×10-8, but 16 CpGs (trimester 1: 5; trimester 2: 1; trimester 3: 10) met the suggestive significance threshold of 1×10-5. DNAm data were also evaluated for differentially methylated regions (DMRs) by PE status. Three DMRs in each trimester were significant after Bonferonni-adjustment. Since only third-trimester samples were available from an independent replication sample (n=64 cases, n=50 controls), the top suggestive hits from trimester 3 (cg16155413 and cg21882990 associated with TRAF3IP2-AS1/TRAF3IP2 genes, which also made up the top DMR) were carried forward for replication. During replication, DNAm data were also generated for validation purposes from discovery phase third trimester samples. While significant associations between DNAm and PE status were observed at both sites in the validation sample, no associations between DNAm and PE status were observed in the independent replication sample. The discovery phase findings for cg16155413/cg21882990 (TRAF3IP2-AS1/TRAF3IP2) were validated with a new platform but were not replicated in an independent sample. Given the differences in participant characteristics between the discovery and replication samples, we cannot rule out important signals for these CpGs. Additional research is warranted for cg16155413/cg21882990, as well as top hits in trimesters 1-2 and significant DMRs that were not examined in the replication phase.


Metabolomics analysis of the therapeutic effects of Qiwei Tongbi oral liquid on rheumatoid arthritis in rats.
Qiwei Tongbi oral liquid (QWTB), a classical traditional Chinese medicine (TCM) formula, has a good therapeutic effect on rheumatoid arthritis (RA) and is widely used in China. To comprehensively elucidate the therapeutic mechanism of QWTB in the treatment of RA, the effects of QWTB on biomarkers and metabolic pathways in a rat model of kidney deficiency arthritis were investigated in this study. The effects of QWTB on pharmacodynamic indicators, including paw swelling, arthritis score; interleukin-1β, interleukin-6, interleukin-17 F, tumor necrosis factor-α, tartrate-resistant acid phosphatase 5b, bone alkaline phosphatase, bone-specific alkaline phosphatase, bone glaprotein, urea, and creatinine levels; and histopathology, suggested that QWTB significantly improved renal function, inhibited the inflammatory response, and reduced bone loss. In total, 39 differential metabolites were screened by comparing the endogenous components between blank and model rat plasma, among which 16 metabolites were altered by QWTB. The metabolism pathway analysis revealed that α-linolenic acid metabolism, phenylalanine metabolism, sphingolipid metabolism, histidine metabolism and glycerophospholipid metabolism were greatly disturbed. Thus, the biomarkers investigated included (1) α-linolenic acid, (2) hippuric acid, (3) phosphatidylethanolamine (15:0/22:2(13Z,16Z)), (4) phenylpyruvic acid, (5) sphinganine, and (6) urocanic acid. QWTB affected three abnormal biomarkers: (3), (4), and (6). Phenylphruvic acid, sphinganine and urocanic acid were significantly associated with pharmacodynamic indicators, as shown by Pearson correlation analysis. These results indicated that RA-related biomarkers had certain reliability and biological significance. In summary, QWTB regulated the metabolic disorders in rats with RA. Its therapeutic mechanism may involve the regulation of phenylalanine metabolism, histidine metabolism, and glycerophospholipid metabolism. The results of this study are useful for understanding the therapeutic mechanisms of TCM.


Antiphospholipid antibodies in the obstetric antiphospholipid syndrome: Detection and antibodies profile at the Maternity and Neonatal Medicine Center of Monastir, Tunisia.
This study aimed to implement lupus anticoagulant (LAC) detection techniques according to the International Society on Thrombosis and Hemostasis (ISTH) recommendations, in the Biological Laboratory of the Maternity and Neonatal Medicine Center (Monastir, Tunisia) and to evaluate the profile and the prevalence of antiphospholipid antibodies (aPL) in the obstetric antiphospholipid syndrome (OAPS). We collected two groups: a "case group" (53 women who presented one or more obstetrical criteria of APS) and a "control group." LAC was detected following the four steps recommended by ISTH 2009. Anticardiolipin (aCL) and antibeta-2-glycoprotein I (aβ2GPI) antibodies testing were performed by enzyme-linked immunosorbent assay (ELISA). aPL were found in five patients: three patients with isolated LAC, one patient with isolated IgG aCL, and one patient with triple positivity (LAC, aCL IgM, aβ2GPI IgM). Concerning LAC, 13 (24.52%) of 53 patients had a screening step with at least one positive test. The mixing step was positive in four patients and then confirmed in the confirmatory test. Thus, the prevalence of LAC in our study group is 7.54%. Surprisingly, among these positive patients, one patient had an associated combined factor V (FV) and factor VIII (FVIII) deficiency. There is no single test and no algorithm that can detect all types of LAC. It seems that the recent 2020 ISTH algorithm allows a better detection of low activity LAC than the 2009 algorithm. In our study, the most frequently identified antiphospholipid antibodies were LAC more than aCL and aβ2GPI.


Reproducibility of food and nutrient intake estimates using a semi-quantitative FFQ in Australian adults.
To assess the reproducibility of a 135-item self-administered semi-quantitative FFQ. Control subjects who had previously completed an FFQ relating to usual dietary intake in a nationwide case-control study of cancer between November 2003 and April 2004 were randomly selected, re-contacted, and invited to complete the same FFQ a second time approximately one year later (between January and April 2005). Agreement between the two FFQ was compared using weighted kappa statistics and intraclass correlation coefficients (ICC) for food groups and nutrients. Summary questions, included in the FFQ, were used to assess overall intakes of vegetables, fruits and meat. General community in Australia. One hundred men and women aged 22-79 years, randomly selected from the previous control population. The weighted kappa and ICC measures of agreement for food groups were moderate to substantial for seventeen of the eighteen food groups. For nutrients, weighted kappa ranged from 0.44 for starch to 0.83 for alcohol while ICC ranged from 0.51 to 0.91 for the same nutrients. Estimates of meat, fruit and vegetable intake using summary questions were similar for both survey periods, but were significantly lower than estimates from summed individual food items. The FFQ produced reproducible results and is reasonable in assessing the usual intake of various foods and nutrients among an Australian adult population.


Mixing postharvest fungicides and sanitizers results in unpredictable survival of microbes that affect cantaloupes.
Postharvest treatments with sanitizers and fungicides are applied to increase the quality, safety and shelf life of fresh produce including cantaloupes (also known as rockmelons). The primary role of sanitizers during cantaloupe washing is to prevent cross contamination of potentially pathogenic bacteria in washwater. Postharvest fungicide sprays or dips are employed to inhibit spoilage-causing fungi. While assessing the compatibility of these antimicrobials based on the measurement of active ingredients levels provides some indication of antimicrobial capacity, there is limited data on whether the interaction between these chemicals in wash water modifies their overall efficacy against relevant microorganisms. The aim of this research was to determine how chlorine- and peroxyacetic acid-based sanitizers interact with commercial guazatine- and imazalil-based fungicide formulations used on cantaloupes, and whether mixing these augments or suppresses anti-microbial activity against relevant human pathogens and spoilage fungi in wash water. The results were unpredictable: while most combinations were antimicrobial, the chlorine-based sanitizer when mixed with the guazatine-based fungicide had significantly reduced efficacy against pathogenic Salmonella spp. (~2.7 log) and the fungal spoilage organisms, Trichothecium roseum and Rhizopus stolonifera. Mixing the chlorine-based sanitizer with an imazalil-based fungicide produced a range of outcomes with antagonistic, indifferent and synergistic interactions observed for the fungal species tested. The peroxyacetic acid-based sanitizer led to indifferent interactions with the guazatine-based fungicide, while antagonism and synergy were observed when mixed with the imazalil-based fungicide. This study demonstrates that mixing postharvest agrichemicals used in the cantaloupe industry may increase the risk of microbial contamination and thereby potentially compromise food safety and quality.


Exploring the central molecular zone of the Galaxy using spectroscopy of H3+ and CO.
The central 400 parsecs of the Milky Way, a region known as the central molecular zone (CMZ), contains interstellar gas in a wide range of physical environments, from ultra-hot, rarified and highly ionized to warm, dense and molecular. The combination of infrared spectroscopy of H(3)(+) and CO is a powerful way to determine the basic properties of molecular interstellar gas, because the abundance ratio of H(3)(+) to CO in 'dense' clouds is quite different from that in 'diffuse' clouds. Moreover, the energy-level structure and the radiative properties of H(3)(+) combined with the unusually warm temperatures of molecular gas in the CMZ make H(3)(+) a unique probe of the physical conditions there. This paper describes how, using infrared absorption spectroscopy of H(3)(+) and CO, it has been discovered that a large fraction of the volume of the CMZ is filled with warm, diffuse and partially molecular gas moving at speeds of up to approximately 200 km s(-1) and that the mean cosmic ray ionization rate in the CMZ exceeds by roughly an order of magnitude values found in diffuse molecular clouds elsewhere in the Galaxy.


Silencing of KIF18B restricts proliferation and invasion and enhances the chemosensitivity of breast cancer via modulating Akt/GSK-3β/β-catenin pathway.
Kinesin family member 18B (KIF18B) is a new tumor-associated protein that contributes to the carcinogenesis of multiple malignancies. However, the detailed relevance of KIF18B in breast cancer has not been fully elucidated. This work aimed was to evaluate a possible relationship between KIF18B and breast cancer progression. Our findings show KIF18B is increased in breast cancer and demonstrate that high KIF18B level predicts a reduced survival rate. Cellular functional studies revealed that knockdown of KIF18B markedly reduces the proliferation, invasion, and epithelial-mesenchymal transition of breast cancer cells and enhances their chemosensitivity toward doxorubicin. Further studies showed that KIF18B modulates the level of phospho-Akt, phospho-glycogen synthase kinase-3β, and β-catenin. Notably, suppression of Akt abolished KIF18B-overexpression-induced increases in activation of Wnt/β-catenin pathway. In addition, re-expression of β-catenin reversed KIF18B-silencing-induced cancer-promoting effect. In vivo animal experiments elucidated that knockdown of KIF18B significantly weakened the tumorigenicity of breast cancer cells. Taken together, data of this study illustrate that KIF18B exerts a potential cancer-promoting function in breast cancer via enhancement of Wnt/β-catenin pathway through modulation of the Akt/GSK-3β axis.


The complete primary structure of GTP:AMP phosphotransferase from beef heart mitochondria.
To complete the amino acid sequence of GTP:AMP phosphotransferase (MgGTP + AMP in equilibrium with MgGDP + ADP) from beef heart mitochondria it was necessary to sequence an intermediate region of about 33 residues after position 102 [(1984) Eur. J. Biochem. 143, 331-339] and find a suitable overlap with the rest of the protein. The required peptides were obtained by cleaving the enzyme with endoproteinase Lys-C. One peptide, covering the region from residue 79 to 144, was sequenced up to residue 124. Another peptide, extending from residue 79 to 169, was subcleaved with Staphylococcus aureus V8 protease and provided the fragment from residue 99 to 139 which was sequenced. Several other peptides from endoproteinase Lys-C cleavage were used to check large sections of the previously published sequence work. The complete sequence contains 225 amino acids and has an Mr of 25 469.


The effect of nitroglycerin upon pulmonary and left atrial pressures in patients with mitral stenosis.
In all nine patients studied with mitral stenosis and no evidence of left ventricular failure, nitroglycerin caused a decrease in pulmonary arterial, left atrial, and left ventricular pressures and pulmonary vascular resistance. The decrease in left atrial pressure was attributable to the combination of a reduction in left ventricular filling pressure and a reduction in mitral valve gradient. While there was no significant mean change in heart rate, cardiac index, or mitral valve flow, there was a significant correlation between a decrease in each of these determinants of mitral valve gradient and the observed decline in left atrial pressure in individual patients. However, even those patients who had an increase in heart rate or cardiac output, either of which normally aggravates pulmonary congestion in mitral stenosis, had a decrease in their pulmonary and left atrial pressures in response to TNG. It is likely that nitroglycerin reduced pulmonary and left atrial pressures by either (1) systemic venous dilatation, causing a reduction in right heart filling and pulmonary blood volume, or (2) pulmonary arteriolar and venous dilatation, causing a decrease in pulmonary vascular resistance and an increase in pulmonary vascular compliance. Because of the efficacy of TNG in lowering pulmonary and left atrial pressures in this study, TNG may prove useful in the clinical management of symptomatic pulmonary congestion in mitral stenosis.


Effect of adenosine and AICAR on ATP content and regional contractile function in reperfused canine myocardium.
We investigated whether the postischemic acceleration of adenosine triphosphate (ATP) synthesis by means of precursor infusion is beneficial for the contractile function of reperfused myocardium. A coronary artery was occluded for 45 min in 21 dogs to produce a marked but reversible ischemia. During the following 3 hours of reperfusion either adenosine (n = 6) or AICAR (5-amino-imidazole-4-carboxamide-riboside) (n = 6) was infused intracoronarily by a small transfemoral catheter positioned in the LAD. ATP repletion by adenosine was nearly 50% of the deficit caused by the previous ischemia, the effect of AICAR on steady-state tissue ATP concentration was insignificant. Regional systolic function of these both groups was compared to that of a control group (n = 9) receiving only a saline infusion. We measured the regional function by subendocardially implanted ultrasound transducers using the transit time method. All three groups showed a reduction to about 25% of the initial segment shortening at the end of ischemia, followed by a quick recovery to half of the preocclusion segment shortening after reopening of the vessel. No further changes were observed in the control series during the 3 hours of reperfusion (50 +/- 10% SE segment shortening at the end). With adenosine infusion - in spite of the resulting considerable ATP elevation - no significant change of segmental contractile function occurred (44 +/- 5% SE segment shortening). Only the AICAR treated group differed from control. It produced a continuous deterioration during reflow resulting in a holosystolic bulging of -20% +/- 10% SE at the end of 3 hours of reperfusion. Our results show that there is no correlation between different ATP tissue levels achieved by adenosine infusion and systolic function in reperfused myocardium after regional reversible ischemia. We hypothesize that reperfusion dyskinesia is caused by a failure of energy utilisation rather than of energy supply.


Effectiveness of Messenger RNA Coronavirus Disease 2019 (COVID-19) Vaccines Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in a Cohort of Healthcare Personnel.
In a large cohort of United States healthcare personnel without prior coronavirus disease 2019 (COVID-19) infection, 94 382 doses of messenger RNA (mRNA) COVID-19 vaccine were administered to 49 220 individuals. The adjusted vaccine effectiveness following 2 doses of each of the 2 available brands of mRNA vaccine exceeded 96%.


[Clinical features and prognostic analysis of 51 drug-induced case of liver failure].
To enhance the understanding of drug-induced liver failure by analyzing the etiology, clinical features and prognosis associated factors of patients with drug-induced liver failure. Fifty-one cases of drug-induced liver failure admitted to our hospital from 2002 - 2007 were reviewed according to their drug history, clinical features, Laboratory tests, complications and prognosis associated factors. The predominant etiological drugs were the traditional Chinese medicine (54.9%) and antitubercular agent (25.5%). Two predominant types of liver failure were acute liver failure (13.7%) and subacute liver failure (78.4%). The common complications were electrolyte disturbance, ascites and hepatic encephalopathy. The total improvement rate in patients was 29.4%. The incidences of hepatic encephalopathy, electrolyte disturbance and PTA value had statistical difference between improvement group and ineffective group. The etiologies of drugs-induced liver failure are traditional Chinese medicine and antitubercular agent in China. The prognosis of drug-induced liver failure remains poor. During the therapy of these drugs treatment, liver function test should be monitored.


Controlling photoionization using attosecond time-slit interferences.
When small quantum systems, atoms or molecules, absorb a high-energy photon, electrons are emitted with a well-defined energy and a highly symmetric angular distribution, ruled by energy quantization and parity conservation. These rules are based on approximations and symmetries which may break down when atoms are exposed to ultrashort and intense optical pulses. This raises the question of their universality for the simplest case of the photoelectric effect. Here we investigate photoionization of helium by a sequence of attosecond pulses in the presence of a weak infrared laser field. We continuously control the energy of the photoelectrons and introduce an asymmetry in their emission direction, at variance with the idealized rules mentioned above. This control, made possible by the extreme temporal confinement of the light-matter interaction, opens a road in attosecond science, namely, the manipulation of ultrafast processes with a tailored sequence of attosecond pulses.


Spatiotemporal trends of PM2.5 and its major chemical components at urban sites in Canada.
To evaluate the effectiveness of emission control regulations designed for reducing air pollution, chemically resolved PM2.5 data have been collected across Canada through the National Air Pollution Surveillance network in the past decade. 24-hr time integrated PM2.5 collected at seven urban and two rural sites during 2010-2016 were analyzed to characterize geographical and seasonal patterns and associated potential causes. Site-specific seven-year mean gravimetric PM2.5 mass concentrations ranged from 5.7 to 9.6 µg/m3. Seven-year mean concentrations of SO42-, NO3-, NH4+, organic carbon (OC), and elemental carbon (EC) were in the range of 0.68 to 1.6, 0.21 to 1.5, 0.27 to 0.71, 1.1 to 1.9, and 0.37 to 0.71 µg /m3, accounting for 10.8%-18.1%, 3.7%-16.7%, 4.7%-7.4%, 18.4%-21.0%, and 6.4%-10.6%, respectively, of gravimetric PM2.5 mass. PM2.5 and its five major chemical components showed higher concentrations in southeastern Canada and lower values in Atlantic Canada, with the seven-year mean ratios between the two regions being on the order of 1.7 for PM2.5 and 1.8-7.1 for its chemical components. When comparing the concentrations between urban and rural sites within the same region, those of SO42- and NH4+ were comparable, while those of NO3-, OC, and EC were around 20%, 40%-50%, and 70%-80%, respectively, higher at urban than rural sites, indicating the regional scale impacts of SO42- and NH4+ and effects of local sources on OC and EC. Monthly variations generally showed summertime peaks for SO42- and wintertime peaks for NO3-, but those of NH4+, OC, and EC exhibited different seasonality at different locations.


Two cases of mycosis fungoides treated by reduced-intensity cord blood transplantation.
Mycosis fungoides is a cutaneous T-cell lymphoma, which is clinically divided into three stages: patch, plaque and tumor. Despite a variety of treatments the prognosis is poor in advanced mycosis fungoides. Recently, allogeneic hematopoietic stem cell transplantation has been successfully applied for such cases. We performed reduced-intensity umbilical cord blood transplantation for two advanced mycosis fungoides patients. Case 1 was a 56-year-old man and case 2 was a 30-year-old woman. Tumors of each case were refractory to conventional chemotherapy. Although radiation therapy was considerably effective, tumors relapsed after several months. Reduced-intensity umbilical cord blood transplantation was performed because case 1 had no human leukocyte antigen-identical siblings and the sibling of case 2 did not agree to be the donor. The male patient died of pulmonary failure 23 days after reduced-intensity umbilical cord blood transplantation. The case 2 patient succeeded in reduced-intensity umbilical cord blood transplantation and remained in complete/partial remission for 13 months. However, chemotherapy-resistant tumors relapsed, and allogeneic hematopoietic stem cell transplantation was performed at 17 months. She died of cerebral hemorrhage 23 days after the procedure. Reduced-intensity umbilical cord blood transplantation may be included in the treatments for advanced mycosis fungoides, where graft-versus-lymphoma effect seems to be a significant factor for the success of the treatment.


Regulation of cytokine production by human Th0 cells following stimulation with peptide analogues: differential expression of TGF-beta in activation and anergy.
The different biological activities of T-cell-derived cytokines and their level of production influences the qualitative nature of immune responses and, in certain forms of T-cell tolerance, the lack of antigen responsiveness is associated with the production of transforming growth factor-beta (TGF-beta) and interleukin-4 (IL-4). In this study we have investigated the effects of T-cell receptor (TCR) ligation with peptide analogues and the native peptide, in the presence and absence of costimulation, on cytokine production by human T-helper type 0 (Th0) cells reactive with influenza virus haemagglutinin (HA) peptide (HA306-318) and restricted by HLA-DRB1*0101. We observed that resting Th0 cells constitutively produced TGF-beta, but when stimulated with peptide and antigen-presenting cells (APC) under conditions that induce clonal expansion, TGF-beta secretion was abrogated. Furthermore, exposure of the T cells to the wild-type HA peptide under conditions that induce T-cell anergy resulted in the secretion of TGF-beta, and subsequent antigenic rechallenge was unable to override this signal and down-regulate TGF-beta production. Stimulation with altered TCR ligands that failed to induce proliferation also resulted in marked production of TGF-beta, although in many instances the levels were less than those observed in the total absence of antigen, suggesting that partial signalling has occurred. Although in general, there was a direct positive correlation between proliferation and the production of IL-2, IL-4 and interferon-gamma (IFN-gamma) following stimulation with certain analogues, the production of selected cytokines was dissociated.


Structural signatures in EPR3 define a unique class of plant carbohydrate receptors.
Receptor-mediated perception of surface-exposed carbohydrates like lipo- and exo-polysaccharides (EPS) is important for non-self recognition and responses to microbial associated molecular patterns in mammals and plants. In legumes, EPS are monitored and can either block or promote symbiosis with rhizobia depending on their molecular composition. To establish a deeper understanding of receptors involved in EPS recognition, we determined the structure of the Lotus japonicus (Lotus) exopolysaccharide receptor 3 (EPR3) ectodomain. EPR3 forms a compact structure built of three putative carbohydrate-binding modules (M1, M2 and LysM3). M1 and M2 have unique βαββ and βαβ folds that have not previously been observed in carbohydrate binding proteins, while LysM3 has a canonical βααβ fold. We demonstrate that this configuration is a structural signature for a ubiquitous class of receptors in the plant kingdom. We show that EPR3 is promiscuous, suggesting that plants can monitor complex microbial communities though this class of receptors.


Long-term Impact of Bariatric Surgery on Major Adverse Cardiovascular Events in Patients with Obesity, Diabetes and Hypertension: a Population-level Study.
The literature on long-term impact of bariatric/metabolic surgery on incidence of major adverse cardiovascular events (MACE) in patients with obesity and metabolic syndrome is still lacking. We aimed to evaluate the long-term relationship between metabolic surgery and MACE in such patients. In a population-based cohort study, we compared all patients with obesity, diabetes mellitus (DM) and/or hypertension (HTN), who underwent bariatric surgery in Quebec, Canada during 2007-2012, with matched controls with obesity. The incidence of a composite MACE outcome (coronary artery events, heart failure, cerebrovascular events, and all-cause mortality) after bariatric surgery was compared between both groups. Cox regression was used to evaluate the long-term impact of surgery on MACE outcomes. The study cohort included 3627 surgical patients, who were matched to 5420 controls with obesity. Baseline demographics were comparable between groups, but DM was more prevalent among the surgical group. Median follow-up time was 7.05 years for the study cohort (range: 5-11 years). There was a significant long-term difference in the incidence of MACE between the surgical group and controls (19.6% vs. 24.8%, respectively; p < 0.01). After accounting for confounders, bariatric surgery remained an independent protective predictor of long-term MACE (hazard ratio [HR], 0.83 [95%CI, 0.78-0.89]). The 10-year absolute risk reduction (ARR) for the surgical group was 5.14% (95%CI, 3.41-6.87). Among patients with obesity, DM and HTN, bariatric/metabolic surgery is associated with a sustained (≥ 10 years) decrease in the incidence of MACE. The results from this population-level observational study should be validated in randomized controlled trials.


The Arts in Medicine: setting up and evaluating a new special study module at Leicester Warwick Medical School.
A special study module (SSM) option was introduced for medical students at Leicester Warwick Medical School in January 2000. Its aim was to enhance students' knowledge and understanding of people's experiences and emotions in relation to health and sickness through study of the arts. The module was set up and run through collaboration between the medical school and the University of Leicester's Department of English. This paper describes the context of SSMs in the arts and their relevance to medicine, and examines student perceptions of the benefits gained from this particular course. Students were exposed to a core series of arts-based seminars, and were given time to research a chosen study topic looking at an artist or art form in relation to health and sickness issue(s). They were assessed on their written submissions on these study topics according to the module objectives. Students were encouraged to develop a reflective style of learning by keeping learning journals. Evaluation demonstrated that the students considered that their professional development had been enhanced by taking time to study the arts. Students also felt that they would continue to use the arts to this end after the module had finished. Summative assessment showed that the objectives were achievable by the great majority of students.


Formulation of a novel synthetic medium for selectively culturing rat CNS neurons.
Dissociated cells from rat fetal cerebral hemispheres were grown in surface adhering culture using a novel synthetic medium (Maat medium) and compared with those grown either in the presence of serum or in the chemically defined medium described by Bottenstein and Sato. The addition of various compound combinations allowed us to lower insulin concentration to almost physiological levels. Maat medium improved the purity and longevity of neuronal cultures. The purity of neuronal cultures grown in different media was checked both by immunofluorescence and by the analysis of [3H]thymidine incorporation.


Opiate peptide modulation of amino acid responses suggests novel form of neuronal communication.
Mouse spinal neurons grown in tissue culture were used to study the electrophysiological pharmacology of the opiate peptide leucine-enkephalin. Enkephalin depressed glutamate-evoked responses in a noncompetitive manner independent of any other effects on membrane properties. The results demonstrate a neuromodulatory action of opiate peptide functionally distinct from the conventional neurotransmitter class of operation.


Early life antibiotic use and the risk of asthma and asthma exacerbations in children.
The use of antibiotic therapy early in life might influence the risk of developing asthma. Studies assessing the influence of early life antibiotic use on the risk of asthma exacerbations are limited, and the results are inconsistent. Therefore, the aim of this study was to assess the association between use of antibiotic during the first 3 years of life and the risk of developing childhood asthma and the occurrence of asthma exacerbations. Data from four large childhood cohorts were used; two population-based cohorts to study the risk of developing asthma: Generation R (n=7393, The Netherlands) and SEATON (n=891, Scotland, UK), and two asthma cohorts to assess the risk of asthma exacerbations: PACMAN (n=668, The Netherlands) and BREATHE (n=806, Scotland, UK). Odds ratios (ORs) were derived from logistic regression analysis within each database followed by pooling the results using a fixed- or random-effect model. Antibiotic use in early life was associated with an increased risk of asthma in a meta-analysis of the Generation R and SEATON data (OR: 2.18, 95% CI: 1.04-4.60; I2 : 76.3%). There was no association between antibiotic use in early life and risk of asthma exacerbations later in life in a meta-analysis of the PACMAN and BREATHE data (OR: 0.93, 95% CI: 0.65-1.32; I2 : 0.0%). Children treated with antibiotic in the first 3 years of life are more likely to develop asthma, but there is no evidence that the exposure to antibiotic is associated with increased risk of asthma exacerbations.


DNA measurement, proliferation markers, and other factors in pituitary adenomas.
To assess the proliferative activity of pituitary adenomas, 36 surgically removed adenomas were studied by light microscopical parameters; mitotic count; expression of PCNA, Ki-67, cathepsin D, and EGF; and image cytometry. Three adenomas (9%) showed high, 11 (34%) medium, 17 (53%) moderate, and 1 (3%) low structural differentiation. In 10 adenomas (31%), no mitosis was observed. The average was 2.4 mitoses/100 HPF; the highest count was 7.1 mitoses/100 HPF. Eleven adenomas (33.3%) were PCNA-negative; in 20 adenomas (60.6%), between 0.05 and 3.9, and in 2 adenomas (6.0%), between 10.5 and 16.4 PCNA-positive nuclei were observed. Only a recurrent null-cell adenoma (9%) was Ki-67-negative. Three adenomas (9.1%) were EGF-negative, 28 (84.8%) showed up to 10% positive cells, and 2 (6.1 %) showed between 10 and 30% positive cells; 19 adenomas (68%) were cathepsin D-negative, including all endocrine-inactive adenomas. Half the adenomas had an euploid DMA stem line. Endocrine-inactive adenomas displayed a higher rate of euploid DNA stem lines than endocrine-active adenomas. The S-phase fraction varied between 2.97 and 28%, with a mean value of 14.4%. Half the adenomas showed an S-phase fraction of 11.65% or lower.


Honeybee gut microbiota promotes host weight gain via bacterial metabolism and hormonal signaling.
Social bees harbor a simple and specialized microbiota that is spatially organized into different gut compartments. Recent results on the potential involvement of bee gut communities in pathogen protection and nutritional function have drawn attention to the impact of the microbiota on bee health. However, the contributions of gut microbiota to host physiology have yet to be investigated. Here we show that the gut microbiota promotes weight gain of both whole body and the gut in individual honey bees. This effect is likely mediated by changes in host vitellogenin, insulin signaling, and gustatory response. We found that microbial metabolism markedly reduces gut pH and redox potential through the production of short-chain fatty acids and that the bacteria adjacent to the gut wall form an oxygen gradient within the intestine. The short-chain fatty acid profile contributed by dominant gut species was confirmed in vitro. Furthermore, metabolomic analyses revealed that the gut community has striking impacts on the metabolic profiles of the gut compartments and the hemolymph, suggesting that gut bacteria degrade plant polymers from pollen and that the resulting metabolites contribute to host nutrition. Our results demonstrate how microbial metabolism affects bee growth, hormonal signaling, behavior, and gut physicochemical conditions. These findings indicate that the bee gut microbiota has basic roles similar to those found in some other animals and thus provides a model in studies of host-microbe interactions.


Efficacy of acupuncture in prevention of delayed chemotherapy induced nausea and vomiting in gynecologic cancer patients.
To compare the efficacy between acupuncture and ondansetron in the prevention of delayed chemotherapy induced nausea and vomiting (CINV). 70 patients were randomized to receive either 1) acupuncture at P6 point before chemotherapy infusion or 2) ondansetron 8 mg intravenously 30 min before chemotherapy infusion in their first cycle with cross-over of antiemetic regimen in the consecutive cycle. All patients received dexamethasone 5mg orally twice a day for 3 days. Patients were given additional does of ondansetron 4 mg orally every 12h if they experienced emesis. Emetic episode, severity of nausea score of 0-10 and adverse events were recorded. Complete response was defined as no nausea, no vomiting and no requirement of additional antiemetic drugs. FACT-G scale was used to evaluate quality of life (QOL) 7 days after each cycle of chemotherapy. The acupuncture group had a significantly higher rate of complete response in the prevention of delayed CINV (52.8% and 35.7%, P = 0.02). Compared to another group, the acupuncture group reported significantly lower delayed nausea (45.7% and 65.7%, P = 0.004), nausea score (P < 0.001) and fewer dosages of additional oral ondansetron (P = 0.002). Adverse effects were also significantly lower in the acupuncture group with less frequent constipation (P = 0.02) and insomnia (P = 0.01). Overall FACT-G scores were significantly higher in the acupuncture group. Acupuncture is effective in preventing delayed CINV and in promoting better QOL. With fewer adverse effects, it may be used as an alternative treatment option for CINV.


PD-L1 recruits phospholipase C and enhances tumorigenicity of lung tumors harboring mutant forms of EGFR.
Cancer immunotherapy focuses on inhibitors of checkpoint proteins, such as programmed death ligand 1 (PD-L1). Unlike RAS-mutated lung cancers, EGFR mutant tumors have a generally low response to immunotherapy. Because treatment outcomes vary by EGFR allele, intrinsic and microenvironmental factors may be involved. Among all non-immunological signaling pathways surveyed in patients' datasets, EGFR signaling is best associated with high PD-L1. Correspondingly, active EGFRs stabilize PD-L1 transcripts and depletion of PD-L1 severely inhibits EGFR-driven tumorigenicity and metastasis in mice. The underlying mechanisms involve the recruitment of phospholipase C-γ1 (PLC-γ1) to a cytoplasmic motif of PD-L1, which enhances PLC-γ1 activation by EGFR. Once stimulated, PLC-γ1 activates calcium flux, Rho GTPases, and protein kinase C, collectively promoting an aggressive phenotype. Anti-PD-L1 antibodies can inhibit these intrinsic functions of PD-L1. Our results portray PD-L1 as a molecular amplifier of EGFR signaling and improve the understanding of the resistance of EGFR+ tumors to immunotherapy.


Radial Approach Expertise and Clinical Outcomes of Percutanous Coronary Interventions Performed Using Femoral Approach.
We sought to evaluate the impact of experience and proficiency with radial approach (RA) on clinical outcomes of percutaneous coronary interventions (PCI) performed via femoral approach (FA) in the "real-world" national registry. A total of 539 invasive cardiologists performing PCIs in 151 invasive cardiology centers in Poland between 2014 and 2017 were included. Proficiency threshold was set at >300 PCIs during four consecutive years per individual operator. The majority of operators performed >75% of all PCIs via RA (449 (65.4%)), 143 (20.8%) in 50-75% of cases, 62 (9.0%) in 25-50% and only 33 (4.8%) invasive cardiologists were using RA in <25% of all PCIs. Operators with the highest proficiency in RA were associated with increased risk of periprocedural death, stroke and bleeding complications at access site during angiography via FA. Similarly, higher prevalence of periprocedural mortality during PCI with FA was observed in most experienced radial operators as compared to other groups. The detrimental effect of FA utilization by the most experienced radial operators was observed in both stable angina and acute coronary syndromes. Higher experience and utilization of RA might be linked to worse outcomes of PCIs performed via femoral artery in both stable and acute settings.


A prospective histomorphometric and cephalometric comparison of bovine bone substitute and autogenous bone grafting in Le Fort I osteotomies.
The aim of the present study was the histomorphometric and cephalometric comparison of autogenous bone grafting of the anterior iliac crest and the application of bovine bone substitute concerning new bone formation and postoperative stability in patients undergoing orthognathic Le Fort I osteotomy. Twenty-five patients requiring orthognathic surgery with Le Fort I osteotomy were included in this study. Patients were randomly divided into three groups receiving either autogenous iliac crest BONE grafting (BONE; n = 8) or xenogenic bovine bone grafting (Bio-Oss®) in INTER (n = 12) or in ONLAY (n = 5) position. Histomorphometric analysis was performed using trephine bone biopsies from the autogenous, respectively xenogenic bone grafting region. Postoperative stability was evaluated using teleradiographies of three different timepoints. All groups showed comparable mineralized fractions in bone biopsies of 50.2% (±13.2%) INTER, 46.48% (±12.3%) ONLAY and 57.1% (±20.6%) BONE as well as comparable percentage of connective tissue. Patients in the INTER-group revealed the lowest relapse rate of 20.5% (INTER) compared to 30.3% (ONLAY) and 33.0% (BONE). All groups underwent comparable maxillary advancement and healing time. Present results indicate that block shaped bovine bone substitute is a promising alternative to autogenous bone grafting to bridge the Le Fort I osteotomy gap in orthognathic surgery.


Evolutionary relationships of flying foxes (genus Pteropus) in the Philippines inferred from DNA sequences of cytochrome b gene.
Six flying fox species, genus Pteropus (four from the Philippines) were investigated using complete cytochrome b gene sequences (1140 bp) to infer their evolutionary relationships. The DNA sequences generated via polymerase chain reaction were analyzed using the neighbor-joining, parsimony, and maximum likelihood methods. We estimated that the first evolutionary event among these Pteropus species occurred approximately 13.90 +/- 1.49 MYA. Within this short period of evolutionary time we further hypothesized that the ancestors of the flying foxes found in the Philippines experienced a subsequent diversification forming two clusters in the topology. The first cluster is composed of P. pumilus (Philippine endemic), P. speciosus (restricted in western Mindanao) with P. scapulatus, while the second one comprised P. vampyrus and P. dasymallus species based on the analysis from first and second codon positions. Consistently, all phylogenetic analyses divulged close association of P. dasymallus with P. vampyrus contradicting the previous report categorizing P. dasymallus under subniger species group with P. pumilus. P. speciosus, and P. hypomelanus. The Philippine endemic species (P. pumilus) is closely linked with P. speciosus. The representative samples of P. vampyrus showed a large genetic distance of 1.87%. The large genetic distance between P. dasymallus and P. hypomelanus, P. pumilus and P. speciosus denotes a distinct species group.


Clinical significance of serum levels of matrix metalloproteinase-13 in patients with systemic sclerosis.
To investigate the clinical significance of serum matrix metalloproteinase-13 (MMP-13) levels in patients with systemic sclerosis (SSc). Serum MMP-13 levels were determined by using a peptide substrate cleavage assay in 20 patients with diffuse cutaneous SSc (dcSSc), 20 with limited cutaneous SSc (lcSSc) and 10 normal controls. The serum MMP-13 levels in patients with dcSSc or lcSSc were significantly lower than those in normal controls (53.4 +/- 14.1 vs 73.2 +/- 11.5 ng/ml, P < 0.0005; 59.4 +/- 14.8 vs 73.2 +/- 11.5 ng/ml, P < 0.005, respectively), but there was no significant difference in the serum MMP-13 levels between patients with dcSSc and those with lcSSc. Disease duration prior to the diagnosis was significantly shorter in SSc patients with decreased serum MMP-13 levels than in those with normal levels (3.0 +/- 2.2 vs 8.6 +/- 7.6 yr, P < 0.0005). In addition, serum MMP-13 levels were moderately correlated with the duration of the disease (r = 0.451, P < 0.05). Though there was no significant difference in the frequencies of pulmonary fibrosis or reduced %DLco (diffusing capacity of lung for carbon monoxide), the frequency of reduced %VC (vital capacity) was significantly greater in patients with decreased serum MMP-13 levels than in those with normal levels (73 vs 24%, P < 0.05). Matrix metalloproteinase-13 may be involved in the fibrotic process of SSc, especially in the initiation of fibrosis. The serum MMP-13 levels may serve as a useful marker for the severity of pulmonary fibrosis in patients with SSc.


Measurement of plasma and platelet tissue factor pathway inhibitor, factor V and Protein S in people with haemophilia.
Tissue factor pathway inhibitor (TFPI) is a naturally occurring anticoagulant found in plasma, where it circulates bound to lipoproteins, factor V (FV) or Protein S (PS), and in platelets. Therapeutic agents targeting TFPI are under development for the treatment of haemophilia A and haemophilia B. To begin to understand how TFPI, FV and PS interact to modulate haemophilia bleeding. Plasma and platelet antigen concentrations of these factors were determined in 73 people with haemophilia A and 18 with haemophilia B. Using multiple regression models, these were compared to the same analytes measured in 224 male blood donors. There were no differences in plasma or platelet TFPI, FV or PS concentrations between haemophilia types or severities. However, compared to blood donors, people with haemophilia had approximately one-third lower plasma PS, 9% lower plasma TFPIα, 50% higher platelet FV and 26% lower platelet Protein S. Together, the presented data suggest that individuals with haemophilia may have a compensatory procoagulant response of both plasma and platelet proteins to the decreased concentrations of FVIII or FIX.


High-Valence Metal-Organic Framework Materials Constructed from Metal-Oxo Clusters: Opportunities and Challenges.
Metal-organic framework (MOF), which possesses stable framework structure constructed by highly connected metal-oxo cluster nodes and organic linkers, has shown great promise in gas storage, adsorption, and separation, owing to the high surface areas, tunable pore aperture, and rich functional groups. In this review article, we summarized recent progress made in synthesizing high-valence MOF (e. g., UiO-66, MIL-125, PCN-22, and MIP-207) with metal-oxo cluster as metal source. Of particular note, recent breakthroughs in the preparation of UiO-66 and MIL-125 membranes with the corresponding Zr6 -oxo and Ti8 -oxo cluster sources (e. g., Zr6 O4 (OH)4 (OAc)12 and Ti8 O8 (OOCR)16 clusters) possessing superior separation performance were highlighted. In the end, an outlook on the preparation of versatile high-valence MOF membranes with the corresponding metal-oxo clusters as metal sources was highlighted.


Biological relevance of Cytomegalovirus genetic variability in congenitally and postnatally infected children.
Human cytomegalovirus (HCMV) is the leading cause of congenital infections resulting in severe morbidity and mortality among infected children. Although the virus is highly polymorphic, particularly in genes contributing to immune evasion, the mechanisms underlying its genetic variability and pathogenicity are only partially understood. We aimed to characterize different HCMV clinical strains isolated from 21 congenitally- or postnatally-infected children for in vitro growth properties and genetic polymorphisms. The growth of various HCMV isolates was analyzed in different cell culture models. Genetic polymorphism was assessed by genetic and phylogenetic analysis of viral genes involved in virulence (UL144, US28, and UL18), latency (UL133-138), or drug resistance (UL54 and UL97). Here, we report a high degree of genetic and phenotypic diversity in distinct HCMV clinical isolates, as shown by their in vitro growth properties. In particular, HCMV isolates displayed the highest degree of genetic variability in the UL144 gene, where we were able to define four distinct genotypes within the cohort based on UL144 heterogeneity. Lastly, among all isolates we were able to identify 36 mutations in UL54 and 2 in UL97. Our findings indicate that surprisingly high levels of genetic HCMV variability correlate with a high degree of phenotypic polymorphism, which in turn might differentially influence the growth, fitness, and drug susceptibility of HCMV.


The technology of magnetic resonance imaging.
In the clinical use of magnetic resonance imaging (MRI) it may be more important to understand some of the technical aspects of the imaging technique, rather than the fundamental physical principles. This review, therefore, sets out to present the essential aspects of the technique, including T1 and T2 relaxation times in relation to biological tissue, MRI equipment, pulse sequences, factors affecting image quality and patient throughput.


High-throughput spatial sensitive quantitative phase microscopy using low spatial and high temporal coherent illumination.
High space-bandwidth product with high spatial phase sensitivity is indispensable for a single-shot quantitative phase microscopy (QPM) system. It opens avenue for widespread applications of QPM in the field of biomedical imaging. Temporally low coherence light sources are implemented to achieve high spatial phase sensitivity in QPM at the cost of either reduced temporal resolution or smaller field of view (FOV). In addition, such light sources have low photon degeneracy. On the contrary, high temporal coherence light sources like lasers are capable of exploiting the full FOV of the QPM systems at the expense of less spatial phase sensitivity. In the present work, we demonstrated that use of narrowband partially spatially coherent light source also called pseudo-thermal light source (PTLS) in QPM overcomes the limitations of conventional light sources. The performance of PTLS is compared with conventional light sources in terms of space bandwidth product, phase sensitivity and optical imaging quality. The capabilities of PTLS are demonstrated on both amplitude (USAF resolution chart) and phase (thin optical waveguide, height ~ 8 nm) objects. The spatial phase sensitivity of QPM using PTLS is measured to be equivalent to that for white light source and supports the FOV (18 times more) equivalent to that of laser light source. The high-speed capabilities of PTLS based QPM is demonstrated by imaging live sperm cells that is limited by the camera speed and large FOV is demonstrated by imaging histopathology human placenta tissue samples. Minimal invasive, high-throughput, spatially sensitive and single-shot QPM based on PTLS will enable wider penetration of QPM in life sciences and clinical applications.


Spiritual climate in hospitals influences nurses' professional quality of life.
To assess the nurses' perceptions of spiritual climate of their hospital and to examine how it influences their professional quality of life (ProQoL). Despite the advantages of positive spiritual organisational climate on the personal and professional lives of nurses, no study has attempted to investigate the influence of spiritual climate on nurses' ProQoL. We surveyed 302 nurses in three general hospitals in Saudi Arabia in this cross-sectional study using the 'Spiritual Climate Scale' and the 'ProQoL scale version 5'. Our findings indicated a modest spiritual climate and average scores in ProQoL. Marital status, religion and education were significant predictors of the nurses' perception of spiritual climate. The spiritual climate, hospital, marital status, nationality, religion, education, experience in the country and experience in the present hospital played multivariate effects on the nurses' ProQoL. Our study concludes that the spiritual climate in hospitals influences nurses' ProQoL. This research provides direction for hospital policymakers and nurse leaders on the areas that could be improved to ensure excellent ProQoL among nurses. Making sure that the nurses' unique spirituality is encouraged, respected and accepted in clinical areas could contribute to improving compassion satisfaction and decreasing compassion fatigue among nurses.


CircSCUBE3 Reduces the Anti-gastric Cancer Activity of Anti-PD-L1.
The progression of gastric cancer (GC) is closely related to tumor immune escape. The research, therefore, studied the impact of possible circRNAs on the immune escape of GC tumors and the underlying mechanisms. Here, to explore circRNAs that may affect GC, the differential circRNAs in six normal gastric mucosal tissues and six GC samples (GSM2005868-GSM2005879) were analyzed through the bioinformatics website circmine, and hsa_circ_0076092 (circSCUBE3) was identified as the research object. In vitro assays revealed the functions of circSCUBE3 and its downstream miRNA/mRNA axis in GC cells. The effect of circSCUBE3 against PD-1 anti-tumor activity was evaluated in vivo. The relationship between circSCUBE3 and miR-744-5p, miR-744-5p, and SLC7A5 was identified by RNA immunoprecipitation and dual-luciferase reporter experiments. The effect of SLC7A5 on GC immune escape by regulating PD-L1 expression was assessed by co-culture system and flow cytometry. CircSCUBE3 was up-regulated in human GC tissues and GC cell lines. circSCUBE3 was associated with poor prognosis in GC patients. Functional experiments reported that circSCUBE3 knockdown could suppress GC immune escape. Mechanistically, circSCUBE3 bound to miR-744-5p, which further targeted SLC7A5, and SLC7A5 can affect GC immune escape by regulating PD-L1. Furthermore, in vivo assay manifested that circSCUBE3 attenuated the anti-tumor effect of PD-L1. Our study revealed the importance of the circSCUBE3/miR-744-5p/SLC7A5 axis in GC immune escape and anti-PD-1 resistance.


Efficacy and safety of anti-PD-1 inhibitor combined with nab-paclitaxel in Chinese patients with refractory melanoma.
This retrospective study aimed to evaluate the combined effect of anti-PD-1 inhibitor and nanoparticle albumin-bound (nab)-paclitaxel for refractory melanoma among Chinese patients. Data from January 2018 to March 2021 were retrospectively collected and analyzed. Sixty-four patients were eligible for analysis from a single Chinese cancer center. The median follow-up was 16.0 months at data cutoff. The objective response rate (ORR) was 29.7%, and the disease control rate (DCR) was 67.2% in all patients. Treatment-naïve patients had significantly higher ORR than pretreated patients (42.9% vs 13.8%, p = 0.011). Cutaneous melanoma patients with NRAS gene mutation benefited more than non-mutated patients (DCR of 100% vs. 54.5%) (p = 0.030). The median progression-free survival (mPFS) of all patients was 5.2 months and the duration of response was 10.8 months. Median duration of disease control was 7.7 months. Prior treatment-naïve patients had significantly longer PFS than those who accepted prior treatments (7.2 vs. 5.1 months, p = 0.024). Patients with abnormally high LDH level had shorter mPFS (3.6 months vs. 6.6 months, p = 0.020). Median overall survival was not reached in this study. Most patients experienced adverse events (AEs), but only 17.2% of patients experienced grade 3 severe AEs. The most common AEs were alopecia (89.1%), neutropenia (18.8%), pruritus (15.6%), and arthralgia (14.1%). Some patients had immune related AEs (irAEs). No grade 4 or 5 AEs were observed. Patients with ≥ 3 AEs or with irAEs had longer mPFS (p < 0.05). Nab-paclitaxel combined with PD-1 antibody is a well-tolerated and effective regimen for Chinese patients with refractory melanoma.


Myocardial pharmacokinetics of ebastine, a substrate for cytochrome P450 2J, in rat isolated heart.
It is well established that cytochrome P450 2J (CYP2J) enzymes are expressed preferentially in the heart, and that ebastine is a substrate for CYP2J, but it is not known whether ebastine is metabolized in myocardium. Therefore, we investigated its pharmacokinetics in the rat isolated perfused heart. Rat isolated hearts were perfused in the recirculating mode with ebastine for 130 min. The concentrations of ebastine and its metabolites, hydroxyebastine and carebastine, were measured using liquid chromatography with a tandem mass spectrometry. The data were analysed by a compartmental model. The time course of negative inotropic response was linked to ebastine concentration to determine the concentration-effect relationship. Ebastine was metabolized to an intermediate compound, hydroxyebastine, which was subsequently further metabolized to carebastine. No desalkylebastine was found. The kinetics of the sequential metabolism of ebastine was well described by the compartmental model. The EC(50) of the negative inotropic effect of ebastine in rat isolated heart was much higher than free plasma concentrations in humans after clinical doses. The kinetics of ebastine conversion to carebastine via hydroxyebastine resembled that observed in human liver microsomes. The results may be of interest for functional characterization of CYP2J activity in rat heart.


A 5-year prospective study of non-surgical treatment of retro-trochanteric pain.
Diffuse retro-trochanteric pain occasionally radiating to the lower extremity could be caused by the piriformis or internal obturator muscle syndromes. Thirteen patients, with retro-trochanteric pain were included in the study. All patients suffered from a diffuse, but intense and often radiating hip pain. The median duration of the symptoms was 8 (1-20) years. The patients were treated by a specific supervised stretching programme with special emphasis on the internal obturator muscle. The duration of the stretching programme was 4 weeks. At inclusion, the median pain on the visual analogue scale (VAS) was 6.0 (3-7). The VAS for pain decreased to 4.0 (0-7) (p = 0.01) at 12 weeks. Five years after treatment, the VAS for pain was still significantly lower than at inclusion, 4.0 (0-7) (p = 0.018). A significant reduction in the number of positive Freiberg's tests and in the number of patients limping was also observed, both at 3 months and at 5 years after treatment. It appears that a supervised stretching programme renders significant short and long term decrease in symptom for patients with retro-trochanteric pain.


Probing the pH sensitivity of R-phycoerythrin: investigations of active conformational and functional variation.
Crystal structures of phycobiliproteins have provided valuable information regarding the conformations and amino acid organizations of peptides and chromophores, and enable us to investigate their structural and functional relationships with respect to environmental variations. In this work, we explored the pH-induced conformational and functional dynamics of R-phycoerythrin (R-PE) by means of absorption, fluorescence and circular dichroism spectra, together with analysis of its crystal structure. R-PE presents stronger functional stability in the pH range of 3.5-10 compared to the structural stability. Beyond this range, pronounced functional and structural changes occur. Crystal structure analysis shows that the tertiary structure of R-PE is fixed by several key anchoring points of the protein. With this specific association, the fundamental structure of R-PE is stabilized to present physiological spectroscopic properties, while local variations in protein peptides are also allowed in response to environmental disturbances. The functional stability and relative structural sensitivity of R-PE allow environmental adaptation.


Suitability of the modified fluctuation assay for evaluating the mutagenicity of unconcentrated drinking water.
Filter-sterilized, unconcentrated tap water induced mutagenic responses (p less than 0.01) in Salmonella strain TA100 in fluctuation assays, usually with dose-related increases in positive tubes. Additional experiments were performed to study possible artifacts that could lead to falsely positive results. Determinations of bacterial survival revealed that cell populations in the tubes containing tap water were larger than in the controls. Since spontaneous mutation is a function of cell generation, the increased numbers of bacteria appeared to be responsible for the higher numbers of mutants observed. Therefore, the positive responses must be regarded as artifactual. This study suggests that survival determination should be a routine part of this method, and care should be exercised in the interpretation of positive results.


[Perpetrators of sexual violence against minors].
Sexual violence against minors is diverse and is subject to different criminal qualifications. Health professionals, and clinicians in general, may get to know certain perpetrators in order to assess, guide and/or treat them. This can be complicated if these professionals are not aware of the reality of the situations mentioned. Good knowledge, caution and critical distance must accompany their assessments and clinical acts.


Impact of a randomized controlled educational trial to improve physician practice behaviors around screening for inherited breast cancer.
Many primary care physicians (PCPs) are ill-equipped to provide screening and counseling for inherited breast cancer. To evaluate the outcomes of an interactive web-based genetics curriculum versus text curriculum for primary care physicians. Randomized two-group design. 121 California and Pennsylvania community physicians. Web-based interactive genetics curriculum, evaluated against a control group of physicians who studied genetics review articles. After education, physicians interacted with an announced standardized patient (SP) at risk for inherited breast cancer. Transcripts of visit discussions were coded for presence or absence of 69 topics relevant to inherited breast cancer. Across all physicians, history-taking, discussions of test result implications, and exploration of ethical and legal issues were incomplete. Approximately half of physicians offered a genetic counseling referral (54.6%), and fewer (43.8%) recommended testing. Intervention physicians were more likely than controls to explore genetic counseling benefits (78.3% versus 60.7%, P = 0.048), encourage genetic counseling before testing (38.3% versus 21.3%, P = 0.048), ask about a family history of prostate cancer (25.0% versus 6.6%, P = 0.006), and report that a positive result indicated an increased risk of prostate cancer for male relatives (20.0% versus 1.6%, P = 0.001). Intervention-group physicians were less likely than controls to ask about Ashkenazi heritage (13.3% versus 34.4%, P = 0.01) or to reply that they would get tested when asked, "What would you do?" (33.3% versus 54.1%, P = 0.03). Physicians infrequently performed key counseling behaviors, and this was true regardless of whether they had completed the web-based interactive training or read clinical reviews.


Stress, social support and well-being of Arab mothers of children with intellectual disability who are served by welfare services in northern Israel.
The present study examined the influence of a social support system on the level of stress and the sense of personal well-being of 100 Israeli Arab mothers of young children with special needs. Fifty mothers were served by the welfare services in the Nazareth area while 50 did not get help on a regular basis. A comparison was done between educated, urban mothers, and less-educated, rural mothers. The research results point to a relationship between informal support resources, and the marital and economic stress of the mothers: the higher the amount of the informal support resources, the lower the level of stress that was experienced by the mothers. A relationship between the amount of informal support and level of parental stress was not confirmed. A relationship between the amount of support resources and the personal well-being of the mothers was found: the higher the amount of informal support resources, the higher the sense of well-being of the mothers. A relationship between formal support (the welfare services), and level of stress or personal well-being was not found. Education and place of living were not related to level of stress or personal well-being. Educated mothers from urban areas used the formal support (the welfare services) less than less-educated mothers who lived in rural areas. The findings are interpreted with respect to practice and previous studies.


ACS chemical neuroscience molecule spotlight on Suvorexant.
Suvorexant is a dual orexin antagonist currently in Phase III clinical trials for the modulation of sleep and is being developed by Merck. Recent Phase III results showed that patients taking the drug fell asleep faster and slept longer than those on placebo.


Results of selective management of ureteropelvic junction obstruction.
Controversy continues over the need to image the ureteropelvic junction (UPJ) before endopyelotomy to detect crossing vessels. We evaluated a selective management model for UPJ obstruction. Intraoperative ultrasonography was performed before endopyelotomy in 19 men and 16 women. Patients with large (>4-mm) crossing vessels underwent open or laparoscopic pyeloplasty; the others had ureteroscopic or percutaneous endopyelotomy with electrocautery or the holmium laser. Crossing vessels were found in 25 of the 35 patients and a high-inserting ureter in 4. The vessels were >4 mm in nine patients, seven of whom had successful pyeloplasty and two of whom were managed expectantly with good results. Endopyelotomy was successful in 94% without a crossing vessel and 70% of those with a crossing vessel. The overall success rate (absence of symptom and resolution of obstruction on renal scintigraphy) was 89%. Selective management of UPJ obstruction, avoiding endopyelotomy in the presence of a large crossing vessel, appears to improve the success rate.


Thymoma.
A review of the evaluation, treatment, and end results for 52 patients with thymoma treated at The University of Texas M.D. Anderson Cancer Center (1950-1984) is presented. The objective of the study was to examine the influence of a number of clinical characteristics on survival, including histologic and staging classifications, associated diseases, symptom status, and treatment. Forty-nine patients (94%) underwent surgical exploration; 13 were stage I, 12 were stage II, and 24 were stage III. Complete resection was accomplished in all of the stage I and II groups and in 6 of the stage III patients. An asymptomatic history, surgical stage I disease, lymphocytic thymoma cell type, and complete resection favorably influenced prognosis. The cumulative 5-year survival rate for all patients was 40%. No patient with stage I thymoma had recurrent disease, however, there were 9 recurrences (50%) in the completely resected stage II/III patients, six of whom remained disease-free following treatment with radiotherapy, chemotherapy, or a combined approach.


Erratum: Orbital Angular Momentum of Magnons in Collinear Magnets [Phys. Rev. Lett. 129, 167202 (2022)].
This corrects the article DOI: 10.1103/PhysRevLett.129.167202.


Association of cyclophosphamide use with dental developmental defects and salivary gland dysfunction in recipients of childhood antineoplastic therapy.
The aim of this study was to examine the effect of antineoplastic therapy on dental development and saliva function in recipients of childhood antineoplastic therapy. Patients attending the long-term follow-up clinic at Children's Hospital at Westmead, NSW, Australia, were included if they had received treatment prior to 16 years of age and were in remission for more than 5 years. A dental examination and saliva test were performed for each participant. Holtta's Defect Index (HDI) was used to assess tooth aplasia, microdontia, and root-crown ratio on an orthopantomogram (OPG). Multivariable-adjusted regression analyses were used to estimate the association of patient characteristics and treatment modalities with dental outcomes. One hundred six participants (61% male) were recruited (response rate = 88%). The mean HDI score was 24.7 ± 17.8. A cumulative dose of cyclophosphamide >7500 mg/m(2) increased the HDI score by 13.06 (P = .01). Recipients of cyclophosphamide also had significantly increased odds of exhibiting very low saliva flow (<0.7 mL/min) (odds ratio = 12.43; 95% confidence interval, 2.08-74.35; P = .006). Children and adolescents who received high doses of cyclophosphamide were at increased risk of dental disturbances. Cyclophosphamide recipients were also at greater risk of exhibiting very low saliva flow. This study applied the HDI to patients receiving all forms of antineoplastic treatment and highlights the dose-dependent relation between cumulative dose of cyclophosphamide and dental disturbances.


Evidence for intrinsic charm quarks in the proton.
The theory of the strong force, quantum chromodynamics, describes the proton in terms of quarks and gluons. The proton is a state of two up quarks and one down quark bound by gluons, but quantum theory predicts that in addition there is an infinite number of quark-antiquark pairs. Both light and heavy quarks, whose mass is respectively smaller or bigger than the mass of the proton, are revealed inside the proton in high-energy collisions. However, it is unclear whether heavy quarks also exist as a part of the proton wavefunction, which is determined by non-perturbative dynamics and accordingly unknown: so-called intrinsic heavy quarks1. It has been argued for a long time that the proton could have a sizable intrinsic component of the lightest heavy quark, the charm quark. Innumerable efforts to establish intrinsic charm in the proton2 have remained inconclusive. Here we provide evidence for intrinsic charm by exploiting a high-precision determination of the quark-gluon content of the nucleon3 based on machine learning and a large experimental dataset. We disentangle the intrinsic charm component from charm-anticharm pairs arising from high-energy radiation4. We establish the existence of intrinsic charm at the 3-standard-deviation level, with a momentum distribution in remarkable agreement with model predictions1,5.We confirm these findings by comparing them to very recent data on Z-boson production with charm jets from the Large Hadron Collider beauty (LHCb) experiment6.


Management of chronic anal fissure: results of a national survey among gastrointestinal surgeons in the Netherlands.
Chronic anal fissure (CAF) is a common, bothersome condition frequently accompanied by pelvic floor complaints. Despite current guidelines, optimal management is challenging. The aim of this study is to evaluate current management of CAF among gastrointestinal surgeons in the Netherlands. Dutch gastrointestinal surgeons and residents were sent a survey invitation by email, which was available online between June 2021 and September 2021. The questionnaire consisted of 21 questions concerning work experience, physical examination, diagnostic and surgical techniques, and follow-up. Overall, 106 (33%) respondents completed the survey. Most respondents (59%) had at least 10 years of experience in treating CAF. Only 23% always addressed pelvic floor complaints. Fifty-one percent performed digital rectal examination and 22% always, or almost always, examined the pelvic floor muscles. Most respondents started treatment with fibers and/or laxatives and ointment (96%). Diltiazem was in 90% the preferred ointment. Twenty-two percent referred patients for pelvic floor physical therapy. Botulinum toxin was in 54% performed under general or spinal anesthesia or sedation. The surgical procedure of choice was fissurectomy (71%) followed by lateral internal sphincterotomy (27%). Fissurectomy was in 51% always combined with botulinum toxin. Fifty-seven percent of the respondents preferred a physical follow-up appointment. Guideline recommendations are largely followed in the Netherlands, starting with conservative measures followed by surgical procedures. Surgeons do not consistently assess pelvic floor complaints, nor do they routinely examine the pelvic floor muscles. Awareness of pelvic floor dysfunctions is important to refer patients for pelvic floor physical therapy.


Moderate-intensity exercise training or high-intensity interval training to improve aerobic fitness during exercise prehabilitation in patients planned for elective abdominal cancer surgery?
Low preoperative aerobic fitness is associated with an increased risk of postoperative complications and delayed recovery in patients with abdominal cancer. Surgical prehabilitation aims to increase aerobic fitness preoperatively to improve patient- and treatment-related outcomes. However, an optimal physical exercise training program that is effective within the short time period available for prehabilitation (<6 weeks) has not yet been established. In this comparative review, studies (n = 8) evaluating the effect of short-term (<6 weeks) moderate-intensity exercise training (MIET) or high-intensity interval training (HIIT) on objectively measured aerobic fitness were summarized. The content of exercise interventions was critically appraised regarding the frequency, intensity, time, type, volume, and - monitoring of - progression (FITT-VP) principles. Three out of four studies evaluating HIIT showed statistically significant improvements in oxygen uptake at peak exercise (VO2peak) by more than 4.9%, the coefficient of variation for VO2peak. None of the two studies investigating short-term MIET showed statistically significant pre-post changes in VO2peak. Although short-term HIIT seems to be a promising intervention, concise description of performed exercise based on the FITT-VP principles was rather inconsistent in studies. Hence, interpretation of the results is challenging, and a translation into practical recommendations is premature. More emphasis should be given to individual responses to physical exercise training. Therefore, adequate risk assessment, personalized physical exercise training prescription using the FITT-VP principles, full reporting of physical exercise training adherence, and objective monitoring of training progression and recovery is needed to ensure for a personalized and effective physical exercise training program within a multimodal prehabilitation program.


Screening for cognitive and behavioural impairment in amyotrophic lateral sclerosis: Frequency of abnormality and effect on survival.
To screen for cognitive and behavioural impairment in people with amyotrophic lateral sclerosis (ALS) and controls with neuromuscular disease and to correlate these with clinical features. 108 people with ALS and 60 controls with other neuromuscular diseases were recruited and assessed with the Addenbrooke's cognitive examination-III (ACE-III), the frontal assessment battery (FAB), and the executive function component of the Edinburgh cognitive and behavioural ALS screen (ECAS). The Amyotrophic lateral sclerosis-Frontotemporal dementia questionnaire (ALS-FTD-Q) and the Motor Neuron Disease Behavioural instrument (MiND-B) were administered to the caregivers of people with ALS. The prevalence of abnormalities was determined and correlated with clinical features and survival. In 37 people with ALS, serial studies were performed. The frequencies of cognitive impairment based on the ACE-III and FAB were 30.0% and 14.0%, in ALS and 11.7% and 3.3% in controls, respectively. Age and years of education influence the results of the ACE-III and ECAS executive function. In ALS, the frequencies of behavioural impairment based on ALS-FTD-Q and MiND-B were 32.1% and 39.4%, respectively. There is significant correlation of ALS-FTD-Q and MiND-B with the ALSFRS-R score. ALS participants with cognitive impairment measured with ACE-III had significantly shorter survival time than those without. ALS participants with behavioural impairment measured with ALS-FTD-Q had worse prognosis than those without. No significant difference was found between the first two serial cognitive tests based on ACE-III and FAB by using generalized estimating equation. There is a greater frequency of cognitive impairment in people with ALS than in patients with other neuromuscular diseases. The cognitive and behavioural tests are potential biomarkers of the prognosis of ALS. The results of cognitive tests are stable over 6months and possibly longer.