Knigth's Move in the Periodic Table, From Copper to Platinum, Novel Antitumor Mixed Chelate Copper Compounds, Casiopeinas, Evaluated by an in Vitro Human and Murine Cancer Cell Line Panel.
We synthesized a novel anticancer agents based on mixed chelate copper (II) complexes, named Casiopeínas((R)) has of general formula [Cu(N-N)(N-O)H(2)O]NO(3) (where, N-N = diimines as 1,10- phenanthroline, 2,2-bipyridine, or substituted and N-O=aminoeidate or [Cu(N-N)(O-O)H(2)O]NO(3) (where NN= diimines as 10-phenanthroline, 2,2-bipyridine or substituted Casiopeínas I, II, IV, V, VI, VII VIII and O-O=acetylacetonate, salicylaldehidate Casiopínas III). We evaluated the in vitro antitumor activity using a human cancer cell panel and some nurine cancer cells. Eleven Casiopeinas are evaluated in order to acquire some structure-activity correlations and some monodentated Casiopeinäs analogues; cisplatinum was used as control drug. The 50% growth inhibition observed is, in all cases reach with concentrations of Casiopeina's 10 or 100 times lower than cisplatinum. In a previous work we reported the induction of apoptosis by Casiopeina II. The results indicate that Casiopeinass are a promising new anticancer drug candidates to be developed further toward clinical trials.


Purification and partial characterization of aldehyde dehydrogenase from human erythrocytes.
Human erythrocyte aldehyde dehydrogenase (aldehyde:NAD+ oxidoreductase, EC 126.96.36.199) was purified to apparent homogeneity. The native enzyme has a molecular weight of about 210,000 as determined by gel filtration, and SDS-polyacrylamide gel electrophoresis of this enzyme yields a single protein and with a molecular weight of 51,500, suggesting that the native enzyme may be a tetramer. The enzyme has a relatively low Km for NAD (15 microM) and a high sensitivity to disulfiram. Disulfiram inhibits the enzyme activity rapidly and this inhibition is apparently of a non-competitive nature. In kinetic characteristic and sensitivity to disulfiram, erythrocyte aldehyde dehydrogenase closely resembles the cytosolic aldehyde dehydrogenase found in the liver of various species of mammalians.


Shared decision-making in advance care planning among hospitalized older COVID-19 patients: a multicenter, retrospective cohort study.
In the Netherlands, it is customary to discuss directives regarding resuscitation, intubation, and ICU-admission with patients and/or their relatives upon hospital-admission. The outcome of this discussion is documented in a code status. Ideally, these advance care planning (ACP)-related decisions are made by a patient (and/or their relatives) and a professional together in a shared decision-making (SDM) process, to improve patient satisfaction and prevent undesired care. Given the bad outcomes in older COVID-19 patients, it is particularly important to discuss the code status upon admission. This study aims to describe the practice of SDM regarding code status during the COVID-pandemic. Specific aims were to find out to what extend patients took part in this decision-making process and whether all key elements of SDM for a shared decision were documented in medical reports. In this retrospective cohort study, we included COVID-19 patients aged 70 years and older, admitted to two large teaching hospitals in the Netherlands, during the first months of the COVID-19 pandemic in 2020. Data about code status and the decision-making process were extracted from electronic healthcare records. Code status was documented for 274 of 275 included patients. Patient participation in the decision-making process was described in 48%. In 19% all key elements of shared decision-making have been described. Key elements of SDM were defined as the presence of a completed code status form, the presence of clinical notes showing that both patient's wishes and values and the opinion of the healthcare professional about the predicted outcome was taken into consideration and clinical notes of a patient-healthcare professional interaction during the admission. Our results show that a proper SDM process regarding code status is possible, even in hectic times like the COVID-19-pandemic. However, shared decision-making was not common practice in older patients with COVID-19 regarding code status (an ACP-related decision) in the early phase of the COVID-19 pandemic. Only in 19% of the patients, all key elements of SDM regarding code status were described.


Overview of biopolymers as carriers of antiphlogistic agents for treatment of diverse ocular inflammations.
Inflammation of the eye is a usual clinical condition that can implicate any part of the eye. The nomenclature of variety of such inflammations is based on the ocular part involved. These diseases may jeopardize normal functioning of the eye on progression. In general, corticosteroids, antihistamines, mast cell stabilizers and non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat inflammatory diseases/disorders of the eye. There have been several attempts via different approaches of drug delivery to overcome the low ocular bioavailability resulting from shorter ocular residence time. The features like safety, ease of elimination and ability to sustain drug release have led to application of biopolymers in ocular therapeutics. Numerous polymers of natural origin such as gelatin, collagen, chitosan, albumin, hyaluronic acid, alginates etc. have been successfully employed for preparation of different ocular dosage forms. Chitosan is the most explored biopolymer amongst natural biopolymers because of its inherent characteristics. The emergence of synthetic biopolymers (like PVP, PACA, PCL, POE, polyanhydrides, PLA, PGA and PLGA) has also added new dimensions to the drug delivery strategies meant for treatment of ophthalmic inflammations. The current review is an endeavor to describe the utility of a variety of biomaterials/polymers based drug delivery systems as carrier for anti-inflammatory drugs in ophthalmic therapeutics.


Unlocking foraminiferal genetic diversity on estuarine mudflats with eDNA metabarcoding.
Environmental biomonitoring is a prerequisite for efficient evaluation and remediation of ecosystem degradation due to anthropogenic pressure or climate change. Estuaries are key habitats subject to multiple anthropogenic and natural stressors. Due to these multiple stressors, the detection of anthropogenic pressure is challenging. The fact that abundant natural stressors often lead to negative quality assessments has been coined the "estuarine quality paradox". To solve this issue, the application of molecular approaches with successful bioindicators like foraminifera is promising. However, sampling protocols, molecular procedures and data analyses need to be validated before such tools can be routinely applied. We conducted an environmental DNA survey of estuarine mudflats along the French Atlantic coast, using a metabarcoding approach targeting foraminifera. Our results demonstrate that estuarine environments have only a few active OTUs dominating the community composition and a large stock of dormant or propagule stages. This last genetic diversity components constitute an important reservoir, with different species which can potentially develop in response to the temporal variability of the multiple stressors. In fact, different OTUs were dominant in the studied estuaries. Our statistical model shows that the physical and chemical characteristics of the sediment and the climatic conditions explain only 43 % of the community composition variance. This suggests that other, less easily quantifiable factors, such as the history and use of the estuaries or the ecological drift could play an important role as well. Environmental DNA biomonitoring opens new perspectives to better characterize the genetic diversity in estuaries.


Transport of marine tracer phage particles in soil.
Marine phages have been applied to trace ground- and surface water flows. Yet, information on their transport in soil and related particle intactness is limited. Here we compared the breakthrough of two lytic marine tracer phages (Pseudoalteromonas phages PSA-HM1 and PSA-HS2) with the commonly used Escherichia virus T4 in soil- and sand-filled laboratory percolation columns. All three phages showed high mass recoveries in the effluents and a higher transport velocity than non-reactive tracer Br-. Comparison of effluent gene copy numbers (CN) to physically-determined phage particle counts or infectious phage counts showed that PSA-HM1 and PSA-HS2 retained high phage particle intactness (Ip > 81%), in contrast to T4 (Ip < 36%). Our data suggest that marine phages may be applied in soil to mimic the transport of (bio-) colloids or anthropogenic nanoparticles of similar traits. Quantitative PCR (qPCR) thereby allows for highly sensitive quantification and thus for the detection of even highly diluted marine tracer phages in environmental samples.


A new potentiometric PVC membrane sensor for the determination of DPPH radical scavenging activity of plant extracts.
In this study, a simple, fast, stable and low-cost potentiometric determination method is recommended for the evaluation of 1,1-diphenyl-1-picrylhydrazil radical (DPPH•) scavenging activity, which is one of the antioxidant activity tests. For this purpose, a new type of solid-state-contact potentiometric polyvinyl chloride (PVC) membrane sensor was developed. Gallic acid compound, which is sensitive to the DPPH•, was used as the active ingredient in the membrane structure of the sensor. The potentiometric behavior of the developed DPPH•-selective PVC membrane sensor was characterized. The detection limit of the developed sensor was obtained as 2.3 µg/mL. The sensor can measure at low volumes with its high selectivity. The measurement results obtained were in accordance with the results of the spectroscopic method in the literature. The developed DPPH•-selective PVC membrane sensor was quickly dipped directly into the plant extracts and successfully used in test measurements of DPPH• scavenging activity.


Ranking NIH Funding of Surgical Departments Based Upon a Modified Index.
The Blue Ridge Institute for Medical Research (BRIMR) reports a ranking of surgical department NIH funding each fiscal year based on more than 41,000 individual investigators. This report is used to measure the research productivity of the faculty or department. However, this method includes institutional grants awarded to Cancer Centers or Centers for Research, which do not reflect individual or departmental research. To measure the research productivity of a surgical department more directly, we created a modified BRIMR index excluding grants to cancer or research centers. We evaluated how our modified index of surgical departments compared to the rankings by BRIMR. Publicly available BRIMR data was filtered for all grants awarded to principal investigators in a surgical department within a medical school. All funding for Cancer Centers or Centers for Research was excluded. The remaining grants were totaled, producing a new ranking of surgical departments. After excluding $42,761,752 in grants to Cancer Centers and Centers for Research, there was individual movement of 33 surgical departments on the ranking list. However, only four departments moved either up or down one quartile. No surgical department moved 2 or more quartiles. NIH funding for Cancer Centers and Centers for Research comprised 10% of all NIH funding for medical school-associated surgical departments. Exclusion of this funding resulted in no significant change within surgical department quartile rankings. This suggests the BRIMR measure of research productivity does not need modification.


Spatio-Temporal-Based Identification of Aggressive Behavior in Group Sheep.
In order to solve the problems of low efficiency and subjectivity of manual observation in the process of group-sheep-aggression detection, we propose a video streaming-based model for detecting aggressive behavior in group sheep. In the experiment, we collected videos of the sheep's daily routine and videos of the aggressive behavior of sheep in the sheep pen. Using the open-source software LabelImg, we labeled the data with bounding boxes. Firstly, the YOLOv5 detects all sheep in each frame of the video and outputs the coordinates information. Secondly, we sort the sheep's coordinates using a sheep tracking heuristic proposed in this paper. Finally, the sorted data are fed into an LSTM framework to predict the occurrence of aggression. To optimize the model's parameters, we analyze the confidence, batch size and skipping frame. The best-performing model from our experiments has 93.38% Precision and 91.86% Recall. Additionally, we compare our video streaming-based model with image-based models for detecting aggression in group sheep. In sheep aggression, the video stream detection model can solve the false detection phenomenon caused by head impact feature occlusion of aggressive sheep in the image detection model.


Exploring the Psychosocial Experiences of Individuals with Developmental Language Disorder During Childhood: A Qualitative Investigation.
Children with Developmental Language Disorder (DLD) often experience co-occurring psychosocial difficulties, the developmental trajectories of which are still not fully understood. This study sought to explore the manifestation of such difficulties during childhood, through first-hand accounts of those with DLD and their close relatives. Individual semi-structured interviews were conducted with 11 mothers of children with DLD (aged 6-12 years old) and were analysed alongside the secondary data from interviews of five adults with DLD. Interviews were conducted online; all participants resided in Europe and were fluent in spoken and written English. A process of interpretive phenomenological analysis resulted in the development of five overall themes: experiencing anxiety, social frustrations, maintaining factors, childhood strengths and the parenting experience. Cognitive appraisals appeared particularly important during childhood in both escalating and maintaining anxiety, low self-esteem, emotion dysregulation and social frustrations. High levels of isolation and stress were experienced by all mothers. The findings suggest parents in the United Kingdom and Ireland require more support and guidance at the point of diagnosis than is currently provided. Emphasis was given to the link between children's experience of anxiety and social behaviours, such as withdrawal, as well as their intolerance of uncertainty. Internalising symptoms were a prioritisation for intervention during childhood by both parents and adults with DLD.


miR-124 interacts with the Notch1 signalling pathway and has therapeutic potential against gastric cancer.
Aberrant Notch signalling plays an important role in cancer progression. However, little is known about the interaction between miRNA and the Notch signalling pathway and its role in gastric cancer (GC). In this study, we found that miR-124 was down-regulated in GC compared with adjacent normal tissue. Forced expression of miR-124 inhibited GC cell growth, migration and invasion, and induced cell cycle arrest. miR-124 negatively regulated Notch1 signalling by targeting JAG1. miR-124 levels were also shown to be inversely correlated with JAG1 expression in GC. Furthermore, we found that the overexpression of the intracellular domain of Notch1 repressed miR-124 expression, promoted GC cell growth, migration and invasion. Conversely, blocking Notch1 using a γ-secretase inhibitor up-regulated miR-124 expression, inhibited GC cell growth, migration and invasion. In conclusion, our data demonstrates a regulatory feedback loop between miR-124 and Notch1 signalling in GC cells, suggesting that the miR-124/Notch axis may be a potential therapeutic target against GC.


Psychometric properties of the awareness questionnaire, patient competency rating scale and Dysexecutive Questionnaire in patients with acquired brain injury.
Lack of self-awareness of impairments is common after acquired brain injury (ABI). We evaluated the psychometric properties of three commonly used instruments for measuring self-awareness: Awareness Questionnaire (AQ), Patient Competency Rating Scale (PCRS) and Dysexecutive questionnaire (DEX). We recruited 105 patients with ABI and their relatives. We determined feasibility, responsiveness, test- retest reliability, internal consistency, and construct validity of AQ, PCRS and DEX. No floor or ceiling effects were present. Total scale scores showed sufficient responsiveness: effect sizes were moderate to large (.57-.85); test-retest reliability was sufficient for patient forms (.75- .88) but mixed for relative forms (.60-.66). Internal consistency was good (.80-.89). Construct validity results confirmed a three-factor structured AQ and a four-factor structured PCRS. A two-facture structure was found for DEX patient forms; a three-factor structure was found for relative forms. Overall, the total scale scores of patient forms of all questionnaires demonstrated sufficient psychometric properties. Psychometric properties of subscales are questionable. We could not replicate the factor structures of AQ, PCRS and DEX: the items within subscales differed with previous findings. Additional research into the test-retest, inter-rater reliability and responsiveness of relative and clinician forms is required.


PAH fluxes in the Laja Lake of south central Chile Andes over the last 50 years: evidence from a dated sediment core.
This paper reports the occurrence of polyaromatic hydrocarbons (PAHs) deposition inferred from a sediment core of an Andean lake in south central Chile. Sediments were carefully collected from one of the deepest section of the lake and sliced every 1 cm. The samples were analyzed for PAHs, (137)Cs, (210)Pb, organic carbon and grain-size. The stratigraphic chronology and the sedimentation rates were estimated using the sedimentary signature left by the (137)Cs and (210)Pb fallout as temporal markers. PAHs were quantified by HPLC-fluorescence detection (HPLC-Fluorescence). 15 priority EPA PAHs were analyzed in this study. Based on these results, PAH deposition over the last 50 years was estimated (a period characterized by an important intervention in the area). PAH concentration ranged from 226 to 620 ng g(-1) d.w. The highest concentrations of PAHs were found in the core's bottom. The PAH profile is dominated by the presence of perylene indicating a natural source of PAH. In addition, two clear PAH deposition periods could be determined: the most recent with two-four rings PAHs, the older one with five-seven rings predomination. Determined fluxes where 71 to 972 microg m(-2) year(-1), dominated by perylene deposition. PAH levels and fluxes are lower compared to the levels found in sediments from remote lakes in Europe and North America. It is concluded that the main source of PAHs into the Laja Lake sediments are of natural origin.


Aromatic Amino Acids and Their Interactions with Gut Microbiota-Related Metabolites for Risk of Gestational Diabetes: A Prospective Nested Case-Control Study in a Chinese Cohort.
The aim of this study was to explore associations of aromatic amino acids (AAA) in early pregnancy with gestational diabetes mellitus (GDM), and whether high AAA and gut microbiota-related metabolites had interactive effects on GDM risk. We conducted a 1:1 case-control study (n = 486) nested in a prospective cohort of pregnant women from 2010 to 2012. According to the International Association of Diabetes and Pregnancy Study Group's criteria, 243 women were diagnosed with GDM. Binary conditional logistic regression was performed to examine associations of AAA with GDM risk. Interactions between AAA and gut microbiota-related metabolites for GDM were examined using additive interaction measures. High phenylalanine and tryptophan were associated with increased GDM risk (OR: 1.72, 95% CI: 1.07-2.78 and 1.66, 1.02-2.71). The presence of high trimethylamine (TMA) markedly increased the OR of high phenylalanine alone up to 7.95 (2.79-22.71), while the presence of low glycoursodeoxycholic acid (GUDCA) markedly increased the OR of high tryptophan alone up to 22.88 (5.28-99.26), both with significant additive interactions. Furthermore, high lysophosphatidylcholines (LPC18:0) mediated both interactive effects. High phenylalanine may have an additive interaction with high TMA, while high tryptophan may have an additive interaction with low GUDCA toward increased risk of GDM, both being mediated via LPC18:0.


Short Course of Eculizumab May Be Effective in Dialysis-Dependent Transplantation-Associated Thrombotic Microangiopathy After Hematopoietic Stem Cell Transplantation: A Case Report.
Allogeneic hematopoietic stem cell transplantation (alloHSCT) could induce several complications. The most frequent viral infections and graft-vs-host disease (GvHD) sometimes lead to thrombotic microangiopathy (TMA). It is associated with significant morbidity and mortality with the risk of death reaching 90%. Effective prevention and treatment are not available to date. Recent attempts at using antibody against C5 have been made. A 19-year-old girl with acute myeloid leukemia twice underwent alloHSCTs from her 10/10 HLA-matched sister. After the second HSCT severe acute steroid-resistant grade 4 GvHD occurred. Despite treatment with high doses of steroids, mycophenolate mofetil, biological therapy, and extracorporeal photopheresis, the patient developed TMA with acute kidney injury and the need for renal replacement therapy. The concentration of complement component 3 and activity of ADAMTS 13 were normal, and infection with Escherichia coli (E. coli) 0157H7 was excluded. Due to failure of all ordered therapies and severity of the condition, an attempt was taken to use eculizumab. Two 900-mg doses of eculizumab (Soliris) were administered at an interval of 2 weeks, which resulted in the improvement of renal function and amelioration of hemolysis and thrombocytopenia. Dialysis therapy was finished after 5 weeks, and then a third dose of the drug was administered. Eighteen months later, the patient is alive and well, with limited chronic GvHD. eGFR remains stable at 40 to 46 mL/min/1.73 m2, and mild hypertension requires treatment with angiotensin converting enzyme inhibitors and furosemide. Even a short course of eculizumab can be sufficient in controlling the TMA after HSCT, provided that the TMA-triggering factors are well controlled.


Preliminary evaluation of β3-adrenoceptor agonist-induced 18F-FDG metabolic activity of brown adipose tissue in obese Zucker rat.
We have investigated β3-adrenoceptor agonist mediated brown adipose tissue (BAT) activation using (18)F-FDG PET/CT in Zucker lean (ZL) and obese (ZF) rats. (18)F-FDG was injected into ZL and ZF rats pretreated with saline or agonist CL316,243 for scans. (18)F-FDG metabolic activity was computed as standard uptake values. CL316,243 in ZL activated BAT up to 4-fold compared to saline, while ZF BAT was only up by 2 fold. The decreased activation was consistent with lower β3-adrenoceptor levels in ZF rats. The genetically modified ZL and ZF rats may provide a useful rat model to evaluate the significance of β3-adrenoceptor agonist-induced BAT activation in obesity.


The sperm centrioles.
Centrioles are eukaryotic subcellular structures that produce and regulate massive cytoskeleton superstructures. They form centrosomes and cilia, regulate new centriole formation, anchor cilia to the cell, and regulate cilia function. These basic centriolar functions are executed in sperm cells during their amplification from spermatogonial stem cells during their differentiation to spermatozoa, and finally, after fertilization, when the sperm fuses with the egg. However, sperm centrioles exhibit many unique characteristics not commonly observed in other cell types, including structural remodeling, centriole-flagellum transition zone migration, and cell membrane association during meiosis. Here, we discuss five roles of sperm centrioles: orchestrating early spermatogenic cell divisions, forming the spermatozoon flagella, linking the spermatozoon head and tail, controlling sperm tail beating, and organizing the cytoskeleton of the zygote post-fertilization. We present the historic discovery of the centriole as a sperm factor that initiates embryogenesis, and recent genetic studies in humans and other mammals evaluating the current evidence for the five functions of sperm centrioles. We also examine information connecting the various sperm centriole functions to distinct clinical phenotypes. The emerging picture is that centrioles are essential sperm components with remarkable functional diversity and specialization that will require extensive and in-depth future studies.


Complications and concurrent disease associated with diabetic ketoacidosis and other severe forms of diabetes mellitus.
The more serious forms of diabetes mellitus such as diabetic ketoacidosis (DKA) and hyperosmolar nonketotic syndrome (HNKS) are precipitated commonly by other underlying disease processes. In addition, the treatment of these severe forms of diabetes mellitus are often complicated by therapy. This article discusses common concurrent disorders and therapeutic complications seen in both canine and feline diabetes mellitus.


MRI identification of the rostral-caudal pattern of pathology within the corpus callosum in the cuprizone mouse model.
To characterize and compare histological and MRI-based changes within the corpus callosum (CC) in the cuprizone mouse model of multiple sclerosis (MS). A total of 12 C57/BL6 mice were fed cuprizone from eight weeks of age for four weeks. One cohort of six cuprizone and two control mice were scanned with a T2-weighted (T2W) sequence. The other cohort of six cuprizone and four control mice were scanned using a dual-echo sequence for T2-mapping and a diffusion-weighted sequence with two orthogonal diffusion encoding directions to calculate water diffusivities parallel and perpendicular to the CC fiber (apparent diffusion coefficients [ADC](parallel) and ADC(perpendicular)). After the mice were killed, the rostral-caudal pattern of CC demyelination and other pathologies were examined using Luxol Fast Blue, neurofilament staining, and immunohistochemistry for microglia and were correlated with MRI. In contrast to control mice, T2W imaging (T2WI) hyperintensity, reduced ADC(parallel), and elevated ADC(perpendicular) were detected in the CC of cuprizone-fed mice, particularly in the caudal segment. The T2 value was increased in the entire CC. Marked demyelination, as well as axonal injury, microglia accumulation, and cellular infiltration were found in the caudal section of the cuprizone mouse CC. The rostral-caudal pattern of abnormalities within the CC in MRI measurements correlated well with histopathological findings. Noninvasive MRI using quantitative T2 and ADC mapping accurately characterized the rostral-caudal pattern of CC demyelination and other pathologies in cuprizone challenged mice, and thus could provide an effective way to assess the structural response to experimental therapeutics being designed for the treatment of MS.


Molecular screening for a personalized treatment approach in advanced adrenocortical cancer.
Adrenocortical cancer (ACC) is a rare cancer with poor prognosis and scant treatment options. In ACC, no personalized approach has emerged but no extensive molecular screening has been performed to date. The objective of the study was to evaluate the presence of a large number of potentially targetable molecular events in a large cohort of advanced ACC. We used hot spot gene sequencing (Ion Torrent, 40 patients) and comparative genomic hybridization (CGH; 28 patients; a subset of the entire cohort) in adult stage III-IV ACC samples to screen for mutations and copy number abnormalities of potential interest for therapeutic use in 46 and 130 genes, respectively. At least one copy number alteration or mutation was found in 19 patients (47.5%). The most frequent mutations were detected on TP53, ATM, and CTNNB1 [6 of 40 (15%), 5 of 40 (12.5%), and 4 of 40 (10%), respectively]. The most frequent copy number alterations identified were: amplification of the CDK4 oncogene (5 of 28; 17.9%) and deletion of the CDKN2A (4 of 28; 14.3%) and CDKN2B (3 of 28; 10.7%) tumor suppressor genes. Amplifications of FGFR1, FGF9, or FRS2 were discovered in three subjects (10.7%). Associated alterations were: deletions of CDKN2A, CDKN2B with ATM mutations, and TP53 mutations with CTNNB1 mutations. No simple targetable molecular event emerged. Drugs targeting the cell cycle could be the most relevant new therapeutic approach for patients with advanced ACC. Inhibitors of the fibroblast growth factor receptor pathway could also be a therapeutic option in a subset of patients, whereas other targeted therapies should be considered on a case-by-case basis.


Fluorescent in situ hybridization and C-banding analyses of highly repetitive DNA sequences in the heterochromatin of rye (Secale montanum Guss.) and wheat incorporating S. montanum chromosome segments.
The molecular characterization of C-banded regions of Secale montanum Guss. by means of in situ hybridization was performed in order to provide new information about their chromosome structure relative to cultivated rye, Secale cereale L. Accurate identification of individual chromosomes was achieved using simultaneous and (or) successive fluorescent in situ hybridization (FISH) and C-banding. FISH identification was performed using total rye DNA, three highly repetitive rye DNA sequences (pSc119.2, pSc74, and pSc34), and the ribosomal RNA probes pTa71 (18S, 5.8S, and 26S rDNA) and pTa794 (5S rDNA). FISH was also used to identify the chromosome segment involved in two spontaneous translocation lines recovered from a 'Chinese Spring'--S. montanum wheat-rye addition line. FISH analysis revealed the exact translocation breakpoints and allowed the identification of the transferred rye segments. The value of this type of analysis is discussed.


Effect of an isolation-coping programme on patients isolated for colonization or infection with multi-drug-resistant organisms: a quasi-experimental study.
The global increase in the prevalence of vancomycin-resistant enterococci (VRE) and carbapenem-resistant Enterobacterales (CRE) among multi-drug-resistant organisms (MDROs) has necessitated contact precaution and isolation in medical institutions. Contact isolation has a negative effect on the mental health of patients, but few interventions have addressed this issue. To evaluate an isolation-coping programme delivered by an infection control nurse for patients colonized or infected with VRE or CRE. An isolation-coping programme was developed to mitigate the negative effects of isolation due to MDROs, and the effects of the programme on uncertainty, anxiety, depression and knowledge of patients isolated because of MDROs (VRE or CRE) were validated using a pre-post quasi-experimental design. The experimental group (N=56) received education and emotional support via the isolation-coping programme, and the control group (M=55) received verbal isolation guidelines alone from the medical institution. Compared with the control group, the experimental group showed a reduction in uncertainty (t=-8.925), anxiety (Z=-6.131) and depression (Z=-5.379), and better knowledge (Z=-8.372) (P<0.001 for all). This novel isolation-coping programme delivered by an infection control nurse was found to be an effective intervention to improve uncertainty, anxiety, depression and knowledge in patients isolated with VRE or CRE.


Pseudoaneurysm of gastroduodenal artery associated with mitral valve prolapse presenting as haemobilia.
Pseudoaneurysms of the hepatic or gastroduodenal arteries may cause Haemobilia. Mitral valve prolapse associated with mycotic pseudoaneurysm of cerebral and extracerebral arteries have been reported. We report a case of gastroduodenal artery pseudoaneurysm presenting as haemobilia. The patient was successfully treated with indigenously fabricated steel coil embolization followed by surgery.


Evaluation of risk factors for cardiovascular diseases among Saudi diabetic patients attending primary health care service.
Cardiovascular disease is currently the primary cause of morbidity and mortality in patients with diabetes. For each risk factor present, the risk of cardiovascular death is about three times greater in people with diabetes than people without diabetes. To determine the risk factors for cardiovascular disease among patients with type 2 diabetes. To stratify the patients into risk categories to develop coronary arteries disease (CAD) based on the British Joint Societies risk chart. To assess the awareness and implementation of the risk assessment charts by primary care physicians Cross sectional study was designed. Sixty six (66 patients) diabetic patients were selected randomly by simple selection, from them 29 were males and 37 were females. Patients' medical records were reviewed. The following parameters were detected; blood pressure, lipid profile, weight, height, smoking and degree of glycemic control. A questionnaire was designed and distributed to randomly selected physicians working in primary health care assessed their awareness and implementation of risk assessment charts was done. Uncontrolled diabetes was found to be the common risk factor followed by uncontrolled lipid profile, obesity, uncontrolled systolic blood pressure and smoking. Seven percent (7%) of male group felled in highest risk group in comparison with 1% in female group (P<0.05), while 31% in male group felled in mild risk group in comparison with 90% in female group (P<0.05). Sixty two percent (62%) in male group felled in high risk group in comparison with 9% in female group (P<0.05). Criteria for ranking in risk class differed between male and female group. Forty one physicians were contacted and received the questionnaire. Twenty nine (70.7%) physicians were responded to the questionnaire. Twenty two (22) informed that they were aware about risk assessment score systems. Fourteen (14) physicians informed that they were aware about the BJSs charts but only two informed that they had used it to assess their patients. Clustering of multi risk factors is a serious event which may raise the risk category of diabetic patients. For each risk category the risk factors may differed between male and female patients. More studies are recommended to study distribution of risk factors between male and female diabetic patients. Attention should be directed toward raising the awareness about the risk assessment scoring system and encouraging physicians to use it.


Anion-dependent self-assembly of near-infrared luminescent 24- and 32-metal Cd-Ln complexes with drum-like architectures.
Two series of 4d-4f clusters [Ln8Cd24L12(OAc)48] and [Ln6Cd18L9Cl8(10)(OAc)28(26)] (Ln = Nd, Gd, Er, and Yb) with novel drum-like structures were prepared using a flexible Schiff base ligand. Their NIR luminescence properties were determined.


Use of thiol-disulfide exchange method to study transmembrane peptide association in membrane environments.
The development of methods for reversibly folding membrane proteins in a two-state manner remains a considerable challenge for studies of membrane protein stability. In recent years, a variety of techniques have been established and studies of membrane protein folding thermodynamics in the native bilayer environments have become feasible. Here we present the thiol-disulfide exchange method, a promising experimental approach for investigating the thermodynamics of transmembrane (TM) helix-helix association in membrane-mimicking environments. The method involves initiating disulfide cross-linking of a protein under reversible redox conditions in a thiol-disulfide buffer and quantitative assessment of the extent of cross-linking at equilibrium. This experimental method provides a broadly applicable tool for thermodynamic studies of folding, oligomerization, and helix-helix interactions of membrane proteins.


Blood Coagulation Disorders Among the Iranian Population: a Systematic Review.
Blood coagulation disorders are one of the causes of mortality. Therefore, the study of coagulation disorders is also important. This systematic review was conducted to investigate blood coagulation disorders in the Iranian population. Searches in electronic databases such as Web of Science, PubMed, Scopus, SID, ProQuest, and Magiran from May 10, 1990 to May 10, 2019 were performed according to PRISMA guidelines. Cross-sectional, cohort, experimental, and case-control studies were included according to the inclusion criteria without gender and language restrictions. After screening and selection, 14 studies were selected for data extraction. Accordingly, the most common blood coagulation disorder in the south of Iran was a defect in FXIII (599 of 1,165). C.559T>C (27 of 189) and c.562T>C (20 of 189) mutations had the highest frequency. The most common FXIII polymorphism among the Iranian Azerbaijanis was Val34Leu (203 of 410). The second most common coagulation disorder was FV Leiden (396 of 1,165). Then, c.1691G>A (151 of 396) was the most common mutation. This study shows that the most critical coagulation disorder among the Iranian population is FXIII deficiency and the most common mutation is c.562T>C.


Towards zero waste production in the paint industry wastewater using an agro-based material in the treatment train.
An attempt has been made to evaluate the use of natural, agro-based material, Moringa oleifera as a coagulant in the treatment of recreated water-based paint effluent. The treatment train sequence comprising coagulation, flocculation, sedimentation, sand filtration, and membrane filtration was used. The efficiency was evaluated in terms of color and turbidity. The influence of experimental parameters such as eluent type, eluent concentration, coagulant dose, coagulant-eluate volume, initial effluent pH, and initial effluent concentration was examined. The recommended conditions to yield maximum removal efficiency are 80 mL of eluate prepared using 3 g of M. oleifera seed powder and 1 N NaCl, under actual pH, to treat a liter of effluent. The treated supernatant from coagulation unit was passed through a sand filtration setup and a membrane filtration, with a maximum removal of color above 95%. The results affirmed the positive coagulation properties of M. oleifera, which could serve as a better alternative for chemical coagulant. The optimized treatment conditions derived for the recreated paint effluent were applied in the real paint effluent treatment. An opportunity was identified for re-using treated wastewater, as a cooling fluid and a diluting agent for lower quality paints.The results affirmed the positive coagulation properties of M. oleifera, which could serve as a better alternative for chemical coagulant. Graphical abstract .


The use of hand grip strength as a predictor of nutrition status in hospital patients.
Hand grip strength (HGS) has been found to respond to nutrition deprivation and repletion but few studies have investigated its use as an independent nutrition assessment tool. We conducted an observational study to determine if HGS can predict nutrition status independently of other factors. The Patient Generated Subjective Global Assessment (PG-SGA) was used to determine nutrition status. PG-SGA and HGS measures were collected from 217 well nourished and malnourished hospital patients for cross-sectional analysis. Of the 217, 18 patients had these assessments repeated two weeks (±3 days) later to assess change. Correlation, and multiple linear and binary regression analyses were conducted. HGS and PG-SGA score were significantly correlated (r = 0.292, P < 0.01). HGS was a significant independent predictor of PG-SGA score and category (P < 0.01), accounting for 4% and 9% of variability respectively. Change-in-HGS was an independent predictor of change-in-PG-SGA score (P = 0.04) and category (P = 0.06) over two weeks, accounting for 47% and 42% of variability respectively. Our results suggest that HGS can independently predict nutrition status and change in nutrition status defined by PG-SGA score and category, although future longer term research is required to confirm the use of HGS as an early detection tool for malnutrition risk.


Dietary Reference Intakes for Koreans with special consideration to older adults.
The Dietary Reference Intakes for Koreans (KDRIs) were revised in 2020. Due to the rapidly aging Korean population, special consideration was given to reclassify the KDRI age group categories of older adults. This article examines the evidence for modifying the current KDRI age group ranges of older adults (65-74 and ≥ 75 yrs). We first reviewed the domestic and international data on the elderly, following which we received expert opinions on age classification from the KDRI Advisory Committee. Finally, the 6th and 7th (2013-2017) Korea National Health and Nutrition Examination Survey (KNHANES) data were used to analyze the nutritional intake statuses by considering the age of older adults. According to the review results of domestic and international data and the inputs received from the expert advisory committee, the minimum age considered for the elderly was maintained at 65 yrs. However, the KNHANES data was analyzed to review whether there was a need to subdivide the later periods. Examining the differences in nutrient intakes by age group through the interaction effect term of the piecewise linear regression model revealed the interaction effect was maximum in the groups divided by 65 yrs (50-64 and 65-80), as compared to the groups divided by 70 yrs (50-69 and 70-80) and 75 yrs (50-74 and 75-80). The mean adequacy ratio was calculated per 1 yr of age, and a 3-yr (age) moving average analysis was performed to examine the change in the trends of overall nutrient intake. However, it was challenging to secure a scientific basis for subdivision into age groups in older adults from the results obtained. This study could not find any scientific evidence for modifying the KDRI age groups for older adults.


Gender differences in the effect of age on adrenergic neurotransmission in the heart.
In male rats, there is an age-associated decline in the capacity of cardiac sympathetic nerves to release norepinephrine. To investigate whether this phenomenon also occurs in female rats, we examined adrenergic neurochemical transmission in the hearts of female and male Fischer 344 rats. Rats aged 6, 12, and 24 months were employed. Hearts with the right cardiac sympathetic nerve intact were isolated and perfused with Krebs-Ringer solution. Stimulations were performed following the administration of cocaine or metanephrine separately and in combination or following the combination of cocaine, metanephrine, and yohimbine. Cocaine (1 microM) was used to block uptake 1, metanephrine (1 x 10(-5) M) to block uptake 2, and yohimbine (3 microM) to block alpha 2 receptor presynaptically. The nerve was stimulated with frequencies of 2, 6, and 12 Hz, and norepinephrine amount in the effluent was determined by high performance liquid chromatography/electrochemical detection methods. Neither norepinephrine release nor the effects of yohimbine, cocaine, or metanephrine were found to be affected in older female rats (24 month). This suggests that age-related changes in adrenergic neurochemical transmission in the heart of female rats differ from those seen in older male rats.


The effect of naproxen on the ocular inflammatory response following extracapsular lens extraction in rabbits.
Naproxen effects on the ocular inflammatory response following extracapsular lens extraction were studied in rabbits. Twelve hours before surgery, rabbits were given 20 mg of a 5 mg/ml naproxen suspension by gavage. A maintenance dose of 10 mg naproxen 3 times per day was started on the day of lensectomy and continued throughout the entire observation period. Phakic and aphakic control rabbits received no drug suspension. Central corneal thickness and intraocular pressure measurements were determined pre-operatively, at 4 and 24 h post-operatively and every 24 h thereafter. Four groups of rabbits, sacrificed at 24, 48, 72, and 168 h after lensectomy, had anterior chamber paracentesis performed for PMN (polymorphonuclear leucocyte) counts and determination of protein content. A 5th group had both paracentesis and iris-ciliary body excision for PGE2 assay at 24 h. No parameter was significantly altered by the naproxen regimen compared to untreated rabbits.


Scientific communication on TikTok.
Abbie Richards is an active scientific communicator on TikTok who posts videos to communicate climate science and to combat misinformation. Cell editor Jia Cheng chatted with Abbie Richards to get her viewpoint on scientific communication through social media. Annotated excerpts from this conversation are presented below, and the full conversation is available with the article online.


ErbB4-mediated regulation of vasculogenic mimicry capability in breast cancer cells.
ErbB4 is a member of the ErbB receptor tyrosine kinase family. It has both pro- and anti-oncogenic activities in tumors. Vasculogenic mimicry (VM), a phenomenon in which cancer cells form capillary-like structures without endothelial cells, has been recognized to be a cause of malignant phenotypes in some solid tumors. Here, we used an in vitro VM formation assay, and demonstrated that ErbB4 negatively regulated VM formation in human breast cancer cells. By using CRISPR/Cas9-mediated gene knockout, we verified that the depletion of endogenous ErbB4 improved the VM formation capability. Although treatment with neuregulin 1 (NRG1), a ligand of ErbB4, induced the phosphorylation of ErbB4 and promoted VM formation in a dose-dependent manner, it did not induce such activities in kinase-dead K751M ErbB4-overexpressing cells. Moreover, we examined the effect of the missense mutation E872K of ErbB4, which has been reported in multiple tumors, on VM formation, and found that the mutation enhanced the basal phosphorylation level and ErbB4-mediated VM formation in the absence of NRG1 stimulation. Whereas NRG1 stimulated VM formation, excessive activation of ErbB4 induced a negative effect. In E872K ErbB4-overexpressing cells, but not in wild-type ErbB4-overexpressing cells, the number of VM tubes was significantly decreased by low-dose treatment with the ErbB inhibitor afatinib. Taken together, our findings demonstrated the significance of ErbB4-mediated VM formation, and suggested the possibility of ErbB4 mutations as effective targets in breast cancer.


New iodinated progestins as potential ligands for progesterone receptor imaging in breast cancer. Part 1: Synthesis and in vitro pharmacological characterization.
Five putative iodinated progesterone receptor (PR) binding ligands were synthesized and evaluated as potential imaging agents for PR-positive human breast tumours. Two compounds (E- and Z-17-hydroxy-21-iodo-19-nor-17alpha-pregna-4,20-dien-3-one; E- and Z-IPG1) were previously described, but are re-evaluated. The other three were novel compounds: two nortestosterone analogues derived from ORG 3236 (E- and Z-13-ethyl-17-hydroxy-21-iodo-11-methylene-18,19-dinor-17alpha-pre gna-4,20-diene-3-one; E- and Z-IPG2) and one norprogesterone analogue derived from ORG 2058 (21-[4-iodophenoxy]-16alpha-ethyl-19-norpregn-4-ene-3, 20-dione; IPG3). The E-iodovinyl nortestosterone compounds were obtained by a new route of synthesis. Competitive binding studies were performed to determine their binding affinities for the PR in three types of tissue (human MCF-7 breast tumour cells and rat uterine and mammary tumour tissue) and for the androgen receptor (AR) in human MCF-7 breast tumour cells, as well as for the sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) in human plasma. All four 17alpha-iodovinyl nortestosterone derivatives displayed high binding affinity for the human PR, that of Z-IPG1 and E- and Z-IPG2 being even higher than that of ORG2058. Their affinities for the rat PR were somewhat lower, especially those of both E-isomers. The affinity of IPG3 was lower for both the human and rat PR. The nortestosterone derivatives also showed AR binding, the relative binding affinities ranging from 4.3 to 17.0% as compared with 5alphaDHT. Additionally, neither of these steroids displayed any significant binding to either SHBG or CBG in human plasma. We conclude that the in vitro binding properties of all four 17alpha-iodovinyl nortestosterone derivatives warrant evaluation of the distribution characteristics of their 123I-labelled analogues to determine their usefulness as PR imaging agents.


N-acetyl-beta-D-glucosaminidase excretion in healthy children and in pediatric patients with urolithiasis.
Hyperoxaluria was reported to induce renal damage, probably due to toxic effects on renal tubules. Such tubular damage might be expressed by an increase in urinary excretion of marker enzymes such as N-acetyl-beta-D-glucosaminidase (NAG). We set out to examine a possible relationship between the excretion of NAG and that of urinary lithogenic and stone-inhibitory substances by analyzing 24-h urine specimens from 56 children with urolithiasis and 25 healthy children with normal renal function and without a history of urolithiasis. The NAG excretion was higher in patients with urolithiasis (3.5 +/- 0.51 U/g creatinine) as compared with healthy subjects (1.33 +/- 0.14 U/g creatinine, P < 0.05). A positive correlation between NAG and oxalate excretion was observed in female patients (r = 0.56: P < 0.01). In conclusion, the increase in urinary NAG in children with urolithiasis might express renal tubular damage. It seemed, however, not to be specifically related to the excretion of a single lithogenic substance.


Dioscin inhibits human endometrial carcinoma proliferation via G0/G1 cell cycle arrest and mitochondrial-dependent signaling pathway.
The present study emphasized on the anti-cancerous effects of dioscin and its underlying molecular mechanism in human endometrial cancer Ishikawa cells. Dioscin significantly suppressed the proliferation of Ishikawa cells at IC50 of 2.37 μM. Besides, dioscin could inhibit the proliferation of Ishikawa cells by blocking the G0/G1 cell cycle through up-regulation of p16, p21, and p27 and down-regulation of cycle-cellular protein (Cyclin A/D/E) and cyclin-dependent kinase (CDK2/4/6). Also, it promoted apoptosis through the mitochondrial pathway, including the regulation of Bcl family proteins, the increase of ROS levels, the activation of caspases (Caspase 9/3), and the decrease of mitochondrial membrane permeability. Whereas dioscin also effectively activated the marker genes and proteins (Fas, TNF-R1, and Caspase 8) related to the death receptor-mediated pathway which confirmed the involvement of both the pathways for dioscin-induced apoptosis. The current results demonstrated that dioscin possessed potential health benefits with respect to endometrial cancer prevention and treatment.


Modulation of mitogenic activity and cellular binding of basic fibroblast growth factor by basic proteins.
Polycationic molecules were studied either for their ability to displace the binding of basic fibroblast growth factor (bFGF) to high- and low-affinity membrane interaction sites and/or to modulate bFGF-induced proliferation of fibroblasts. Heparin-binding polypeptides, such as polylysine, protamine, histones, and thrombin-displaced [125I]bFGF bound to bovine brain membrane receptors. The most displacing polypeptides were those with the strongest affinity to heparin. Two of these polypeptides, protamine and polylysine, inhibited (at 5 microM) by more than 90% the mitogenic effect induced by bFGF on Chinese hamster lung fibroblast cells (CCL39). At the same dose, no effect was observed with basic proteins that do not bind to heparin, such as cytochrome C and lysozyme. An interesting observation was that protamine at 1 microM potentiated by 1.5-fold the mitogenic activity of bFGF, while it acted as an inhibitor at higher concentration.


Machine Learning Improves Upon Clinicians' Prediction of End Stage Kidney Disease.
Chronic kidney disease progression to ESKD is associated with a marked increase in mortality and morbidity. Its progression is highly variable and difficult to predict. This is an observational, retrospective, single-centre study. The cohort was patients attending hospital and nephrology clinic at The Canberra Hospital from September 1996 to March 2018. Demographic data, vital signs, kidney function test, proteinuria, and serum glucose were extracted. The model was trained on the featurised time series data with XGBoost. Its performance was compared against six nephrologists and the Kidney Failure Risk Equation (KFRE). A total of 12,371 patients were included, with 2,388 were found to have an adequate density (three eGFR data points in the first 2 years) for subsequent analysis. Patients were divided into 80%/20% ratio for training and testing datasets.ML model had superior performance than nephrologist in predicting ESKD within 2 years with 93.9% accuracy, 60% sensitivity, 97.7% specificity, 75% positive predictive value. The ML model was superior in all performance metrics to the KFRE 4- and 8-variable models.eGFR and glucose were found to be highly contributing to the ESKD prediction performance. The computational predictions had higher accuracy, specificity and positive predictive value, which indicates the potential integration into clinical workflows for decision support.


Response mechanisms of domoic acid in Pseudo-nitzschia multiseries under copper stress.
A complex relationship exists between copper stress and the accumulation and release of domoic acid (DA) in toxin-producing Pseudo-nitzschia cells. To clarify the changes and role of DA in this process, we exposed the toxin-producing P. multiseries and the non-toxin-producing P. pungens to copper stress (5 and 9 μM) for 96 h. Results showed that P. multiseries grew better than P. pungens under the two aforementioned copper concentrations. DA content in the cells of P. multiseries increased with increased copper stress, and the dissolved DA in the medium under the 9 μM copper treatment increased. DA addition at a 9 μM copper concentration reduced the copper content in P. multiseries cells and cell walls, but did not change the free copper ion content in culture medium. Adding DA to the medium reduced the malondialdehyde (MDA) content in the cells of P. multiseries under copper stress, DA addition also reduced the activities of catalase (CAT) and superoxide dismutase (SOD) at 5 μM Cu, and the activity of peroxidase (POD) at 9 μM Cu. This suggests that DA may not alleviate copper stress by improving the antioxidant defense system of algal cells, nor can it be complexed with copper ions in the medium to alleviate copper stress. Furthermore, the reactive oxygen species (ROS) scavenger N-tert-butyl-α-phenylnitrone (BPN) was used to study the DA accumulated in cells. The BPN addition significantly reduced the accumulation of DA in the cells under copper stress, suggesting that DA content in cells was closely related to ROS. Moreover, further experiments demonstrated that DA addition can improve the growth of P. multiseries under hydrogen peroxide stress. Our results indicate that DA alleviates P. multiseries oxidative damage when expose to copper stress.


Spatial and temporal dispersion of Doryctobracon areolatus (Szépligeti) (Hymenoptera: Braconidae) in orchards infested with Anastrepha fraterculus (Wiedemann) (Diptera: Tephritidae).
Doryctobracon areolatus (Szépligeti) is an endoparasitoid and promising fruit fly control agent. The objective of the study was to determine the spatial (horizontal and vertical) and temporal dispersion of D. areolatus in the field. To evaluate the horizontal and temporal dispersion, two peach orchards were selected. In each orchard, 50 points were marked at different distances from the central point, from where 4,100 couples of D. areolatus were released. Four hours after release, parasitism units (PU) (3 per point) were fixed to the trees at a height of 1.5 m from the ground. The PUs were composed of ripe apples artificially infested with second instar larvae of Anastrepha fraterculus (30 larvae/fruit). For the evaluation of vertical dispersion, in an olive orchard six points were selected (trees of ≈4 m in height). Each tree was divided into three heights in relation to the ground (1.17, 2.34, and 3.51 m). Doryctobracon areolatus was able to disperse horizontally at a distance >60 m from the release point. However, the highest parasitism rates [15-45% (area 1); 15-27% (area 2)] were observed up to 25 m. Higher percentages of parasitism and of recovered offspring occur in the first days after the release of the parasitoid (2 DAR). As for vertical dispersion, D. areolatus parasitized A. fraterculus larvae up to the highest attachment height of the evaluated PUs (3.51). The results showed the potential use of D. areolatus in the management of fruit flies in the field.


Chronic rhinosinusitis disease control: a review of the history and the evidence.
Control is an important concept and outcome measure for chronic incurable diseases, defined as the extent to which manifestations of a disease are within acceptable limits. Control reflects a global metric of disease status and serves as the goal of treatment. This review will encompass the history of the disease control concept applied to chronic rhinosinusitis (CRS) and the body of scientific literature that has focused on the definition of CRS disease control. A review of the scientific literature identified historical studies and guidelines that have developed definitions of CRS disease control, as well as recent studies identifying the most significant determinants of CRS control. A particular focus was made on studies that investigated patients' and physicians' perspectives of CRS control. Patients and physicians have well-aligned perspectives about the definition, criteria, and application of CRS disease control, with a specific prioritization of patients' assessments of their own CRS control, as well as the symptoms of nasal obstruction and nasal drainage. The development of future guidelines for assessing CRS control must be based on criteria supported by evidence as essential to the assessment of CRS control but should also be the subject of broad international consensus.


Decision-making impact on adjuvant chemotherapy allocation in early node-negative breast cancer with a 21-gene assay: systematic review and meta-analysis.
Risk stratification based on results provided by a 21-gene assay (Oncotype DX(®)) in early stage breast cancer can help optimize hormone therapy (HT) and/or chemotherapy (CT) decisions. We performed a systematic review and meta-analysis of decision impact (DI) and net change in CT use before and after assay results, both in the whole studies' population and by recurrence risk score (RS) strata. A systematic search of studies with prospective data collection reported physician's decision on treatment allocation in early stage node-negative breast cancer was performed. DI reflects the proportion of patients whose management was changed, and net change focuses on CT change. A random-effects model is reported. Fifteen studies (N = 2229) met our inclusion criteria: 50.09, 37.35, and 13.38 % of patients with low, intermediate, and high RS. Treatment decision changed in 29.5 % (95 % CI 26.29-32.86). Net reduction of CT use was 12 % (8-17 %). It was 16 % (12.00-19.00) in the low RS group, 0 % (-3.00 to 3.00) in the intermediate RS group, and increased by 2 % (-1.00 to 3.00) in the high RS group. Use of a 21-gene assay showed a significant impact on treatment decisions. From 100 women tested, 30 could have their treatment optimized, and 12 could avoid CT. Its main effects consist of sparing chemotherapy in low risk patients and slightly increasing it in the high risk category. DI could be higher in selected patient populations with greater uncertainty regarding initial treatment decisions.


Improved red blood cell survival after cardiac operations with administration of urea during cardiopulmonary bypass.
The plasma hemoglobin and red blood cell survival (half-life of 51Cr) was studied in 48 patients undergoing single valve replacement or coronary artery bypass graft. Urea or placebo was administered during cardiopulmonary bypass in a prospective, randomized, double-blind manner to test the potential effect on mechanical hemolysis. The mean plasma hemoglobin level at the end of extracorporeal circulation was significantly lower in the urea-treated groups (coronary artery bypass 342 mg/L; valve replacement 364 mg/L) than in the control groups (coronary artery bypass 635 mg/L, p less than 0.05; valve replacement 518 mg/L, p less than 0.01). The half-life of 51Cr was significantly longer in the urea-treated patients (coronary artery bypass 18 days; valve replacement 16 days) than in the control groups (coronary artery bypass 12.4 days, p less than 0.01; valve replacement 12.7 days, p less than 0.001) but still below the normal reference value (29 +/- 4 days). The plasma hemoglobin returned to near normal values (50 mg/L) the day after operation (day 1) and remained low with no differences between control and urea-treated groups. The total blood hemoglobin was followed for 2 weeks after operation and showed significantly less anemia in the urea-treated group. The lowest mean blood hemoglobin level was noted between days 5 and 9-114 (coronary artery bypass) and 107 (valve replacement) gm/L in the urea-treated patients compared to 92.3 (coronary artery bypass, p less than 0.01) and 92.2 (valve replacement, p less than 0.01) gm/L in the control subjects. The reduction in the severity of the anemia led to less transfusion in the urea-treated patients (approximately 0.5 unit/patient) than in the control subjects (approximately 1 unit/patient, p less than 0.05) between days 3 and 14.


Neuropathology in seven cases of locked-in syndrome.
The neuropathology of 7 cases of the locked-in syndrome has been reviewed and compared with 3 cases of akinetic mutism, all of them occurring after brainstem vascular disease (9 infarctions, 1 hematoma). Including other published cases of verified locked-in syndrome, the extent of lesions has been studied in order to understand, among other symptoms, the preservation of consciousness, voluntary eye movements, auditory comprehension and vital functions. It is concluded that, at the time of autopsy, although most of the clinical signs can be explained by the pathological findings, it is not yet possible to individualize specific brainstem lesions responsible for this syndrome.


Inhibition of platelet aggregation by carbon monoxide-releasing molecules (CO-RMs): comparison with NO donors.
Carbon monoxide (CO) and CO-releasing molecules (CO-RMs) inhibit platelet aggregation in vitro. Herein, we compare the anti-platelet action of CORM-3, which releases CO rapidly (t (½) 1 min), and CORM-A1, which slowly releases CO (t(½) = 21 min). The anti-platelet effects of NO donors with various kinetics of NO release were studied for comparison. The effects of CO-RMs and NO donors were analyzed in washed human platelets (WP), platelets rich plasma (PRP), or whole blood (WB) using aggregometry technique. CORM-3 and CORM-A1 inhibited platelet aggregation in human PRP, WP, or WB, in a concentration-dependent manner. In all three preparations, CORM-A1 was more potent than CORM-3. Inhibition of platelets aggregation by CORM-A1 was not significantly affected by a guanylate cyclase inhibitor (ODQ) and a phosphodiesterase-5 inhibitor, sildenafil. In contrast, inhibition of platelet aggregation by NO donors was more potent with a fast NO releaser (DEA-NO, t (½) = 2 min) than slow NO releasers such as PAPA-NO (t (½) = 15 min) or other slow NO donors. Predictably, the anti-platelet effect of DEA-NO and other NO donors was reversed by ODQ while potentiated by sildenafil. In contrast to NO donors which inhibit platelets proportionally to the kinetics of NO released via activation of soluble guanylate cyclase (sGC), the slow CO-releaser CORM-A1 is a superior anti-platelet agent as compared to CORM-3 which releases CO instantly. The anti-platelet action of CO-RMs does not involve sGC activation. Importantly, CORM-A1 or its derivatives representing the class of slow CO releasers display promising pharmacological profile as anti-platelet agents.


Assessment of ion recombination correction and polarity effects for specific ionization chambers in flattening-filter-free photon beams.
To investigate ion recombination correction and polarity effects in four ion chamber models in flattening-filter-free (FFF) beams to (1) evaluate their suitability for reference dosimetry; (2) assess the accuracy of the two-voltage technique (TVA) against the Bruggmoser formalism; and (3) examine the influence of the accelerator type on the recombination correction. Jaffé plots were created for a variety of microchambers, small-volume and Farmer-type chambers to obtain kS, the recombination correction factor, using two different types of accelerators. These values were plotted against dose-per-pulse and Jaffé plots for opposite polarities were created to determine which chambers meet the AAPM TG-51 addendum recombination and polarity specifications. Nearly all small-volume chambers exhibited reference-class behavior with respect to ion recombination and polarity effects. The microchambers exhibited anomalous recombination and polarity effects, precluding their use for reference dosimetry in FFF beams. For the reference-class chambers, agreement between TVA-determined kS values and Jaffé and Bruggmoser formalisms-determined kS values was within 0.1%. No significant differences were found between the kS values obtained with the two different accelerators used in this work. This study stresses the need to characterize ion recombination correction and polarity effects for small-volume chambers and microchambers on an individual chamber basis and with the more rigorous criteria of the AAPM TG-51 addendum. Furthermore, the study demonstrated the suitability of the TVA method for chambers that exhibit reference-class behavior in FFF beams. Finally, this work has shown that the recombination correction does not depend on the type of accelerator but on its dose-per-pulse.


Image processing for identification and quantification of filamentous bacteria in in situ acquired images.
In the activated sludge process, problems of filamentous bulking and foaming can occur due to overgrowth of certain filamentous bacteria. Nowadays, these microorganisms are typically monitored by means of light microscopy, commonly combined with staining techniques. As drawbacks, these methods are susceptible to human errors, subjectivity and limited by the use of discontinuous microscopy. The in situ microscope appears as a suitable tool for continuous monitoring of filamentous bacteria, providing real-time examination, automated analysis and eliminating sampling, preparation and transport of samples. In this context, a proper image processing algorithm is proposed for automated recognition and measurement of filamentous objects. This work introduces a method for real-time evaluation of images without any staining, phase-contrast or dilution techniques, differently from studies present in the literature. Moreover, we introduce an algorithm which estimates the total extended filament length based on geodesic distance calculation. For a period of twelve months, samples from an industrial activated sludge plant were weekly collected and imaged without any prior conditioning, replicating real environment conditions. Trends of filament growth rate-the most important parameter for decision making-are correctly identified. For reference images whose filaments were marked by specialists, the algorithm correctly recognized 72 % of the filaments pixels, with a false positive rate of at most 14 %. An average execution time of 0.7 s per image was achieved. Experiments have shown that the designed algorithm provided a suitable quantification of filaments when compared with human perception and standard methods. The algorithm's average execution time proved its suitability for being optimally mapped into a computational architecture to provide real-time monitoring.


I've been thinkin' bout you: socially distant relationship pursuit during COVID-19.
The COVID-19 pandemic has radically altered everyday interactions, potentially disrupting the process of romantic relationship formation. Prior research suggests that threats to the basic psychological need for relatedness, along with negative mental imagery, can lead to an obsessive preoccupation with a romantic interest. The present research examines how the relatedness-threatening nature of the pandemic may similarly facilitate problematic relationship behaviors. Two studies-a small-scale natural experiment with measurements before and during the pandemic (Study 1) and a daily diary study (Study 2)-investigated how relatedness frustration and negative fantasies predict presumptuous romantic intentions. In Study 1 these threats unexpectedly corresponded to reduced presumptuous romantic intentions, though no such main effect was present in Study 2. Replicating prior experimental work, in both studies, more negative fantasies about a romantic target predicted greater presumptuous romantic intentions. Study 2 also revealed that at the between-person level the combinatory effect of relatedness frustration and negative fantasies led to greater intentions. At the within-person level, this combinatory effect led unexpectedly to reduced intentions. Finally, there was substantial heterogeneity in the within-person effect of COVID-induced relatedness frustration: although frustration stoked intentions for some individuals, for others it reduced intentions. This work suggests that for many, the early social ramifications of COVID-19 reduced motivation to presumptuously pursue romantic relationships. Yet, certain individuals, particularly those with more negative fantasies, are more prone to pursue presumptuously amidst the pandemic.


Suppression of the Excitability of Rat Nociceptive Primary Sensory Neurons Following Local Administration of the Phytochemical, Quercetin.
Although the modulatory effect of quercetin on voltage-gated Na, K, and Ca channels has been studied in vitro, the in vivo effect of quercetin on the excitability of nociceptive primary neurons remains to be determined. The aim of the present study was to examine whether acute local quercetin administration to rats attenuates the excitability of nociceptive trigeminal ganglion (TG) neurons in response to mechanical stimulation in vivo. Extracellular single unit recordings were made from TG neurons of anesthetized rats in response to orofacial non-noxious and noxious mechanical stimulation. The mean firing frequency of TG neurons in response to both non-noxious and noxious mechanical stimuli was dose-dependently inhibited by quercetin, and maximum inhibition of the discharge frequency of both non-noxious and noxious mechanical stimuli was seen within 10 min. The inhibitory effect of quercetin lasted for 15 minutes and was reversible. The mean magnitude of inhibition on TG neuronal discharge frequency with 10 mM quercetin was almost equal to that of the local anesthetic, 2% lidocaine. These results suggest that local injection of quercetin into the peripheral receptive field suppresses the excitability of nociceptive primary sensory neurons in the TG, possibly via inhibition of voltage-gated Na channels and opening voltage-gated K channels. PERSPECTIVE: Local administration of the phytochemical, quercetin, as a local anesthetic may provide relief from trigeminal nociceptive pain with smallest side effects, thus contributing to the area of complementary and alternative medicines.


[Genetico-neurochemical analysis of the role of brain catecholamines in population hierarchy in male laboratory mice].
Comparative genetic analysis of social dominance in micropopulations of male mice as well as noradrenaline and dopamine levels in brain was carried out. The RT male mice had maximal level of social dominance and the greatest content of brain catecholamines. It is suggested that the capacity for social dominance may depend on the function of the central catecholamine neurons. This suggestion has been confirmed by the data obtained both for interstrain and intrastrain relations between social dominance and catecholamine levels.


Prognostic aspects of aplastic anemia in pregnancy. Experience on six cases and review of the literature.
Our resent experience on six cases of aplastic anemia complicated with pregnancy is described. In addition, 43 similar cases were collected from the literature and reviewed to analyze some prognostic aspects of this relatively rare but potentially serious complication. Clinical and hematological data were treated to extract some clinically meaningful factors in relation to the success and failure of pregnancy. Among initial hematological parameters, no significant difference was found between successful and unsuccessful cases with an exception of hemoglobin concentration. The patients diagnosed as aplastic anemia prior to conception demonstrated an better outcome of pregnancy as well as survival rate of mother when compared with those diagnosed during pregnancy. Mortality has apparently improved after the late 1950's. Success rate of pregnancy before 1958 was 21%, while it was 67% and 71% in the era of 1959-1969 and after 1970, respectively. However, hemorrhage and infection remained to be two major causes of maternal death in both eras. Based on these observations, the currently recommendable attitude to this complication is discussed.


Use of the tyrosinase gene from Streptomyces to probe promoter sequences for Escherichia coli.
We have constructed a promoter-probe vector utilizing the expression of a promoter-less tyrosinase derived from Streptomyces plasmid pIJ702. The vector, pMX100, has single sites for EcoRI, KpnI, BamHI, XbaI, SalI, and SphI for cloning promoter sequences. When the tac promoter was inserted into pMX100, E. coli harboring the chimeric plasmid produced the melanin pigment.


Renal-tubule metabolism of ifosfamide to the nephrotoxic chloroacetaldehyde: pharmacokinetic modeling for estimation of intracellular levels.
Ifosfamide (IF) improves survival in children with solid tumors but causes a high rate of nephrotoxicity. We hypothesized that this is caused by an oxidative metabolite of IF, chloroacetaldehyde, which is produced locally by the cells of the renal tubule (RT). For this hypothesis to be viable, one must document that chloroacetaldehyde concentrations in the RT cell are consistent with levels shown to cause nephrotoxicity in experimental systems. Using pharmacokinetic modeling of experimental data, we show that the median level of chloroacetaldehyde in RT cells is 80 micromol/L, ranging from 35 to 320 micromol/L. These concentrations are consistent with levels shown experimentally to cause functional and structural RT damage and lends validity to the hypothesis that local renal production of chloroacetaldehyde causes nephrotoxicity.


Sulphate ion-induced slow transformation of succinate dehydrogenase.
A new type of slow change of succinate dehydrogenase (EC 1.3.99), activity which is induced by sulphate ion is described. After preincubation of submitochondrial particles or soluble succinate dehydrogenase with sulphate both preparations catalyze succinate:phenazine methosulphate reductase reaction with a significant lag. When added to the assay medium sulphate ion induces biphasic time-dependent competitive inhibition of the enzyme. The sulphate-induced inhibition is apparently due to a rapid interaction of the anion with an active site of the enzyme which is followed by a slow pH-dependent (pKa = 7.2) transformation of the enzyme-inhibitor complex. pH profiles of the overall succinate dehydrogenase reaction and of equilibrium between fast and slow enzyme-sulphate complexes suggest that the same protolytic equilibrium step is involved in the formation of an active intermediate and an inactive enzyme-sulphate complex.


Continuity of care in general surgery resident education.
Lack of continuity of care for patients managed by general surgery residents is a commonly recognized problem but objective data evaluating its incidence are limited. The goal of this pilot study was to determine the extent to which senior residents at a large American urban academic center participate in the full course of care for patients on whom they operate. Two hundred twenty-eight total cases performed between January 1, 2012 and December 31, 2012 were reviewed and the operative senior resident was noted: laparoscopic cholecystectomy (n = 50), breast lumpectomy (n = 33), thyroidectomy (n = 50), laparoscopic appendectomy (n = 50), and open partial colectomy (n = 45). Frequency of operative resident involvement in the initial preoperative clinic visit, initial postoperative visit, or both (the entire course of care) was recorded. Overall rate of operative resident involvement was 9.2% for the initial preoperative consultation, 9.0% for the initial follow-up visit, and 0% for the entire course of a patient's care. Residents were on service for greater than 40 days, whereas the average total duration of care for an individual patient was 26 days. The results of this pilot study suggest that continuity of care among general surgery residents is lacking and cannot be entirely accounted for by rotation-specific time constraints. Further research is needed to identify and validate effective curricular strategies for improving opportunities to participate in this essential experience.


Pneumonectomy for non-tumoral diseases: etiologies and follow-up in 38 cases.
Pneumonectomy is a surgical procedure associated with high rates of morbidity and mortality. Chronic inflammatory pathologies increase these rates, depending on the degree of pleural symphysis and the underlying pulmonary pathology. The occurrence of a bronchopleural fistula after pneumonectomy remains of great concern to the thoracic surgeon, because it leads to empyema in the pneumonectomy cavity, which requires protracted and difficult management. A retrospective single-center study was carried out on 38 patients who underwent pneumonectomy for non-tumoral pathologies between 2010 and 2017. Of the 38 patients, 22 (57.8%) men and 16 (42.2%) women, the average age was 40.3 years, and 30 (79%) patients were treated for tuberculosis. The symptoms were predominantly hemoptysis with bronchorrhea in 22 (57.9%) cases. Chest computed tomography showed right-sided involvement in 15 (39.5%) patients, with destroyed lung in 31 (81.5%). Early postoperative complications included bleeding in 11 (28.9%) patients, postpneumonectomy empyema in 4 (10.5%), and death in 2 (5.2%). The average duration of follow-up was 2 years, without any recurrence. The endemicity of tuberculosis in our context, and the absence of screening for lung cancer, explain the frequency of pneumonectomy for chronic inflammatory diseases, and the rate of complications after this surgical procedure.


Trends of people using drugs and opioid substitute treatment recorded in England and wales general practice (1994-2012).
Illicit drug use is a multifaceted public-health problem with potentially serious impacts. The United Kingdom has one of the highest prevalence of illegal drug use in Europe. Reduction of overall illegal drug use in England and Wales has decreased from 11% to 8.2% (2012/13) over the past 10 years. People who use drugs often seek help from their family doctors. To investigate General Practitioners (family doctors) first recording of drug use and opioid substitute treatment in primary care settings. A descriptive study design. Males and females (16-64 years old) were extracted from The Health Improvement Network (THIN) database. England and Wales primary care. The first recording of drug use and opioid substitution treatment in primary care was estimated for the period (1994-2012). Poisson regressions were conducted to estimate incidence risk ratios (IRR). We identified 33,508 first recordings of drug use and 10,869 individuals with prescriptions for opioid substitute treatment. Overall, males (IRR 2.02, 95% CI:1.97-2.07), people in the age-group; 16-24 (IRR 6.7, 95% CI:6.4-6.9) compared to those over 25 years and the most deprived (IRR 4.2, 95% CI:3.9-4.4) were more likely to have a recording of drug use. Males (IRR 1.2 95% CI:1.2-1.3), in the age-group; 25-34 (IRR 1.8 95% CI:1.7-1.9) and the most deprived (IRR 3.9 95% CI:3.6-4.3) were the groups more likely to have a opioid substitute treatment prescription. It is evident from this study that there is little recording of drug use and opioid substitute treatment in primary care. Most drug users do not receive treatment in primary care.


Unfolded protein response (UPR) signaling regulates arsenic trioxide-mediated macrophage innate immune function disruption.
Arsenic exposure is known to disrupt innate immune functions in humans and in experimental animals. In this study, we provide a mechanism by which arsenic trioxide (ATO) disrupts macrophage functions. ATO treatment of murine macrophage cells diminished internalization of FITC-labeled latex beads, impaired clearance of phagocytosed fluorescent bacteria and reduced secretion of pro-inflammatory cytokines. These impairments in macrophage functions are associated with ATO-induced unfolded protein response (UPR) signaling pathway characterized by the enhancement in proteins such as GRP78, p-PERK, p-eIF2α, ATF4 and CHOP. The expression of these proteins is altered both at transcriptional and translational levels. Pretreatment with chemical chaperon, 4-phenylbutyric acid (PBA) attenuated the ATO-induced activation in UPR signaling and afforded protection against ATO-induced disruption of macrophage functions. This treatment also reduced ATO-mediated reactive oxygen species (ROS) generation. Interestingly, treatment with antioxidant N-acetylcysteine (NAC) prior to ATO exposure, not only reduced ROS production and UPR signaling but also improved macrophage functions. These data demonstrate that UPR signaling and ROS generation are interdependent and are involved in the arsenic-induced pathobiology of macrophage. These data also provide a novel strategy to block the ATO-dependent impairment in innate immune responses.


Novel lncRNA UPLA1 mediates tumorigenesis and prognosis in lung adenocarcinoma.
With the development of molecular biotechnology and sequencing techniques, long non-coding RNAs (lncRNAs) have been shown to play a vital role in a variety of cancers including lung cancer. In our previous study, we used RNA sequencing and high-content screening proliferation screening data to identify lncRNAs that were significantly associated with tumour biological functions such as LINC01426. Herein, based on previous work, we report a novel lncRNA UPLA1 (upregulation promoting LUAD-associated transcript-1), which has not been explored or reported in any previous studies. Our results showed that UPLA1 is highly expressed and regulates important biological functions in lung adenocarcinoma. In vitro experiments revealed that UPLA1 promoted the migration, invasion, and proliferation abilities, and is related to cell cycle arrest, in lung adenocarcinoma cells. Moreover, the upregulation of UPLA1 significantly improved the growth of tumours in vivo. We identified that UPLA1 was mainly located in the nucleus using fluorescence in situ hybridisation, and that it promoted Wnt/β-catenin signalling by binding to desmoplakin using RNA pulldown assay and mass spectrometry. Additionally, luciferase reporter assay revealed that YY1 is the transcription factor of UPLA1 and suppressed the expression of UPLA1 as a transcriptional inhibitor. This finding provides important evidence regarding the two roles of YY1 in cancer. Furthermore, in situ hybridisation assay results showed that UPLA1 was closely related to the prognosis and tumour, node, metastasis (TNM) stage of lung adenocarcinoma. In summary, our results suggest that the novel lncRNA UPLA1 promotes the progression of lung adenocarcinoma and may be used as a prognostic marker, and thus, has considerable clinical significance.


Impaired metabolism of senescent muscle satellite cells is associated with oxidative modifications of glycolytic enzymes.
Accumulation of damaged macromolecules, including irreversibly oxidized proteins, is a hallmark of cellular and organismal ageing. Failure of protein homesotasis is a major contributor to the age-related accumulation of damaged proteins. In skeletal muscle, tissue maintenance and regeneration is assured by resident adult stem cells known as satellite cells. During senescence their replication and differentiation is compromised contributing to sarcopenia. In this study we have addressed the impact of oxidatively modified proteins in the impaired metabolism of senescent human satellite cells. By using a targeted proteomics analysis we have found that proteins involved in protein quality control and glycolytic enzymes are the main targets of oxidation (carbonylation) and modification with advanced glycation/lipid peroxidation end products during replicative senescence of satellite cells. Inactivation of the proteasome in aged cells appeared as a key contributor to the accumulation of such damaged proteins. Untargeted metabolomic profiling and functional analyses indicated glucose metabolism impairment in senescent cells, although mitochondrial respiration remained unaffected. A metabolic shift leading to increased mobilization of non-carbohydrate substrates as branched chain amino acids or long chain fatty acids was observed in senescent cells. In addition, phospho-and glycerolipids metabolism was altered. Increased levels of acyl-carnitines indicated augmented turnover of storage and membrane lipids for energy production. Such changes reflect alterations in membrane composition and dysregulation of sphingolipids signaling during senescence. This study establishes a new concept connecting oxidative protein modifications with the altered cellular metabolism associated with the senescent phenotype. In addition, these findings highlight the molecular mechanisms implicated in satellite cells dysfunction during ageing, paving the road for future therapeutic interventions aimed at preventing oxidative modifications of proteins and/or stimulating their elimination.


Moderating effect of cognitive reserve on brain integrity and cognitive performance.
Dementia syndrome is one of the most devastating conditions in older adults. As treatments to stop neurodegeneration become available, accurate and timely diagnosis will increase in importance. One issue is that cognitive performance sometimes does not match the corresponding level of neuropathology, affecting diagnostic accuracy. Cognitive reserve (CR), which can preserve cognitive function despite underlying neuropathology, explains at least some variability in cognitive performance. We examined the influence of CR proxies (education and occupational position) on the relationship between hippocampal or total gray matter volume and cognition. We used data from the Czech Brain Aging Study. Participants were clinically confirmed to be without dementia (n = 457, including subjective cognitive decline and amnestic mild cognitive impairment) or with dementia syndrome (n = 113). For participants without dementia, higher education magnified the associations between (a) hippocampal volume and executive control (b = 0.09, p = 0.033), (b) total gray matter volume and language (b = 0.12, p < 0.001), and (c) total gray matter volume and memory (b = 0.08, p = 0.018). Similarly, higher occupational position magnified the association between total gray matter volume and (a) attention/working memory (b = 0.09, p = 0.009), (b) language (b = 0.13, p = 0.002), and (c) memory (b = 0.10, p = 0.013). For participants with dementia, the associations between hippocampal (b = -0.26, p = 0.024) and total gray matter (b = -0.28, p = 0.024) volume and visuospatial skills decreased in magnitude with higher education. We found that the association between brain volume and cognitive performance varies based on CR, with greater CR related to a stronger link between brain volume and cognition before, and a weaker link after, dementia diagnosis.


A simple strategy for managing many recessive disorders in a dairy cattle breeding program.
High-density single nucleotide polymorphism genotypes have recently been used to identify a number of novel recessive mutations that adversely affect fertility in dairy cattle, as well as to track other conditions such as red coat color and polled. Most current methods for mate allocation fail to consider this information, and it will become increasingly difficult to manage matings as the number of recessive mutations to be accounted for increases. A modified version of a mating strategy that constrains inbreeding based on genomics (the Pryce method) was developed that also accounts for the economic effects of Mendelian disorders on overall economic merit (modified Pryce method) and compared with random mating, truncation selection, and the Pryce scheme. Several scenarios were considered, including scenarios with six hypothetical recessive alleles and 12 recessive alleles that are currently segregating in the US Holstein population. The Pryce method and the modified Pryce method showed similar ability to reduce frequencies of recessive alleles, particularly for loci with frequencies greater than 0.30. The modified Pryce method outperformed the Pryce method for low-frequency alleles with small economic value. Cumulative genetic gain for the selection objective was slightly greater when using the Pryce method, but rates of inbreeding were similar across methods. The proposed method reduces allele frequencies faster than other methods, and also can be used to maintain or increase the frequency of desirable recessives. It can be easily implemented in software for mate allocation, and the code used in this study is freely available as a reference implementation.


The effect of odor valence on olfactory performance in schizophrenia patients, unaffected relatives and at-risk youth.
Given the presence of odor identification impairment in individuals with schizophrenia and recent evidence of aberrant odor hedonic processing, the aim of this investigation was to examine the influence of valence and intensity on odor identification in schizophrenia patients, their first-degree family members, and young persons at clinical risk for psychosis. Participants completed the 16-item Sniffin' Stick Odor Identification Test. A logistic regression was conducted to assess the influence of valence and intensity on odor identification accuracy. Identification performance in the schizophrenia patients and youths at clinical risk for psychosis was significantly influenced by odor valence, but not intensity. Identification accuracy in first-degree family members was not influenced by valence or intensity. These data suggest that abnormalities in odor valence perception may represent an environmentally-mediated marker for hedonic disturbance that could have predictive utility in future conversion to psychosis. Further research examining the utility of odor valence measures as markers for psychosis risk is warranted.


New approaches in drug development and novel compounds.
This report focuses on the novel compounds which are in development and clinical trials and also highlights some of the data presented at the poster sessions.


A modification of the Papanicolaou exfoliative cytology stain to demonstrate keratin in paraffin-block tissue sections.
A method of staining for keratin by application of a modified Papanicolaou staining procedure to formalin-fixed paraffin-embedded tissues is described. The modification is achieved by increasing the staining time for the three basic Papanicolaou stains and incorporating phloxine B as an additional staining component. Since the Papanicolaou staining components are common to most histopathology laboratories and phloxine B is not a rare stain component, this procedure can be instituted with a modicum of effort. The procedure is less time consuming than the usual staining methods for demonstrating keratin and does so with a high degree of reliability.


Lack of short-term increase in serum mediators of fibrogenesis and in non-invasive markers of liver fibrosis in HIV/hepatitis C virus-coinfected patients starting maraviroc-based antiretroviral therapy.
The aim of this study was to analyze serum changes in mediators of fibrogenesis and in non-invasive markers of liver fibrosis among HIV/HCV-coinfected patients starting maraviroc (MVC)-based antiretroviral therapy. Patients included in this prospective pilot study met the following criteria: (1) HIV-infection, (2) detectable serum HCV-RNA, and ((3) started MVC. Transforming growth factor-β1 (TGF-beta1), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) were measured in serum samples at baseline and 6 months after starting MVC. AST-to-platelet ratio index (APRI) was assessed at the same time points. Twenty-four patients were analyzed. Median (IQR) serum levels at baseline and after 6 months on MVC of TGF-beta1 were 27,295 (20,562-36,844) and 33,753 (18,973-46,130) pg/mL (p=0.116), of MMP-2 were 216 (186-274) and 241 (194-306) ng/mL (p=0.247), and of TIMP-1 were 237 (170-284) and 216 (171-271) ng/mL (p=0.415). APRI levels were 0.99 (0.53-3.46) at baseline and 0.83 (0.48-2.34) at 6 months (p=0.16). Serum mediators of liver fibrogenesis and fibrosis do not change significantly in HIV/HCV-coinfected patients in the short-term after starting MVC. As TGF-beta1 levels have been shown to increase over time in HCV infection and liver fibrosis worsens rapidly in HIV/HCV coinfection, these parameters seem to evolve in a different way in MVC-treated patients.


Diversity in health professional education scholarship: a document analysis of international author representation in leading journals.
The global distribution of health professionals and associated training programmes is wide but prior study has demonstrated reported scholarship of teaching and learning arises from predominantly Western perspectives. We conducted a document analysis to examine authorship of recent publications to explore current international representation. The table of contents of seven high-impact English-language health professional education journals between 2008 and 2018 was extracted from Embase. The journals were selected according to highest aggregate ranking across specific scientific impact indices and stating health professional education in scope; only original research and review articles from these publications were included for analysis. The table of contents was extracted and eligible publications screened by independent reviewers who further characterised the geographic affiliations of the publishing research teams and study settings (if applicable). A total 12 018 titles were screened and 7793 (64.8%) articles included. Most were collaborations (7048, 90.4%) conducted by authors from single geographic regions (5851, 86%). Single-region teams were most often formed from countries in North America (56%), Northern Europe (14%) or Western Europe (10%). Overall lead authorship from Asian, African or South American regions was less than 15%, 5% and 1%, respectively. Geographic representation varied somewhat by journal, but not across time. Diversity in health professional education scholarship, as marked by nation of authors' professional affiliations, remains low. Under-representation of published research outside Global North regions limits dissemination of novel ideas resulting in unidirectional flow of experiences and a concentrated worldview of teaching and learning.


Diagnostic Performance of Ultrasound Computer-Aided Diagnosis Software Compared with That of Radiologists with Different Levels of Expertise for Thyroid Malignancy: A Multicenter Prospective Study.
The aim of the work described here was to evaluate the diagnostic performance of ultrasound thyroid computer-aided diagnosis (CAD) software. This multicenter prospective study included 494 patients (565 thyroid nodules) who underwent surgery or biopsy after ultrasonography at four hospitals from January 2019 to September 2019. The diagnostic performance metrics of different readers were calculated and compared with the pathologic results. The sensitivity of CAD was outstanding and was equivalent to that of a senior radiologist (90.51% vs. 88.47%, p > 0.05). The area under the curve of CAD was equivalent to that of a junior radiologist (0.748 vs. 0.739, p > 0.05). However, the specificity was only 49.63%, which was lower than those of the three radiologists (75.56%, 85.93% and 90.37% for the junior, intermediate and senior radiologists, respectively). The diagnostic performance of the junior radiologist was significantly improved with the aid of CAD (junior + CAD). The sensitivity and area under the curve of junior + CAD were improved from 72.20% to 89.93% and from 0.739 to 0.816, respectively (both p values <0.05), and the positive predictive value, negative predictive value and κ coefficient improved from 76.3% to 78.6%, 82.0% to 86.8% and 0.394 to 0.511, respectively. Though specificity slightly decreased from 75.56% to 73.33%, the difference was not statistically significant (p > 0.05). In general, the clinical application value of CAD is promising, and its instrumental value for junior radiologists is significant.