Historical contamination of the Anacostia River, Washington, D.C.
The tidal Anacostia River in Washington DC has long been impacted by various sources of chemical pollution over the past 200 years. To explore more recent inputs of various chemicals, six sediment cores were collected for dating and chemical analysis in the downstream section of the tidal Anacostia River. Profiles of contaminants in sediment cores can be useful in determining management direction and effectiveness of pollution controls over time. There were two main objectives for this investigation: (1) determine current sediment contaminant levels; (2) determine a historical perspective of the sediment changes in contamination using (137)Cs and (210)Pb dating. The determination of an age-depth relationship using (210)Pb and (137)Cs dating gave somewhat different results, suggesting that the assumptions of (210)Pb dating were not met. Using the (137)Cs horizon allowed an assignment of approximate sediment accumulation rates and hence an age-depth relationship to contaminant events in the upper portions of the cores. Total PAHs showed higher concentrations at depth and lower surface concentrations. In the upper sections, PAHs were a mixture of combustion and petrogenic sources, while at depth the signature appeared to be of natural origins. Total PCBs, DDTs and chlordane concentrations showed a maximum in recent sediments, decreasing towards the surface. PCBs had lower molecular weight congeners near the surface and higher molecular weights at depth. A phthalate ester, DEHP, appeared in the mid 1940-1950s, and decreased towards the surface. Trace elements fell roughly into three groups. Fe, Mn, and As were in approximately constant proportion to Al, except in some deeper, sandy sediments, where they showed enrichments linked to redox conditions. Ag, Cd, Cu, Hg, Pb, and Zn had low concentrations in the deepest sediments, high concentrations at mid-depths, and declines to intermediate levels at the surface. Ni and Cr followed neither of these patterns closely. We observed that many contaminants appeared in the Anacostia sediments at various times, and reached relatively high concentrations in the past, but are now showing declines in loadings. In some cases, such as PCBs, DDT, chlordane, and Pb from leaded gasoline, these declines can be clearly linked to the discontinuation of their use for environmental reasons. For other contaminants (e.g., PAHs, DEHP, selected metals) these declines are more likely the result of changes in production, usage and waste control.


Time-resolving characterization of molecular weight retention changes among three synthetic high-flux dialyzers.
Toxin removal capacity (i.e., performance) of a dialyzer is not constant but diminishes during treatment, as the adsorption of proteins to the membrane provides an additional barrier to uremic solutes. We investigated time-resolving molecular weight retention changes among synthetic high-flux dialyzers and compared the results with recent data from a randomized controlled trial. In plasma recirculation experiments over 240 min, sieving coefficients (SC) for β2-microglobulin, myoglobin, and albumin were determined for the FX CorAL (Fresenius Medical Care), ELISIO (Nipro), and xevonta (B. Braun). Molecular weight retention (MWR) curves were generated and the shifts over 120 min were characterized. Effective pore radius was determined, and the predicted albumin loss was compared with clinical data. SC decreased over time for all dialyzers (mean relative decrease across all dialyzers: β2-microglobulin: 8.0% (120 min); myoglobin: 56.6% (240 min); albumin: 94.1% (240 min)). FX CorAL (7.3%, 52.6% and 91.1%) and ELISIO (7.7%, 51.0%, and 93.8%) showed a lower decrease than xevonta (9.0%, 66.2%, and 97.4%). For all dialyzers, MWR curves shifted toward lower molecular weight, with the lowest shift for FX CorAL (by 0.23 nm at SC50%, 120 min) and highest for xevonta (0.50 nm). FX CorAL had the highest slope over time and the smallest decrease in the effective pore radius (2 min: 2.31 nm, 120 min: 2.08 nm). Predicted albumin loss over 4 h was highest for xevonta (609.3 mg) and comparable between ELISIO (283.6 mg) and FX CorAL (313.3 mg). Substantial differences in the temporal performance profile of dialyzers exist. The present approach allows the characterization of dialyzer permeability changes over time using standard, clinically relevant protein markers.


Coupling between the phase of a neural oscillation or bodily rhythm with behavior: Evaluation of different statistical procedures.
Growing experimental evidence points at relationships between the phase of a cortical or bodily oscillation and behavior, using various circular statistical tests. Here, we systematically compare the performance (sensitivity, False Positive rate) of four circular statistical tests (some commonly used, i.e. Phase Opposition Sum, Circular Logistic Regression, others less common, i.e., Watson test, Modulation Index). We created semi-artificial datasets mimicking real two-alternative forced choice experiments with 30 participants, where we imposed a link between a simulated binary behavioral outcome with the phase of a physiological oscillation. We systematically varied the strength of phase-outcome coupling, the coupling mode (1:1 to 4:1), the overall number of trials and the relative number of trials in the two outcome conditions. We evaluated different strategies to estimate phase-outcome coupling chance level, as well as significance at the individual or group level. The results show that the Watson test, although seldom used in the experimental literature, is an excellent first intention test, with a good sensitivity and low False Positive rate, some sensitivity to 2:1 coupling mode and low computational load. Modulation Index, initially designed for continuous variables but that we find useful to estimate coupling between phase and a binary outcome, should be preferred if coupling mode is higher than 2:1. Phase Opposition Sum, coupled with a resampling procedure, is the only test retaining a good sensitivity in the case of a large unbalance in the number of occurrences of the two behavioral outcomes.


Volatility connectedness of GCC stock markets: how global oil price volatility drives volatility spillover in GCC stock markets?
The study investigated the volatility connectedness of GCC stock market return and S&P global oil index returns using Diebold and Yilmaz (2012) method. The current study has also analyzed the possible impact of oil price volatility on net volatility spillover in GCC stock market returns pre- and post-COVID-19 period. The current study results suggest that the GCC stock markets have volatility connectedness with S&P Global Oil Index returns' volatility and across GCC stock markets. The GCC stock markets have greater volatility in their stock markets than volatility spillover from other GCC countries. Further investigation also suggests that global oil price volatility has a divergent causal impact on net spillover in GCC stock markets. Such results would enhance the understanding of GCC stock market connection, spillover, and economic channels through which GCC markets are connected.


Large-vessel vasculitis in graft-versus-host disease: a case report.
Graft-versus-host disease is a common complication seen with allogenic stem cell transplant, which is used to treat a variety of hematological malignancies. Graft-versus-host disease is an allogenic syndrome and can present in a variety of ways, including symptoms mimicking various autoimmune diseases; however, it is quite rare to see graft-versus-host disease affecting the vascular system and causing vasculitis. We describe a case of a 59-year-old Caucasian man with follicular lymphoma and diffuse large B-cell transformation who developed graft-versus-host disease post allogenic hematopoietic stem cell transplantation and later progressed to neurological complication foot drop and large-vessel vasculitis. The life-threatening vascular complications associated with large-vessel vasculitis include arterial aneurysms and dissections, and ischemic or hemorrhagic stroke. Thus, this rare immunological association needs to be recognized and treated in a timely manner to prevent the long-term complications.


Enzymatic control of cycloadduct conformation ensures reversible 1,3-dipolar cycloaddition in a prFMN-dependent decarboxylase.
The UbiD enzyme plays an important role in bacterial ubiquinone (coenzyme Q) biosynthesis. It belongs to a family of reversible decarboxylases that interconvert propenoic or aromatic acids with the corresponding alkenes or aromatic compounds using a prenylated flavin mononucleotide cofactor. This cofactor is suggested to support (de)carboxylation through a reversible 1,3-dipolar cycloaddition process. Here, we report an atomic-level description of the reaction of the UbiD-related ferulic acid decarboxylase with substituted propenoic and propiolic acids (data ranging from 1.01-1.39 Å). The enzyme is only able to couple (de)carboxylation of cinnamic acid-type compounds to reversible 1,3-dipolar cycloaddition, while the formation of dead-end prenylated flavin mononucleotide cycloadducts occurs with distinct propenoic and propiolic acids. The active site imposes considerable strain on covalent intermediates formed with cinnamic and phenylpropiolic acids. Strain reduction through mutagenesis negatively affects catalytic rates with cinnamic acid, indicating a direct link between enzyme-induced strain and catalysis that is supported by computational studies.


Congenital hepatic fibrosis in children.
Twenty-seven children with congenital hepatic fibrosis were followed for three months to 12 years. Hepatosplenomegaly, normal liver function tests, and kidney abnormalities were present in most patients, indicating that a correct diagnosis of congenital hepatic fibrosis could be made using simple clinical, biologic, and radiologic criteria. Esophageal endoscopy showed varices in 21 patients. Sixteen children underwent portal-systemic shunt surgery. Follow-up examinations did not show any impairment of liver function or any sign of hepatic encephalopathy. Cholangitis was present in only three children.


The H2A.Z-nuclesome code in mammals: emerging functions.
H2A.Z is a histone variant that provides specific structural and docking-side properties to the nucleosome, resulting in diverse and specialised molecular and cellular functions. In this review, we discuss the latest studies uncovering new functional aspects of mammalian H2A.Z in gene transcription, including pausing and elongation of RNA polymerase II (RNAPII) and enhancer activity; DNA repair; DNA replication; and 3D chromatin structure. We also review the recently described role of H2A.Z in embryonic development, cell differentiation, neurodevelopment, and brain function. In conclusion, our cumulative knowledge of H2A.Z over the past 40 years, in combination with the implementation of novel molecular technologies, is unravelling an unexpected and complex role of histone variants in gene regulation and disease.


Nickel oxide microfibers immobilized onto electrode by electrospinning and calcination for nonenzymatic glucose sensor and effect of calcination temperature on the performance.
Nickel oxide microfibers (NiO-MFs) were directly immobilized onto the surface of fluorine tin oxide (FTO) electrode by electrospinning and calcination without using any immobilization matrix for nonenzymatic glucose sensor. Morphology and structure of NiO-MFs were characterized by scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), and X-ray diffraction pattern (XRD). The electrochemical and electrocatalytic performances of the NiO-MFs modified electrodes prepared at different calcination temperatures ranging from 300 to 500°C were evaluated by cyclic voltammetry (CV). The CV results have demonstrated that NiO-MFs modified electrode prepared at 300°C displayed distinct increase in electrocatalytic activity toward the oxidation of glucose, which is explored to develop an amperometric nonenzymatic glucose sensor. The NiO-MFs prepared at 300°C based amperometric nonenzymatic glucose sensor has ultrasensitive current (1785.41 μA mM(-1) cm(-2)) response and low detection limit of 3.3×10(-8) M (signal/noise ratio (S/N)=3), which are among the best values reported in literature. Additionally, excellent selectivity and stability have also been obtained.


SpaceOAR Hydrogel Spacer for Reducing Radiation Toxicity During Radiotherapy for Prostate Cancer. A Systematic Review.
To evaluate the association between SpaceOAR and radiation dosing, toxicity and quality-of-life vs no spacer across all radiotherapy modalities for prostate cancer. A systematic search of the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase was performed from database inception through May 2020. Two reviewers independently screened titles/abstracts and full papers. Data extraction was performed, and quality assessed by 1 reviewer and checked by a second, using a third reviewer as required. The synthesis was narrative. 19 studies (3,622 patients) were included (only 1 randomized controlled trial, in image-guided intensity-modulated radiotherapy (IG-IMRT), 18 comparatives non-randomized controlled trials in external-beam radiotherapy (EBRT), brachytherapy, and combinations thereof). No hypofractionation studies were found. Regardless of radiotherapy type, SpaceOAR significantly reduced rectal radiation dose (eg, V40 average difference -6.1% in high dose-rate brachytherapy plus IG-IMRT to -9.1% in IG-IMRT) and reduced gastrointestinal and genitourinary toxicities (eg, late gastrointestinal toxicity 1% vs 6% (P = .01), late genitourinary toxicity of 15% vs 32% (P < .001) in stereotactic body radiotherapy). Improvements were observed in most Expanded Prostate Cancer Index Composite quality-of-life domains (eg, bowel function score decrease at 3 and 6 months: Average change of zero vs -6.25 and -3.57 respectively in low dose-rate brachytherapy plus EBRT). The randomized controlled trial in IG-IMRT demonstrated that SpaceOAR reduces rectal radiation dose and late gastrointestinal and genitourinary toxicities, with urinary, bowel, and sexual quality-of-life improvement. These advantages were verified in observational studies in various radiotherapy types. Further research is required in hypofractionation.


Anatomy of the pleura: reflection lines and recesses.
Knowledge of the anatomy of the lines of pleural reflection, triangular ligaments, and pleural recesses is important to thoracic surgeons because their anatomic areas are used daily for radiographic interpretation as well as for the performance of procedures such as chest tube insertion, thoracentesis, and pericardiocentesis. Their knowledge is also important for thoracic surgeons doing surgical procedures such as parietal pleurectomies, extrapleural mobilization and resection of the lungs, and pleuroneumonectomies for destroyed lungs or malignant pleural neoplasms.


Effects of estradiol treatments on PGF2α release in beef heifers submitted to estrous resynchronization 14 days after timed-AI.
The effects of 17β-estradiol (E2) or estradiol benzoate (EB) on PGF2α release were studied in bred-non-pregnant and pregnant Nelore beef heifers. The day of timed artificial insemination (TAI) was designated day 0 (D0), and a single treatment was given on D14. All heifers also received an intravaginal P4 device on D14, and were randomly assigned to three groups: Control (C, P4 device only, n = 12); E2 (1 mg E2 + 9 mg P4, n = 10); or EB (1 mg, n = 10). Blood samples were collected hourly for 8 hours after treatment (Hours 0-8) to measure plasma concentrations (pg/mL) of a PGF2α metabolite (PGFM). The P4 device was removed on D22 and pregnancy was diagnosed on D28. Pregnancy rate was not different among groups (C, n = 7/12; E2, n = 5/10; EB, n = 5/10). More (P < 0.05) heifers had a CV-identified prominent PGFM pulse (peak of > 100 pg/mL) in E2 group (6/10) than in EB (1/10) and C (0/12) groups. Hourly concentration of PGFM for Hours 0 to 8 showed significant effects of group and hour and an interaction of group by hour but did not show an interaction of group or hour with pregnancy status. In preliminary post-hoc analyses, PGFM concentrations during Hours 0 to 8 and pulse characteristics were analyzed within each pregnancy status. For the non-pregnant heifers, a group-by-hour interaction was detected tentatively indicating an increase (P < 0.005) in PGFM concentrations in E2 group from Hours 4 to 6 and in EB group at Hours 5 and 6. Maximum PGFM concentration during Hours 0 to 8 did not differ (P > 0.1) between E2 (124 ± 23) and EB (110 ± 30) groups, but was greater (P < 0.05) in each group than in C (32 ± 3). Furthermore, PGFM concentrations of pulses at the peak, amplitude, and area under pulse curve (pg/mL/h) were greater (P < 0.05) in E2 group than in C group whereas the EB group did not differ (P > 0.1) from the other groups. For pregnant heifers, no effects of group, hour, or their interaction were detected in PGFM concentrations during the hourly sessions, except that maximum PGFM concentration was greater (P < 0.05) in E2 than in EB and C groups. In addition, the number of prominent pulses was greater in E2 group than in Control or EB groups. In conclusion, PGFM increased earlier and in greater concentration combined for bred-non-pregnant and pregnant heifers treated 14 days after TAI with 1 mg E2 plus 9 mg P4 than with 1 mg EB. Tentatively, a positive effect for each of E2 and EB on PGFM concentrations was attenuated in pregnant heifers.


Becoming an older caregiver: A study of gender differences in family caregiving at the end of life.
Older people are not traditionally expected to become caregivers. For this reason, the experience of caregiving in older persons has not been explored adequately in the research on gender differences. The objective of this study was to assess the caregiver burden among older family members who care for cancer patients facing the end of their lives, in order to compare their differences according to gender (male vs. female). This is a cross-sectional study. A total of 102 older caregivers (aged ≥65 years) of hospice patients were interviewed through the Caregiver Burden Inventory (CBI). The sample group was divided into two gender subgroups. Compared with male caregivers, the older female group reported significantly higher scores in the CBI-physical subscale (P = 0.028), and in the CBI, the overall score (P = 0.0399) confirmed by the generalized linear model (multivariate) evaluation that included possible predictors in the model. There were no significant differences in the other CBI subscale scores (time-dependent, developmental, social, and emotional). Older female caregivers are at higher risk of experiencing burden and worse physical health compared with men. Further research is needed in modern palliative care to assess the role of gender differences in the experience of caregiving when the caregiver is an older person.


Towards the Influence of Media on Suicidality: A Systematic Review of Netflix's 'Thirteen Reasons Why'.
Online streaming series 'Thirteen Reasons Why' (13RW), released in March 2017, was criticized for its sensationalist portrayal of the main character's suicide, leading some people to voice fears of a global contagion of self-harm behaviors. The current investigation provides a systematic review of original studies analyzing the role of 13RW as an influencing factor for suicide. Articles were identified through a systematic search of Medline, Web of Science, Scopus, PsycInfo, and a manual search of reference lists from inception until the 16 January 2023. Twenty-seven published articles were identified from an initial search of 496 studies. The positive effects of watching 13RW included a reduction in suicide stigma and a greater likelihood to discuss mental health concerns and seek for help. However, several studies reported negative outcomes, including significant increases in the rate of deaths by suicide in adolescents, the number of admissions for suicidal reasons, and the prevalence and severity of suicidal ideation and self-harm behaviors in vulnerable viewers. Still, due to methodological limitations, no causal relationship could be established. Preventive measures are required to alert of the risk and should be particularly addressed to susceptible subjects. Psychoeducational programs should be focused on this kind of phenomena in vulnerable populations.


Prognostic value of thallium-201 myocardial perfusion imaging in three primary patient populations.
Knowledge of a patient's coronary anatomy alone is often insufficient to predict who will benefit from revascularization. Risk of cardiac events is related more to the presence of viable myocardium supplied by coronary arteries that are hemodynamically significant. Myocardial perfusion imaging with thallium-201 has been shown to reveal the presence and extent of jeopardized viable myocardium. In addition, thallium-201 imaging can demonstrate exercise-induced left ventricular dysfunction, manifested by increased thallium-201 myocardial imaging has important prognostic value in a wide spectrum of patients with coronary artery disease. The use of thallium-201 to predict cardiac events in patients with known or suspected coronary artery disease, in patients following myocardial infarction, and in patients undergoing noncardiac surgery is reviewed.


Activation of MUC1 mucin expression by bile acids in human esophageal adenocarcinomatous cells and tissues is mediated by the phosphatidylinositol 3-kinase.
In esophageal adenocarcinoma, MUC1 mucin expression increases in early stages of the carcinogenetic sequence, during which bile reflux has been identified as a major carcinogen. However, no link between MUC1 overexpression and the presence of bile acids in the reflux has been established so far, and molecular mechanisms regulating MUC1 expression during esophageal carcinogenetic sequence are unknown. Our aim was to identify (1) the bile acids able to upregulate MUC1 expression in esophageal cancer cells and mucosal samples, (2) the regulatory regions in MUC1 promoter responsive to bile acids, and (3) the signaling pathway(s) involved in this regulation. MUC1 mRNA and mucin expression were studied by the means of real-time reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry, both in the human esophageal OE33 adenocarcinoma cell line and in an ex vivo explant model. MUC1 promoter was cloned and transcription regulation was studied by transient cell transfection to identify the bile acid-responsive regions. Signaling pathways involved were identified using specific pharmacologic inhibitors and siRNA approach. Taurocholic, taurodeoxycholic, taurochenodeoxycholic, glycocholic, sodium glycocholate, and deoxycholic bile acids upregulated MUC1 mRNA and protein expression. The highest induction was obtained with deoxycholic and taurocholic acids in both cellular and explant models. The bile acid-mediated upregulation of MUC1 transcription occurs at the promoter level, with responsive elements located in the -1472/-234 region of the promoter, and involves the phosphatidylinositol 3-kinase signaling pathway. Bile acids induce MUC1 mucin overexpression in human esophageal adenocarcinoma cells and tissues by activating its transcription through a process involving phosphatidylinositol 3-kinase.


Familiarisation to body weight supported treadmill training for patients post-stroke.
Walking on a treadmill with body weight support (BWS) may require familiarisation. Patients post-stroke fatigue easily and the time needed to reach stable walking is important. However, even if body weight supported treadmill training (BWSTT) is commonly used in gait rehabilitation for patients post-stroke, it is not known how much time that is needed before stable walking is reached in this population. The objective of this study therefore, was to investigate if patients post-stroke manage to stabilise walking patterns during a 5-min familiarisation-trial on the treadmill with BWS. 35 patients post-stroke walked on a treadmill at preferred speed and with 20 percent BWS during a 5-min familiarisation-period. A body-worn sensor assessed trunk acceleration. Intraclass correlation coefficient (ICC) was used for pairwise comparisons of successive 30s intervals during familiarisation, and one-way repeated-measures analysis of variance was used to investigate if there were linear trends between intervals. Mean ICCs across all variables stabilised above 0.90 after 3 min. Across intervals, walk ratio, cadence and step length obtained mean ICCs that were high, while interstride trunk regularity and trunk asymmetry obtained lower ICCs. However, except for mediolateral trunk acceleration, there was no linear trend after the first 3 min indicating that differences between intervals during the last 2 min were random. This was the first study investigating familiarisation to BWSTT for patients post-stroke. Findings revealed that most of the familiarisation occurred within the first 3 min of walking, and therefore relatively stable walking could be achieved within a 5-min walking trial on the treadmill with BWS.


Origin of flight: Could 'four-winged' dinosaurs fly?
Our understanding of the origin of birds, feathers and flight has been greatly advanced by new discoveries of feathered non-avian dinosaurs, but functional analyses have not kept pace with taxonomic descriptions. Zhang and Zhou describe feathers on the tibiotarsus of a new basal enantiornithine bird from the Early Cretaceous of China. They infer, as did Xu and colleagues from similar feathers on the small non-avian theropod Microraptor found in similar deposits, that these leg feathers had aerodynamic properties and so might have been used in some kind of flight.


TERT Promoter Revertant Mutation Inhibits Melanoma Growth through Intrinsic Apoptosis.
Human telomerase is a specialized DNA polymerase whose catalytic core includes both TERT and human telomerase RNA (hTR). Telomerase in humans, which is silent in most somatic cells, is activated to maintain the telomere length (TEL) in various types of cancer cells, including melanoma. In the vast majority of tumor cells, the TERT promoter is mutated to promote proliferation and inhibit apoptosis. Here, we exploited NG-ABEmax to revert TERT -146 T to -146 C in melanoma, and successfully obtained TERT promoter revertant mutant cells. These TERT revertant mutant cells exhibited significant growth inhibition both in vitro and in vivo. Moreover, A375-146C/C cells exhibited telomere shortening and the downregulation of TERT at both the transcription and protein levels, and migration and invasion were inhibited. In addition, TERT promoter revertant mutation abrogated the inhibitory effect of mutant TERT on apoptosis via B-cell lymphoma 2 (Bcl-2), ultimately leading to cell death. Collectively, the results of our work demonstrate that reverting mutations in the TERT promoter is a potential therapeutic option for melanoma.


An integrated methodological approach to the computer-assisted gas chromatographic screening of basic drugs in biological fluids using nitrogen selective detection.
This paper presents the methodological aspects of a computerized system for the gas-chromatographic screening and primary identification of central nervous system stimulants and narcotic analgesics (including some of their respective metabolites) extracted from urine. The operating conditions of a selective nitrogen detector for optimized analytical functions are discussed, particularly the effect of carrier and fuel gas on the detector's sensitivity to nitrogen-containing molecules and discriminating performance toward biological matrix interferences. Application of simple extraction techniques, combined with rapid derivatization procedures, computer data acquisition, and reduction of chromatographic data are presented. Results show that this system approach allows for the screening of several drugs and their metabolites in a short amount of time. The reliability and stability of the system have been tested by analyzing several thousand samples for doping control at major international sporting events and for monitoring drug intake in addicts participating in a rehabilitation program. Results indicate that these techniques can be used and adapted to many different analytical toxicology situations.


Experimental and theoretical support for costs of plasticity and phenotype in a nematode cannibalistic trait.
Developmental plasticity is the ability of a genotype to express multiple phenotypes under different environmental conditions and has been shown to facilitate the evolution of novel traits. However, while the associated cost of plasticity, i.e., the loss in fitness due to the ability to express plasticity in response to environmental change, and the cost of phenotype, i.e., the loss of fitness due to expressing a fixed phenotype across environments, have been theoretically predicted, empirically such costs remain poorly documented and little understood. Here, we use a plasticity model system, hermaphroditic nematode Pristionchus pacificus, to experimentally measure these costs in wild isolates under controlled laboratory conditions. P. pacificus can develop either a bacterial feeding or predatory mouth morph in response to different external stimuli, with natural variation of mouth-morph ratios between strains. We first demonstrated the cost of phenotype by analyzing fecundity and developmental speed in relation to mouth morphs across the P. pacificus phylogenetic tree. Then, we exposed P. pacificus strains to two distinct microbial diets that induce strain-specific mouth-form ratios. Our results indicate that the plastic strain does shoulder a cost of plasticity, i.e., the diet-induced predatory mouth morph is associated with reduced fecundity and slower developmental speed. In contrast, the non-plastic strain suffers from the cost of phenotype since its phenotype does not change to match the unfavorable bacterial diet but shows increased fitness and higher developmental speed on the favorable diet. Furthermore, using a stage-structured population model based on empirically derived life history parameters, we show how population structure can alleviate the cost of plasticity in P. pacificus. The results of the model illustrate the extent to which the costs associated with plasticity and its effect on competition depend on ecological factors. This study provides support for costs of plasticity and phenotype based on empirical and modeling approaches.


The promise of eye-tracking in the detection of concealed memories.
There is a need for validated, theory-driven methods for memory detection. We review how physiological, neurophysiological, and oculomotor measures can be utilized to reveal concealed memories. Recent advances and future directions are discussed in light of the potential of eye-tracking to improve detection efficiency and resolve problems in real-world settings.


FT-IR microscopic mappings of early mineralization in chick limb bud mesenchymal cell cultures.
Chick limb bud mesenchymal cells differentiate into chondrocytes and form a cartilaginous matrix in culture. In this study, the mineral formed in different areas within cultures supplemented with 4 mM inorganic phosphate, or 2.5, 5.0, and 10 mM beta-glycerophosphate (beta GP), was characterized by Fourier-transform infrared (FT-IR) microscopy. The relative mineral-to-matrix ratios, and distribution of crystal sizes at specific locations throughout the matrix were measured from day 14 to day 30. The only mineral phase detected was a poorly crystalline apatite. Cultures receiving 4 mM inorganic phosphate had smaller crystals which were less randomly distributed around the cartilage nodules than those in the beta GP-treated cultures. beta GP-induced mineral consisted of larger, more perfect apatite crystals. In cultures receiving 5 or 10 mM beta GP, the relative mineral-to-matrix ratios (calculated from the integrated intensities of the phosphate and amide I bands, respectively) were higher than in the cultures with 4 mM inorganic phosphate or in the in vivo calcified chick cartilage.


Posttranslational modification of proprotein convertase subtilisin/kexin type 9 is differentially regulated in response to distinct cardiometabolic treatments as revealed by targeted proteomics.
The proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that interacts with the low-density lipoprotein (LDL) receptor at the surface of hepatocytes to regulate circulating LDL cholesterol levels. High circulating PCSK9 levels have been associated with elevated LDL cholesterol. Recently, the Food and Drug Administration of the United States approved new LDL cholesterol-lowering drugs that specifically target the inhibition of PCSK9. Similar to most human proteins, PCSK9 exists in multiple forms as it is the target of posttranslational modifications (PTMs) such as proteolytic cleavage, phosphorylation, and others, which can affect its biological activity. However, commercially available assays, such as enzyme-linked immunosorbent assays, do not discriminate between these forms. To investigate, in 2 patient cohorts, the relationships between circulating levels of multiple forms of PCSK9 and cardiometabolic interventions or treatments known to reduce LDL cholesterol levels. PCSK9 forms were measured in plasma: (1) in 20 patients before and 6 months after bariatric surgery and (2) in 132 patients before and 12 months after daily statin treatment. A series of specific peptides used as surrogates for various PCSK9 forms were quantified by a novel semiautomated proteomic assay termed protein affinity capture coupled to quantitative mass spectrometry. Bariatric surgery resulted in a decrease in the plasma level of PCSK9 prodomain (P < .05), but did not result in a significant change in other measured PCSK9 forms. Statin treatment resulted in an increase in all measured plasma PCSK9 peptides (P < .001), but a 25% decrease in the phosphorylated state of PCSK9 at S688 (P < .05). These unexpected findings indicate that measuring the circulating levels of the various domains and PTMs of PCSK9 provides more in depth information than total PCSK9 and that the prodomain and the phosphorylated state of S688 may represent novel biomarkers to explore in cardiometabolic diseases and response to treatment. In addition, our data generated new hypotheses on the function of PCSK9 PTMs in health and disease.


An autocrine mechanism for constitutive Wnt pathway activation in human cancer cells.
Autocrine Wnt signaling in the mouse mammary tumor virus model was the first identified mechanism of canonical pathway activation in cancer. In search of this transformation mechanism in human cancer cells, we identified breast and ovarian tumor lines with upregulation of the uncomplexed transcriptionally active form of beta-catenin without mutations afflicting downstream components. Extracellular Wnt antagonists FRP1 and DKK1 caused a dramatic downregulation of beta-catenin levels in these tumor cells associated with alteration of biological properties and increased expression of epithelial differentiation markers. Colorectal carcinoma cells with knockout of the mutant beta-catenin allele retained upregulated beta-catenin levels, which also could be inhibited by these Wnt antagonists. Together, these findings establish the involvement of autocrine Wnt signaling in human cancer cells.


A Large-Scale Observational Study on the Temporal Trends and Risk Factors of Opioid Overdose: Real-World Evidence for Better Opioids.
The USA is in the midst of an opioid overdose epidemic. To address the epidemic, we conducted a large-scale population study on opioid overdose. The primary objective of this study was to evaluate the temporal trends and risk factors of inpatient opioid overdose. Based on its patterns, the secondary objective was to examine the innate properties of opioid analgesics underlying reduced overdose effects. A retrospective cross-sectional study was conducted based on a large-scale inpatient electronic health records database, Cerner Health Facts®, with (1) inclusion criteria for participants as patients admitted between 1 January, 2009 and 31 December, 2017 and (2) measurements as opioid overdose prevalence by year, demographics, and prescription opioid exposures. A total of 4,720,041 patients with 7,339,480 inpatient encounters were retrieved from Cerner Health Facts®. Among them, 30.2% patients were aged 65+ years, 57.0% female, 70.1% Caucasian, 42.3% single, 32.0% from the South, and 80.8% in an urban area. From 2009 to 2017, annual opioid overdose prevalence per 1000 patients significantly increased from 3.7 to 11.9 with an adjusted odds ratio (aOR): 1.16, 95% confidence interval (CI) 1.15-1.16. Compared to the major demographic counterparts, being in (1) age group: 41-50 years (overall aOR 1.36, 95% CI 1.31-1.40) or 51-64 years (overall aOR 1.35, 95% CI 1.32-1.39), (2) marital status: divorced (overall aOR 1.19, 95% CI 1.15-1.23), and (3) census region: West (overall aOR 1.32, 95% CI 1.28-1.36) were significantly associated with a higher odds of opioid overdose. Prescription opioid exposures were also associated with an increased odds of opioid overdose, such as meperidine (overall aOR 1.09, 95% CI 1.06-1.13) and tramadol (overall aOR 2.20, 95% CI 2.14-2.27). Examination on the relationships between opioid analgesic properties and their association strengths, aORs, and opioid overdose showed that lower aOR values were significantly associated with (1) high molecular weight, (2) non-interaction with multi-drug resistance protein 1 or interaction with cytochrome P450 3A4, and (3) non-interaction with the delta opioid receptor or kappa opioid receptor. The significant increasing trends of opioid overdose at the inpatient care setting from 2009 to 2017 suggested an ongoing need for efforts to combat the opioid overdose epidemic in the USA. Risk factors associated with opioid overdose included patient demographics and prescription opioid exposures. Moreover, there are physicochemical, pharmacokinetic, and pharmacodynamic properties underlying reduced overdose effects, which can be utilized to develop better opioids.


Dipyridamole reduces cholesterol and triglyceride levels in plasma and lipoproteins from young chicks fed a saturated fat-enriched diet.
We have studied the value of dipyridamole for the prevention of hypercholesterolemia caused by saturated fat. This study shows that supplementation of 10-20% coconut oil to the diet induced a significant hypercholesterolemia under postprandial conditions. Simultaneous administration of dipyridamole and 10% coconut oil for 2 weeks maintained plasma cholesterol and triglycerides at levels similar to control, counteracting the increase induced by coconut oil. Dipyridamole significantly reduced cholesterol levels in all the chick plasma lipoproteins that were increased by coconut oil administration. However, it should be emphasized that cholesterol and other chemical components were more drastically reduced by dipyridamole in intermediate- and very-low-density lipoproteins than in other lipoprotein fractions.


Circ_002664/miR-182-5p/Herpud1 pathway importantly contributes to OGD/R-induced neuronal cell apoptosis.
Apoptosis is a prominent form of neuron death in cerebral ischemia-reperfusion-induced injury. Accompanied with the pathogenesis, Circ_002664 is upregulated. However, its role in the neuron apoptosis and the underlying mechanisms are unknown. In this study, HT22 cells were treated with oxygen glucose deprivation and reoxygenation (OGD/R). The cell viability, apoptosis, proliferation and mitochondrial potential were examined. The expressions of interested genes, Circ_002664, miR-182-5p and Herpud1, were measured. The roles of these genes in OGD/R-induced cell injury were investigated by knockdown, overexpression alone or in combination. Additionally, the interactions between Circ_002664, miR-182-5p and Herpud1 were validated by luciferase report assay. The levels of MAP2, CHOP, Cytochrome C (CYC) and cleaved caspase-3 were determined. OGD/R treatment significantly increased cell apoptosis, decreased cell proliferation and mitochondrial potential, as well as increased Circ_002664 and Herpud1 expressions, and decreased miR-182-5p level. Circ_002664 knockdown markedly inhibited the effects by OGD/R on cell survival and altered expression of miR-182-5p and Herpud1. MiR-182-5p was observed sponged by Circ_002664 and negatively mediated its effect above mentioned, and this was by directly targeting Herpud1. Additionally, it was observed that CHOP expressions were regulated by Circ_002664/miR-182-5p/Herpud1 pathway, and in turn mediated its regulation in CYC and cleaved caspase-3. In summary, our data showed that the Circ_002664 importantly contributed to neuronal cell apoptosis induced by OGD/R treatment, and this might be achieved by directly targeting miR-182-5p/Herpud1 pathway.


Synthesis, characterization and biological evaluation of ruthenium flavanol complexes against breast cancer.
Four Ru(II) DMSO complexes (M1R-M4R) having substituted flavones viz. 3-Hydroxy-2-(4-methoxyphenyl)-4H-chromen-4-one (HL1), 3-Hydroxy-2-(4-nitrophenyl)-4H-chromen-4-one (HL2), 3-Hydroxy-2-(4-dimethylaminophenyl)-4H-chromen-4-one (HL3) and 3-Hydroxy-2-(4-chlorophenyl)-4H-chromen-4-one (HL4) were synthesized and characterized by elemental analysis, IR, UV-Vis, 1H NMR spectroscopies and ESI-MS. The molecular structures of the complexes were investigated by integrated spectroscopic and computational techniques (DFT). Both ligands as well as their complexes were screened for anticancer activities against breast cancer cell lines MCF-7. Cytotoxicity was assayed by MTT [3-(4, 5-dimethyl thiazol-2-yl)-2, 5-diphenyl tetrazolium bromide] assay. All ligands and their complexes exhibited significant cytotoxic potential of 5-40μM concentration at incubation period of 24h. The cell cytotoxicity increased significantly in a concentration-dependent manner. In this series of compounds, HL2 (IC50 17.2μM) and its complex M2R (IC50 16μM) induced the highest cytotoxicity.


Screening for HPV-related oropharyngeal, anal, and penile cancers in middle-aged men: Initial report from the HOUSTON clinical trial.
The Human papillomavirus (HPV)-related Oropharyngeal and Uncommon Cancers Screening Trial of Men (HOUSTON) was designed to determine the prevalence of IgG antibodies to HPV type 16 E proteins (HPV16EAbs), to screen for persistence of HPV and/or detect HPV-related premalignancies and cancers, and to assess acceptance of screening among middle-aged men. HOUSTON consists of a cross-sectional study and a longitudinal cohort study of men aged 50-64 years. Serologic HPV16EAb status and oral rinse HPV16 status were determined. All HPV16EAb-positive (HPV16EAb+) men and a matched cohort of HPV16EAb-negative (HPV16EAb-) men as well as all oral rinse HPV16-positive (HPV16+) men were included in the longitudinal study (blinded to their results) and underwent oropharyngeal screening every 6 months as well as one-time anal and penile screening. Of 553 men enrolled in the cross-sectional study, six (1.1%) were HPV16EAb+ (two were also oral rinse HPV16+), and 41 (7.4%) were HPV16EAb- but oral rinse HPV16+. These 47 men, along with five matched controls, were invited to participate in the longitudinal study, and 42 (81%) agreed and completed baseline in-person screening, with 93% and 90% completeing 6-month and 12-month follow-up visits. One HPV16EAb+ (also oral rinse HPV16+) man, who declined participation in the longitudinal study, presented 4 months after enrollment with an early-stage HPV16-related pharyngeal cancer. Additionally, one HPV16EAb+ (oral rinse HPV16-) man and two oral rinse HPV16+ (HPV16EAb-) men were diagnosed with oncogenic HPV-associated anal dysplasia. This biomarker panel deserves further prospective study to explore potential utility for HPV-related cancer screening among men.


Identify and analysis crotonylation sites in histone by using support vector machines.
Lysine crotonylation (Kcr) is a newly discovered histone posttranslational modification, which is specifically enriched at active gene promoters and potential enhancers in mammalian cell genomes. Although lysine crotonylation sites can be correctly identified with high-resolution mass spectrometry, the experimental methods are time-consuming and expensive. Therefore, it is necessary to develop computational methods to deal with this problem. We proposed a new encoding scheme named position weight amino acid composition to extract sequence information of histone around crotonylation sites. We chose protein data from Uniprot database. A series of steps were used to construct a strict and objective benchmark dataset for training and testing the proposed method. All samples were characterized by a significant number of features derived from position weight amino acid composition. The support vector machine was used to perform classification. Based on a series of experiments, we found that the sensitivity (Sn), specificity (Sp), accuracy (Acc), and Matthew's correlation coefficient (MCC) were respectively 71.69%, 98.7%, 94.43%, and 0.778 in jackknife cross-validation. Comparison results demonstrated that our proposed model was better than random forest algorithm. We also performed the feature analysis on samples. Identification of the Kcr sites in histone is an indispensable step for decoding protein function. Therefore, the method can promote the deep understanding of the physiological roles of crotonylation and provide useful information for developing drugs to treat various diseases associated with crotonylation.


Recommendations to prevent urinary tract injuries during laparoscopic hysterectomy: a systematic Delphi procedure among experts.
To reach consensus among experts in the field of laparoscopic gynaecology in uniform recommendations on the prevention and early detection of urinary tract injuries during laparoscopic hysterectomy (LH). A systematic Delphi consensus procedure (Canadian Task Force Classification III). A tertiary-care university hospital. International gynecologic experts in the field of LH. Experts were selected according to standard criteria with regard to surgical experience and research. Twenty of 40 experts were willing to participate. Three questionnaires were sent. Each questionnaire was formulated and based on the answers of the previous one. Fourteen experts completed the third questionnaire. In 40 of 65 proposed recommendations, consensus was achieved. Consensus was achieved with respect to required education, learning curve, equipment, restoration of distorted anatomy and on the application of diagnostic tools in early detection of urinary tract injuries. The Delphi technique is a useful tool to achieve consensus regarding urologic complications in LH. Recommendations may serve as a basis for further research and the development of educational programs.


Reconstructive nature of temporal memory for movie scenes.
Remembering when events took place is a key component of episodic memory. Using a sensitive behavioral measure, the present study investigates whether spontaneous event segmentation and script-based prior knowledge affect memory for the time of movie scenes. In three experiments, different groups of participants were asked to indicate when short video clips extracted from a previously encoded movie occurred on a horizontal timeline that represented the video duration. When participants encoded the entire movie, they were more precise at judging the temporal occurrence of clips extracted from the beginning and the end of the film compared to its middle part, but also at judging clips that were closer to event boundaries. Removing the final part of the movie from the encoding session resulted in a systematic bias in memory for time. Specifically, participants increasingly underestimated the time of occurrence of the video clips as a function of their proximity to the missing part of the movie. An additional experiment indicated that such an underestimation effect generalizes to different audio-visual material and does not necessarily reflect poor temporal memory. By showing that memories are moved in time to make room for missing information, the present study demonstrates that narrative time can be adapted to fit a standard template regardless of what has been effectively encoded, in line with reconstructive theories of memory.


Diaphragmatic Thickness and Excursion in Preterm Infants With Bronchopulmonary Dysplasia Compared With Term or Near Term Infants: A Prospective Observational Study.
Diaphragmatic atrophy associated with mechanical ventilation is reported in pediatric and adult patients, but a similar association has not been described in preterm infants with bronchopulmonary dysplasia (BPD). Does BPD impact the diaphragm thickness (DT) and diaphragm excursion (DE) in infants born before 32 weeks' gestation compared with healthy late preterm or term infants? In this prospective observational case-control study, DT at end of expiration (DTexp), DT at end of inspiration (DTins), DT fraction (DTF), and DE (DE) were assessed using bedside ultrasound. Two groups were compared: infants with BPD (patients) and healthy, postmenstrual age-matched infants (control participants). To account for variations in body size between groups, diaphragmatic measurements were expressed as a ratio of body surface area (BSA). Statistical analyses were conducted using SAS software version 9.4 (SAS Institute, Inc.). We enrolled 111 infants, including 56 preterm infants with BPD (mean ± SD study age, 37.7 ± 1.7 weeks) and 55 healthy control participants (mean ± SD study age, 38.1 ± 1.5 weeks). DTexp and DTexp to BSA ratio were significantly lower in the BPD group compared with the healthy control group (mean ± SD, 1.3 ± 0.4 mm vs 1.5 ± 0.4 mm [P = .01] and 7.1 ± 1.4 mm/m2 vs 7.8 ± 1.8 mm/m2 [P = .03]). DTF and DE were significantly higher in the BPD group vs the healthy control group (mean ± SD, 61.8 ± 26.0 vs 43.3 ± 19.7 [P < .01] and 6.0 ± 1.7 mm vs 4.4 ± 1.6 mm [P < .01], respectively). In infants with BPD, DTexp was significantly lower, whereas DTF and DE were significantly higher, compared with healthy, age-matched control participants. Future studies are required and should focus on describing the evolution of diaphragmatic dimensions in preterm infants with and without BPD. ClinicalTrials.gov; No.: NCT04941963; URL: www. gov.


Extracting Polaron Recombination from Electroluminescence in Organic Light-Emitting Diodes by Artificial Intelligence.
Direct exploring the electroluminescence (EL) of organic light-emitting diodes (OLEDs) is a challenge due to the complicated processes of polarons, excitons, and their interactions. This study demonstrated the extraction of the polaron dynamics from transient EL by predicting the recombination coefficient via artificial intelligence, overcoming multivariable kinetics problems. The performance of a machine learning (ML) model trained by various EL decay curves is significantly improved using a novel featurization method and input node optimization, achieving an R2 value of 0.947. The optimized ML model successfully predicts the recombination coefficients of actual OLEDs based on an exciplex-forming cohost, enabling the quantitative understanding of the overall polaron behavior under various electrical excitation conditions.


Determination of 1,4- and 1,5-benzodiazepines in urine using a computerized gas chromatographic-mass spectrometric technique.
A method for the determination of benzodiazepines and their main metabolites in urine after acid hydrolysis is described. The extract is analyzed by computerized gas chromatography-mass spectrometry. An on-line computer allows rapid detection using mass fragmentography with the masses m/e 211, 230, 241, 244, 249, 262, 276, and 285. The mass fragmentogram and the underlying mass spectra of the hydrolysis products (benzophenones and analogues) are documented.


Intention and motivation to pursue higher education among registered nurses and midwives: a cross-sectional study during COVID-19.
To determine the intention and motivation of nurses and midwives to pursue their higher education considering several factors. This is a cross-sectional study were a 16-item online survey was distributed using a convenience sampling method to approximately 12,000 nurses and midwives between May - July 2021. A total of 513 eligible nurses and midwives participated in the study. Most of the respondents were females (76.61%), with a bachelor's degree (72.3%) and well experienced (11-15 years) (35.4%). Most nurses and midwives are highly motivated to pursue higher education (79.14%). The most motivating factor for the respondents is their professional goals (85.2%), While the most dissuading factor was the cost. Regarding COVID-19, about 28% of the respondents said that the COVID-19 pandemic has a negative effect on their desire to go for higher education. The nurses and midwives were highly motivated to pursue higher education regardless of their demographic status, available resources, and barriers. Furthermore, the eagerness of the nurses and midwives to pursue higher education, which is rooted in their desire to grow in their profession.


Developing and piloting a communication assessment tool assessing patient perspectives on communication with pharmacists (CAT-Pharm).
Effective communication strategies in health care help to enhance patient empowerment and improve clinical outcomes. Adapt the original Communication Assessment (CAT) instrument for the pharmacist profession (CAT-Pharm) and to test its validity and reliability in two different settings. Five hospital pharmacies in Italy and five community pharmacies in Malta. Pilot study involving a standardized multi-step process adhering to internationally accepted and recommended guidelines. Corrections and adjustments to the translation addressed linguistic factors and cultural components. CAT-Pharm, compared to the original CAT, maintained 10 out of the 14 items: one was slightly modified; three were changed to better fit the pharmacist role; one was added. CAT-Pharm development and testing its practicality to assess patient perceptions of pharmacists' interpersonal and communication skills. CAT-Pharm was tested on 97 patients in the Italian setting and 150 patients in the Maltese setting to assess the practicality of the tool and its usefulness in investigating gaps and priorities for improving pharmacist-patient communication. Results Show reliability and internal validity of the CAT-Pharm tool. The analysis of patient perceptions of communication with the pharmacist in Italy indicated differences from that in Malta. The different settings provided insight into the utility of CAT-Pharm. This study provided a valid and reliable tool that could be applied to assess patient perception of the pharmacist's communication abilities.


Autoimmune thyroiditis in antinuclear antibody positive children without rheumatologic disease.
Children are commonly referred to a pediatric rheumatology center for the laboratory finding of an Anti-nuclear antibody (ANA) of undetermined significance. Previous studies regarding adult rheumatology patients have supported an association between ANA and anti-thyroid antibodies, with the prevalence of thyroid antibodies being significantly higher in patients referred to a rheumatology center for an ANA without evidence of connective tissue disease compared to the general population. The purpose of the present study was to determine the frequency of thyroid antibodies in children referred to a pediatric rheumatology center for a positive ANA without evidence of a connective tissue disease. A retrospective chart review was performed on children who were referred to our pediatric rheumatology center between August 2003 and March 2007 for positive ANA with concurrent thyroid antibody and thyroid function tests performed who did not fulfill criteria for a specific connective tissue disease. Laboratory and clinical features were recorded and analyzed. Mean and standard deviation were used to describe continuous data. Chi-square or Fisher's exact tests were used to compare proportions between variables. One-hundred and four ANA-positive patients with concurrent thyroid studies were evaluated (88% female, 93% Caucasian, mean age 11.9 +/- 4.0 years). Half of patients had an ANA titer >/= 1:320. The ANA pattern was speckled in 60% of the patients. Thyroid antibodies were detected in 30% of the patients. Anti-Thyroglobulin (ATG) was detected in 29% and Anti-thyroid peroxidase (ATPO) in 21% of the patients; of these children, 14% had hypothyroidism. ANA pattern and titer were not associated with anti-thyroid antibody positivity. Thyroid antibodies associated with chronic lymphocytic thyroiditis, ATG and ATPO, were detected significantly higher in ANA-positive children without a rheumatologic condition (30%) as compared to the general pediatric population (1.3 - 3.4%). ANA titer and pattern did not help predict the presence or absence of thyroid antibodies. Given the high frequency of thyroid antibodies and increased risk of developing hypothyroidism over time, routine evaluation of ATG and ATPO with thyroid function tests in ANA-positive children is recommended.


Cancer cell genotype associated tumor immune microenvironment exhibits differential response to therapeutic STING pathway activation in high-grade serous ovarian cancer.
High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy characterized by resistance to chemotherapy and high rates of recurrence. HGSC tumors display a high prevalence of tumor suppressor gene loss. Given the type 1 interferon regulatory function of BRCA1 and PTENgenes and their associated contrasting T-cell infiltrated and non-infiltrated tumor immune microenvironment (TIME) states, respectively, in this study we investigated the potential of stimulator of interferon genes (STING) pathway activation in improving overall survival via enhancing chemotherapy response, specifically in tumors with PTEN deficiency. Expression of PTEN protein was evaluated in tissue microarrays generated using pretreatment tumors collected from a cohort of 110 patients with HGSC. Multiplex immunofluorescence staining was performed to determine spatial profiles and density of selected lymphoid and myeloid cells. In vivo studies using the syngeneic murine HGSC cell lines, ID8-Trp53 -/-; Pten -/- and ID8-Trp53 -/-; Brca1 -/-, were conducted to characterize the TIME and response to carboplatin chemotherapy in combination with exogenous STING activation therapy. Patient tumors with absence of PTEN protein exhibited a significantly decreased disease specific survival and intraepithelial CD68+ macrophage infiltration as compared with intact PTEN expression. In vivo studies demonstrated that Pten-deficient ovarian cancer cells establish an immunosuppressed TIME characterized by increased proportions of M2-like macrophages, GR1+MDSCs in the ascites, and reduced effector CD8+ cytotoxic T-cell function compared with Brca1-deficient cells; further, tumors from mice injected with Pten-deficient ID8 cells exhibited an aggressive behavior due to suppressive macrophage dominance in the malignant ascites. In combination with chemotherapy, exogenous STING activation resulted in longer overall survival in mice injected with Pten-deficient ID8 cells, reprogrammed intraperitoneal M2-like macrophages derived from Pten-deficient ascites to M1-like phenotype and rescued CD8+ cytotoxic T-cell activation. This study reveals the importance of considering the influence of cancer cell intrinsic genetic alterations on the TIME for therapeutic selection. We establish the rationale for the optimal incorporation of interferon activating therapies as a novel combination strategy in PTEN-deficient HGSC.


Motion-compensated data decomposition algorithm to accelerate dynamic cardiac MRI.
In dynamic cardiac magnetic resonance imaging (MRI), the spatiotemporal resolution is often limited by low imaging speed. Compressed sensing (CS) theory can be applied to improve imaging speed and spatiotemporal resolution. The combination of compressed sensing and low-rank matrix completion represents an attractive means to further increase imaging speed. By extending prior work, a Motion-Compensated Data Decomposition (MCDD) algorithm is proposed to improve the performance of CS for accelerated dynamic cardiac MRI. The process of MCDD can be described as follows: first, we decompose the dynamic images into a low-rank (L) and a sparse component (S). The L component includes periodic motion in the background, since it is highly correlated among frames, and the S component corresponds to respiratory motion. A motion-estimation/motion-compensation (ME-MC) algorithm is then applied to the low-rank component to reconstruct a cardiac motion compensated dynamic cardiac MRI. With validations on the numerical phantom and in vivo cardiac MRI data, we demonstrate the utility of the proposed scheme in significantly improving compressed sensing reconstructions by minimizing motion artifacts. The proposed method achieves higher PSNR and lower MSE and HFEN for medium to high acceleration factors. The proposed method is observed to yield reconstructions with minimal spatiotemporal blurring and motion artifacts in comparison to the existing state-of-the-art methods.


Prevalence and associated factors of depression among elderly patients attending the primary health clinic in Prince Mansour Military Hospital in Taif, Saudi Arabia.
Depression in the elderly is a common, debilitating, and costly condition. Little is known about the prevalence and correlates of geriatric depression in Saudi Arabia. This study evaluates the prevalence of depression among the elderly and its associated risk factors. A cross-sectional, questionnaire-based descriptive study was conducted on 259 elderly patients attending the Prince Mansour Military Hospital emergency department family medicine clinic in Taif city. Geriatric Depression Scale (GDS) was used. The mean score was 4.4 (standard deviation [SD] = 2.56), ranging between 0 and 13. The median GDS score was 4. According to the results of this study, Cronbach's alpha for the GDS was 0.61 (95% confidence interval: 0.54-0.68). The prevalence of depression among the study participants was 43.2%. According to the GDS score categorization, 36.3% were mildly depressed, 4.2% were moderately depressed, and 2.7% were severely depressed. The adjusted effect was statistically significant for male gender (odds = 0.39, P < 0.001), older age (odds = 1.11, P = 0.007), diabetes mellitus (odds = 3.04, P = 0.02), asthma (odds = 25.94, P < 0.001), and renal failure (odds = 114.27, P = 0.03). Identification and treatment of geriatric depression should be prioritized by the family physicians in Saudi Arabia. Further research should focus on designing better culture-friendly geriatric depression screening tools.


Confined-microtubule assembly shapes three-dimensional cell wall structures in xylem vessels.
Properly patterned deposition of cell wall polymers is prerequisite for the morphogenesis of plant cells. A cortical microtubule array guides the two-dimensional pattern of cell wall deposition. Yet, the mechanism underlying the three-dimensional patterning of cell wall deposition is poorly understood. In metaxylem vessels, cell wall arches are formed over numerous pit membranes, forming highly organized three-dimensional cell wall structures. Here, we show that the microtubule-associated proteins, MAP70-5 and MAP70-1, regulate arch development. The map70-1 map70-5 plants formed oblique arches in an abnormal orientation in pits. Microtubules fit the aperture of developing arches in wild-type cells, whereas microtubules in map70-1 map70-5 cells extended over the boundaries of pit arches. MAP70 caused the bending and bundling of microtubules. These results suggest that MAP70 confines microtubules within the pit apertures by altering the physical properties of microtubules, thereby directing the growth of pit arches in the proper orientation. This study provides clues to understanding how plants develop three-dimensional structure of cell walls.


Postnatal development of the cat's retina: a concept of maturation obtained by qualitative and quantitative examinations.
From a coherent morphological and morphometrical investigation of the postnatal development of the cat's retina, some main aspects are presented concerning the structures lying outside the outer limiting membrane, the neuropile layers and the nuclear layers. It is shown by means of qualitative and quantitative results, that the maturation process of the various cellular elements in the cat's retina can be devided into three phases and is presumably finished between the 4th to the 5th month of life.


Dementia and behavioral neurology: recent advances.
In this review, progress in dementia and behavioral neurology research published in the Journal of Neurology during the past year is summarized.


Wormholes in virtual space: From cognitive maps to cognitive graphs.
Humans and other animals build up spatial knowledge of the environment on the basis of visual information and path integration. We compare three hypotheses about the geometry of this knowledge of navigation space: (a) 'cognitive map' with metric Euclidean structure and a consistent coordinate system, (b) 'topological graph' or network of paths between places, and (c) 'labelled graph' incorporating local metric information about path lengths and junction angles. In two experiments, participants walked in a non-Euclidean environment, a virtual hedge maze containing two 'wormholes' that visually rotated and teleported them between locations. During training, they learned the metric locations of eight target objects from a 'home' location, which were visible individually. During testing, shorter wormhole routes to a target were preferred, and novel shortcuts were directional, contrary to the topological hypothesis. Shortcuts were strongly biased by the wormholes, with mean constant errors of 37° and 41° (45° expected), revealing violations of the metric postulates in spatial knowledge. In addition, shortcuts to targets near wormholes shifted relative to flanking targets, revealing 'rips' (86% of cases), 'folds' (91%), and ordinal reversals (66%) in spatial knowledge. Moreover, participants were completely unaware of these geometric inconsistencies, reflecting a surprising insensitivity to Euclidean structure. The probability of the shortcut data under the Euclidean map model and labelled graph model indicated decisive support for the latter (BFGM>100). We conclude that knowledge of navigation space is best characterized by a labelled graph, in which local metric information is approximate, geometrically inconsistent, and not embedded in a common coordinate system. This class of 'cognitive graph' models supports route finding, novel detours, and rough shortcuts, and has the potential to unify a range of data on spatial navigation.


Long-term functional outcomes after robotic vs. retropubic radical prostatectomy in routine care: a 6-year follow-up of a large German health services research study.
To compare long-term functional outcomes after robotic vs. retropubic RP for patients with localized prostate cancer in routine care. "HAROW" was a large German noninterventional health services research study that prospectively evaluated the treatment of patients with localized prostate cancer (≤ T2c). We sent validated questionnaires to 1260 patients who underwent RP to evaluate long-term outcomes. After a median follow-up of 6.3 [interquartile range (IQR) 4.8-7.6] years, 42 (3%) patients had died. The return rate of the questionnaire was 76.8% (936/1218). The approach was robotic in 404 and retropubic in 532 patients. In the multivariate analysis, lack of postoperative radiotherapy [odds ratio (OR) 3.1], younger patient age (< 60 years: OR 2.8; 60-69 years: OR 2.1), preoperative urinary continence (OR 2.4), and higher annual hospital caseload (≥ 200 cases: OR 1.6) were independent predictors of urinary continence. The potency rate after nerve-sparing RP in preoperatively potent men was 40.5% (111/274). In the multivariate analysis, younger patient age (< 60 years: OR 17.9; 60-69 years: OR 8.0), lower oncologic risk (OR 2.8), and lack of postoperative radiotherapy (OR 2.2) were independent predictors of potency. Younger age and lack of postoperative radiotherapy were associated with better urinary continence and erectile function. Additionally, a high annual caseload (≥ 200 RP/year) was associated with better urinary continence. Younger age, low or intermediated oncological risk and lack of postoperative radiotherapy were independent predictors for a trifecta outcome. The surgical approach did not affect long-term functional outcomes.


Adolf von Strümpell: a key yet neglected protagonist of neurology.
German internist and neurologist Adolf von Strümpell (1853-1925) was a leading figure in German neurosciences around 1900 and helped to establish neurology as a discipline in its own right. He made contributions that were crucial to the development of the subject and in many cases his were the first descriptions of complex diseases such as Bechterew disease (ankylosing spondylitis), primary lateral sclerosis, hereditary spastic paraplegia, and syphilis. His Textbook of Special Pathology and Therapy of Internal Diseases, published in English as Text-book of Medicine for Students and Practitioners, and in particular the subvolume on neurological diseases, were the guiding manuals for the training in neurology for decades. However, despite his pioneering achievements, his name has almost become unknown within medical terminology. This article, therefore, wishes to revive an awareness not only of the most important stages in Strümpell's life in Erlangen, Leipzig, Breslau (Wrocław), and Vienna, but also of his scientific achievements, focusing primarily on his neurological studies. To this end, the article reviews his most important publications on the subject and seeks to evaluate their and hence Strümpell's impact on the understanding of certain illnesses.


Gastrin effects on growth and exocrine secretion in the neonatal rat pancreas.
In adult rats, cholecystokinin (CCK) binds to pancreatic CCK-A receptors and stimulates exocrine secretion and pancreatic growth. In newborn rats there is very little mature intestinal CCK and few pancreatic CCK-A receptors. However, there is an abundant source of the related peptide gastrin, and in addition, there are pancreatic CCK-B/gastrin receptors. In this study, we have explored the hypothesis that gastrin may "deputise" for CCK in the neonate and cause pancreatic exocrine secretion, growth, and maturation. Newborn rats were injected intraperitoneally with the gastrin antagonist, C1-988, or placebo for 5 days and sacrificed on day 6. Body weight (CI-988, 8.25 +/- 0.48 g; placebo, 10.17 +/- 0.93 g) and pancreatic weight (19.41 +/- 1.5 vs. 21.58 +/- 1.72 mg) were the same. Protein (1,202 +/- 78 vs. 1,254 +/- 56 micrograms), amylase (22.3 +/- 0.9 vs. 19.2 +/- 1.00 U), RNA (117 +/- 7 vs. 126 +/- 5 micrograms), and DNA (95 +/- 8 vs. 100 +/- 7 micrograms) contents of the pancreas were similar in the two groups. The weight of the stomach was reduced (p = 0.04) in the treated group (50.8 +/- 2.5 mg) compared to the placebo group (59.8 +/- 3.7 mg). In both neonates and adults, CCK-8 was approximately 1,000 times more potent than gastrin-17 in stimulating amylase release from isolated pancreatic acini. This suggests that enzyme release is probably mediated by the same receptors in both adults and neonates, and in adults previous work has shown this to be the CCK-A receptor. In conclusion, these data show that gastrin has very weak effects on neonatal pancreatic exocrine secretion, and furthermore, gastrin is not essential for growth and maturation of the neonatal pancreas. The role of gastrin and CCK-B/gastrin receptors in the neonatal pancreas remains speculative.


Pharmacokinetics in mice and metabolism in murine and human liver fractions of the putative cancer chemopreventive agents 3',4',5',5,7-pentamethoxyflavone and tricin (4',5,7-trihydroxy-3',5'-dimethoxyflavone).
The flavones tricin (4',5,7-trihydroxy-3',5'-dimethoxyflavone) and 3',4',5',5,7-pentamethoxyflavone (PMF) are under development as potential colorectal cancer chemopreventive agents as they reduced adenoma development in the Apc(Min) mouse model of intestinal carcinogenesis. Here, the pharmacokinetic properties and metabolism of these flavones after oral administration were compared in mice. C57BL/6 J mice received an oral bolus of PMF or tricin (807 μmol/kg). Parent flavone and metabolites were analyzed by HPLC/UV in plasma, liver and gastrointestinal tissues. Flavones were incubated with mouse or human hepatic microsomes or 9000xg supernatant (S9), both fortified with a NADPH-generating system and either uridine 5'-diphosphoglucuronic acid (UDPGA, microsomes) or 3'-phosphoadenosine-5'-phosphosulfate (PAPS, S9). Disappearance of substrate was assessed by HPLC/UV, metabolites were characterized by HPLC/MS/MS. Plasma concentrations and area under the plasma concentration versus time curve for PMF were higher than those for tricin. A mono-O-desmethyl PMF and several isomeric mono-O-desmethyl PMF glucuronides and sulfonates were major PMF metabolites in murine plasma, liver and intestinal tissue. In murine and human liver fractions, in vitro metabolic removal of tricin was faster than that of PMF. On kinetic analysis of metabolite generation in these incubations, apparent maximal velocity (V(max)) values for the generation of tricin O-glucuronide or O-sulfonate were consistently several fold higher than those characterizing the production of mono-O-desmethyl PMF glucuronides or sulfonates via the intermediacy of O-desmethyl PMF. The results suggest that inclusion of methoxy moieties confers metabolic stability onto the flavone scaffold.


A comparative study of virus isolation, polymerase chain reaction, and antigen detection in children of mothers infected with human immunodeficiency virus.
We report on an investigation designed to compare the polymerase chain reaction (PCR) with culture and p24 measurement for the diagnosis of human immunodeficiency virus (HIV) infection in infants and children. Forty-five children born of mothers with antibodies to HIV type 1 were studied; P24 antigen was measured in plasma, and HIV-1 proviral DNA was sought in peripheral blood mononuclear cells after amplification by PCR. In 26 cases, blood specimens were cultured for HIV; in all but two instances cultures were established at the same time that the PCR test was performed. Primer pairs in three regions of the proviral genome were used for the PCR test. There was good agreement between the results obtained from PCR tests and from cultures; of 24 children in whom both tests were done at the same time, 10 had positive results on both the culture and the PCR test, 1 had positive results on the PCR test but negative culture results, and 13 had negative results on both tests (concordance 96%). Measurement of p24 antigen in plasma was, in contrast, an insensitive marker of infection: 6 of 12 infants with positive cultures had positive p24 test results, and 8 of 18 infants had positive PCR test results. Sixteen children with subsequent seronegativity for HIV-1 had negative PCR results. This study provides further evidence that the PCR test is a valid alternative to viral culture for the diagnosis of pediatric HIV infection.


A new synthesis of d-lyxose from d-arabinose.
A new synthesis of rare d-lyxose from easily available d-arabinose is disclosed. The route includes 7 steps with a total 40% yield. Inversion of configuration at C3 promoted by DAST reagent is utilized on trans-2,3-di-hydroxy pentofuranose to provide cis-2,3-di-hydroxy pentofuranose, which is hardly synthesized using normal method.


Development of primer-special TaqMan PCR: a novel SNP detection method to detect CYP2C9 3 in South Chinese.
CYP2C9 3 (1075A/C) is an inherited single nuclear polymorphism (SNP) of cytochrome P450 (CYP) 2C9, which affects the activity of the enzyme. In vitro studies with several drugs have indicated that the CYP2C9 3 variant has an impaired capacity for drug metabolism. Therefore an efficient detection assay for this mutation may be important for clinical dose adjustment. The aim of this work was to develop an appropriate tool for detection of the CYP2C9 3 polymorphism in the clinical laboratory. The previously described TaqMan mismatch amplification mutation assay (TaqMAMA) was modified to a primer-special (PS)-TaqMan PCR to satisfy the high-throughput requirements of a clinical laboratory. 404 genomic DNA samples from South Chinese individuals were genotyped to test the detection system. The results were checked by bi-directional sequencing. PS-TaqMan PCR could correctly genotype the CYP2C9 allele from a genomic template at a concentration of 1 x 104 to 1 x 1011 copies/PCR. Among the 404 genomic DNA samples, 24 heterozygotes and 380 wild-type homozygotes were detected and confirmed by bi-directional sequencing. PS-TaqMan PCR was successfully developed for CYP2C9 3 detection. This efficient, reliable, high-throughput tool could satisfy the requirements of a clinical laboratory test.


Associations between a history of binge drinking during adolescence and self-reported responses to alcohol in young adult Native and Mexican Americans.
Binge drinking during adolescence is common and may predict increased drinking in young adulthood and enhanced risk of alcohol dependence. Variation in level of response to the hedonic and adverse effects of alcohol is in part an inherited factor that may also influence its use, abuse, and dependence. This study investigated, in young adults, whether an association could be demonstrated between variation in self-reported responses to alcohol and a history of binge drinking during adolescence. Young adult (18 to 30 years, n = 790) Native Americans and Mexican Americans were recruited from the community and completed a structured diagnostic interview. Response to alcohol was indexed using the expectation version of the Subjective High Assessment Scale (SHAS-E). An adolescent history of regular binge drinking was defined as drinking 5 or more drinks for boys and 4 or more drinks for girls per drinking occasion at least once a month during their highest drinking period prior to the age of 18. An adolescent history of regular binge drinking was found to be associated with a lower level of self-reported responses to the negative aspects of alcohol intoxication (feeling terrible) as well as to the overall level of intoxication, but not to the positive impressions of intoxication (feeling great) on the SHAS-E. A history of regular adolescent binge drinking was also correlated with less feelings of the "terrible" and "total" effects of alcohol, as indexed by the SHAS-E, in a linear regression model that included several diagnostic and demographic variables such as a history of conduct disorder and current levels of drinking. These data suggest that a history of adolescent binge drinking is associated with a reduction in the self-reported level of intoxication in young adulthood, a factor that could theoretically lead to increased risk of alcohol dependence.


Long-term followup of buccal mucosa onlay graft for hypospadias repair: analysis of complications.
We review the long-term results of buccal mucosa onlay grafting for urethral reconstruction in hypospadias surgery in patients with followup of at least 5 years. We retrospectively evaluated 132 patients who underwent buccal mucosa onlay graft for hypospadias repair, including 34 who underwent "salvage" grafting, during a 10-year period at our institution. In 49 cases with available followup longer than 5 years (average 6.2) complications were analyzed in detail. The overall complication rate was 24% (12 of 49 patients), with all but 3 complications occurring during the first postoperative year (3 fistulas, 1 stricture, 1 meatal stenosis, 2 graft contractures, 2 scars at oral harvesting site). The remaining 3 complications manifested during postoperative years 2 and 3, and encompassed 2 anastomotic strictures at the proximal anastomosis and 1 meatal stenosis. Buccal mucosa onlay grafts for urethral reconstruction in hypospadias repair seem to provide stable long-term results, with complications occurring primarily during the first 12 months postoperatively.


Four new bi-phenylethylchromones from artificial agarwood.
Four new bi-phenylethylchromones (1-4) were isolated from the EtOAc extract of artificial agarwood induced by holing method originating from Aquilaria sinensis (Lour.) Gilg. The structures of new compounds were unambiguously elucidated by one- and two-dimensional NMR and HRESIMS measurements, and the absolute configuration was determined by analysis of circular dichroism (CD) spectra. All compounds were tested for acetylcholinesterase (AChE) inhibitory activity using modified Ellman's colorimetric method and α-glucosidase inhibitory activity using PNPG method. Compounds 2-4 exhibited different levels of inhibitory activity against AChE with the inhibition ratios in the range of 10-45%. However, none of the compounds was active against the α-glucosidase.


Proposed ACGME change in length of radiology residency training before independent call: results of a survey of program directors and chief residents.
To assess radiology residency program directors' and chief residents' views regarding the Radiology Residency Review Committee's proposed revision of program requirements which would delay independent call until a resident has had 12 months of radiology training. A Web-based survey was distributed electronically to the program directors and chief residents of 188 radiology residency programs. Survey responses were collected for two weeks in November-December 2006. The survey was completed by 91 Program Directors and 165 Chief Residents. There were no statistically significant differences between the two groups of respondents on any of the 9 questions pertaining to the proposed call requirement change. Approximately 70% of the program directors and 80% of the chief residents disagreed or disagreed strongly that they were in favor of the proposed ACGME change. Strong opposition to the change was independent of both program size and current compliance with the proposed change. Over 70% in both groups disagree or strongly disagree that the proposed change would positively affect residency training. The majority of survey respondents oppose changing the minimum required length of radiology residency training prior to residents' providing independent on-call radiology interpretations from 6 months to 12 months.


Genetic structure and phylogeography of Aedes aegypti, the dengue and yellow-fever mosquito vector in Bolivia.
Between the 16th and 18th centuries, Aedes aegypti (Diptera: Culicidae), a mosquito native to Africa, invaded the Americas, where it was successively responsible for the emergence of yellow fever (YF) and dengue (DEN). The species was eradicated from numerous American countries in the mid-20th century, but re-invaded them in the 1970s and 1980s. Little is known about the precise identities of Ae. aegypti populations which successively thrived in South America, or their relation with the epidemiological changes in patterns of YF and DEN. We examined these questions in Bolivia, where Ae. aegypti, eradicated in 1943, re-appeared in the 1980s. We assessed the genetic variability and population genetics of Ae. aegypti samples in order to deduce their genetic structure and likely geographic origin. Using a 21-population set covering Bolivia, we analyzed the polymorphism at nine microsatellite loci and in two mitochondrial DNA regions (COI and ND4). Microsatellite markers revealed a significant genetic structure among geographic populations (F(ST)=0.0627, P<0.0001) in relation with the recent re-expansion of Ae. aegypti in Bolivia. Analysis of mtDNA sequences revealed the existence of two genetic lineages, one dominant lineage recovered throughout Bolivia, and the second restricted to rural localities in South Bolivia. Phylogenic analysis indicated that this minority lineage was related to West African Ae. aegypti specimens. In conclusion, our results suggested a temporal succession of Ae. aegypti populations in Bolivia, that potentially impacted the epidemiology of dengue and yellow fever.


Dance Improves Motor, Cognitive, and Social Skills in Children With Developmental Cerebellar Anomalies.
In this multiple single-cases study, we used dance to train sensorimotor synchronization (SMS), motor, and cognitive functions in children with developmental cerebellar anomalies (DCA). DCA are rare dysfunctions of the cerebellum that affect motor and cognitive skills. The cerebellum plays an important role in temporal cognition, including SMS, which is critical for motor and cognitive development. Dancing engages the SMS neuronal circuitry, composed of the cerebellum, the basal ganglia, and the motor cortices. Thus, we hypothesized that dance has a beneficial effect on SMS skills and associated motor and cognitive functions in children with DCA. Seven children (aged 7-11) with DCA participated in a 2-month dance training protocol (3 h/week). A test-retest design protocol with multiple baselines was used to assess children's SMS skills as well as motor, cognitive, and social abilities. SMS skills were impaired in DCA before the training. The training led to improvements in SMS (reduced variability in paced tapping), balance, and executive functioning (cognitive flexibility), as well as in social skills (social cognition). The beneficial effects of the dance training were visible in all participants. Notably, gains were maintained 2 months after the intervention. These effects are likely to be sustained by enhanced activity in SMS brain networks due to the dance training protocol.


Dengue disease dynamics are modulated by the combined influences of precipitation and landscape: A machine learning approach.
Dengue is an endemic vector-borne disease influenced by environmental factors such as landscape and climate. Previous studies separately assessed the effects of landscape and climate factors on mosquito occurrence and dengue incidence. However, both factors concurrently coexist in time and space and can interact, affecting mosquito development and dengue disease transmission. For example, eggs laid in a suitable environment can hatch after being submerged in rain water. It has been difficult for conventional statistical modeling approaches to demonstrate these combined influences due to mathematical constraints. To investigate the combined influences of landscape and climate factors on mosquito occurrence and dengue incidence. Entomological, epidemiological, and landscape data from the rainy season (July-December) were obtained from respective government agencies in Metropolitan Manila, Philippines, from 2012 to 2014. Temperature, precipitation and vegetation data were obtained through remote sensing. A random forest algorithm was used to select the landscape and climate variables. Afterward, using the identified key variables, a model-based (MOB) recursive partitioning was implemented to test the combined influences of landscape and climate factors on ovitrap index (vector mosquito occurrence) and dengue incidence. The MOB recursive partitioning for ovitrap index indicated a high sensitivity of vector mosquito occurrence on environmental conditions generated by a combination of high residential density areas with low precipitation. Moreover, the MOB recursive partitioning indicated high sensitivity of dengue incidence to the effects of precipitation in areas with high proportions of residential density and commercial areas. Dengue dynamics are not solely influenced by individual effects of either climate or landscape, but rather by their synergistic or combined effects. The presented findings have the potential to target vector surveillance in areas identified as suitable for mosquito occurrence under specific climatic conditions and may be relevant as part of urban planning strategies to control dengue.


Functional crosstalk of the glycine transporter GlyT1 and NMDA receptors.
NMDA-type glutamate receptors (NMDARs) constitute one of the main glutamate (Glu) targets in the central nervous system and are involved in synaptic plasticity, which is the molecular substrate of learning and memory. Hypofunction of NMDARs has been associated with schizophrenia, while overstimulation causes neuronal death in neurodegenerative diseases or in stroke. The function of NMDARs requires coincidental binding of Glu along with other cellular signals such as neuronal depolarization, and the presence of other endogenous ligands that modulate their activity by allosterism. Among these allosteric modulators are zinc, protons and Gly, which is an obligatory co-agonist. These characteristics differentiate NMDARs from other receptors, and their structural bases have begun to be established in recent years. In this review we focus on the crosstalk between Glu and glycine (Gly), whose concentration in the NMDAR microenvironment is maintained by various Gly transporters that remove or release it into the medium in a regulated manner. The GlyT1 transporter is particularly involved in this task, and has become a target of great interest for the treatment of schizophrenia since its inhibition leads to an increase in synaptic Gly levels that enhances the activity of NMDARs. However, the only drug that has completed phase III clinical trials did not yield the expected results. Notwithstanding, there are additional drugs that continue to be investigated, and it is hoped that knowledge gained from the recently published 3D structure of GlyT1 may allow the rational design of more effective new drugs. This article is part of the Special Issue on "The receptor-receptor interaction as a new target for therapy".


Effect of clinical pharmacists' interventions on dementia treatment adherence and caregivers' knowledge.
Poor adherence with dementia medications is common among patients and caregivers, owing to the absence of perceived effect, polypharmacy, and adverse effects. The aim of this study was to evaluate the effect of clinical pharmacists' interventions on the adherence to dementia treatment and the caregivers' knowledge of dementia. This study was conducted at a geriatric outpatient clinic of the university hospital between October 2018 and April 2019. The Morisky Green Levine Adherence Scale (MGLS) to patients or caregivers and the Dementia Knowledge Assessment Tool Version Two (DKAT2) to caregivers were applied at the beginning of the study and 4 months later by a clinical pharmacist. After the scales were applied in the first interview, verbal information about the importance of adherence to dementia treatment, and incorrect answers of caregivers in DKAT2 were provided by the clinical pharmacist. A total of 94 patients and 91 caregivers were included in the study. High adherence to treatment was determined in 70.2% of the patients in the first interview and in 95.7% in the second interview (P < 0.001). The mean score of DKAT2 was 15.53 ± 2.44 in the first interview, while the median score of DKAT2 in the second interview was 19.11 ± 1.25 (P < 0.001). The intervention of clinical pharmacists significantly increased the adherence to dementia treatment and the caregivers' knowledge of dementia. Close monitoring of dementia patients and caregivers by clinical pharmacists and collaboration with a multidisciplinary team play an important role in dementia care. Geriatr Gerontol Int 2021; 21: 506-511.


Axial spondyloarthritis: concept, construct, classification and implications for therapy.
The axial spondyloarthritis (axSpA) disease concept has undergone substantial change from when the entity ankylosing spondylitis was defined by the modified New York criteria in 1984. Developments in imaging, therapy and genetics have all contributed to changing the concept of axSpA from one of erosions in the sacroiliac joints to a spectrum of disease with and without changes evident on plain radiographs. Changes to the previously held concept and construct of the disease have also necessitated new classification criteria. The use of MRI, primarily of the sacroiliac joints, has substantially altered the diagnosis and differential diagnosis of axSpA. Many in the axSpA community believe that the current classification criteria lack specificity, and the CLASSIC study is underway to examine this area. Although much about the evolving axSpA disease concept is universally agreed, there remains disagreement about operationalizing aspects of it, such as the requirement for the objective demonstration of axial inflammation for the classification of axSpA. New imaging technologies, biomarkers and genetics data will probably necessitate ongoing revision of axSpA classification criteria. Advances in our knowledge of the biology of axSpA will settle some differences in opinion as to how the disease concept is applied to the classification and diagnosis of patients.


An Integrated Approach to Mandarin Processing: Food Safety and Nutritional Quality, Consumer Preference, and Nutrient Bioaccessibility.
Mandarins are a member of the Citrus genus and are the focus of growing commercial interest, with satsuma mandarins (Citrus unshiu) and the common mandarin (Citrus reticulata Blanco) being the most important mandarin varieties. The possible health benefits and functional properties of those fruits are often associated with the antioxidative function of vitamin C, carotenoids, and phenolic compounds. While most mandarins are consumed fresh, many are processed into juices (mostly cloudy), usually via thermal processing which can lead to the creation of off-flavors and may diminish nutritional quality. The aim of this review is to summarize the most significant and recent information on the safety, sensorial properties, and nutritional benefits of mandarins and their processing into juice. The article also discusses recent information regarding the bioaccessibility of valuable, mandarin specific, compounds.


Amino acid sequence around a hormonogenic tyrosine residue in the N-terminal region of human thyroglobulin after in vivo and in vitro iodination.
Reduced and S-alkylated human thyroglobulin (hTgb), normally iodinated, was previously shown by SDS/PAGE to contain a small peptide (Mr 26 000) rich in thyroxine. This peptide was not found when very poorly iodinated hTgb was treated under the same conditions but was present after iodination in vitro. Peptide 26 K was purified from in vivo and in vitro iodinated hTgb. The study of these peptides shows that: 1/ at the iodination levels studied (0.18 and 0.25% iodine) one of the preferential hormonogenic sites is the same in hTgb iodinated both in vivo and in vitro; 2/ the amino acid sequence around the thyroxine residue: Asn-Ile-Phe-Glu-T4-Gln-Val is identical with the previously described hormonogenic site of bovine thyroglobulin. Most probably the hormone-containing peptide 26 K is the N-terminal peptide of the hTgb chain.


Economic perspectives on injecting drug use.
Injecting drug use (IDU) has traditionally been seen as a law enforcement problem and a stain on society. With the emergence of human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), however, the discourse on IDU has widened to include crucial public health and human rights concerns. Economic analysis, too, has much to contribute to the policy debate. By examining the costs and benefits of drug use from the perspective of injecting drug users, economic analysis can shed light on the problem of IDU and the transmission of HIV among users. This chapter also presents new results on the economic analysis of needle exchange programmes.


Mental health problems of black and white children in a nationally representative epidemiologic survey.
Black children face more numerous socio-economic disadvantages than White children, but whether they have more adverse mental health problems remains understudied. Using nationally-representative data from the 2018-2019 National Survey of Children's Health, we examined differences in mental health problems between non-Hispanic Black (n = 2,890) and White (n = 30,015) children aged 6-17. Multivariate analyses were used to determine whether differences in mental health conditions could be accounted for by other factors. We found Black children were significantly less likely than White children to have clinically-identified internalizing conditions (especially anxiety) and more likely to be identified with conduct problems. Black children were also substantially more likely to have greater exposure to adverse childhood experiences (ACEs), to be uninsured, experience poverty, and less likely to receive needed mental health services. After adjusting for these potential confounders, Black children remained half as likely to have clinically-recognized internalizing conditions, but were no longer more likely to have clinically-identified conduct problems. Differences in ACEs alone fully accounted for the racial difference in conduct problems. These results point to the potential impact of assessment bias by clinicians and underscore the potential benefit of routine screening for depression/anxiety in racial/ethnic minority children, especially in light of rising suicide rates among Black youth.