Crystal structure of the monoclinic phase (phase IV) of bis-(tetra-methyl-ammonium) tetra-chlorido-cuprate(II).
The crystal structure of the low-temperature monoclinic phase of the title compound, [(CH3)4N]2[CuCl4], was determined at 120 K. The structure of the room-temperature phase has been determined in the ortho-rhom-bic space group Pmcm [Morosin & Lingafelter (1961 ▸). J. Phys. Chem. 50-51; Clay et al. (1975 ▸). Acta Cryst. B31 289-290]. The asymmetric unit consists of one discrete tetra-chlorido-cuprate anion with a distorted tetra-hedral geometry and two tetra-methyl-ammonium cations. In the crystal, the cations and the anions are linked via weak C-H⋯Cl hydrogen bonds.


Investigation of plasma von Willebrand factor and circulating platelet aggregating activity in mitomycin C-related hemolytic-uremic syndrome.
We have studied the ability of the plasma to induce aggregation of both homologous and heterologous platelets in four patients with hemolytic-uremic syndrome (HUS) associated with chemotherapy with mitomycin C (MMC). Neither platelet aggregation was elicited by patients' plasmas nor the in vitro addition of purified von Willebrand factor (vWF) had any effect on the aggregation pattern. In addition, ristocetin-induced binding of patients' vWF to formaldehyde-fixed platelets was normal, and multimeric vWF analysis revealed a normal structure of patients' plasmatic vWF whatever the clinical stage in which it was studied. These findings suggest that, in spite of the existence of common clinical and biological features in the various forms of HUS, the pathogenesis of MMC-related HUS may be, at least in part, different from that of the other forms of HUS in which both platelet-aggregating activity and alterations in the vWF are found.


The Role of Real-World Evidence in FDA-Approved New Drug and Biologics License Applications.
The US Food and Drug Administration (FDA) is open to accepting real-world evidence (RWE) to support its assessment of medical products. However, RWE stakeholders lack a shared understanding of FDA's evidentiary expectations for the use of RWE in applications for new drugs and biologics. We conducted a systematic review of publicly available FDA approval documents from January 2019 to June 2021. We sought to quantify, by year, how many approvals incorporated RWE in any form, and the intended use of RWE in those applications. Among approvals with RWE intended to support safety and/or effectiveness, we classified whether and how those studies impacted FDA's benefit-risk considerations, whether those studies were incorporated into the product label, and the therapeutic area of the medical product. Finally, we qualified FDA's documented feedback where available. We found that 116 approvals incorporated RWE in any form, with the proportion of approvals incorporating RWE increasing each year. Of these approvals, 88 included an RWE study intended to provide evidence of safety or effectiveness. Among these 88 approvals, 65 of the studies influenced FDA's final decision and 38 were included in product labels. The 88 approvals spanned 18 therapeutic areas. FDA's feedback on RWE study quality included methodological issues, sample size concerns, omission of patient level data, and other limitations. Based on these findings, we would anticipate that future guidance on FDA's evidentiary expectations of RWE use will incorporate fit-for-purpose real-world data selection and careful attention to study design and analysis.


Identification of patients at high risk of fragility fractures in an Indian clinical setting using FRAX.
A case-control study was done to decipher whether the FRAX tool was useful in India. Several values around the mean and median of the FRAX score of the case group were assessed to calculate sensitivity, specificity, positive predictive value, negative predictive value, Youden's index and odds ratio, and to detect high-risk individuals. The Fracture Risk Assessment Tool (FRAX) appears useful to diagnose fragility fractures. The study aims to answer whether the FRAX tool has utility in India. One hundred ten cases with a history of recent fragility fractures and 84 controls with no fractures were included in the study. FRAX scores without bone mineral density (BMD), and also with it, of participants were calculated. Several cutoff FRAX scores were chosen around mean and median FRAX score of cases. The odds ratio was calculated along with sensitivity, specificity, positive predictive value, negative predictive value and Youden's index. The most ideal cutoff was chosen to construct a hypothetical model to detect individuals at high risk. The FRAX score with BMD and without BMD exhibited relatively high specificity and moderate to low sensitivity implying that FRAX scores above cutoff have diagnostic value. Cutoffs at which FRAX score without BMD exhibited high specificity (> 90%) were chosen to construct a hypothetical model. Patients with FRAX score without BMD in the intermediate range be advised dual-energy X-ray absorptiometry (DEXA) followed by recalculation of FRAX score with BMD. DEXA scan T score less than - 2.5 or FRAX score with BMD above the cutoff at which specificity was high (> 80%) were included to construct the hypothetical model. Patients with low FRAX score could be followed up. The hypothetical model was applied to the case group to analyse its detection potential. FRAX has utility in India. It cuts the cost of screening and limits the use of expensive investigation.


Different in vivo tolerogenicity of MHC class I peptides.
The efficacy of MHC class I-derived peptides to induce tolerance was tested in a cardiac transplantation model. Two 25-mer peptides from the polymorphic region of the DA class I molecule (RT1.Aa) were synthesized by F-moc chemistry and injected intrathymically or intraperitoneally into LEW (RT1.1) responder animals. Intrathymic treatment of the recipient animals with peptide 1 (residues 56-80) accompanied by intraperitoneal treatment with peptide 4 (residues 96-120) led to indefinite survival of allogeneic DA cardiac allografts (n = 7; > 100 days). The tolerogenicity of both peptides differed according to the site of inoculation, as donor-specific tolerance was only observed after administration of peptide 1 into the thymus and injection of peptide 2 into the abdominal cavity of LEW recipients, but not vice versa. Donor-specific tolerance was confirmed in vivo by grafting of full-thickness skin and in vitro by appropriate proliferation and cytotoxicity assays using donor and third-party rats. Donor-specific tolerance was associated with up-regulation of interleukin-4, transforming growth factor beta, and interleukin-10 gene expression within cardiac allografts, thus suggesting intrathymic clonal deletion and external suppression with expansion of T-helper 2-type lymphocytes as the underlying mechanisms of tolerance induction.


The OSUMMER lines: A series of ultraviolet-accelerated NRAS-mutant mouse melanoma cell lines syngeneic to C57BL/6.
An increasing number of cancer subtypes are treated with front-line immunotherapy. However, approaches to overcome primary and acquired resistance remain limited. Preclinical mouse models are often used to investigate resistance mechanisms, novel drug combinations, and delivery methods; yet most of these models lack the genetic diversity and mutational patterns observed in human tumors. Here we describe a series of 13 C57BL/6J melanoma cell lines to address this gap in the field. The Ohio State University-Moffitt Melanoma Exposed to Radiation (OSUMMER) cell lines are derived from mice expressing endogenous, melanocyte-specific, and clinically relevant Nras driver mutations (Q61R, Q61K, or Q61L). Exposure of these animals to a single, non-burning dose of ultraviolet B accelerates the onset of spontaneous melanomas with mutational patterns akin to human disease. Furthermore, in vivo irradiation selects against potent tumor antigens, which could prevent the outgrowth of syngeneic cell transfers. Each OSUMMER cell line possesses distinct in vitro growth properties, trametinib sensitivity, mutational signatures, and predicted antigenicity. Analysis of OSUMMER allografts shows a correlation between strong, predicted antigenicity and poor tumor outgrowth. These data suggest that the OSUMMER lines will be a valuable tool for modeling the heterogeneous responses of human melanomas to targeted and immune-based therapies.


Cerebellar infarction caused by vertebral artery dissection: A case report.
Vertebral artery dissection is an important cause of posterior circulation ischemic stroke in young and middle-aged people. We reported a young man with cerebellar infarction caused by dissection of the right vertebral artery. A 34-year-old man presented with intermittent dizziness, blurred vision, nausea, and transient tinnitus 10 days before admission. All these symptoms were gradually aggravated and followed by vomiting and unfavorable movement of the right limbs. All these symptoms gradually aggravated. Neurological examination on admission showed ataxia of the right limbs. Magnetic resonance imaging of the head revealed a right cerebellar infarction. High-resolution vessel wall magnetic resonance imaging showed dissection of the right vertebral artery. Whole-brain CT digital subtraction angiography revealed occlusion of the third segment (V3) of the right vertebral artery. This supports the diagnosis of vertebral artery dissection. The patient received anticoagulant treatment with warfarin. After 2 weeks of treatment, the patient showed remarkably alleviated dizziness and unfavorable movement of the right limbs. After 3 months of treatment, the modified Rankin Scale score was 0. MRI of the head revealed that the original right cerebellar focus was softened, and there were no newly formed infarct foci. When young and middle-aged patients without atherosclerotic risk factors encounter sudden dizziness, tinnitus, and unfavorable limb movement, vertebral artery dissection may be considered. Careful inquiry into the medical history may help make a final diagnosis. Further high-resolution vessel wall magnetic resonance imaging is an effective means to find arterial dissection. Early diagnosis and treatment for vertebral artery dissection has a favorable prognosis.


Transtracheal endoluminal resection of a pleomorphic adenoma occluding subglottis.
A 71-year-old male was treated for suspected bronchial asthma because of dyspnea and stridor for 3 months before presenting at our hospital. Chest computed tomogram and a laryngotracheoscopy revealed a mass occupying the subglottic cavity. Instead of a laryngotracheal resection, the tumor was extirpated from the posterior wall of the subglottis and the first two tracheal rings successfully through a vertical tracheotomy just above the life-saving trachestomy tube, and was diagnosed as pleomorphic adenoma. The patient is alive and well with no recurrent tumor 12 years after surgery, without any effect on the function of the voice or swallowing.


Genetic Structure and Asymmetric Migration of Wheat Stripe Rust Pathogen in Western Epidemic Areas of China.
Puccinia striiformis f. sp. tritici causes severe global epidemics of wheat stripe rust primarily by airborne urediniospores. Understanding long-distance migration patterns of P. striiformis f. sp. tritici is critical for disease forecasting and management. Although the western epidemic areas in China have been considered as the source of inoculum spread eastward across the country, migration pathways among different populations within the western epidemic areas are poorly understood. In this study, we investigated the population genetics of 200 P. striiformis f. sp. tritici isolates from western epidemic areas using amplified fragment length polymorphism and simple sequence repeat markers. A coalescent approach was also used to calculate the migration rates among populations. Data analyses with both marker systems indicated high genetic diversity in each regional population. The Mantel test revealed significant positive correlation between genetic and geographic distances. Both discriminant analysis of principal components and STRUCTURE analysis supported moderate population structure shaped by seasonality and geography. The calculated migration rates indicated the presence of asymmetric migration between major populations in western epidemic areas, with greater migration rates from high elevation, oversummering areas to low elevation, overwintering areas. Sichuan Basin, one of the low elevation, overwintering areas, sampled in both fall and spring, was inferred as a recipient in fall but a donor in spring. Migration among P. striiformis f. sp. tritici populations may be partly attributable to terrace farming and prevailing wind direction in different seasons. Our study provides a better understanding of fine-scale population structure and the interregional migration pattern of P. striiformis f. sp. tritici in northwestern China and will inform future rust management.


Inflammatory bowel disease: progress and current concepts of etiopathogenesis.
Over the past few years, none of the numerous conditions that are grouped under the broad designation of 'chronic inflammatory or autoimmune disorders' has undergone as much scientific and clinical progress as the two main forms of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC). Progress has occurred in all major areas relevant to IBD pathogenesis, which include the external environment, genetics, microbial factors, and the immune system. This review presents an update on the specific major advances that have occurred in each of these four areas, briefly discusses the therapeutic implications of the observed progress, and points out the additional work that needs to be accomplished in the next few years to reach a full understanding of IBD etiopathogenesis.


Enhanced recovery after surgery (ERAS) strategies: possible advantages also for head and neck surgery patients?
Enhanced recovery after surgery (ERAS) programs have recently been developed in order to reduce morbidity, improve recovery, and shorten hospital stays of surgical patients. Since the 1990 s, ERAS programs have been successfully applied in many centres, especially in northern Europe and America, to perioperative management for colorectal surgery, vascular surgery, thoracic surgery, and then also to urological and gynaecologic surgery. Purpose of this paper is to evaluate and discuss the very recent introduction of ERAS programs also in head and neck surgery. Embase and Pubmed database searches were performed for relevant published studies. There are still no reports concerning the results of the application of ERAS protocols in the head and neck field. ERAS programs, however, could offer also to head and neck surgery patients an advantage in terms of fastening recovery, reducing hospital stay, and favouring early return to daily activities after hospital discharge. Therefore, the investigation of specific ERAS protocol in head and neck surgery patients should be encouraged.


Efficient removal of Cd(II) from aqueous solution by pinecone biochar: Sorption performance and governing mechanisms.
Cadmium (Cd) is one of the most harmful and widespread environmental pollutants. Despite decades-long research efforts, the remediation of water contaminated by Cd has remained a significant challenge. A novel carbon material, pinecone biochar, was previously hypothesized to be a promising adsorbent for Cd, while so far, it has received little attention. This study evaluated the sorption capacity of pinecone biochar through isotherm experiments. Based on Langmuir model, the adsorption maximum for Cd(II) was up to 92.7 mg g-1. The mechanism of Cd(II) adsorption on pinecone biochar was also explored through both thermodynamic and kinetics adsorption experiments, as well as both solution and solid-phase microstructure characterization. The solid-solution partitioning behaviour of Cd(II) fitted best with the Tόth model while the adsorption process followed a pseudo-second-order rate, suggesting that the Cd(II) adsorption on the pinecone biochar was mainly a chemisorption process. Microstructure characteristics and mechanism analysis further suggested that coprecipitation and surface complexation were the main mechanisms of Cd adsorption by biochar. Coprecipitation occurred mainly through the forms of Cd(OH)2 and CdCO3. Our results demonstrated that pinecone biochar was an efficient adsorbent which holds a huge potential for Cd(II) removal from aqueous solution.


Standard two-compartment formulation for total parenteral nutrition in the neonatal intensive care unit: A fluid tolerance based system.
The nutrient requirements of most (pre) term newborns receiving intensive care appear to be relatively fixed. The range of optimal fluid load however, is perceived as being quite narrow and highly variable in time. We designed four amino acid-dextrose mixtures for a standardized neonatal parenteral nutrition, delivering a fixed amount of nutrients in four dilutions with water and corresponding to a fluid load of 90, 110, 130 or 170 ml/kg per day. The addition of a lipid emulsion completes the TPN. In a pilot study, we followed the weight of 30 very low birthweight infants on this parenteral nutrition. After a stabilisation period, the weight gain was found to be similar to the normal fetal weight accretion in utero. We have now infused these solutions in to more than 1000 infants, without significant complications. These formulations proved to have substantial advantages compared to the individualized prescription in terms of availability, safety and time- and cost-effectiveness.


Effects of temperature and CO2 enrichment on kinetic properties of NADP+-malate dehydrogenase in two ecotypes of Barnyard grass (Echinochloa crus-galli (L.) Beauv.) from contrasting climates.
The apparent energy of activation (E a), Michaelis-Menten constant (K mfor oxaloacetate), V max/K mratios and specific activities of NADP+-malate dehydrogenase (NADP+-MDH; EC 126.96.36.199) were analyzed in plants of Barnyard grass from Québec (QUE) and Mississippi (MISS) acclimated to two thermoperiods 28/22°C, 21/15°C, and grown under two CO2 concentrations, 350 μl l-1 and 675 μl l-1. E avalues of NADP+-MDH extracted from QUE plants were significantly lower than those of MISS plants. K mvalues and V max/K mratios of the enzyme from both ecotypes were similar over the range of 10-30°C but reduced V max/K mratios were found for the enzyme of QUE plants at 30 and 40°C assays. MISS plants had higher enzyme activities when measured on a chlorophyll basis but this trend was reversed when activities were expressed per fresh weight leaf or per leaf surface area. Activities were significantly higher in plants of both populations acclimated to 22/28°C. CO2 enrichment did not modify appreciably the catalytic properties of NADP+-MDH and did not have a compensatory effect upon catalysis or enzyme activity under cool acclimatory conditions. NADP+-MDH activities were always in excess of the amount required to support observed rates of CO2 assimilation and these two parameters were significantly correlated. The enhanced photosynthetic performance of QUE plants under cold temperature conditions, as compared to that of MISS plants, cannot be attributed to kinetic differences of NADP+-malate dehydrogenase among these ecotypes.


Mitosis detection in breast cancer histopathology images using hybrid feature space.
Breast Cancer grading is a challenging task as regards image analysis, which is normally based on mitosis count rate. The mitotic count provides an estimate of aggressiveness of the tumor. The detection of mitosis is a challenging task because in a frame of slides at X40 magnification, there are hundreds of nuclei containing few mitotic nuclei. However, manual counting of mitosis by pathologists is a difficult and time intensive job, moreover conventional method rely mainly on the shape, color, and/or texture features as well as pathologist experience. The objective of this study is to accept the atypaia-2014 mitosis detection challenge, automate the process of mitosis detection and a proposal of a hybrid feature space that provides better discrimination of mitotic and non-mitotic nuclei by combining color features with morphological and texture features. To exploit color channels, they were first selected, and then normalized and cumulative histograms were computed in wavelet domain. A detailed analysis presented on these features in different color channels of respective color spaces using Random Forest (RF) and Support Vector Machine (SVM) classifiers. The proposed hybrid feature space when used with SVM classifier achieved a detection rate of 78.88% and F-measure of 72.07%. Our results, especially high detection rate, indicate that proposed hybrid feature space model contains discriminant information for mitotic nuclei, being therefore a very capable are for exploration to improve the quality of the diagnostic assistance in histopathology.


Computational analysis of adhesion between a cancer cell and a white blood cell in a bifurcated microvessel.
Cancer is one of the diseases caused by irregular and uncontrolled growth of cells and their propagation into various parts of the body. The motion and adhesion of cancer cells in a blood vessel is a critical step in tumor progression that depends on some vascular parameters such as vessel branching. In this study, effect of microvessel branching on the bonds between a cancer cell and a white blood has been investigated as compared to an analogous problem in a straight vessel. The analysis is performed using finite elements and fluid-structure interaction methods. Moreover, the equations for adhesion of the cancer cell to white blood cell are coded in MATLAB for calculating forces between them and the code is coupled directly and simultaneously with the COMSOL software. For fluid-structure interaction analysis, it is assumed that the properties of the blood and the cells are homogeneous and the fluid is incompressible and Newtonian. Cancer cell is modeled as a rigid body and white blood cell is assumed as linear elastic. The results show that although the geometry of the vessel does not affect on the separation distance of cancer cell considerably, but at the area near a bifurcation, high fluctuations in cancer cell velocity is occurred due to increasing in number of bond formation between the cancer cell and the white blood cell. Accordingly, it can be predicted that higher concentration of adhered particles occurs near the bifurcations. Moreover, shear stress at the point of contact of the cancer cell and the white blood cell in the branched vessel is greater than that in the straight path. In addition to, the probability of breaking of the bond between the cancer cell and the white blood cell increases in the branched vessel. Through consideration in the adhesion charts of this study along with observations from medical interventions such as drug delivery to cancer patients, considerable developments on the treatment or prevention of cancer metastasis may be achieved.


Fluid accumulation within the uterine cavity reduces pregnancy rates in women undergoing IVF.
The occurrence of fluid accumulation within the uterine cavity was examined in women undergoing IVF to investigate its correlation with tubal disease and impact on the pregnancy outcome. A registry of ultrasound procedures spanning 5 years was retrospectively studied. Thirty five out of 746 (4.7%) IVF cycles were identified as having uterine fluid accumulation, and 15 (2.0%) persisted until the day of embryo transfer. Two of the 20 cycles of women with transient fluid accumulation were pregnant, and none of those with fluid retention on the day of embryo transfer conceived. The pregnancy rate was only 5.7% (2/35) in women with uterine fluid accumulation detected during IVF cycles. In contrast, the pregnancy rate was 27.1% (193/711) among women in whose cycles no fluid accumulation was detected (P = 0.0048). Uterine fluid accumulation during IVF cycles was found in 8% (18/225) of women documented with tubal factor compared with 3.3% (17/521) with non-tubal factor (P = 0.005). Fluid accumulation within the uterine cavity during the IVF transfer treatment could be observed in patients with both tubal and non-tubal factors; however, it mainly occurred in women with tubal infertility. Although it is not a common complication of IVF cycles, excessive uterine fluid is detrimental to embryo implantation.


dELL, a drosophila homologue of transcription elongation factor ELL (Eleven-nineteen Lysine rich Leukemia), is required for early development.
ELL (Eleven-nineteen Lysine rich Leukemia) is known to be an elongation factor resembling elongin for RNA polymerase II transcription. A homologue of human ELL (hELL) was identified in Drosophila melanogaster (dELL) and several cDNA clones were isolated from the embryonic cDNA library. We showed that dELL is expressed mainly in the ovaries and early embryonic stages by developmental Northern blot. dELL encodes a protein of 912 amino acids which is substantially longer than the hELL (612 aa). Immunostaining revealed that dELL was localized to nuclei in early embryos and to nuclei of nurse cells and follicle cells in the ovary suggesting its important role in early development of drosophila. To elucidate the function of this gene in drosophila, P-element mobilization was performed by utilizing a P-element inserted upstream of dELL. Southern analysis showed that isolated mutants are internal P-element deletions. These P-element deletions can now be used to isolate dELL mutations by EMS mutagenesis.


Assessment of expression levels of leptin and leptin receptor as potential biomarkers for risk of prostate cancer development and aggressiveness.
Prostate cancer (PCa) is one of the most frequently diagnosed cancers worldwide. Despite the growing evidence associating obesity and adipokines, particularly leptin and its receptors, with cancer development and progression, it is still a debatable matter in PCa. We aimed to assess the role of leptin and its receptors as potential biomarkers for the risk of PCa development and aggressiveness. In this study, 176 men were included and categorized according to an established histopathological diagnosis into three age- and BMI-matched groups. The PCa group included 56 patients while the BPH group and the control group comprised 60 men each. Serum levels of total PSA (tPSA) were assessed by ELISA and mRNA expression levels of leptin and leptin receptors were assessed by RT-PCR. Leptin and leptin receptor mRNA expression levels were significantly higher in PCa patients relative to BPH and to healthy control men. Both were overexpressed in PCa patients with aggressive and distantly metastasizing tumors compared to patients with confined tumors. Leptin receptor mRNA was an independent predictor of high Gleason score ≥ 7, distant metastasis, LN, and seminal vesicles invasion. Leptin and its receptors are suggested to be potential biomarkers for PCa; leptin receptor mRNA might predict risk and aggressiveness of PCa.


Comparison of angiographic findings, risk factors, and long term follow-up between young and old patients with a history of myocardial infarction.
We compared the angiographic findings, coronary risk factors and five years prognosis in 200 patients < or =45, and 260 patients >45 years old who where admitted with an acute myocardial infarction. We found that family history and smoking were the most common risk factors in patients < or =45 years old P<0.04, P<0.0001, respectively, and hypertension and diabetes mellitus were more prevalent in patients >45 years, P<0.00001 for both. Young patients had a higher incidence of normal coronary arteries and a lesser one of triple vessel disease in comparison with old ones P<0.001 and P<0.04, respectively. There was also a tendency for young patients to have a higher frequency of single vessel disease. The long-term prognosis was favourable in the younger age group since the survival rate was much better, as well as the quality of life. Death in the young patients seems to be very often electrical owing to sudden ventricular fibrillation, whereas death in the elderly is more often associated with congestive heart failure.


A pharmacokinetic-pharmacodynamic model for quantal responses with thiopental.
The pharmacokinetic-pharmacodynamic model developed here characterizes the relationship between simulated plasma concentrations of thiopental and two dichotomous endpoints determined at induction of anesthesia: loss of voluntary motor power (clinical endpoint), and burst suppression of the electroencephalogram (EEG endpoint). The model incorporated data from two separate thiopental patient studies: a pharmacokinetic study with 21 males, and a pharmacodynamic study with 30 males. In the pharmacodynamic study, cumulative quantal dose-response curves for the clinical and EEG endpoints were developed from observations made during a constant-rate infusion of thiopental. Population mean parameters, derived from the bolus pharmacokinetic thiopental study, were used to simulate concentration-time data for the 150 mg.min-1 thiopental infusion rate used in the dose-response study. A single biophase model incorporating the two endpoints was generated, combining the pharmacokinetic and pharmacodynamic data from the two groups. Estimates of the mean effective thiopental concentrations affecting 50% of the population (EC50S) for the clinical and EEG endpoints were 11.3 and 33.9 micrograms.ml-1, respectively. The half-time for equilibration between arterial thiopental and the effect compartment was 2.6 min. These results are in reasonable agreement with previously described quantal concentration-response data, and with pharmacodynamic models developed for graded EEG responses. Simulation of bolus doses of thiopental with the new model provided ED50s for the clinical and EEG endpoints of 265 mg and 796 mg, respectively; the dose predicted to produce loss of voluntary motor power in 90% of an adult male population was 403 mg. A model combining population pharmacokinetics with cumulative dose-response relationships could prove useful in predicting dosage regimens for those drugs with responses that are categorical.


A case series on lung deposition analysis of inhaled medication using functional imaging based computational fluid dynamics in asthmatic patients: effect of upper airway morphology and comparison with in vivo data.
Asthma affects 20 million Americans resulting in an economic burden of approximately $18 billion in the US alone (Allergies and Asthma Foundation 2000; National Center for Environmental Health (NCEH) 1999). Research studies based on differences in patient-specific airway morphology for asthma and the associated effect on deposition of inhaled aerosols are currently not available in the literature. Therefore, the role of morphological variations such as upper airway (extrathoracic) occlusion is not well documented. Functional imaging based computational fluid dynamics (CFD) of the respiratory airways for five asthmatic subjects is performed in this study using computed tomography (CT) based patient-specific airway models and boundary conditions. CT scans for 5 asthma patients were used to reconstruct 3D lung models using segmentation software. An averaged inhalation profile and patient-specific lobar flow distribution were used to perform the simulation. The simulations were used to obtain deposition for BDP/Formoterol® HFA pMDI in the patient-specific airway models. The lung deposition obtained using CFD was in excellent agreement with available in vivo data using the same product. Specifically, CFD resulted in 30% lung deposition, whereas in vivo lung deposition was reported to be approximately 31%. It was concluded that a combination of patient-specific airway models and lobar boundary conditions can be used to obtain accurate lung deposition estimates. Lower lung deposition can be expected for patients with higher extrathoracic resistance. Novel respiratory drug delivery devices need to accommodate population sub-groups based on these morphological and anatomical differences in addition to subject age.


Are sweetened drinks a gateway to alcohol, opiate and stimulant addiction? Summary of evidence and therapeutic strategies.
1. Drinks sweetened with both sugar and artificial additives lead to dopamine release at the nucleus accumbens (NAc) in rat models; the basis of experiences of pleasure in humans, resulting in impulsive binging behaviour at times. 2. Evidence from rat models show cross sensitisation between sweetened drinks, alcohol, opiates and stimulants. Therefore, it could be hypothesised that sweetened drinks could be a gateway to multiple substance abuse among humans via 'alcopops'. 3. Identification of an allelic variant of the cyclic adenosine monophosphate responsive element modulator gene (CREM), linking impulsivity and multiple substance abuse, opens up prospects of mass screening to advice on harm reduction. 4. Furthermore, therapies involving cannabinoid receptor antagonists and transcranial brain stimulation are being currently investigated; of benefit to limit binge use of sweetened drinks.


Polymorphisms Falling Within Putative miRNA Target Sites in the 3'UTR Region of SIRT2 and DRD2 Genes Are Correlated With Human Longevity.
Many studies have suggested that individual differences in aging phenotypes may be associated to polymorphisms affecting gene regulation. As single-nucleotide polymorphisms (SNPs) in the 3'-untranslated regions (3'UTR) targeted by microRNAs (miRNAs) can alter the strength of miRNA binding (and, consequently, the regulation of target genes), we wondered whether these SNPs (known as miRSNPs) affect the individual chance to become long-lived. Thus, we estimated the effect of miRSNPs falling in the 3'-untranslated regions of 140 aging-related genes on the DNA/miRNA bond. The 24 miRSNPs with the highest difference of binding energy between the two alleles were then investigated for their association with longevity by case-control analysis. Two SNPs,SIRT2-rs45592833 G/T and DRD2-rs6276 A/G, provided a significant association with human longevity, also after correcting for multiple comparisons. For both SNPs, the minor allele was associated with a significantly decreased chance to became long-lived in an allele dose-dependent manner (p= 1.090 × 10(-6)and 1.964 × 10(-4)forSIRT2 and DRD2, respectively). The results indicate that the individual aging phenotype may be affected by the variability of specific miRNA targeted regions, as shown for SIRT2 and DRD2, and may suggest further studies to analyze the variability of gene expression regulation as a modulator of aging phenotypes.


Spontaneous breakage of malleable penile prosthesis.
The reported complications of malleable penile prosthesis include infection, erosion and chronic pain. We report the first two cases of bilateral breakage of malleable penile prosthesis.


Laser-tuned whispering gallery modes in a solid-core microstructured optical fibre integrated with magnetic fluids.
A laser-assisted tuning method of whispering gallery modes (WGMs) in a cylindrical microresonator based on magnetic-fluids-infiltrated microstructured optical fibres (MFIMOFs, where MF and MOF respectively refer to magnetic fluid and microstructured optical fibre) is proposed, experimentally demonstrated and theoretically analysed in detail. The MFIMOF is prepared by infiltrating the air-hole array of the MOF using capillary action effect. A fibre-coupling system is set up for the proposed MFIMOF-based microresonator to acquire an extinction ratio up to 25 dB and a Q-factor as large as 4.0 × 10(4). For the MF-infiltrated MOF, the light propagating in the fibre core region would rapidly spread out and would be absorbed by the MF-rod array cladding to induce significant thermal effect. This has been exploited to achieve a WGM resonance wavelength sensitivity of 0.034 nm/mW, which is ~20 times higher than it counterpart without MF infiltration. The wavelength response of the resonance dips exhibit linear power dependence, and owing to such desirable merits as ease of fabrication, high sensitivity and laser-assisted tunability, the proposed optical tuning approach of WGMs in the MFIMOF would find promising applications in the areas of optical filtering, sensing, and signal processing, as well as future all-optical networking systems.


Unmet needs from the first diagnosis of cancer until the end of medical treatment: A longitudinal study.
This study aimed to examine (1) The courses of Chinese cancer patients' unmet supportive care needs (psychological, physical and daily living, health system and information, patient care and support, and sexual) from the first cancer diagnosis until the end of medical treatment; (2) The predictive role of socio-demographic and medical characteristics (i.e., age, gender, and cancer stage) in the courses of unmet needs; and (3) The associations of courses of unmet needs with courses of depressive and anxiety symptoms. A longitudinal study was performed at Shaanxi Provincial Tumour Hospital in Xi'an, China. A total of 153 heterogeneous cancer patients were assessed after the first diagnosis (T1), at the beginning (T2) and the end (T3) of the receipt of medical treatment. Latent growth curve models were used to examine the research questions. Psychological needs and health system and information needs showed a decrease over time, whereas physical needs, patient care needs and sexual needs remained stable. Younger and female patients tended to report higher levels of unmet psychological needs at T1 and experienced slower decreases from T1 to T3. Only the courses of unmet psychological needs were associated with the courses of depressive and anxiety symptoms from T1 to T3. More attention can be given to young and female cancer patients, as they were more likely to suffer from high unmet psychological needs over the disease trajectory. Future research may focus more on addressing unmet needs reported by Chinese cancer patients.


A comparison between one- and two-stage revisional gastric bypass.
The safety of performing a one-stage revision from laparoscopic adjustable gastric banding (LAGB) to laparoscopic Roux-en-Y gastric bypass (LRYGB) has been questioned. The objective of this study was to compare safety and outcomes of one-stage versus two-stage revisional LRYGB performed after failed LAGB. A retrospective analysis of all patients undergoing revisional LRYGB after failed LAGB between January 2007 and March 2017 was performed. Patients undergoing one- and two-stage revisions were compared. The primary outcome assessed was the early complication rate, while secondary outcomes included late complications, weight loss, and improvement of comorbidities. During the study period, 161 revisional LRYGB's were performed, including 121 one-stage and 40 two-stage procedures. Baseline demographic data, BMI and presence of comorbidities were similar between the groups. In patients undergoing a two-stage procedure, band slippage, port infection, and erosion were more commonly cited as indications for revision. Similar early complication rates were demonstrated between the groups. However, late complications were more common in the two-stage group (20.0% vs. 7.4%, P = 0.03), including higher rates of gastro-gastric fistula (5.0% vs. 0%, P = 0.01) and anemia (10.0% vs. 1.1%, P = 0.02). Three-fourths of the cohort had a follow-up of more than 6 months, and the two groups demonstrated similar weight loss results and improvement/resolution of comorbidities. The performance of one-stage revisional LRYGB after failed LAGB seems to be a safe procedure, with noninferior outcomes when compared to a two-stage revisional procedure. It is a valid option, except in cases of mechanical and infectious band complications.


Ultrahigh strength ductile microalloyed steel with a very low yield ratio developed by quenching and partitioning heat treatment.
In this study, a microalloyed low carbon steel was subjected to quenching and partitioning (Q&P) heat treatment processes. The primary ferrite-pearlite microstructure of the steel was transformed into a bainitic microstructure containing interlath and sporadic blocks of retained austenite. The applied heat treatment process partitioned the carbon into the retained austenite to a weight percentage of 0.136. The microalloyed low-carbon steel acquired a continuous yield with high yield strength, a gigapascal level of ultimate tensile strength (i.e., ~ 1.1 GPa), and a very low yield ratio (i.e., 0.55) while retaining reasonable ductility and toughness when compared to the preheat-treated values.


Supplementing Merino ewes with melatonin during the last half of pregnancy improves tolerance of prolonged parturition and survival of second-born twin lambs.
High preweaning mortality rates continue to limit sheep production globally, constituting a major economic and welfare concern. Greater losses in twin lambs (≥30%) compared with singletons (≥10%) are attributed primarily to lower birth weight and increased risk of intrapartum hypoxia, leading to impairment of thermoregulation, neuromotor activity, and maternal bonding behavior. Previous intensive studies demonstrated that supplementing pregnant ewes with melatonin reduced the adverse effects of fetal growth restriction and perinatal hypoxia on the neonatal brain via increased umbilical blood flow, placental efficiency, and antioxidant actions. The current study examined the effects of supplementing pregnant ewes with melatonin on lamb survival, birth weight, and behavior under intensive conditions. From gestational day (gD) 80 until parturition, pregnant singleton and twin-bearing ewes were supplemented with melatonin via a 2-mg capsule fed daily (Mel-FED, n = 61) or 18 mg subcutaneous implant (Regulin), with one implant administered at gD80 and another at gD125 (Mel-IMP, n = 60). Control ewes received no supplementation (CTL, n = 60). Ewes and lambs were monitored via video throughout parturition. Postpartum measures were taken from lambs at 4 and 24 h (live weight [LW], rectal temperature, serum immunoglobulin G, and latency to stand and suck after birth) and LW at 72 h, 7 d, marking (49.7 ± 0.2 d), and weaning (124.2 ± 0.8 d). Chi-square analysis was used to compare lamb survival between treatment groups. There were no treatment effects on singleton lamb survival. Melatonin supplementation tended to increase the proportion of twin lambs surviving from birth to weaning (Mel-FED = 85.5%; Mel-IMP = 85.9%; CTL = 72.9%; each P < 0.1). Survival of first-born twins did not differ between treatment (each ~90%, P = 0.745) but within second-born twins, survival of Mel-FED was greater than CTL (81.6 vs. 57.1%, P = 0.023), and Mel-IMP (78.1%) tended to be greater than CTL (P = 0.068). Similarly, in second-born twins exposed to prolonged parturition (≥ 90 min), survival of lambs from Mel-FED ewes was greater than CTL (86.7% vs. 42.9%, P = 0.032), while Mel-IMP was intermediate (66.7%). These data suggest that the neuroprotective actions of melatonin may improve twin lamb survival by increasing tolerance of prolonged parturition and provide a sound basis for continued testing in extensively managed sheep flocks.


Fabrication of Conductive 3D Gold-Containing Microstructures via Direct Laser Writing.
3D conductive microstructures containing gold are fabricated by simultaneous photopolymerization and photoreduction via direct laser writing. The photoresist employed consists of water-soluble polymers and a gold precursor. The fabricated microstructures show good conductivity and are successfully employed for 3D connections between gold pads.


Tranexamic acid has no advantage in head and neck surgical procedures: a randomised, double-blind, controlled clinical trial.
To assess the effect of tranexamic acid in head and neck surgical procedures. A prospective, double-blind and randomised, parallel group, placebo-controlled clinical trial was conducted. Ninety-two patients undergoing various head and neck surgical procedures were randomised. Subjects received seven infusions of coded drugs (tranexamic acid or normal saline) starting at the time of skin closure. Haematological, biochemical, blood loss and other parameters were observed by the staff, who were blinded to patients' group allocation (case or control). Patients were analysed on the basis of type of surgery. Fifty patients who had undergone surgical procedures, including total thyroidectomy, total parotidectomy, and various neck dissections with or without primary tumour excision, were included in the first group. The second group comprised 41 patients who had undergone hemithyroidectomy, lobectomy or superficial parotidectomy. There was no statistical difference in blood parameters between both groups. There was a reduction in post-operative drain volume, but this was not significant. Although this prospective, randomised, placebo-controlled clinical trial found a reduction in post-operative drain volume in tranexamic acid groups, the difference was not statistically significant between the various head and neck surgical procedure groups.


Metabotropic glutamate receptors in cultured cerebellar granule cells: developmental profile.
Excitatory amino acid (EAA)-induced polyphosphoinositide (PPI) hydrolysis was studied during the development in culture of cerebellar granule cells. The developmental pattern was similar using metabotropic glutamate (Glu) receptor (mGluR) agonists, including L-Glu, quisqualate, and trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid: The stimulation of [3H]inositol monophosphate ([3H]-InsP) formation was low at 2 days in vitro (DIV), but the response increased steeply, reaching a peak at 4 DIV, followed by a progressive decline. In contrast, carbamylcholine-induced PPI hydrolysis exhibited a plateau after a pronounced increase during the first week in vitro. At 6 DIV, but not at 4 DIV, when the activity peaked, PPI hydrolysis elicited by Glu was reduced by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, indicating that in cultured granule cells, NMDA receptors contribute to [3H]-InsP formation and that this component of the response develops relatively late. Accordingly, NMDA-induced [3H]-InsP formation, estimated under Mg(2+)-free conditions, increased markedly from very low values at 2 DIV to a plateau at 8-10 DIV. The developmental pattern of EAA-induced PPI hydrolysis was paralleled by changes in the level of an mRNA for a specific mGluR subtype (mGluR1 mRNA). RNA blot analysis performed with the pmGR1 cDNA probe revealed that the hybridization signal in RNA extracts from cultures at 1 DIV was very weak, but mGluR mRNA levels increased dramatically between 1 and 3 DIV, followed by a progressive decrease, so that by 15 DIV the mRNA levels were only approximately 10% of the values at 3 DIV.(ABSTRACT TRUNCATED AT 250 WORDS)


[Prevalence and characteristics of anemia and iron deficiency in patients hospitalized for gastrointestinal diseases in Spain].
To determine the prevalence and characteristics of anemia and iron deficiency in patients hospitalized for gastrointestinal diseases. An epidemiological, multicenter, mixed design study (retrospective review of randomized clinical records and prospective visits) conducted between February 2010 and March 2011 in 22 Spanish gastroenterology departments. Severe anemia was defined as Hb < 10g/dL, mild/moderate as Hb ≥ 10g/dL, and iron deficiency as ferritin < 30ng/ml or transferrin saturation < 16%. We included 379 patients. The mean±SD age was 57±19 years and 47% were men. The prevalence of anemia at admission was 60% (95% CI 55 to 65), and anemia was severe (Hb <10g/dl) in half the patients. The prevalence of iron deficiency was 54% of evaluable patients (95% CI 47 to 61). Gastrointestinal bleeding at admission was found in 39% of the patients, of whom 83% (121/146) were anemic. At discharge, the proportion of anemic patients was unchanged (from 60% at admission to 58% at discharge) (95% CI 53 to 63) and iron deficiency was found in 41% (95% CI 32 to 50): anemia was severe in 17% and mild/moderate in 41%. During follow-up, at 3-6 months after admission, 44% (95% CI 39 to 50) of evaluable patients continued to have iron deficiency and 28% (95% CI 23 to 32) were still anemic: 5% severe and 23% mild/moderate. The prevalence of iron deficiency was 44% (95% CI: 39-50). During admission, 50% of patients with anemia did not receive treatment. At discharge, 55% were untreated. The prevalence of anemia in patients hospitalized for gastroenterological diseases was very high. Anemia persisted in over a quarter of patients at the follow-up visit. Only half of hospitalized patients received treatment for anemia, even when the anemia was severe.


Sublingually administered scopolamine for nausea in terminally ill cancer patients.
The primary aim of this study was to clarify the effect of sublingual scopolamine on the intensity of nausea. This was an open uncontrolled study, and the study participants were cancer patients consecutively admitted to a palliative care unit in Japan. When the patients had nausea, they were administered a solution of scopolamine at 0.15 mg sublingually. The intensities of nausea were assessed using the 6-point Numerical Rating Scale (NRS 0 = no nausea to 5 = worst nausea) before and 15, 30, and 60 min after administration. Primary endpoints were (1) changes in the NRS of nausea and (2) percentage of patients who achieved a decrease in NRS of 1 or more points 15 min after treatment. Twenty-six patients were recruited for this study. The median NRS significantly decreased from 3.0 (range, 1-5) to 1.5 (0-5) after 15 min, and 84 % (n = 21) of the patients achieved a decrease in NRS of 1 or more points after 15 min. In addition, the median NRS significantly decreased from 3.0 (before) to 0 (30 min) and 0 (60 min). The percentage of patients who achieved a decrease in NRS over 1 point was 96 % (n = 25) in 30 min and 100 % (n = 26) in 60 min. Fifteen percent (n = 4) showed drowsiness. No other adverse effects were reported. Sublingually administered scopolamine may be effective for managing nausea in terminally ill cancer patients. Randomized controlled trials are promising.


Epidemic viral gastroenteritis.
Epidemic viral gastroenteritis is a significant world wide problem. In developed countries, gastroenteritis accounts for significant morbidity and loss of time from work; in the Third World it is the leading cause of mortality among infants and children. Recent technologic advances have been associated with an explosion of research activity. Two virus groups, the Norwalk-like agents and the rotaviruses, are currently accepted as causative agents of viral gastroenteritis in man. The problem of viral gastroenteritis is reviewed both from a current and a historic perspective.


Distraction by steady-state sounds: Evidence for a graded attentional model of auditory distraction.
Sound disrupts short-term retention in working memory even when the sound is completely irrelevant and has to be ignored. The dominant view in the literature is that this type of disruption is essentially limited to so-called changing-state distractor sequences with acoustic changes between successive distractor objects (e.g., "ABABABAB") and does not occur with so-called steady-state distractor sequences that are composed of a single repeated distractor object (e.g., "AAAAAAAA"). Here we show that this view can no longer be maintained. What is more, disruption by steady-state distractors is significantly reduced after preexposure to the distractor item, directly confirming a central assumption of attentional explanations of auditory distraction and parallel to what has been shown earlier for changing-state sounds. Taken together, the findings reported here are compatible with a graded attentional account of auditory disruption, and they are incompatible with the duplex-mechanism account. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Uptake of silica covered Quantum Dots into living cells: Long term vitality and morphology study on hyaluronic acid biomaterials.
Quantum Dots (QDs) are promising very bright and stable fluorescent probes for optical studies in the biological field but water solubility and possible metal bio-contamination need to be addressed. In this work, a simple silica-QD hybrid system is prepared and the uptake in bovine chondrocytes living cells without any functionalization of the external protective silica shield is demonstrated. Moreover, long term treated cells vitality (up to 14days) and the transfer of silica-QDs to the next cell generations are here reported. Confocal fluorescence microscopy was also used to determine the morphology of the so labelled cells and the relative silica-QDs distribution. Finally, we employ silica-QD stained chondrocytes to characterize, as proof of concept, hydrogels obtained from an amphiphilic derivative of hyaluronic acid (HA-EDA-C18) functionalized with different amounts of the RGD peptide.


[Echotomography in the diagnosis of pancreatic carcinoma. Its reliability in a controlled normal and pathological series of cases].
Considering the different points of view about the echotomographic findings in pancreatic carcinoma, the authors refer their results about 89 controlled cases (38 normal pancreas and 51 pancreatic carcinomas). The pancreatic space was correctly identified as normal in 37/38 cases. Echotomography also revealed the presence of 48 pancreatic carcinomas; it gave 3 false negative and 3 false positive results; in 21 cases the size of the tumour was 5 cm or less. In a large number of cases echotomography has correctly defined the extent of the lesion by evaluating its size, the secondary liver localization (95% of accuracy) and the vascular involvement (compressions on the inferior vena cava and obstruction of the splenic vein). Basing on the echotomographic findings the authors classify the pancreatic carcinoma in 2 main types.


Does employment-based private health insurance increase the use of covered health care services? A matching estimator approach.
This study estimates the effect of employment-based private health insurance (EPHI) on the use of covered health care services based on Danish survey data collected in 2009. The paper provides some of the first estimates of how EPHI affects the use of health care services in a Scandinavian context. The effect of EPHI is estimated using propensity score matching. This method is shown to provide plausible estimates given the institutional setting of EPHI in Denmark and a wide set of relevant covariates. Considering the full sample of occupationally active, it is found that EPHI does not significantly affect the probability of having had any hospitalisations, physiotherapist, chiropractor, psychologist, specialist, or ambulatory contacts within a 12 month period. Restricting the analysis to the subsample of privately employed, the estimated effects for ambulatory contacts and hospitalisation are somewhat higher and statistically significant. More precisely, it is found that EPHI increases the probability of hospitalisation from 5.1 to 8.5% and the probability of having had any ambulatory contacts from 17.9 to 23.3% among the privately employed.


UV mutagenesis in E. coli with excision repair initiated by uvrABC or denV gene products.
Mutation frequency responses produced by ultraviolet light are compared in 4 closely related strains of E. coli B/r having the same tyr(Oc) allele and different excision-repair capabilities: uvr+ (excision repair initiated by wild-type UvrABC activity), uvrA (excision repair defective), uvrA/pdenV-7 (excision repair initiated by endonuclease V of bacteriophage T4, DenV activity), and uvr+/pdenV-7 (excision repair initiated by UvrABC and DenV activities). The production of Tyr+ prototrophic mutants is classified into back-mutations and de novo or converted glutamine tRNA suppressor mutations to indicate different mutation events. Cells transformed with the plasmid pdenV-7 require larger exposures than the parent strains to produce comparable mutation frequency responses, indicating that DenV activity can repair mutagenic photoproducts. When damage reduction by UvrABC or DenV is compared for each of the specific categories of mutation, the results are consistent with the idea that pyrimidine dimers infrequently or never target back-mutations of this allele, frequently target the de novo suppressor mutations, and extensively or exclusively target the converted suppressor mutations. This analysis is based on the distinction that UvrABC-initiated excision repair recognizes dimer and non-dimer (pyrimidine (6-4) pyrimidone) photoproducts but that DenV-initiated repair recognizes only pyrimidine dimers.


Neural pathway mediating somatic evoked responses in the caudate nucleus of cats.
The course of somatic afferents to caudate nucleus (CN) was investigated. In curaized cats discrete lesions in intralaminar nuclei, n. centralis medialis (NCM) affect evoked response (ER) in CN to radial nerve stimulation. NCM lesions totally abolish these somatic responses, while after subthalamic lesions ER appear only when a high stimulus intensity is used. Lesions in the specific relay nuclei, ventralis posterior lateralis (VPL) have no effect on somatic ER in CN. Barbiturates (10 mg/kg) abolish somatic ER in CN. Stimulation of the ponto-mesencephalic reticular formation (RF) in a region where visual and somatic responses are recorded shows lowest threshold values for eliciting evoked responses in NCM and CN. The potentials in CN to RF stimulation are restricted to this nucleus and disappear in the internal capsule.


Calcium carbonate precipitation by cave bacteria isolated from Kashmir Cave, Khyber Pakhtunkhwa, Pakistan.
The participation of numerous physicochemical and biological functions maintains the evolution and expansion of the remarkable nature. Due to its vast applicability in several engineering disciplines, naturally occurring bio-mineralization or microbially induced calcium carbonate (MICP) precipitation is attracting more interest. Cave bacteria contribute to the precipitation of calcium carbonate (CaCO3 ). In the present study, soil sediments were collected from Kashmir cave, KPK, Pakistan, and plated on B4 specific nutrients limited medium for bacterial isolation and the viable bacterial count was calculated. Three bacterial strains named GSN-11, TFSN-14, and TFSN-15 were capable of precipitating CaCO3 . These bacterial isolates were identified through 16S rRNA gene sequencing and strain GSN-11 was identified as Bacillus toyonensis, TFSN-14 as Paracoccus limosus and TFSN-15 as Brevundimonas diminuta. Enhanced CaCO3 precipitation potential of these bacteria strains was observed at 25°C and pH 5. The precipitated CaCO3 was confirmed by scanning electron microscopy, X-ray powder diffraction, and Fourier transform infra-red spectroscopy. The findings showed that the precipitates were dominated by calcite, aragonite, and nanosize vaterite. Current research suggests that precipitation of CaCO3 by proteolytic cave bacteria is widespread in Kashmir cave and these bacterial communities can actively contribute to the formation of CaCO3 by enhancing the pH of the microenvironment. RESEARCH HIGHLIGHTS: Kashmir cave inhabit potentially active bacteria in terms of biogeochemical processes. Cave bacteria significantly precipitated CaCO3 . Calcite, aragonite, and nanosize vaterite were dominant in precipitates.


Effect of lipids and other substances on the adsorption of dipalmitoyl phosphatidylcholine.
The effect of various lipids, proteins, and other substances on the adsorption rate of dipalmitoyl phosphatidylcholine (DPC) was investigated. Each substance was added to a sonicated suspension of DPC in saline, and the surface pressure of the adsorbed surface film was measured using a platinum plate suspended from an electrobalance. Pure DPC adsorbed very slowly, being complete only after 8 hr; its half-adsorption time was 91.8 +/- 8.3 min. Four additives markedly reduced the half-adsorption time of DPC: dipalmitoyl phosphatidylglycerol (1.1 +/- 0.2 min), and surfactant apoprotein (0.9 +/- 0.1 min). The half adsorption times of mixtures of DPC and the other additives ranged from 15.3 +/- 1.9 to 107.8 +/- 12.1 min.


Evaluating the capability of municipal solid waste separation in China based on AHP-EWM and BP neural network.
With the increase in municipal solid waste (MSW), most cities face solid waste management issues. In this study, the analytic hierarchy process (AHP) and artificial neural network (ANN) models were improved to assess the MSW separation capability based on 18 selected indicators of solid waste separation in 15 cities in China. The entropy weight method (EWM) was used in AHP to optimize and determine the indicators and then evaluate their weights, which showed that the general public budget expenditure had the highest weight (0.5239). This implied that the MSW separation capability could be mainly influenced by government financial support. ANN based on scan optimization and machine learning methods were established (R2 = 0.9992) to predict the missing indicators. The mapping relationship between MSW separation indicators and capabilities was also significantly improved from R2 = 0.5317 to R2 = 0.9993, thereby increasing the prediction accuracy of MSW separation capabilities to 95.15%. Thus, this research provides a new avenue for MSW separation and establishes a combined model to predict the separation capability in practical applications.


Shared Decision-Making in Acute Pain Services.
The implementation of shared decision-making (SDM) in acute pain services (APS) is still in its infancies especially when compared to other medical fields. Emerging evidence fosters the value of SDM in various acute care settings. We provide an overview of general SDM practices and possible advantages of incorporating such concepts in APS, point out barriers to SDM in this setting, present common patient decisions aids developed for APS and discuss opportunities for further development. Especially in the APS setting, patient-centred care is a key component for optimal patient outcome. SDM could be included into everyday clinical practice by using structured approaches such as the "seek, help, assess, reach, evaluate" (SHARE) approach, the 3 "MAking Good decisions In Collaboration"(MAGIC) questions, the "Benefits, Risks, Alternatives and doing Nothing"(BRAN) tool or the "the multifocal approach to sharing in shared decision-making"(MAPPIN'SDM) as guidance for participatory decision-making. Such tools aid in the development of a patient-clinician relationship beyond discharge after immediate relief of acute pain has been accomplished. Research addressing patient decision aids and their impact on patient-reported outcomes regarding shared decision-making, organizational barriers and new developments such as remote shared decision-making is needed to advance participatory decision-making in acute pain services.


Do night naps impact driving performance and daytime recovery sleep?
Short, nighttime naps are used as a fatigue countermeasure in night shift work, and may offer protective benefits on the morning commute. However, there is a concern that nighttime napping may impact upon the quality of daytime sleep. The aim of the current project was to investigate the influence of short nighttime naps (<30min) on simulated driving performance and subsequent daytime recovery sleep. Thirty-one healthy subjects (aged 21-35 y; 18 females) participated in a 3-day laboratory study. After a 9-h baseline sleep opportunity (22:00h-07:00h), subjects were kept awake the following night with random assignment to: a 10-min nap ending at 04:00h plus a 10-min nap at 07:00h; a 30-min nap ending at 04:00h; or a no-nap control. A 40-min driving simulator task was administered at 07:00h and 18:30h post-recovery sleep. All conditions had a 6-h daytime recovery sleep opportunity (10:00h-16:00h) the next day. All sleep periods were recorded polysomnographically. Compared to control, the napping conditions did not significantly impact upon simulated driving lane variability, percentage of time in a safe zone, or time to first crash on morning or evening drives (p>0.05). Short nighttime naps did not significantly affect daytime recovery total sleep time (p>0.05). Slow wave sleep (SWS) obtained during the 30-min nighttime nap resulted in a significant reduction in SWS during subsequent daytime recovery sleep (p<0.05), such that the total amount of SWS in 24-h was preserved. Therefore, short naps did not protect against performance decrements during a simulated morning commute, but they also did not adversely affect daytime recovery sleep following a night shift. Further investigation is needed to examine the optimal timing, length or combination of naps for reducing performance decrements on the morning commute, whilst still preserving daytime sleep quality.


Free arterial graft with domino patch for coronary revascularization.
To improve the outcomes of coronary revascularization with free arterial grafts, we have devised a composite method that uses free arterial grafts with an arterial wall patch. After an arterial graft is anastomosed to the left external iliac artery (EIA), the EIA wall is excised (like a collar) and anastomosed to the aorta. The defect on the EIA is repaired with a vascular graft patch. Our domino patch method is simple, and it causes minimal wall thickness mismatch and allows the use of various arterial grafts anastomosed to any coronary artery. The procedures and early results are reported.


Phase III randomized trial of second-line ixabepilone versus paclitaxel or doxorubicin in women with advanced endometrial cancer.
The purpose of this multicenter, open label, randomized phase III study was to determine whether ixabepilone resulted in improved overall survival (OS) compared with commonly used single-agent chemotherapy (doxorubicin or paclitaxel) in women with locally advanced, recurrent, or metastatic endometrial cancer with at least one failed prior platinum-based chemotherapeutic regimen. Patients were randomized 1:1 to ixabepilone (40mg/m(2)), or either paclitaxel (175mg/m(2)) or doxorubicin (60mg/m(2)), every 21days. Patients that had previously received an anthracycline were randomized to ixabepilone or paclitaxel; all other patients were randomized to ixabepilone or doxorubicin. An interim analysis of futility for OS was planned. At the time of database lock, 496 patients were randomized to receive ixabepilone (n=248) or control (n=248); nine patients in the control arm were not treated. The interim analysis of futility for OS (219 events) favored the control chemotherapy arm (hazard ratio=1.3 [95% confidence interval: 1.0-1.7], stratified log rank test P=0.0397), indicating that the study would not meet its primary objective. The study was discontinued based on the interim OS results. The frequency of adverse events was comparable between the treatment arms. The study did not meet its primary objective of improving OS in the ixabepilone arm compared to the control chemotherapy arm. A favorable risk/benefit ratio was not observed for ixabepilone versus control at the time of the interim analysis. The safety results were consistent with the known safety profiles of ixabepilone and control.


Peptidyl human heart chymase inhibitors. 1. Synthesis and inhibitory activity of difluoromethylene ketone derivatives bearing P' binding subsites.
Peptidyl difluoromethylene ketone derivatives were designed to take advantage of probable additional interactions with the S' subsite of human heart chymase. They showed potent inhibitory activities against human heart chymase and were more efficient than bovine chymotrypsin.


Synthesis of chitosan nanocomposites for controlled release applications.
Chitosan (CS) was modified using hydroxyapatite (HA) and multiwalled carbon nanotubes (MWCNT) followed by crosslinking with glutaraldehyde (GA). The obtained products were characterized and investigated with thermal analysis. The modified CS suffered a slight weight loss % up to 240 °C then extensive weight loss (EWL)% up to 420 °C and a slight weight loss again until the end of measurement at 700 °C. The treatment showed more thermal stability of modified CS over the blank CS. The 20% HA modified CS showed the highest thermal stability among CS/HA composites while adding CNT to the matrix in CS/HA/CNT composites enhances their thermal stability. Ability of the modified CS to uptake metal ions was investigated by using Cu(NO3)2 where CS/HA/CNT/GA showed higher metal ion uptake than CS/HA/GA. Modified CS was preliminary checked for controlled release of 5-fluorouracil (FU), as an antitumor model drug, in aqueous media where the maximum release of FU was obtained after 48 h. This is concluding the ease of release of FU from the investigated matrices which can be arranged in the order of P111F > P121F > P211F > P311F > P221F > P321F.


Thermally induced structural organization of nanodiscs by coarse-grained molecular dynamics simulations.
Membrane scaffold proteins (MSP) nanodiscs have been extensively used in structural study of membrane proteins. In cryo-EM, an incorporation of target proteins into nanodiscs is conducted under a rapid change from cryogenic to ambient temperatures. We present a coarse-grained molecular dynamics (CGMD) study for investigating an effect of temperature on the structural organization of DPPC-nanodisc and POPC-nanodisc. A non-monotonic response of physical quantities (i.e. the lipid order parameter, nanodisc flatness, structural change, solvation property, radius of gyration) with increase in temperature (T = 200-350 K) is found to be associated with the gel-ripple-liquid crystalline phase change within nanodiscs. The reorganization of lipids upon temperature variation induced conformational changes of MSP to minimize hydrophobic exposure of the lipid membrane to an aqueous environment. Structural response to temperature is different to a certain extent between the saturated DPPC and unsaturated POPC.


Genomic insights into a multidrug-resistant Acinetobacter bereziniae strain co-carrying blaOXA-301 and blaNDM-1 from China.
Acinetobacter bereziniae has been found to cause health care-associated infections, especially in immunocompromised patients. The emergence of two carbapenemase-producing A. bereziniae strains complicates clinical management. Here, we present the genome sequence of a clinical A. bereziniae strain from China co-carrying blaOXA-301 and blaNDM-1. The genomic DNA of BZAB1 was subjected to whole-genome sequencing using the Illumina NovaSeq 6000 system and assembled using SPAdes 3.13.0. Using the resfinder database of ABRicate V1.01, antimicrobial resistance genes were identified. The Snippy application was used to carry out the phylogenetic analysis. The genome sequence of A. bereziniae BZAB1 consists of 122 contigs consisting of 4 596 983 bp. A total of nine antimicrobial resistance genes were predicted in BZAB1, including two carbapenemase genes: blaOXA-301 and blaNDM-1. Sixty-nine A. bereziniae strains can be retrieved from the National Centre for Biotechnology Information database, 29 of which possess the blaOXA-301 gene and five of which contain the blaNDM-1 gene. Only three strains carry both blaNDM-1 and blaOXA-301. It is worth noting that all three strains carrying both blaNDM-1 and blaOXA-301 are from China, two of which are clonally related to BZAB1. We report the genome sequence of a multidrug-resistant A. bereziniae strain co-carrying blaOXA-301 and blaNDM-1. A. bereziniae strains carrying various beta-lactam resistance genes have been identified sporadically over the world. Our findings could help us aid in understanding the genomic insights of this pathogen. Their future prevalence must be given more consideration.


Suppressive effect of leflunomide on rat hepatic stellate cell proliferation involves on PDGF-BB-elicited activation of three mitogen-activated protein kinases.
In this manuscript, we demonstrated that following stimulus by Kupffer cell-conditioned medium (KCM) and PDGF-BB, hepatic stellate cells (HSCs) showed significant increases in DNA synthesis and PDGFR-beta expression. Furthermore, phosphorylation of PDGFR-beta and three major members of the mitogen-activated protein kinase (MAPK) family were also significantly increased. Studies with respective neutralizing antibodies against released cytokines in conditioned medium demonstrated that PDGF-BB played an essential role in this complex activation process. Administration of A771726, leflunomide's metabolite, markedly blunted these effects. However, the combination of A771726 with any of the three MAPK inhibitors potentiated this inhibitory effect and showed completely blockage on PDGFR-beta expression and phosphorylation. Collectively, these data demonstrate that leflunomide inhibits KCM-mediated HSC proliferation via PDGFR-beta phosphorylation and the subsequent activation of the MAPK pathway. Accordingly, targeted intervention against the PDGF-BB isoform may also offer a promising therapeutic approach to liver fibrosis.


Serum procalcitonin in septic meningitis.
To evaluate the role of serum procalcitonin (PCT) in diagnosis of septic meningitis in children and its efficacy in differential diagnosis. The study included 40 children of septic meningitis admitted in pediatric ward with fever, headache, vomiting and seizure, up to 14 y of age. The diagnosis of septic meningitis was based on clinical features; physical examination, blood and cerebrospinal fluid (CSF) cytochemical findings, gram's stain and bacterial culture. Fifteen cases of aseptic meningitis admitted during same period were also included in the study, and 15 children with normal CSF were taken as control. Serum PCT was measured by ELISA Kit. Serum PCT level was significantly higher in children with septic meningitis than those with aseptic meningitis or in controls (p < 0.001). In culture and gram's stain positive 7 cases, serum procalcitonin was significantly elevated (24,768.21 ± 6,567.45 pg/mL) than aseptic meningitis(14,451.24 ± 4,266.15 pg/mL) (p < 0.001). Further its level was found significantly elevated in partially treated septic meningitis as compared to aseptic meningitis cases (p < 0.001). At optimum cut off value of ≥ 5,000 pg/mL, based on area under ROC curve, PCT showed sensitivity, specificity, positive predictive value and negative predictive value of 98.5 %, 93.5 %, 98.6 % and 93.3 % respectively. Serum PCT with cut off level of 15,000 pg/ml showed sensitivity, specificity, PPV and NPV of 92 %, 67 %, 91.4 % and 71.4 % respectively for the differentiation of septic from aseptic meningitis. Serum PCT may be used as diagnostic marker for septic meningitis and its differentiation from aseptic meningitis.


Mental health symptoms and sleep quality of asymptomatic/mild SARS-CoV-2 infected individuals during the Omicron wave of the COVID-19 pandemic in Shanghai China.
To investigate mental health symptoms (anxiety, depression, and sleep status) and their associated factors among people infected with the SARS-CoV-2 omicron variant during the quarantine period in Shanghai. To investigate the mental health symptoms among participants with SARS-CoV-2 omicron infection, an anonymous online survey questionnaire was used. The survey panel included the 9-item Patient Health Questionnaire-9 (PHQ-9), 7-item Generalized Anxiety Disorder Scale (GAD-7), Pittsburgh Sleep Quality Index (PSQI), and 22-item Ruminative Responses Scale (RRS). Group comparisons and correlation analyses were employed to explore the epidemiological characteristics of patients and factors related to depression and anxiety symptoms. A total of 960 participants completed the survey. Of the total respondents, 583 participants (60.7%) were male, and the mean (SD) age was 34.33 (9.21) years (95% CI: 33.74-34.91). The prevalence of depressive and anxiety symptoms among the participants was 13.7% (n = 151, 95% CI: 11.6%-15.7%) and 8.6% (n = 90, 95% CI: 6.9%-10.3%), respectively. Age-stratified analysis showed that the prevalence of anxiety among the 36- to 45-year-old group (12.9%; n = 35, 8.9%-16.9%) was significantly higher than that of the 18- to 15-year-old group (7.4%; n = 42, 5.3%-9.6%, p = .011). Spearman's correlation analyses showed that rumination (assessed by the RRS) was significantly and positively correlated with depression (rho = .706, p < .001) and anxiety symptoms (rho = .758, p < .001). The results suggest that female and middle-aged populations manifest higher susceptibility to mental health distress during the current Omicron wave of the COVID-19 pandemic. Population-specific psychological crisis intervention is warranted to improve the quality of epidemic prevention methods and to promote the mental well-being of the public.


Insight into the bovine milk peptide LPcin-YK3 selection in the proteolytic system of Lactobacillus species.
Antimicrobial peptides are class of small, positively charged peptides known for their broad-spectrum antimicrobial activity. Antimicrobial activities for most antimicrobial peptides have largely remained elusive, particularly in the lactic acid bacteria. However, recently our investigation using LPcin-YK3, an antimicrobial peptide from bovine milk, suggests that in vitro antimicrobial activity was reduced over 100-fold compared with pathogenic bacteria. Additionally, for the structural study of how antimicrobial peptide undergoes its reaction at the proteolytic pathway of lactic acid bacteria based on degradation assay and propidium iodide staining, we performed molecular docking for interaction between oligopeptide-binding protein A and LPcin-YK3 peptide. Given that degradation related to the LPcin-YK3 peptide in lactic acid bacteria proteolytic system, the inhibitory inactivity of LPcin-YK3 against beneficial lactic acid bacteria strains may be one of the primary pharmacological properties of recombinant peptide discovered in bovine milk. These results provide structural and functional insights into the proteolytic mechanism and possibility as a putative substrate of oligopeptide-binding protein A in respect of LPcin-YK3 peptide.


Total synthesis and absolute stereochemistry of pentenocin B, a novel interleukin-1 beta converting enzyme inhibitor.
Four possible diastereomers of pentenocin B were synthesized in a stereocontrolled manner, and the first total synthesis of a natural enantiomer of (+)-pentenocin B unequivocally established the absolute stereochemistry to be 4S,5R,6R.


[Endovascular closure of the left atrial appendage in patients with atrial fibrillation: review of modern data and own experience of application].
Atrial fibrillation (AF) is the most often disturbance of cardiac rhythm met in clinical practice. Long term therapy with anticoagulants is used for prevention of thrombi formation in left atrial appendage and consequent thromboembolism. However some patients have contraindications to this therapy. This article contains consideration of various alternative methods of prevention of thromboembolic complications in particular those 2 which are most widely used at present - percutaneous transcatheter isolation of left atrial appendage with Amplatzer Cardiac Plug () or Watchman Device. We present also data on own experience of the use of the ACP device.


RECALMIN. Four years of growth of the internal medicine units of the Spanish National Health System (2013-2016).
To compare the structure, resources and activity of the internal medicine units (IMUs) of the Spanish National Health System (SNHS) in 2013 and 2016. To analyse the differences between IMUs in 2016 by hospital size. We conducted a comparison of 2 descriptive cross-sectional studies of IMUs in general acute care hospitals of the Spanish National Health System, with data referring to 2013 and 2016. The variables were collected via an ad hoc questionnaire (RECALMIN survey). Between 2013 and 2016, the demand for care increased dramatically (with an annual average of 11% in hospital discharges and 16% in first consultations), and comorbidity slightly increased (2%). During this period, the mean productivity of IMUs increased 16.7% (0.6±0.3 vs. 0.7±0.3; P=.09), and the mean stay decreased 10% (9±2.2 vs. 8.1±2.1 days; P=.001). Progress in implementing good practices and systematic care for complex chronic patients was scarce. Both surveys found variability among IMUs and marked differences among IMUs of hospitals of different sizes. IMUs responded to the increased burden of care they supported during 2013-2016 by improving their efficiency and productivity; however, advances in implementing good practices, including care for chronic complex patients, were scare. The significant variability in the indicators of structure, activity and management models found in 2013 remained in 2016.


SerpinB1 is required for Rev-erbα-mediated protection against acute lung injury induced by lipopolysaccharide-in mice.
Acute lung injury (ALI) is a serious, life-threatening inflammation of the lungs that still lacks effective treatment. We previously showed that serine protease inhibitor B1 (SerpinB1) protects against ALI induced by orthotopic autologous liver transplantation. However, the role of SerpinB1 in lipopolysaccharide (LPS)-induced ALI and its regulatory mechanisms are not known. Wild-type (WT) and SerpinB1 knockout (KO) mice were treated with intratracheal LPS stimulation to induce ALI. Some of the WT and KO mice were injected i.p. with melatonin, a rhythm-related protein Rev-erbα agonist. The circadian rhythm in WT mice was disrupted by exposing mice to 24 h of continuous dark or light conditions after intratracheal LPS. Neutrophils were isolated from alveolar lavage fluid of WT and KO mice, and from human peripheral blood. Neutrophils were treated with LPS and melatonin. Disruption of circadian rhythm by either 24-h dark or light conditions exacerbated LPS-induced ALI and decreased expression of Rev-erbα and SerpinB1 protein in lung, whereas melatonin treatment increased SerpinB1 expression and attenuated LPS-induced ALI in WT mice, but not in KO mice. In isolated neutrophils, Rev-erbα was co-localized with SerpinB1 and bound to its promoter to trigger SerpinB1 transcription. Furthermore, LPS stimulation increased formation of neutrophil extracellular traps, which was reversed by melatonin treatment in neutrophils from WT mice, but not from KO mice. In mice, SerpinB1 is rhythmically regulated by Rev-erbα, and its down-regulation exacerbates LPS-induced ALI by inducing formation of neutrophil extracellular traps.


Comparing the Effects of SUREE Programs on People With Scapular Downward Rotation Syndrome: A Randomized Clinical Trial.
Scapular downward rotation syndrome (SDRS) is an impaired alignment that causes shoulder and neck pain. Interventions may lead to the reduction of pain intensity and joint position error (JPE) and improved range of motion (ROM). To evaluate the effects of 6-week Scapular Upward Rotation and Elevation Exercises (SUREE) with and without visual feedback on pain, ROM, and JPE in people with SDRS. Randomized control trial. Institutional practice. Forty-two young and active subjects (22.61 [1.80] y; 27 males and 15 females) with unilateral SDRS randomly assigned into 3 groups (2 intervention groups and 1 control group). SUREE without and with visual feedback programs. Pain, neck-flexion and rotation ROMs, and JPE were measured using visual analog scale (score), double inclinometer method, universal goniometer method (degrees), and a dual digital inclinometer (degrees), respectively, before and after interventions. The results showed statistically significant changes within the experimental groups in all variables except for the neck rotation ROM in the SUREE intervention without visual feedback (P < .05). However, there were no changes in the control group before and after the interventions in all dependent variables (P < .05). Also, there were no significant differences between both experimental groups concerning all dependent variables except for the rotation ROM (P < .05). The results suggest that the 6-week SUREE with and without visual feedback programs result in decreased neck pain and improved flexion ROM and JPE during active neck motions in subjects with unilateral SDRS. However, the 6-week SUREE with visual feedback may improve the neck rotation ROM in subjects with unilateral SDRS. However, further studies are needed to confirm the results of this study.


[Hepatic amebiasis: various aspects in Brazzaville].
The authors present the results of a study of 27 cases of hepatic amoebiasis observed in the general hospital of Brazzaville from the 1st January to the 30th June 1982; then they precise the various aspects of this frequent infection in Congo.


The high-riding superior aortic recess of the pericardium: MRI visualization in a child.
We report a 4-year-old child with a high-riding superior aortic recess of the pericardium, initially misdiagnosed as a possible vascular malformation. The anatomy of the pericardial recesses is reviewed.


Comparison of bacterial communities of biofilms formed on different membrane surfaces.
Bacterial biofilm communities formed on different membrane surfaces were investigated based on 16S rRNA gene sequence analysis. The biofilm communities were distinct from those of mixed-liquor and consisted mainly of Beta- and Gammaproteobacteria. Sequences of Xathomonas and Aquabacterium were mostly retrieved from the biofilm samples rather than from the mixed liquor. Furthermore, statistical analyses demonstrated the importance of a physico-chemical property of membrane, surface roughness, in structuring the bacterial biofilm communities.


Regulation of Flagellar Gene Expression in Bacteria.
The flagellum of a bacterium is a supramolecular structure of extreme complexity comprising simultaneously both a unique system of protein transport and a molecular machine that enables the bacterial cell movement. The cascade of expression of genes encoding flagellar components is closely coordinated with the steps of molecular machine assembly, constituting an amazing regulatory system. Data on structure, assembly, and regulation of flagellar gene expression are summarized in this review. The regulatory mechanisms and correlation of the process of regulation of gene expression and flagellum assembly known from the literature are described.


Synthesis, spectral studies and solvatochromic analysis of novel imidazole derivatives.
Bioactive imidazole derivatives were synthesized and characterized by spectral techniques. The photophysical properties of imidazole derivatives were studied in several solvents. The observed spectral shift is attributed to a loss of planarity in the excited state provided by the non-co-planarity of the aryl rings attached to C(2) and N(1) atoms of the imidazole ring. The observed solvatochromic shifts were analyzed in detail by Kamlet-Taft and Catalan parameters. The interaction between bioactive imidazole derivative and bovine serum albumin (BSA) was also investigated.


Incidence of human papillomavirus-related oropharyngeal cancer and outcomes after chemoradiation in a population of heavy smokers.
Incidence of human papillomavirus (HPV)-related oropharyngeal carcinomas is increasing worldwide. The purpose of this study was to report the incidence in our region, and to determine the influence of HPV status on survival among a heavy smoking population. p16 expression was analyzed in 102 patients with stage II to IV treated with chemoradiation. Overall survival (OS), locoregional control, and disease-free survival (DFS) were compared for HPV+ and HPV- status. The majority of patients were smokers (86%). p16 positivity was found in 26.7%. Patients who were HPV+ were younger (56 vs 59 years old; p = .052). No differences were observed regarding tumor stage, sex, or smoking between HPV+ and HPV-. Three-year OS was 67.4% for patients who were HPV+ versus 49.7% for HPV- (hazard ratio [HR], 0.55; p = .095). Incidence of HPV-related oropharyngeal carcinoma in Spain is similar to that reported in other European countries. In this sample of heavy smokers, we observed a nonsignificant trend for better outcomes in patients who were HPV+.


Bilateral recession-resection surgery for convergent strabismus fixus associated with high myopia.
The authors report two patients with more than 20 diopters of myopia, severely restricted abduction, and more than 90Delta of acquired esotropia. Marked axial elongation of the globes was present. Each underwent large bilateral medial rectus recessions and bilateral lateral rectus resections. The deviations were significantly reduced and abduction improved with combined horizontal recession-resection surgery on both eyes.


Mutagenicity of 8-methoxypsoralen and long-wave ultraviolet irradiation in V-79 Chinese hamster cells. A first approach to a risk estimate in photochemotherapy.
The effect of 8-methoxypsoralen (8-MOP) and long-wave ultraviolet irradiation (UVA) on cell killing and mutation induction was studied in V-79 Chinese hamster cells. No effect was observed after treatment with 8-MOP alone (50 microgram/ml, 4 h), UVA alone (9000 J/m2), or 8-MOP metabolized by rat-liver microsomes. Combined treatment with 8-MOP and UVA induced both cell killing and mutation. This was also observed under conditions approaching patient treatment with PUVA photochemotherapy with respect to the concentration of 8-MOP in the skin and the amount of UVA received by the epidermal cells. A simple relation proved to apply for mutation induction under different treatment conditions: 5.5 X 10(-8) per J/m2 per microgram 8-MOP/ml. On this basis the mutation induction in dividing cells per session of PUVA-photochemotherapy amounts to 12.4 X 10(-5), which is probably an over-estimation.


Selective fruit and seed maturation in Asphodelus albus Miller (Liliaceae).
The fruiting patterns of the rhizomatous perennial Asphodelus albus Miller (Liliaceae) were studied in five populations during 1989 and in one population over 3 years (1988-1990). Fruit/flower (Fr/Fl) ratio and seed/ovule (S/O) ratio varied markedly between populations. Although there were differences between years within the population studied over 3 years, these variations, although statistically signifcant, were less important than those between populations. Neither flowering phenology nor plant size influenced Fr/Fl or S/O ratios. Field experiments tested whether fruit and seed set were pollenor resource-limited. Hand-pollination had no effect on Fr/Fl or S/O ratios, but the reduction of resources by defoliation at the time of flowering decreased both relative components of fecundity. Manipulation of resources by hand-thinning flowers and tiny fruits had no demonstrable effect on these ratios, although brood size of individual fruits was significantly affected. It may be concluded that fruit maturation is resource-limited rather than pollen-limited. Most of the fruits aborted early in the fruiting season, and fruits with higher numbers of developing seeds had a lower probability of abortion than fruits with fewer seeds. Analyses of position effects revealed that the fruits in lower positions in the inflorescence matured preferentially. Furthermore, the two ovules in the same carpel tended either both to fail or both to develop into seeds. The plant's ability to selectively mature only high quality embryos may be limited.


Fractures of the tibial spine: epidemiology and outcome.
We documented functional outcome in 83 knees with tibial spine fractures. The mean age at injury was 35 years. There was a medial collateral ligament sprain in 17 knees and posterolateral corner injury in three knees. Twenty patients with displaced tibial spine fractures were treated with fixation of the tibial spine and 63 patients with undisplaced or minimally displaced fractures were treated non-operatively. Fourteen (22%) non-operatively treated knees developed symptomatic instability, three of which underwent ACL reconstruction. Tibial spine fixation restored stability in 18 of 20 knees, but knee stiffness was more common in this group when compared to non-operatively treated knees (60% vs 19%, p<0.0005). Patients with postoperative knee stiffness had a mean age of 28 years compared to 18 in patients with no knee stiffness (p<0.05). We concluded that tibial spine fracture in skeletally mature patients is associated with a significant risk of knee stiffness and instability.


Applications of SNAP-tag technology in skin cancer therapy.
Cancer treatment in the 21st century has seen immense advances in optical imaging and immunotherapy. Significant progress has been made in the bioengineering and production of immunoconjugates to achieve the goal of specifically targeting tumors. In the 21st century, antibody drug conjugates (ADCs) have been the focus of immunotherapeutic strategies in cancer. ADCs combine the unique targeting of monoclonal antibodies (mAbs) with the cancer killing ability of cytotoxic drugs. However, due to random conjugation methods of drug to antibody, ADCs are associated with poor antigen specificity and low cytotoxicity, resulting in a drug to antibody ratio (DAR) >1. This means that the cytotoxic drugs in ADCs are conjugated randomly to antibodies, by cysteine or lysine residues. This generates heterogeneous ADC populations with 0 to 8 drugs per an antibody, each with distinct pharmacokinetic, efficacy, and toxicity properties. Additionally, heterogeneity is created not only by different antibody to ligand ratios but also by different sites of conjugation. Hence, much effort has been made to find and establish antibody conjugation strategies that enable us to better control stoichiometry and site-specificity. This includes utilizing protein self-labeling tags as fusion partners to the original protein. Site-specific conjugation is a significant characteristic of these engineered proteins. SNAP-tag is one such engineered self-labeling protein tag shown to have promising potential in cancer treatment. The SNAP-tag is fused to an antibody of choice and covalently reacts specifically in a 1:1 ratio with benzylguanine (BG) substrates, eg, fluorophores or photosensitizers, to target skin cancer. This makes SNAP-tag a versatile technique in optical imaging and photoimmunotherapy of skin cancer. SNAP-tag technology has the potential to contribute greatly to a broad range of molecular oncological applications because it combines efficacious tumor targeting, minimized local and systemic toxicity, and noninvasive assessment of diagnostic/prognostic molecular biomarkers of cancer.


Linkage of premature and early menopause with psychosocial well-being: a moderated multiple mediation approach.
Menopause occurring before the age of 40 is premature and between 40 and 44 years age is early, since the natural age of menopause lies between 45 and 50. The endocrine changes that come with menopause include an erratic decline in estrogen levels which affects the brain. Thus, leading to changes in cognitive function in the longer term due to the menopausal transition. The study aims to explore the effect of premature and early menopause on cognitive health, and psychosocial well-being. The moderated multiple mediation hypothesis of the study is that the effect of premature or early menopause is mediated by depression and insomnia, while all the pathways are moderated by smoking habits. The study utilized Longitudinal Aging Study in India (LASI), 2017-2018, Wave 1 data. The sample of 31,435 women were aged 45 and above and did not undergo hysterectomy. A moderated multiple mediation model was used to understand the association between premature or early menopause (X), insomnia (M1), depression (M2), moderator (W), and cognitive health (Y), while controlling for possible confounders. Premature menopause was negatively associated with cognition (β:-0.33; SE:0.12; p < 0.05), whereas positively associated with insomnia (β:0.18; SE:0.03; p < 0.001) and depression (β:0.25; SE:0.04; p < 0.001). There is a moderating effect of smoking or tobacco consumption has a significant moderating effect on the pathways among premature menopause, depression, insomnia and cognition. When the same model was carried out for early menopause (40-44 years), the results were not significant. The findings emphasize the fact that smoking is associated with premature menopause, depression and insomnia. Women who experienced premature menopause has lower cognitive scores, depressive symptoms and insomnia symptoms, which were higher among those who consumed tobacco. The study, strongly recommends the dissemination of information on the negative effects of tobacco consumption and making more informed choices to maintain a healthy life. More research into various methods and therapy is needed to determine the relationship between the age of early menopause and their psychosocial well-being.


Colocalization of expression transcripts with COVID-19 outcomes is rare across cell states, cell types and organs.
Identifying causal genes at GWAS loci can help pinpoint targets for therapeutic interventions. Expression studies can disentangle such loci but signals from expression quantitative trait loci (eQTLs) often fail to colocalize-which means that the genetic control of measured expression is not shared with the genetic control of disease risk. This may be because gene expression is measured in the wrong cell type, physiological state, or organ. We tested whether Mendelian randomization (MR) could identify genes at loci influencing COVID-19 outcomes and whether the colocalization of genetic control of expression and COVID-19 outcomes was influenced by cell type, cell stimulation, and organ. We conducted MR of cis-eQTLs from single cell (scRNA-seq) and bulk RNA sequencing. We then tested variables that could influence colocalization, including cell type, cell stimulation, RNA sequencing modality, organ, symptoms of COVID-19, and SARS-CoV-2 status among individuals with symptoms of COVID-19. The outcomes used to test colocalization were COVID-19 severity and susceptibility as assessed in the Host Genetics Initiative release 7. Most transcripts identified using MR did not colocalize when tested across cell types, cell state and in different organs. Most that did colocalize likely represented false positives due to linkage disequilibrium. In general, colocalization was highly variable and at times inconsistent for the same transcript across cell type, cell stimulation and organ. While we identified factors that influenced colocalization for select transcripts, identifying 33 that mediate COVID-19 outcomes, our study suggests that colocalization of expression with COVID-19 outcomes is partially due to noisy signals even after following quality control and sensitivity testing. These findings illustrate the present difficulty of linking expression transcripts to disease outcomes and the need for skepticism when observing eQTL MR results, even accounting for cell types, stimulation state and different organs.