Endovascular treatment of complex cerebral aneurysms with onyx hd-500® in 38 patients.
To report our experience with Onyx HD-500(®) (Micro Therapeutics, Inc., Irvine, CA, USA) in the endovascular treatment of complex intracranial aneurysms as an alternative to treatment with platinum coils. Between October 2003 and December 2007, 38 patients (20 female and 18 male) were selected for inclusion in the study based on aneurysm size and dome-to-neck ratio. Altogether, 37 (97.3%) aneurysms were located in the anterior circulation, and one (2.7%) was in the posterior circulation. Of these, 35 (92.1%) had wide necks (>4mm and/or a dome-to-neck ratio<2). Clinical and angiographic follow-ups were performed at six and 12 months. Successful embolization was achieved in 36 of the 38 patients. Complete occlusion was seen in 29 patients (80.5%), and seven (19.4%) had subtotal occlusion on the immediate angiographic control. After six months, 29 patients (80.5%) initially with total occlusion were stable, while four with subtotal occlusion had progressed to total occlusion and three showed recanalization. Of the latter, two were reembolized and the third patient did not return for retreatment. The one-year angiographic follow-up showed no changes. The morbidity rate was 8.3% (3/36) and procedural mortality was 0%. The Onyx HD-500 liquid embolic system is a feasible and safe therapeutic option for patients presenting with complex aneurysms, but who are not candidates for other techniques or in whom previous treatment has failed.


Strategies for Radioiodine Treatment: What's New.
Radioiodine treatment (RAI) represents the most widespread and effective therapy for differentiated thyroid cancer (DTC). RAI goals encompass ablative (destruction of thyroid remnants, to enhance thyroglobulin predictive value), adjuvant (destruction of microscopic disease to reduce recurrences), and therapeutic (in case of macroscopic iodine avid lesions) purposes, but its use has evolved over time. Randomized trial results have enabled the refinement of RAI indications, moving from a standardized practice to a tailored approach. In most cases, low-risk patients may safely avoid RAI, but where necessary, a simplified protocol, based on lower iodine activities and human recombinant TSH preparation, proved to be just as effective, reducing overtreatment or useless impairment of quality of life. In pediatric DTC, RAI treatments may allow tumor healing even at the advanced stages. Finally, new challenges have arisen with the advancement in redifferentiation protocols, through which RAI still represents a leading therapy, even in former iodine refractory cases. RAI therapy is usually well-tolerated at low activities rates, but some concerns exist concerning higher cumulative doses and long-term outcomes. Despite these achievements, several issues still need to be addressed in terms of RAI indications and protocols, heading toward the RAI strategy of the future.


Rice Husk Research: From Environmental Pollutant to a Promising Source of Organo-Mineral Raw Materials.
Rice husk is a large-tonnage waste left from rice production. It is not subject to humification and therefore becomes a serious environmental pollutant. Due to the presence of two essential elements-carbon and silicon-in its composition, rice husk is a promising organo-mineral raw material. The known methods for processing of rice husk are associated with the formation of even more aggressive waste. The creation of a waste-free technology for processing this plant material requires a detailed study. Rice husk of yzylorda oblast was studied using IR, SEM, TA, TPD-MS, EPR, and TEM methods. It was determined that under a temperature up to 500 °C, the ligno-carbohydrate component of rice husk decomposes almost completely. Three main peaks are recorded during the decomposition: hemicellulose at 200 °C, cellulose at 265 °C, and lignin at 350-360 °C. This process is endothermic. However, above of 300 °C the exothermic reactions associated with the formation of new substances and condensation processes in the solid residue begin to prevail. This explains the increase in the concentration of paramagnetic centers (PMCs) in products of rice husk carbonization in the range of up to 450 °C. Further increase in temperature leads to a decrease in the number of PMCs as a result of carbon graphite-like structures formation. The silicon-carbon product of rice husk carbonization (nanocomposite) is formed by interconnected nanoscale particles of carbon and silicon dioxide, the modification of which depends on the temperature of carbonization. The obtained data allow management of the rice husk utilization process while manufacturing products in demand based on ecofriendly technologies.


Identification of hub genes and construction of transcriptional regulatory network for the progression of colon adenocarcinoma hub genes and TF regulatory network of colon adenocarcinoma.
The aim of this study was to identify key genes related to the progression of colon adenocarcinoma (COAD), and to investigate the regulatory network of hub genes and transcription factors (TFs). Dataset GSE20916 including 44 normal colon, 55 adenoma, and 36 adenocarcinoma tissue samples was used to construct co-expression networks via weighted gene co-expression network. Gene Ontology annotation and the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis for the objective module were performed using the online Database for Annotation, Visualization and Integrated Discovery. Hub genes were identified by taking the intersection of differentially expressed genes between dataset GSE20916 and GSE39582 and validated using The Cancer Genome Atlas (TCGA) database. The correlations between microRNA (miRNA) and hub genes were analyzed using the online website StarBase. Cytoscape was used to establish a regulatory network of TF-miRNA-target gene. We found that the orange module was a key module related to the tumor progression in COAD. In datasets GSE20916 and GSE39582, a total of eight genes (BGN, SULF1, COL1A1, FAP, THBS2, CTHRC1, COL5A2, and COL1A2) were selected, which were closely related with patients' survivals in TCGA database and dataset GSE20916. COAD patients with higher expressions of each hub gene had a worse prognosis than those with lower expressions. A regulatory network of TF-miRNA-target gene with 144 TFs, 26 miRNAs, and 7 hub genes was established, including model KLF11-miR149-BGN, TCEAL6-miR29B2-COL1A1, and TCEAL6-miR29B2-COL1A2. In conclusion, during the progression of COAD, eight core genes (BGN, SULF1, COL1A1, FAP, THBS2, CTHRC1, COL5A2, and COL1A2) play vital roles. Regulatory networks of TF-miRNA-target gene can help to understand the disease progression and optimize treatment strategy.


Study on the association of COX-2 genetic polymorphisms with risk of gastric cancer in high incidence Hexi area of Gansu province in China.
To investigate the possible association of polymorphisms, cyclooxygenase-2 (COX-2) promoter region -899G>C, COX-2 codon 587G>A, with risk of gastric cancer in the high incidence Hexi area of Gansu province in China. Blood samples from 140 patients with gastric carcinoma and 125 normal persons were collected in Hexi area of Gansu province in China. Polymorphisms of COX-2 -899G>A and COX-2 587G>A were genotyped by PCR-TaqMan. For detection Helicobacter pylori infection, Warhin-Starry staining was used. Three kinds of polymorphisms of COX-2 -899G>C were GG, GC and CC. The frequencies in gastric cancer patients were 72.9, 21.4 and 5.7%, and the frequencies in controls were 84.0, 12.8 and 3.2%, respectively. COX-2 -899C carrier (GC + CC) increased risk of gastric carcinoma with an odds ratio 1.950 (95% CI: 1.067-3.586, P=0.029). The genotype of COX-2 587G>A polymorphism were GG, GA and AA. The frequencies in patients group were 86.4, 11.4 and 2.2%, and the frequencies in controls were 89.6, 9.6 and 0.8%, respectively. There was no significant difference between cases and controls in each genotype. Helicobacter pylori infection rate was 68.6% in patients group and 50.4% in healthy controls. Helicobacter pylori infection rate in gastric cancer patients was remarkably higher than that in normal people (OR: 2.147, 95% CI: 1.302-3.541, P=0.003). Stratification analysis was showed that COX-2 -899C carrier genotype with Helicobacter pylori infection was significantly higher in cases than that in healthy controls (OR: 4.000, 95% CI: 1.638-9.770). The polymorphism of COX-2 -899G>C could be a risk factor for gastric cancer in high incidence Hexi area of Gansu Province in China. COX-2 -899C carrier genotype and Helicobacter pylori positive infection may have a synergistic effect on gastric cancer in high incidence Hexi area of Gansu Province in China. However, the polymorphisms of COX-2 587G>A is no association with gastric cancer in the high incidence Hexi area of Gansu Province in China.


A Polymer Guest Transforms Clathrate Cages into Channels: The Single-Crystal X-Ray Structure of Tetra-n-butylammonium Polyacrylate Hydrate, nBu4NPA⋅40 H2O.
The stacking of hydrate cages into channels is effected by the incorporation of polyacrylic acid together with tetra-n-butylammonium hydroxide into a hydrate lattice. The polymer chain (shown in the diagram as large circles) lies in the channel in such a way that some of the carboxy groups displace water molecules from the clathrate framework. The remaining carboxy groups are included in the channel as hydrophobic units without strong directional interactions with the water molecules found there.


A unidimensional pain/disability measure for low-back pain syndromes.
A new measure is presented, suitable for documenting severity and response to treatment in chronic low-back pain syndromes. It is self-administered and combines two pain and seven mobility items. These were selected from pre-existing validated instruments on the basis of their sensitivity to change after treatment. Their Italian validated translation was adopted. The measure was administered to 32 chronic low-back pain Italian patients, all refractory to previous conservative treatments. In most cases they presented with herniation or protrusion of 1-3 lumbar discs. Patients were treated with 3-6 sessions of autotraction over a 5- to 15-day period. Scores on the scale were recorded at admission, discharge and follow-up, 1-3 months after treatment. At discharge and at follow-up, patients were asked if, overall, they felt improved, the same or worse. At follow-up, 20 patients out of 32 reported overall improvement. Scalometric properties of the measure were tested using Rasch analysis. For admission and follow-up, items followed a consistent hierarchical relationship along a unidimensional pain/disability variable, which is being called back illness. The items were not redundant, in that they spread well along a wide range of difficulty/severity. The hierarchy matched well with the expected expression of the conditions of the patients. A study was conducted on 34 chronic back pain patients, showing satisfactory test-retest reliability. Depending on the various items, Cohen's unweighted K ranged from 0.27 to 0.78, with ten of the 11 items above the 0.45 level of acceptability, while intraclass correlation coefficients ranged from 0.42 to 0.89. At follow-up, changes in BACKILL of plus 15% or more, with respect to admission, were consistent with patients' reports of improvement in 19 out of 20 cases. Changes in BACKILL of less than 15% were consistent with patients reports of being the same or worse in 11 out of 12 cases.


Strain echocardiography to describe left ventricular function pre- and postexercise in elite basketball athletes: A feasibility study.
Elite athletes show structural cardiac changes as an adaptation to exercise. Studies examining strain in athletes have largely analyzed images at rest only. There is little data available regarding the change in strain with exercise. Our objectives were: to investigate the feasibility of strain analysis in athletes at peak exercise, to determine the normal range of left ventricular (LV) global longitudinal strain (GLS) within this population postexercise, to describe how LV GLS changes with exercise, and to determine whether any clinical characteristics correlate with the change in GLS that occurs with exercise. We conducted a cross-sectional study on elite athletes who participated in the 2016-2018 National Basketball Association Draft Combines. Echocardiograms were obtained at rest and after completing a treadmill stress test to maximal exertion or completion of Bruce protocol. Primary outcomes included GLS obtained at rest and peak exercise. Secondary outcome was the change in GLS between rest and exercise. Univariate relationships between various clinical characteristics and our secondary outcome were analyzed. Our final cohort (n = 111) was all male and 92/111 (82.9%) were African American. Mean GLS magnitude increased in response to exercise (-17.6 ± 1.8 vs -19.2 ± 2.6, P < .0001). Lower resting heart rates (r = .22, P = .02) and lower heart rates at peak exercise (r = .21, P = .03) correlated with the increase in LV GLS from exercise. Strain imaging is technically feasible to obtain among elite basketball athletes at peak exercise. Normative strain response to exercise from this study may help identify abnormal responses to exercise in athletes.


Editorial Commentary: Hip Arthroscopy-Bimodal Bump and Volume Matters.
In the experience of a high-volume hip arthroscopic surgeon with a referral practice, a bimodal age distribution could be common. Younger patients presenting with symptomatic hip pathology recalcitrant to nonoperative management may seek or be referred to high-volume surgeons, and older patients absent significant osteoarthritis may also be surgical candidates. Lower-volume hip surgeons could have higher complication rates, and it is incumbent on higher-volume surgeons to train upcoming colleagues as hip arthroscopy continues to grow.


The Caregiver Burden of Delirium in Older Adults With Alzheimer Disease and Related Disorders.
To measure the burden of delirium in older adults with or without Alzheimer disease or related disorders (ADRDs). Prospective, observational cohort. Inpatient hospital and study participants' homes. A subset (n = 267) of older medical and surgical patients and their caregivers enrolled in the Better Assessment of Illness study. Delirium burden was measured using the DEL-B instrument (range = 0-40, with higher scores indicating greater burden) in caregivers (DEL-B-C) and patients 1 month after hospitalization. Severity of cognitive impairment (Montreal Cognitive Assessment [MoCA]), delirium presence (Confusion Assessment Method [CAM]), and delirium severity (CAM-Severity [CAM-S]) were measured during hospitalization and at 1-month follow-up. ADRD diagnosis was determined by a clinical consensus process. For patients with (n = 56) and without (n = 211) ADRD, both DEL-B instruments had good internal consistency. DEL-B-C scores had a median (interquartile range) among caregivers of patients with and without ADRD of 9 (5-15) and 5 (1-11), respectively (P < .05). If the patient developed delirium, caregivers experienced greater burden (β[delirium × ADRD] = -.29; P = .42), regardless of ADRD status. Further, caregiver burden was modestly correlated with patient MoCA scores (Spearman correlation coefficient, ρ = -0.18; P = .01). Patients with ADRD who developed delirium self-reported less burden than those without ADRD (β[delirium × ADRD] = -.67; P = .044). As with caregivers, delirium burden was modestly correlated with patient MoCA score (ρ = -0.18; P = .005) and correlated with the CAM-S in patients without ADRD (ρ = 0.38; P < .001) but not for patients with ADRD (ρ = -0.07; P = .61). Delirium resulted in the same degree of increased caregiver burden regardless of whether a patient had ADRD, signifying delirium is equally stressful to caregivers, even among those with experience caring for someone with a chronic cognitive disorder. Delirium burden is only modestly associated with degree of cognitive impairment, suggesting that other aspects of delirium contribute to burden. J Am Geriatr Soc 67:2587-2592, 2019.


Binding mechanism and binding free energy of amino acids and citrate to hydroxyapatite surfaces as a function of crystallographic facet, pH, and electrolytes.
Hydroxyapatite (HAP) is the major mineral phase in bone and teeth. The interaction of individual amino acids and citrate ions with different crystallographic HAP surfaces has remained uncertain for decades, creating a knowledge gap to rationally design interactions with peptides, proteins, and drugs. In this contribution, we quantify the binding mechanisms and binding free energies of the 20 end-capped natural amino acids and citrate ions on the basal (001) and prismatic (010)/(020) planes of hydroxyapatite at pH values of 7 and 5 for the first time at the molecular scale. We utilized over 1500 steered molecular dynamics simulations with highly accurate potentials that reproduce surface and hydration energies of (hkl) hydroxyapatite surfaces at different pH values. Charged residues demonstrate a much higher affinity to HAP than charge-neutral species due to the formation of superficial ion pairs and ease of penetration into layers of water molecules on the mineral surface. Binding free energies range from 0 to -60 kJ/mol and were determined with ∼ 10% uncertainty. The highest affinity was found for citrate, followed by Asp(-) and Glu(-), and followed after a gap by Arg(+), Lys(+), as well as by His(+) at pH 5. The (hkl)-specific area density of calcium ions, the protonation state of phosphate ions, and subsurface directional order of the ions in HAP lead to surface-specific binding patterns. Amino acids without ionic side groups exhibit weak binding, between -3 and 0 kJ/mol, due to difficulties to penetrate the first layer of water molecules on the apatite surfaces. We explain recognition processes that remained elusive in experiments, in prior simulations, discuss agreement with available data, and reconcile conflicting interpretations. The findings can serve as useful input for the design of peptides, proteins, and drug molecules for the modification of bone and teeth-related materials, as well as control of apatite mineralization.


Self-esteem change during the transition from university to work.
The current study examined whether the transition from university to work, a major developmental milestone in young adulthood, was related to stability and change in self-esteem. Self-esteem was assessed in the last year of their master's program (T1) of 163 27-year old students and 14 months later, when they had graduated and half of them had started a full-time job (T2). Daily diaries were used to assess the occurrence of achievement- and affiliation-related experiences on 14 consecutive days at T1 and T2. We compared the full-time job beginners and a comparison group without a full-time job with regard to their mean-level change, rank-order stability and correlated change of self-esteem and daily experiences. First, job beginners increased in self-esteem, but the difference to the mean-level change of the comparison group was only small. Second, self-esteem was less stable among job beginners than among the comparison group. Third, the changes in achievement-related daily experiences and self-esteem correlated positively in the job-beginner group but not in the comparison group. The findings underline the role of daily experiences during life transitions for individual differences in self-esteem change. The discussion calls for accounting for unique transition experiences to advance theory and research on self-esteem development.


Lenalidomide in relapsed and refractory multiple myeloma disease: feasibility and benefits of long-term treatment.
Lenalidomide in combination with dexamethasone is an effective and well-established treatment of relapsed or refractory multiple myeloma (rrMM) disease. Due to the scarcity of reports assessing benefit and risk of long-term lenalidomide treatment in non-selected rrMM patients, we retrospectively analysed the long-term outcome in patients with rrMM treated with lenalidomide and dexamethasone. Sixty-seven patients (pts) who were treated with lenalidomide/dexamethasone for rrMM in the approved indication from 2007 to 2011 were included in this retrospective, single-centre analysis. Kaplan-Meier survival estimates were compared between total population, patients on lenalidomide for more than 12 months (mo) and patients discontinuing therapy earlier than 12 months. Median overall survival (OS) of the total patient population was 33.2 mo. OS of pts treated beyond 12 mo was 42.9 mo compared to 20.2 mo (p = 0.027) for pts stopping lenalidomide earlier than 12 mo for other reasons than progression disease (PD). OS of pts >12 mo on lenalidomide treatment did not significantly differ between pts who had received previous autologous transplantation, allogeneic transplantation or conventional therapy. Main non-hematologic toxicities were infections of grade 3/4 in 25 % and thrombembolic events of all grades in 18 % of patients. To the best of our knowledge, this is the first report on feasibility and efficacy of long-term lenalidomide treatment in a non-selected patient cohort. OS of pts >12 mo on lenalidomide is superior when compared to pts discontinued earlier for reasons other than PD. Our data confirm the current use of lenalidomide as a continuous long-term treatment strategy.


Actomyosin-mediated statolith positioning in gravisensing plant cells studied in microgravity.
The positioning and gravity-induced sedimentation of statoliths is crucial for gravisensing in most higher and lower plants. In positively gravitropic rhizoids and, for the first time, in negatively gravitropic protonemata of characean green algae, statolith positioning by actomyosin forces was investigated in microgravity (<10(-4) g) during parabolic flights of rockets (TEXUS/MAXUS) and during the Space-Shuttle flight STS 65. In both cell types, the natural position of statoliths is the result of actomyosin forces which compensate the statoliths' weight in this position. When this balance of forces was disturbed in microgravity or on the fast-rotating clinostat (FRC), a basipetal displacement of the statoliths was observed in rhizoids. After several hours in microgravity, the statoliths were loosely arranged over an area whose apical border was in the same range as in 1 g, whereas the basal border had increased its distance from the tip. In protonemata, the actomyosin forces act net-acropetally. Thus, statoliths were transported towards the tip when protonemata were exposed to microgravity or rotated on the FRC. In preinverted protonemata, statoliths were transported away from the tip to a dynamically stable resting position. Experiments in microgravity and on the FRC gave similar results and allowed us to distinguish between active and passive forces acting on statoliths. The results indicate that actomyosin forces act differently on statoliths in the different regions of both cell types in order to keep the statoliths in a position where they function as susceptors and initiate gravitropic reorientation, even in cells that had never experienced gravity during their growth and development.


The predictive value of Haller index in patients undergoing pectus bar repair for pectus excavatum.
The Haller index (HI) remains the standard metric to quantify the severity of pectus excavatum deformity. However, little data exist to determine how well this parameter correlates with the difficulty or early outcomes of repair. The study population was comprised of all patients who underwent pectus bar repair for pectus excavatum on whom adequate preoperative images on computed tomography allowed for Haller index calculation, from December 1999 to February 2010. Patients with two bars placed for repair were excluded. All images were reviewed blinded to outcome and Haller index was calculated. Pearson's correlation was used to evaluate the relationship between age, length of operation, postoperative complications, and length of hospitalization. The correlations were performed on the entire population and then individual age groups analyzed: 5-11 y, 12-16 y, and over 17 y. Two-tailed P values were determined from the correlation coefficient and significance was defined as P ≤ 0.05. HI was available for 262 patients. There were 66 patients aged 5-11 y, 165 patients aged 12-16 years, and 30 patients over 17 y. The population was 80% male. In the entire population, there was a small correlation between postoperative pneumothorax and HI (R = 0.131, P = 0.05). There was no correlation between age, operative time, postoperative bar infection, or length of stay. No significant correlations existed in any of the individual age groups. The Haller index holds no correlation with age, operative time, postoperative bar infection, or length of stay.


Zoledronate repositioning as a potential trypanocidal drug. Trypanosoma cruzi HPRT an alternative target to be considered.
Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects 7 million people worldwide. Considering the side effects and drug resistance shown by current treatments, the development of new anti-Chagas therapies is an urgent need. T. cruzi hypoxanthine phosphoribosyltransferase (TcHPRT), the key enzyme of the purine salvage pathway, is essential for the survival of trypanosomatids. Previously, we assessed the inhibitory effect of different bisphosphonates (BPs), HPRT substrate analogues, on the activity of the isolated enzyme. BPs are used as a treatment for bone diseases and growth inhibition studies on T. cruzi have associated BPs action with the farnesyl diphosphate synthase inhibition. Here, we demonstrated significant growth inhibition of epimastigotes in the presence of BPs and a strong correlation with our previous results on the isolated TcHPRT, suggesting this enzyme as a possible and important target for these drugs. We also found that the parasites exhibited a delay at S phase in the presence of zoledronate pointing out enzymes involved in the cell cycle, such as TcHPRT, as intracellular targets. Moreover, we validated that micromolar concentrations of zoledronate are capable to interfere with the progression of cell infection by this parasite. Altogether, our findings allow us to propose the repositioning of zoledronate as a promising candidate against Chagas disease and TcHPRT as a new target for future rational design of antiparasitic drugs.


Ultrastructure of sarcocysts from water buffalo in India.
The ultrastructure of sarcocysts of macro- and microscopic species of Sarcocystis was compared from naturally infected water buffalo from India. Grossly visible sarcocysts had walls consisting of cauliflower-like villar protrusions, typical of S. fusiformis. The sarcocyst wall of the microscopic species of Sarcocystis was 6.4 microns thick and consisted of tightly packed conical villar protrusions that were 9.6 microns long and 3.7 microns wide at the base. At approximately 3 microns above the base, the distal two-thirds of the villar protrusion became conical shaped and was bent laterally at an angle of 45 degrees to the sarcocyst surface. The granular layer beneath the villar protrusions was 0.9 microns thick. In S. levinei the granular layer was 1.9 microns thick, the villar protrusions were narrow and it had a highly undulating primary cyst wall. Whether the microscopic S. levinei-like sarcocysts of Indian and Malaysian water buffalo are distinct species of Sarcocystis will require further investigation.


Multiple, large deletions in rat mitochondrial DNA: evidence for a major hot spot.
This study identified 33 different deletions in mitochondrial DNA from four aging Fischer-344 rat brains and from a cultured rat lymphoma cell line (Nb2 cells). The deletions were located in the longer arc between the heavy and light strand origins of replication. PCR products that spanned across the deleted regions were sequenced, and deletions ranging between 6548 bp and 9977 bp in length were identified. Short direct repeats of < or = 8 bp were present at the end points of all but one of the deletions. The remaining deletion contained, instead, a near-perfect direct repeat (9/10 bp) within two base pairs of its end points. In 24 of the deletions, a sequence equivalent to one member of the paired direct repeats was lost with the deleted segment. In the remaining nine, either more or less of the base pairs of a single repeat were lost. Twelve of the 33 different deletions terminated on one side at a common locus (major hot spot) of 5 bp in length, located at the 5' end of the tRNAThr gene. The opposite ends of these 12 deletions were at different sites. The hot spot was located in a region of the mtDNA with strong potential for secondary structure and was flanked by a pair of AT-rich sequences. The utilization of the hot spot as an end point for deletions appeared to be widespread in that it was represented in 1/3-1/2 of the deletions characterized in each of the five mtDNA sources examined. In addition, several minor hot spots, where one end of two or three different deletions coincided, were also identified.


Characteristics of catechin loading rice porous starch/chitosan functional microsphere and its adsorption towards Pb2.
In this paper, we explore the adsorption potential of catechin (CT) loaded composite microspheres and provide a new micron scale carrier of functional factor. Chitosan (CS) modified rice porous starch (RPS/CS) was used as a CT adsorption carrier to prepare bioactive CT-loaded composite microspheres (CT@RPS/CS). The adsorption kinetics, storage characteristics, and biological activity maintenance of CT@RPS/CS were studied in an aqueous solution, and the sustained-release characteristics of CT@RPS/CS were studied in vitro during simulated gastrointestinal digestion. An aqueous solution further studied the removal characteristics of adsorbed heavy metal ion Pb2+. RPS/CS can significantly improve the ability to adsorb CT. RPS/CS can also significantly improve CT's storage stability, antioxidant stress, and slow-release characteristics, and the sustained release effect in gastric and intestinal juice. CT@RPS/CS can be removed Pb2+ by adsorbing in the solution, and their adsorption was physical adsorption and chemisorption, but the primary interaction is chemisorption. CT@RPS/CS can be used as a micron carrier of new food functional factors, which has potential space for improving and expanding the functional characteristics of its loaded functional factors and the endowing of new functions.


Evaluating the human response to chemicals: odor, irritation and non-sensory factors.
Although airborne chemicals can directly elicit adverse reactions via stimulation of the olfactory and trigeminal nerves, such as sensory irritation of the mucous membranes of the eyes, nose and throat, an individual's subjective experience is often the result of a complex sequence of events involving those sensory, physiological signals and psychological processes involved in perception, memory and judgment. To evaluate the contribution of these processes, an information-processing model of chemosensory perception is introduced. The model incorporates (1) the perception of odor and trigeminal irritation, and accompanying physiological and somatic changes that follow directly from the encounter with volatile organic compounds (VOCs) in the environment (bottom-up processing), and (2) any physiological/ somatic changes and subjective experiences of irritancy that are influenced by cognitive processes that have been primed by the perception of odor (top-down processing). The model is illustrated with data from our laboratory, and its utility in the context of setting occupational exposure limits is discussed.


Crystal structure of class III chitinase from pomegranate provides the insight into its metal storage capacity.
Chitinase hydrolyzes the β-1,4-glycosidic bond in chitin. In higher plants, this enzyme has been regarded as a pathogenesis-related protein. Recently, we identified a class III chitinase, which functions as a calcium storage protein in pomegranate (Punica granatum) seed (PSC, pomegranate seed chitinase). Here, we solved a crystal structure of PSC at 1.6 Å resolution. Although its overall structure, including the structure of catalytic site and non-proline cis-peptides, was closely similar to those of other class III chitinases, PSC had some unique structural characteristics. First, there were some metal-binding sites with coordinated water molecules on the surface of PSC. Second, many unconserved aspartate residues were present in the PSC sequence which rendered the surface of PSC negatively charged. This acidic electrostatic property is in contrast to that of hevamine, well-characterized plant class III chitinase, which has rather a positively charged surface. Thus, the crystal structure provides a clue for metal association property of PSC.


Delay in detection and treatment of perioperative anemia in hip fracture surgery and its impact on postoperative outcomes.
Elderly patients with hip fractures are at high risk for perioperative anemia as a result of fracture- and surgery-related blood loss. The detection of anemia is dependent on intermittent blood samples and therefore might be delayed, potentially leading to a significant delay in transfusion. This study aimed to investigate the possible delay in perioperative anemia detection, accumulated perioperative anemia-associated burden, peripheral perfusion, and their association with patient outcomes in elderly patients with hip fracture. Elderly patients with acute hip fracture scheduled for surgery were enrolled in this prospective study from August 2016 to December 2016. All patients were monitored continuously for hemoglobin concentration (SpHb) and perfusion index (PI) with the Radical-7® Pulse CO-Oximeter® and Rainbow® R1 Adhesive Multi-parameter Sensors (Masimo Corp., Irvine, CA, US) from 12 h presurgery to 24 h postsurgery. Fifty-one patients were enrolled, and 41 were included in the final analyses. Mean delay in the detection of low Hb (<10 g/dL) using intermittent blood samples, when compared with SpHb, was 1.07 h (standard deviation, ±2.84 h). Median perioperative cumulated time with low SpHb (<10 g/dL for at least one min) was 25 min (interquartile range [IQR]: 21-690). There was a significant association between perioperative time with low SpHb and the occurrence of postoperative delirium (median cumulated time with low SpHb: 162 min in patients with delirium vs 22 min in patients without delirium, P = 0.034) and a nonsignificant trend for an association between perioperative time with low SpHb and 90-day mortality or medical complications (median cumulated time with low SpHb: 119 min for patients with mortality or severe complication vs 22 min for patients without mortality or severe complication, P = 0.104). PI values during the perioperative period were not significantly associated with patient outcomes. Cumulated time with low PI (<0.5) preoperatively (but not perioperatively) was significantly associated with the occurrence of postoperative delirium (P = 0.047). This study showed a delay in transfusion threshold detection, and the presence of significant associations between low SpHb or time with low SpHb and postoperative outcomes.


Central-peripheral chemoreceptor ventilatory interaction in awake goats.
This study was designed to characterize the ventilatory interaction between central and carotid body (CB) chemoreceptor stimulation in awake goats undergoing selective CB perfusion. This model allowed us to expose central and CB chemoreceptors to separate blood gas conditions in an animal that is conscious and not systemically hypoxic. Systemic CO2 ventilatory response curves, performed by progressively increasing FICO2 in systemic hyperoxia, were completed in 7 goats during CB perfusion with hypercapnic-hypoxic blood and normocapnic-normoxic blood, and in 3 goats without CB perfusion. The slopes of the curves done with perfusion were not significantly different (P greater than 0.05) in CB hypercapnic hypoxia and CB normocapnic normoxia for VE, VT, f and VT/TI, and the coefficients of variation of slopes generated with and without perfusion were similar. Our data indicate there is addition of central and CB chemoreceptor input in respiratory control, and we conclude that the previously demonstrated stimulus interaction at the CB is the primary source of the hyperadditive hypercapnic-hypoxic ventilatory interaction in an animal unaffected by anesthetics or brain hypoxia.


Osseous genioplasty versus chin implants: early complications and patient satisfaction.
Osseous genioplasty and chin augmentation with implants are the two main treatment options for retrognathia. This retrospective cohort study was performed to compare the prevalence of complications and patient satisfaction following osseous genioplasty and chin augmentation by implant. Eighty patients were included: 38 underwent advancement osseous genioplasty and 42 received chin implants (alloplastic, either Medpor or Silastic) intraorally or extraorally. The patients were assessed for complications 12 months after surgery, including neurosensory disturbances, infection or extrusion, wound dehiscence, and the need for reoperation. Patient satisfaction was evaluated using a visual analogue scale. The infection rate was significantly higher in the chin implant group than in the genioplasty group (P = 0.028). Moreover, dehiscence and the need for reoperation appeared to be more common following chin augmentation with implants. However, there was no significant difference in the prevalence of neurosensory disturbances between the two groups (P = 0.137). In the chin implants group, the extraoral approach resulted in a lower dehiscence rate than the intraoral approach. Patients in the genioplasty group had significantly higher satisfaction scores than those in the chin implant group (P = 0.001). Overall, the rates of the complications assessed were lower and patient satisfaction was higher after osseous genioplasty when compared to chin augmentation with implants.


The real-world health resource use and costs of misdiagnosing bipolar I disorder.
Misdiagnosis of bipolar I disorder (BP-I) as major depressive disorder (MDD) is common. This study evaluated healthcare resource utilization (HRU) and costs among BP-I patients who were initially misdiagnosed with MDD (misdiagnosed BP-I cohort) versus patients diagnosed with BP-I without a known prior MDD diagnosis (BP-I only cohort). Data from IBM® MarketScan® Research Databases were used. The index date was the first MDD diagnosis for misdiagnosed patients or first BP-I diagnosis for BP-I only patients. Inverse probability of treatment weighting was used to balance baseline characteristics between cohorts. All-cause and mental health (MH)-related HRU and costs were compared between weighted cohorts using rate ratios (RRs) and mean cost differences, respectively. Outcomes were reported per patient-year (PPY). Confidence intervals and P-values were calculated using non-parametric bootstrap procedures. Overall, 14,729 misdiagnosed BP-I and 16,072 BP-I only patients met criteria. Baseline characteristics were balanced across weighted cohorts. Misdiagnosed BP-I patients had significantly higher rates of hospitalizations, emergency room visits, and outpatient visits than BP-I only patients during follow-up (all-cause RRs: 1.94, 1.33, and 1.38, respectively, all P < .001; MH-related RRs: 2.19, 1.77, and 1.77, respectively, all P < .001). Similarly, misdiagnosed BP-I patients incurred significantly higher total healthcare costs PPY over follow-up (all-cause: $21,202 vs $14,661, cost difference = $6541; MH-related: $12,901 vs $6749, cost difference = $6152; both P < .001). Cost differences were even higher during the first year (all-cause = $7146; MH-related = $6619; both P < .001). Claims database (e.g., coding inaccuracies); generalizability to uninsured patients. The prompt and correct diagnosis of BP-I may significantly reduce HRU and costs.


Effect of ADHI on hepatic stellate cell activation and liver fibrosis in mice.
The relationship between alcohol dehydrogenase (ADH) and liver fibrosis has been studied, but the mechanism of ADH involvement in liver fibrosis remains unclear. The aim of the present study was to explore the role of ADHI, the classical liver ADH, in hepatic stellate cell (HSC) activation and the effect of 4-methylpyrazole (4-MP), an ADH inhibitor, on liver fibrosis induced by carbon tetrachloride (CCl4) in mice. The results showed that overexpression of ADHI significantly increases proliferation, migration, adhesion and invasion rates of HSC-T6 cells as compared with controls. When HSC-T6 cells were activated by ethanol, TGF-β1 or LPS, the expression of ADHI was elevated significantly (P < 0.05). Overexpression of ADHI significantly increased the levels of COL1A1 and α-SMA, markers of HSC activation. Moreover, the expression of COL1A1 and α-SMA was decreased significantly by transfection of ADHI siRNA (P < 0.01). In a liver fibrosis mouse model ADH activity increased significantly and was highest in the 3rd week. The activity of ADH in the liver was correlated with its activity in the serum (P < 0.05). 4-MP significantly decreased ADH activity and ameliorated liver injury, and ADH activity was positively correlated with the Ishak score of liver fibrosis. In conclusion, ADHI plays an important role in the activation of HSC, and inhibition of ADH ameliorates liver fibrosis in mice.


Suramin blocks intracellular Ca2+ release and growth factor-induced increases in cytoplasmic free Ca2+ concentration.
Suramin, a polysulfonated naphthylurea with antitumor activity, has been shown to be an inhibitor of the release of Ca2+ from non-mitochondrial stores induced by the putative intracellular second messengers inositol 1, 4, 5-trisphosphate and GTP in saponin permeabilized Swiss 3T3 fibroblasts. The IC50 for the effect of suramin was about 40 microM in both cases. Suramin did not block Ca2+ release induced by the Ca2+ ionophore 4-bromo A23187 or by the membrane perturbing agent halothane. Suramin, 7 x 10(-5) M, caused a 49% decrease in the elevation of intracellular free Ca2+ concentration ([Ca2+]i) caused by platelet derived growth factor (PDGF) in intact Swiss 3T3 fibroblasts but did not block the increases in [Ca2+]i caused by bradykinin or vasopressin. Suramin decreased PDGF binding to its receptor on intact Swiss 3T3 fibroblasts but had no effect on the binding of bradykinin and vasopressin. The results show that the effect of suramin in decreasing the [Ca2+]i response to growth factors may be mediated by a block of growth factor-receptor binding, but an effect on intracellular Ca2+ release cannot be ruled out.


IL-17-producing γδ T cells switch migratory patterns between resting and activated states.
Interleukin 17-producing γδ T (γδT17) cells have unconventional trafficking characteristics, residing in mucocutaneous tissues but also homing into inflamed tissues via circulation. Despite being fundamental to γδT17-driven early protective immunity and exacerbation of autoimmunity and cancer, migratory cues controlling γδT17 cell positioning in barrier tissues and recruitment to inflammatory sites are still unclear. Here we show that γδT17 cells constitutively express chemokine receptors CCR6 and CCR2. While CCR6 recruits resting γδT17 cells to the dermis, CCR2 drives rapid γδT17 cell recruitment to inflamed tissues during autoimmunity, cancer and infection. Downregulation of CCR6 by IRF4 and BATF upon γδT17 activation is required for optimal recruitment of γδT17 cells to inflamed tissue by preventing their sequestration into uninflamed dermis. These findings establish a lymphocyte trafficking model whereby a hierarchy of homing signals is prioritized by dynamic receptor expression to drive both tissue surveillance and rapid recruitment of γδT17 cells to inflammatory lesions.


Tracheal Bronchus: An Unusual Cause of Recurrent Lower Respiratory Tract Infection.
A 14-month-old male child presented with a history of recurrent pneumonia of the right upper lobe of the lung. Computed tomography scan showed an accessory bronchus proximal to the carina on the right side with collapse consolidation of the lobe.


Specific distribution of messenger ribonucleic acids for 24-kilodalton proteins in the mouse epididymis as revealed by in situ hybridization: developmental expression and regulation in the adult.
Specific mRNAs for 24-kDa proteins specific to the caput epididymidis were quantified by filter hybridization, and cellular distribution was assessed by in situ hybridization of tissue sections. Messenger RNAs were detectable in 10-day-old animals, rapidly increased in quantity between 15 and 20 days, and reached a maximum at 40 days of age. The marked increase in concentration of mRNAs could be associated with the increase in epididymal testosterone content. Near 26 days of age, specific perinuclear and basal localization of mRNAs occurred in the principal cells of segment I, and a wide cytoplasmic distribution was observed in segment II. In the adult, mRNA levels decreased by 50% 3 days after castration and became undetectable within 30 days. Administration of testosterone to castrated mice caused an increase in mRNA levels, which reach almost normal levels after 3 days of treatment. Nevertheless, the particular organization of segment 1 was not restored. A similar observation was made after hemicastration or ligation of the efferent duct on the operated side. If expression of the mRNAs appears to be mostly under androgenic control, other testicular factors may be involved in the regulation of mRNA distribution in segment I.


The time course of psychological stress as revealed by event-related potentials.
Psychological stress is common in everyday life and is believed to affect emotion, cognition and health. Previous brain imaging studies have been able to identify the brain regions involved in the stress response. However, our understanding of the temporal neurological response to psychological stress is limited. The present work aims to investigate the time course of psychological stress induced by a mental arithmetic task, utilizing event-related potentials (ERPs). The elicitation of stress was verified by self-reports of stress and increases in salivary cortisol levels. The subjective and physiological data showed that the stress-elicitation paradigm successfully induced a mild-to-moderate level of psychological stress. The electrophysiological data showed that the amplitude of occipital N1 was more negative in the control task than in the stress task, and the latency of frontal P2 was shorter in the stress task than in the control task. Our results provide electrophysiological evidence that psychological stress occurs primarily at the early stage of cognitive processing.


Quantification of Microtubule-Bundling Activity of MAPs Using TIRF Microscopy.
Cross-linking of microtubules by microtubule-associated proteins (MAPs) results in the formation of microtubule bundles. It has been shown that a majority of microtubules in interphase plant cells are bundled. Bundling can contribute to maintaining structural stability and sustaining spatial organization of microtubule arrays. While bundling can be readily detected by an electron or fluorescent microscope, quantifying this activity remains technically challenging. Here we describe a method for quantifying microtubule-bundling in vitro using green and red stable microtubules. Furthermore, this method distinguishes between different types of microtubule-microtubule interactions: bundling, annealing, and branching. Our technique can be used to compare bundling activity of different MAPs and generate parameters for modeling their contribution to organization and dynamics of microtubule arrays.


Small RNA-based antimicrobial immunity.
Protection against microbial infection in eukaryotes is provided by diverse cellular and molecular mechanisms. Here, we present a comparative view of the antiviral activity of virus-derived small interfering RNAs in fungi, plants, invertebrates and mammals, detailing the mechanisms for their production, amplification and activity. We also highlight the recent discovery of viral PIWI-interacting RNAs in animals and a new role for mobile host and pathogen small RNAs in plant defence against eukaryotic pathogens. In turn, viruses that infect plants, insects and mammals, as well as eukaryotic pathogens of plants, have evolved specific virulence proteins that suppress RNA interference (RNAi). Together, these advances suggest that an antimicrobial function of the RNAi pathway is conserved across eukaryotic kingdoms.


Predictors of cardiopulmonary resuscitation and automated external defibrillator skill retention.
Few data exist regarding the retention of cardiopulmonary resuscitation (CPR) and automated external defibrillator (AED) skills over time in relationship to characteristics of lay volunteer responders, training, or risk of exposure to victims. The purpose of this study was to describe the characteristics associated with adequate CPR and AED skill retention. Skill retention was tested 3 to 18 months (mean 6.9 +/- 3.5 months) after initial training. Instructors judged adequacy of performance of essential CPR or AED skills and provided an overall assessment (adequate/inadequate), which was used as the outcome. Data on 7261 laypersons trained in CPR (4358 also received AED training) in 24 sites across the United States and Canada were available from the Public Access Defibrillation (PAD) Trial. Characteristics of the volunteers, classes, and facilities were evaluated as predictors of performance adequacy. Adjusting for site, intervention assignment (CPR-only or CPR + AED), and time since initial training, volunteer characteristics associated with adequate CPR performance were age (OR 0.78 per 10-year increment), male sex (OR 1.44), minority (OR 0.62), married (OR 1.35), prior emergency experience (OR 1.66), prior CPR class (OR 1.68), prior advanced training (OR 1.59), and extracurricular CPR training (OR 1.91) (all P < .05). Characteristics associated with AED performance included age (OR 0.69), college education (OR 1.34), and native language other than English (OR 0.51) (all P < .05). Certain subgroups of lay volunteers may need targeted outreach programs in CPR and AED use, classes with longer training time, more practice, or more intense retraining to maintain their CPR and/or AED skills.


Impact of Ti and Zn Dual-Substitution in P2 Type Na2/3 Ni1/3 Mn2/3 O2 on Ni-Mn and Na-Vacancy Ordering and Electrochemical Properties.
High-entropy layered oxide materials containing various metals that exhibit smooth voltage curves and excellent electrochemical performances have attracted attention in the development of positive electrode materials for sodium-ion batteries. However, a smooth voltage curve can be obtained by suppression of the Na+ -vacancy ordering, and therefore, transition metal slabs do not need to be more multi-element than necessary. Here, the Na+ -vacancy ordering is found to be disturbed by dual substitution of TiIV for MnIV and ZnII for NiII in P2-Na2/3 [Ni1/3 Mn2/3 ]O2 . Dual-substituted Na2/3 [Ni1/4 Mn1/2 Ti1/6 Zn1/12 ]O2 demonstrates almost non-step voltage curves with a reversible capacity of 114 mAh g-1 and less structural changes with a high crystalline structure maintained during charging and discharging. Synchrotron X-ray, neutron, and electron diffraction measurements reveal that dual-substitution with TiIV and ZnII uniquely promotes in-plane NiII -MnIV ordering, which is quite different from the disordered mixing in conventional multiple metal substitution.


O-linked N-acetylglucosamine transferase is involved in fine regulation of flowering time in winter wheat.
Vernalization genes underlying dramatic differences in flowering time between spring wheat and winter wheat have been studied extensively, but little is known about genes that regulate subtler differences in flowering time among winter wheat cultivars, which account for approximately 75% of wheat grown worldwide. Here, we identify a gene encoding an O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) that differentiates heading date between winter wheat cultivars Duster and Billings. We clone this TaOGT1 gene from a quantitative trait locus (QTL) for heading date in a mapping population derived from these two bread wheat cultivars and analyzed in various environments. Transgenic complementation analysis shows that constitutive overexpression of TaOGT1b from Billings accelerates the heading of transgenic Duster plants. TaOGT1 is able to transfer an O-GlcNAc group to wheat protein TaGRP2. Our findings establish important roles for TaOGT1 in winter wheat in adaptation to global warming in the future climate scenarios.


Violence and sociodemographic related factors among a sample of Egyptian women during the COVID-19 pandemic.
Violence against women is a worldwide problem that affects different social and economic classes, and this violence has almost increased with pandemics as the COVID-19 pandemic. The present survey aimed to assess the prevalence of violence against women in Egypt during the COVID-19 pandemic and to identify the relationship between sociodemographic factors and violence exposure. A total of 509 women were recruited using a self-completion e-form questionnaire. The prevalence of violence experienced by women was (43.8%); the most common type was the emotional representing (96.0%) of exposed women, while sexual violence was the least common (13.5%). Violence exposure was affected significantly by residence governorates, husbands' working status, reduced husbands' working hours, and history of violence exposure. Violence against women in Egypt was increased during the COVID-19 pandemic, which raises the need for a strong and urgent anti-violence program to control this problem.


Solidification of heavy metals and PCDD/Fs from municipal solid waste incineration fly ash by the polymerization of calcium carbonate oligomers.
Calcium carbonate oligomers are gel-state precursors that can be crystallized by low-temperature heat treatments to form an inorganic material with a monolithic and continuous structure, this material can effectively solidify/stabilize heavy metals in municipal solid waste incineration fly ash (MSWI FA). Calcium chloride addition achieves FA stabilization/solidification by the formation and polymerization of calcium carbonate oligomers. The effects of calcium, triethylamine (TEA), and water-washing pretreatment on the solidification of heavy metals by the polymer were studied. Consequently, as more calcium was added, the solidification improved. When the ratio of TEA/Ca2+ was increased from 2:1 to 3:1, the solidification efficiency of As and Cd increased, but it decreased when the ratio was continuously increased to 4:1. After the water-washing pre-treatment, the MSWI FA had a significantly improved solidification effect on the heavy metals, and the solidification efficiencies of zinc, copper, cadmium, chromium, lead, and arsenic were 81.9%, 90.0%, 93.5%, 91.8%, 99.6% and 95.5%, respectively. Additionally, the solidification efficiency of PCDD/Fs was 56.5%. The heavy metals and PCDD/Fs in MSWI FA solidified by physical adsorption, wrapping and chemical precipitation. The continuous calcium carbonate structure adsorbed and encased the MSWI FA, and the heavy metals in the MSWI FA were converted from a free state to carbonate precipitates through carbonation, and the carbonate precipitate was more likely to be physical solidification by calcium carbonate.


Molecular mechanism of molt-inhibiting hormone (MIH) induced suppression of ecdysteroidogenesis in the Y-organ of mud crab: Scylla serrata.
The present study was focused on the regulation of ecdysteroidogenesis in the Y-organ of Scylla serrata during molting cycle. A strong expression of molt-inhibiting hormone (MIH) and phosphorylation of ERK was predominantly observed in the postmolt and intermolt stages of Y-organs, whereas protein kinase C, steroidogenic acute regulatory protein (StAR) and cytochrome P450(scc) activity were exclusively seen in the premolt stages. Interestingly, inhibition of ERK phosphorylation by PD98059 in the early postmolt (A), middle postmolt (B) and intermolt (C) stages resulted in the prominent expression of PKC and StAR in the postmolt stages. This result indicates that phosphorylation of ERK is required for suppression of ecdysteroid biosynthesis with the involvement of protein kinase C, and StAR protein.


Atrial fibrillation burden, episode duration and frequency in relation to quality of life in patients with implantable cardiac monitor.
To assess the relation between atrial fibrillation (AF) characteristics and health-related quality of life (QoL), and which AF characteristic had the greatest impact. The AF characteristics burden (percentage of time in AF), duration and number of AF episodes/month were obtained from implantable cardiac monitors during the 2-month run-in period in 150 patients included in the randomized CAPTAF trial comparing early ablation and antiarrhythmic drug therapy. The QoL was measured by the General Health and Vitality dimensions of the 36-Item Short-Form Health Survey. AF characteristics were analysed continuously and in quartiles (Q1-Q4). Greater AF burden (p = 0.003) and longer AF episodes (p = 0.013) were associated with impaired QoL (Vitality score only) in simple linear regression analyses. Greater AF burden was, however, the only AF characteristic associated with lower QoL, when adjusted for sex, type of AF, hypertension, heart rate above 110 beats per minute during AF, and beta-blocker use in multiple linear regression analyses. For every 10% increase in AF burden there was a 1.34-point decrease of Vitality score (95% confidence interval (CI) -2.67 to -0.02, p = 0.047). The Vitality score was 12 points lower (95% CI -22.73 to -1.27, p = 0.03) in patients with an AF burden > 33% (Q4) versus those with < 0.45% (Q1), but only in unadjusted analysis. AF burden had a greater impact on QoL (Vitality), than the duration and number of AF episodes, corroborating that AF burden may be the preferred outcome measure of rhythm control in trials including relatively healthy AF populations.


Characterization of an O-glucuronide metabolite of the CCK-B antagonist LY288513 and its plasma levels in mouse, rat, and dog.
LY288513 [(4S,5R)-trans-N-(4-bromophenyl)-3-oxo-4,5-diphenyl-1- pyrazolidinecarboxamide] has been developed as a cholecystokinin-B antagonist for anxiolytic indications. In the drug disposition studies reported herein, we found LY288513 was metabolized rapidly in mice and rats to form a glucuronide adduct. This metabolite was isolated from rodent urine and further characterized to determine whether a ring-nitrogen or the oxygen atom in the pyrazolidinone nucleus of LY288513 was bonded to the glucuronide. Using 13C NMR plus two-dimensional rotating frame Overhauser enhancement spectroscopy analysis and IR analysis of model compounds, we determined the metabolite was an O-glucuronide. The major elimination pathway for [14C]LY288513 was fecal, with > 75% of total radiocarbon excreted within 24 hr. Plasma levels for parent and metabolite in the three species varied substantially. The plasma half-life was significantly longer in dogs (approximately 12 hr) than mice (approximately 24 hr) or rats (2.6-3.6 hr). Consistent with this, in dogs relatively little O-glucuronide was observed in plasma, but in rats and mice the AUCs for glucuronide were greater than the parent AUC. A dose-ranging study in rats revealed oral absorption of LY288513 is nonsaturated, even after 800 mg/kg oral doses. A plot of AUC vs. dose revealed a consistent overproportional increase in AUC for both parent and glucuronide metabolite with increasing dose.


Differential response to 1,3-bis (2-chloroethyl)-1-nitrosourea in drug-resistant and -sensitive 9L rat brain tumor cells pretreated with alpha-difluoromethylornithine and 6-thioguanine.
Pretreatment of 9L cells with either alpha-difluoromethylornithine (DFMO), which depletes intracellular levels of polyamines, or 6-thioguanine (6TG), which substitutes for guanine in DNA, potentiates the cytotoxic effects of 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU). We examined the effects of these 2 agents in combination on the cytotoxicity of BCNU in sensitive (9L) and resistant (BTRC-19) rat brain tumor cell lines. 9L cells were incubated with 0.2 microM 6TG for 72 hr; during the last 48 hr, 1 mM DFMO was added to cell cultures. The cytotoxicity of BCNU in pretreated cells was increased in an additive manner compared with the effects of each agent alone. Results of experiments in which the BCNU-resistant BTRC-19 cell line was treated similarly showed that only 6TG enhanced BCNU cytotoxicity. Flow cytometry studies showed that these effects are not related to cell-cycle processes.


Iliac artery occlusion with "oxbow lake" formation following stent deployment in a tortuous external iliac artery during EVAR: a case report.
In this case report, we describe a complication that we term the "oxbow lake" deformity. This phenomenon occurs when a tortuous elongated external iliac artery segment is artificially straightened by an iliac stent resulting in kinking and compression of a redundant loop with lumen compromise. We describe the anatomy, corrective treatment, and outcome. This occurrence is potentially foreseeable with tortuous vascular anatomy and recognition can allow appropriate management planning avoiding complications for the patient.


[Risk of stenosis and incontinence after using a No. 27 resector and preventive urethrotomy for transurethral resections of the prostate].
The authors report a series of 50 patients undergoing transurethral prostatic resection with a no 27 resector. The resection was preceded by an Otis urethrotomy. The incidence of post-operative urethral stenosis was 2% and there were no cases of incontinence.


Photoreactivating enzyme in the blind cave fish, Anoptichthys jordani.
1. Exposure of cells to ultraviolet light induces molecular changes in DNA which may lead to cellular death. 2. One product, pyrimidine dimers, is reversed during subsequent exposure to visible light by photoreactivating enzyme. 3. Photoreactivating enzyme has been recorded in different organisms, but inconsistencies in its distribution suggest it may have other functions. 4. We have found photoreactivating enzyme in the blind cave dwelling fish, Anoptichthys jordani. 5. Sufficient time has elapsed in the cave environment to allow loss of features of importance to epigean fish, including the eyes and pigmentation. 6. The continued presence of the enzyme indicates that it may have other functions.


Novel potent and selective σ ligands: evaluation of their agonist and antagonist properties.
Novel enantiomers and diastereoisomers structurally related to σ ligand (+)-MR200 were synthesized to improve σ(1)/σ(2) subtype selectivity. The selective σ(1) ligand (-)-8 showed an antagonist profile determined by phenytoin differential modulation of binding affinity in vitro, confirmed in vivo by an increase of κ opioid analgesia. The σ(2) ligand (-)-9 displayed agonist properties in an in vitro isolated organ bath assay and antiproliferative effects on LNCaP and PC3 prostate cancer cell lines.


Preoperative fiducial coil placement facilitates robot-assisted laparoscopic excision of retroperitoneal small solitary metastasis of kidney cancer.
Image-guided fiducial markers are being used in surgery, especially in spine and breast surgery, and radiotherapy, allowing localization of tumor sites precisely. We report a case of fiducial coil use in a man undergoing a robot-assisted laparoscopic resection of a metastatic nodule under the ipsilateral diaphragm after robot-assisted partial nephrectomy performed 2 years ago for a left upper pole renal tumor. The fiducial coil facilitated the localization of the lesion, which would otherwise have been challenging because of its small size and location. In addition, the fiducial coil was helpful to avoid cutting into the lesion directly.


Systemic Lupus Erythematosus Patients with DNASE1L3·Deficiency Have a Distinctive and Specific Genic Circular DNA Profile in Plasma.
Cell-free (cf) extrachromosomal circular DNA (eccDNA) has a potential clinical application as a biomarker. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a complex immunological pathogenesis, associated with autoantibody synthesis. A previous study found that SLE patients with deoxyribonuclease 1-like 3 (DNASE1L3) deficiency exhibit changes in the frequency of short and long eccDNA in plasma compared to controls. Here, using the DifCir method for differential analysis of short-read sequenced purified eccDNA data based on the split-read signal of the eccDNA on circulomics data, we show that SLE patients with DNASE1L3 deficiency have a distinctive profile of eccDNA excised by gene regions compared to controls. Moreover, this profile is specific; cf-eccDNA from the top 93 genes is detected in all SLE with DNASE1L3 deficiency samples, and none in the control plasma. The top protein coding gene producing eccDNA-carrying gene fragments is the transcription factor BARX2, which is involved in skeletal muscle morphogenesis and connective tissue development. The top gene ontology terms are 'positive regulation of torc1 signaling' and 'chondrocyte development'. The top Harmonizome terms are 'lymphopenia', 'metabolic syndrome x', 'asthma', 'cardiovascular system disease', 'leukemia', and 'immune system disease'. Here, we show that gene associations of cf-eccDNA can serve as a biomarker in the autoimmune rheumatic diseases.


[Comparative studies of bronchial flora by means of a conventional and a new technic of taking specimens (author's transl)].
A modification of a method described by LEES and MCNAUGHT for taking of bronchial specimens for bacteriological examination is reported and compared with the usual taking of specimens in a group of 275 patients. Working with the new method the contamination decreased from 55% to 20% of the examined patients. These contaminations in the new method are easy to distinguish from the real settlement of germs to separate. In patients with pyogenic bronchitis a higher percentage of positive bacterial cultures is to be found. The use of this method in hospitals is recommended.


Evaluation of dizziness in the litigating patient.
Evaluation of dizziness in patients who are involved in litigation can deviate significantly from the evaluation of patients who have no ongoing litigation. This article presents the basic principles of the physician's role in the evaluation of litigating patients. Considerations for physical examination, diagnostic testing, and review of medical records are discussed. Topics of malingering and legal "pearls" are presented in the context of providing an objective and unbiased evaluation of the litigating patient.


The use of electrophoresis of the water-soluble (sarcoplasmic) proteins of fish muscle to differentiate the closely related species of hake (Merluccius sp.).
1. Electrophoretic separation patterns of water-soluble proteins of five species of hake, Merluccius merluccius; M. australis; M. productus; M. bilinearis and M. angustimanus, have been examined. 2. The patterns were reproducible within each species and distinguishable from one another. 3. The frequency distribution of numbers of vertebrae and of gillrakers were obtained for the same fish. 4. Only the electrophoretic patterns gave an unequivocal identification of the species.


Exercise adaptations and TGF-β1 levels in recreational cyclists.
Cycling is a physical exercise that is widely performed to improve physical fitness. Regular physical exercise will lead to adaptations to exercise. This adaptation is useful in suppressing the production of reactive oxygen stress (ROS) generated in response to cellular metabolism that uses oxygen. Transforming growth factor beta-1 (TGF-β1) plays a role in increasing the production of ROS, thus, when the concentration is low, it would lead to an improvement in physical fitness. This study aims to compare levels of TGF-β1 between recreational cyclists and sedentary groups. In addition, this research also compares several other parameters, which are fasting blood sugar levels and lipid profiles (triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol) between cyclists and sedentaries. This was an observational analytical study with a cross-sectional design. The research subjects consisted of 2 groups, each consisting of 21 participants, namely the recreational cyclist and the sedentary group. Anthropometric examinations were carried out, including body weight, height, body mass index, waist circumference, and body fat percentage. Fasting blood glucose concentration and lipid profile (Triglyceride - TG, Total Cholesterol - Total C, HDL Cholesterol - HDL-C, and LDL Cholesterol - LDL-C) were determined by the enzymatic colorimetric methods, and TGF-β1 levels were determined using the fluorescence of specific antibodies for TGF-β1 (pg/ml) using ELISA method. Statistical analysis was performed using IBM SPSS v. 25. The anthropometric variables, other than body height, did not differ significantly between the two groups, so did the fasting blood glucose concentration. Nevertheless, the lipid profile (TG, Total C, HDL-C and LDL-C) were found to be significantly better in the cyclist group (p < 0.05).The mean level of TGF-β1 in recreational cyclists was 8, 908.48 pg/ml, lower than the control group, 10, 229.28 pg/ml. The results of the unpaired t-test showed significant mean differences between the two groups, (p = 0.001; p < 0.05). The levels of TGF-β1 in the recreational cyclist group were lower than the sedentary group. Regular physical exercise will trigger exercise adaptations that can suppress latent TGF-β1 activation.


Income-Nutrition Gradient and Intrahousehold Allocation in Rural Pakistan.
To estimate the relationship between household income and child health outcomes for male and female children, aged 0-5 years, in rural Pakistan. The study uses 2014 round of Pakistan Rural Household Panel Survey (PRHPS) and regression analyses to estimate the relationship between household income and child health outcomes for male and female children in rural Pakistan. We find that increase in income is associated with an increase in child weight-for-age and weight-for-height z-scores, and reduction in the likelihood of a child being underweight or wasted. However, our results suggest that these gains associated with an increase in income are greater for male children as compared to female children. These differences in income-nutrition gradient can be explained by the gender-differences in consumption of health inputs (e.g., food intake, vaccinations, and nutritional supplements) associated with an increase in income. Our results indicate the need for policy instruments that can encourage an equitable resource allocation within households.


Electromagnetic articulography appears feasible for assessment of speech motor skills in cochlear-implant users.
The present investigation tested whether there is cross-interference between current electromagnetic articulography (EMA) and cochlear implants (CIs). In an initial experiment, we calibrated EMA sensors with and without a CI present in the EMA field, and measured impedances of all CI electrodes when in and out of the EMA field. In a subsequent experiment, head reference sensor positions were recorded during a speaking task for a normal-hearing talker with and without a CI present in the EMA field. Results revealed minimal interference between the devices, suggesting that EMA is a promising method for assessing speech motor skills in CI users.


Interpretable tree-based ensemble model for predicting beach water quality.
Tree-based machine learning models based on environmental features offer low-cost and timely solutions for predicting microbial fecal contamination in beach water to inform the public of the health risk. However, many of these models are black boxes that are difficult for humans to understand, which may cause severe consequences such as unexplained decisions and failure in accountability. To develop interpretable predictive models for beach water quality, we evaluate five tree-based models, namely classification tree, random forest, CatBoost, XGBoost, and LightGBM, and employ a state-of-the-art explanation method SHAP to explain the models. When tested on the Escherichia coli (E. coli) concentration data collected from three beach sites along Lake Erie shores, LightGBM, followed by XGBoost, achieves the highest averaged precision and recall scores. For all three sites, both models suggest lake turbidity as the most important predictor, and elucidate the crucial role of accurate local data of wave height and rainfall in the model development. Local SHAP values further reveal the robustness of the importance of lake turbidity as its SHAP value increases nearly monotonically with its value and is minimally affected by other environmental factors. Moreover, we found an intriguing interaction between lake turbidity and day-of-year. This work suggests that the combination of LightGBM and SHAP has a promising potential to develop interpretable models for predicting microbial water quality in freshwater lakes.


Stability-Weighted Matrix Completion of Incomplete Multi-modal Data for Disease Diagnosis.
Effective utilization of heterogeneous multi-modal data for Alzheimer's Disease (AD) diagnosis and prognosis has always been hampered by incomplete data. One method to deal with this is low-rank matrix completion (LRMC), which simultaneous imputes missing data features and target values of interest. Although LRMC yields reasonable results, it implicitly weights features from all the modalities equally, ignoring the differences in discriminative power of features from different modalities. In this paper, we propose stability-weighted LRMC (swLRMC), an LRMC improvement that weights features and modalities according to their importance and reliability. We introduce a method, called stability weighting, to utilize subsampling techniques and outcomes from a range of hyper-parameters of sparse feature learning to obtain a stable set of weights. Incorporating these weights into LRMC, swLRMC can better account for differences in features and modalities for improving diagnosis. Experimental results confirm that the proposed method outperforms the conventional LRMC, feature-selection based LRMC, and other state-of-the-art methods.


[Comparison of ready-to-use devices for emergency cricothyrotomy : randomized and controlled feasibility study on a mannequin].
According to various algorithms of airway management, emergency cricothyrotomy (coniotomy) represents the ultimate step for managing the difficult airway. As most physicians have limited experience with this technique several ready-to-use devices have emerged on the market with the aim of simplifying the procedure. However, they differ in details, such as configuration or the order of particular steps. Therefore, the intention of this randomized and controlled feasibility study was to test various sets and compare them to the classical surgical approach. After obtaining informed consent German anesthesiologists who were also board-certified emergency physicians were asked to perform the cricothyrotomy procedure in a cervical mannequin (Frova Crico-Trainer, VBM Medizintechnik) in a randomized order using a scalpel, peripheral intravenous cannula and the commercial devices TracheoQuick, Airfree, Portex-Crico-Kit, Quicktrach I and Quicktrach II. Handling and duration of the procedures were analyzed utilizing the Wilcoxon signed-rank test. A p-value < 0.05 was considered significant. A total of 20 anesthesiologists (11 residents and 9 specialists) with a mean age of 34 years were included in this study and all had the additional qualification of emergency physician, which enabled them to work in prehospital emergency medicine in Germany. Participants had been working in this field for an average of 29.9 months (range 6-84 months) performing a mean of 1.9 24 h shifts per month (range 1-6 shifts/month). Of the participants only 2 (10%) had performed a coniotomy in reality before. In this study surgical coniotomy required a median time of 35.4 s (range 30.0-61.8 s). No significant differences were seen when the cuffed devices Quicktrach II (median: 29.9 s, range 25.0-50.5 s) and Portex-Crico-Kit (median: 46.7 s, range 37.0-67.3 s) were used. A significantly faster airway was established using the non-cuffed devices TracheoQuick (median: 20.2 s, range 11.4-44.7 s), Airfree (median: 22.8 s, range 14.3-33.2 s), Quicktrach I (median: 21.1 s, range 14.5-32.4 s) and the peripheral intravenous cannula (median: 19.2 s, range 10.8-27.8 s). Incorrect tube placements were not observed. This study allowed the comparison of surgical coniotomy to several ready-to-use devices in a standardized setting utilizing a reusable plastic mannequin. The interpretation for real emergency conditions is limited as individual anatomy, traumatic alterations of the neck or complications, such as bleeding or damage of important structures were not part of the study objectives. However, all participating emergency physicians successfully used the coniotomy sets provided at the first attempt. No device required significantly more time than the surgical approach. The procedures using cuffed devices lasted longer in comparison to procedures using uncuffed ones; however, this difference would only play a minor role in reality as effective ventilation with minute volumes greater than 7 l/min will only be achieved by a cuffed cannula with a minimum internal diameter of 4 mm. Devices with no cuff or with tube diameters smaller than 4 mm will only allow oxygenation of the patient, which in turn requires an inspiratory oxygen concentration of 100% and a relatively high ventilation frequency.


Approach to the Superior Ophthalmic Vein for Endovascular Treatment of Cavernous Dural Fistula.
The cavernous sinus area is the second most common location for intracranial dural fistulas. Although these spontaneous dural cavernous fistulas are self-limited, a sizeable number of patients will develop progressive vision loss, diplopia, or intractable glaucoma, which warrant interventional therapy.1,2 We present the case of a 54-year-old male with hypertension and type 2 diabetes, who presented with a red right eye associated with progressive exophthalmos, ophthalmoparesis, and deterioration of visual acuity. The angiotomography showed the exophthalmos with an ingurgitated superior ophthalmic vein, with early filling in the arterial phase. A digital angiography was made, and a diagnosis of dural cavernous fistula, Barrow type D was made.3 Considering several transvenous approaches, alternatives included inferior petrosal sinus, access through the superior ophthalmic vein, and an open approach.4 In this particular case the inferior petrosal sinus was not present, so we tried to catheterize through the facial vein and also puncture the ophthalmic vein. Both procedures were unsuccessful. We decided to perform, then, an open approach with the oculoplastic surgery team (Video 1). Through an eyelid dissection, we localized the superior ophthalmic vein and then canalized it by direct visualization.5 With this approach, we were able to perform the cavernous sinus packing with coils and achieved a complete occlusion of the fistula. We reproduced the direct approach to the superior ophthalmic vein in a cadaveric specimen and schematized it step by step with 3-dimensional photographs.6.


Interaction of the delta-opioid receptor with GM1 ganglioside: conversion from inhibitory to excitatory mode.
Previous studies have shown GM1 ganglioside to play a crucial role in regulating excitatory opioid receptor function, which may underlie some aspects of opioid dependence, tolerance, and supersensitivity. To study the mechanism of this receptor modulation we have employed CHO cells containing a single, transfected opioid receptor of the delta-type. When forskolin was employed to elevate cAMP the reduction affected by 10 microM DADLE was counteracted by preincubation of the cells with GM1. No effect was observed with GD1a, GD1b, GT1b GM3, or the GM1 derivative, GM1-OH. In pertussis toxin-treated cells 10 nM DADLE increased basal levels of cAMP after preincubation with as little as 10 nM GM1. The results suggest conformational alteration of the opioid receptor from a form coupled primarily to G(i)/G(o) to one also capable of interacting with G(s).


The effect of endometriosis on pregnancy outcome following in vitro fertilization-embryo transfer (IVF-ET) in women with decreased egg reserve.
To determine the effect of the presence of endometriosis on the delivered pregnancy rate following in vitro fertilization-embryo transfer. A retrospective cohort analysis of fresh or frozen embryo transfer in women with diminished egg reserve having IVF-ET and who also had had a laparoscopy. The data was analyzed as to whether endometriosis was present or not. The data demonstrated that women with diminished egg reserve can achieve pregnancies following IVF-ET. The presence of endometriosis did not have any negative effects on pregnancy rates. At least in women with diminished egg reserve the presence of endometriosis did not impair outcome following IVF-ET.


Characterisation of particulates and trace metals emitted by a dimethyl ether-fuelled genset engine prototype.
Diesel-fuelled CI engines are the primary sources of particulate matter (PM) emissions which harm human health and the urban environment. Elevated PM emission levels can cause respiratory diseases and deteriorate urban air quality and atmospheric visibility. DME, a carbon-neutral and oxygenated fuel, is fast merging as a strong alternative to diesel to reduce PM emissions. The absence of a direct carbon-carbon bond in the molecular structure of DME improves combustion and reduces PM emissions to negligible levels. DME and baseline diesel are experimentally evaluated in a single-cylinder CI genset engine prototype to find the particulate number-size, surface area-size and mass-size distributions. In addition, total particulate number (TPN), total particulate mass (TPM), count mean diameter (CMD) of particulates, particulate morphology and trace metals were assessed. DME genset engine emitted higher numbers of smaller diameter particles, with lower surface area and mass distribution than baseline diesel. For DME, total PM mass emission and CMD of particulates were lower due to particles being finer. Morphological analysis of particulates showed the presence of larger particles from diesel and less bunched agglomerates of nucleation mode particles from the DME genset engine prototype. The trace metal analysis of particulates showed higher presence of trace metals such as Si, Ca, and Na in DME-fuelled engine than in diesel. As an alternative to diesel, DME can reduce PM emissions from genset engines, significantly enhance urban air quality, and minimise the threat of respiratory diseases.


Tribo-induced melting transition at a sliding asperity contact.
Observation of a tribo-induced transition from solid to liquidlike behavior is reported for a scanning tunneling microscope tip in sliding contact with an indium electrode of a quartz crystal microbalance (QCM). In particular, at a sufficiently high asperity sliding speed (about 1 m/s) and/or sample temperature, a change in the contact mechanics is observed that is consistent with melting in terms of both the QCM response and an energy analysis. The results confirm that the surface, rather than bulk, melting point temperature is the more relevant quantity for tribological considerations.


Effects of intracerebroventricular losartan on angiotensin II-mediated pressor responses and c-fos expression in near-term ovine fetus.
The renin-angiotensin system plays an important role in cardiovascular control. Intracerebroventricular (i.c.v.) angiotensin (ANG) II causes a reliable pressor response in the fetus at 90% gestation. To determine the roles of brain AT1 and AT2 receptors in this response, the effects of the central AT1 and AT2 receptor antagonists losartan and PD123319 were investigated in chronically prepared near-term ovine fetuses. Losartan at 0.5 mg/kg (i.c.v.) abolished central ANG II-induced pressor responses. High-dose losartan (5 mg/kg, i.c.v.) showed a potentiation of the pressor response to i.c.v. ANG II, accompanied by bradycardia. Associated with the pressor responses, c-fos expression in the cardiovascular controlling areas was significantly different between the low and high doses of losartan. These areas included the subfornical organ, median preoptic nucleus, organum vasculosum of the lamina terminalis, and paraventricular nuclei in the forebrain, and the tractus solitarius nuclei, lateral parabrachial nuclei in the hindbrain. Low-dose losartan markedly reduced c-fos in these areas after i.c.v. ANG II, while the high-dose losartan together with ANG II elicited a much stronger FOS-immunoreactivity in these areas than that induced by i.c.v. ANG II alone. This is a novel finding, that c-fos expression in the brain can be both activated and inhibited under the same condition. Central ANG II-induced fetal pressor responses were not altered by PD123319 (0.8 mg/kg). These results indicate that i.c.v. losartan at a high and a low dose has strikingly different effects on central ANG II-induced pressor responses in fetuses at late gestation, and that the AT1 mechanism plays an important role in fetal cardiovascular regulation.


Non-medical cannabis use among Indigenous Canadians: A systematic review of prevalence and associated factors.
Indigenous Canadians may be at an increased risk of non-medical cannabis use. The aim of this review was to synthesize the prevalence of non-medical cannabis use and its associated factors among Indigenous Canadians. We systematically searched MEDLINE, EMBASE, Web of Science, and Scopus from inception to January 29th, 2020 for publications reporting the prevalence of non-medical cannabis use among Indigenous Canadians. We included studies published in English after January 1st, 2000. Included publications were hand-searched for potentially relevant peer-reviewed and gray literature publications. Results were synthesized descriptively. We identified 16 peer-reviewed and 7 gray literature publications which met our inclusion criteria. All data were collected prior to cannabis legalization in Canada (October 17th, 2018). The most recent estimates of prevalence of use in the past year were 27% among on-reserve First Nations adults, 50% among off-reserve First Nations adults, and 60% among Nunavik Inuit. In youth, they were 45% among all Indigenous youth grades 9-12, 27% among on-reserve First Nations youth aged 12-17, and 69% in Nunavik Inuit aged 16-22. Direct comparisons indicated a 1.2-15 times higher prevalence of use in Indigenous compared to non-Indigenous youth. Factors associated with cannabis use in adults included younger age and male sex. In youth, factors included older age, poorer mental and physical health, and a poorer relationship with school. Results suggest that Indigenous Canadians are at a higher risk for non-medical cannabis use than the general Canadian population. Further research is warranted to inform the development of targeted interventions.


Predictive and explanatory themes of NOAEL through a systematic comparison of different machine learning methods and descriptors.
No observed adverse effect level (NOAEL) is an identified dose level which used as a point of departure to infer a safe exposure limit of chemicals, especially in food additives and cosmetics. Recently, in silico approaches have been employed as effective alternatives to determine the toxicity endpoints of chemicals instead of animal experiments. Several acceptable models have been reported, yet assessing the risk of repeated-dose toxicity remains inadequate. This study established robust machine learning predictive models for NOAEL at different exposure durations by constructing high-quality datasets and comparing different kinds of molecular representations and algorithms. The features of molecular structures affecting NOAEL were explored using advanced cheminformatics methods, and predictive models also communicated the NOAEL between different species and exposure durations. In addition, a NOAEL prediction tool for chemical risk assessment is provided (available at: https://github.com/ifyoungnet/NOAEL). We hope this study will help researchers easily screen and evaluate the subacute and sub-chronic toxicity of disparate compounds in the development of food additives in the future.


Phase I study of sapanisertib with carboplatin and paclitaxel in mTOR pathway altered solid malignancies.
Pre-clinically, the mTORC1/2 inhibitor sapanisertib restored sensitivity to platinums and enhanced paclitaxel-induced cancer cell killing. NCT03430882 enrolled patients with mTOR pathway aberrant tumors to receive sapanisertib, carboplatin and paclitaxel. Primary objective was safety and secondary objectives were clinical response and survival. One patient had a dose-limiting toxicity at dose level 4. There were no unanticipated toxicities. Grade 3-4 treatment-related adverse events included anemia (21%), neutropenia (21%), thrombocytopenia (10.5%), and transaminitis (5%). Of 17 patients evaluable for response, 2 and 11 patients achieved partial response and stable disease, respectively. Responders included a patient with unclassified renal cell carcinoma harboring EWSR1-POU5F1 fusion and a patient with castrate resistant prostate cancer harboring PTEN loss. Median progression free survival was 3.84 months. Sapanisertib in combination with carboplatin plus paclitaxel demonstrated a manageable safety profile, with preliminary antitumor activity observed in advanced malignancies harboring mTOR pathway alterations.


Molecular evolutionary history of tubercle bacilli assessed by study of the polymorphic nucleotide within the nitrate reductase (narGHJI) operon promoter.
A well-characterized collection of Mycobacterium tuberculosis complex (MTC) isolates, representing all known subspecies as well as some relevant genotypic families of M. tuberculosis, was analyzed for the newly discovered narGHJI -215 C-to-T promoter single-nucleotide polymorphism (SNP). This point mutation has been shown in earlier studies to be responsible for the differential nitrate reductase activity of M. tuberculosis versus M. bovis. As previously defined by the presence or the absence of the TbD1 genetic locus, the group included both the "modern" W-Beijing, Haarlem, and Central-Asian1 (CAS1) families as well as the "ancestral" East-African-Indian (EAI) clade. Interestingly, among "modern" M. tuberculosis isolates, those previously classified as Principal Genetic Group 1 (PGG1) organisms by katG463-gyrA95 polymorphism analysis did not present the two-banded narGHJI restriction fragment length polymorphism analysis of PCR products pattern common to the other PGG1 MTC members, including the "ancestral" M. tuberculosis isolates. Instead, they showed a one-banded pattern, aligning them with other evolutionarily recent M. tuberculosis isolates of the PGG2 and PGG3 groups, such as Haarlem, Latin-American and Mediterranean (LAM), and X families. The presence of a nitrate reductase producer phenotype in "Mycobacterium canettii" and some "ancestral" M. tuberculosis isolates, despite a two-band -215C genotype, argues in favor of an alternate mechanism to explain the differential nitrate reductase activity of certain PGG1 subspecies of the MTC. Overall, these findings may help to establish the precise evolutionary history of important genotype families such as W-Beijing and suggest that the -215T genotype may have contributed the virulence, spread, and evolutionary success of "modern" M. tuberculosis strains compared to the remaining MTC organisms.


Fibrous Conductive Metallogels with Hybrid Electron/Ion Networks for Boosted Extreme Sensitivity and High Linearity Strain Sensor.
Fibrous strain sensing materials with both high sensitivity and high linearity are of significant importance for wearable sensors, yet they still face great challenges. Herein, a photo-spun reaction encapsulation strategy is proposed for the continuous fabrication of fibrous strain sensor materials (AMGF) with a core-sheath structure. Metallogels (MOGs) formed by bacterial cellulose (BC) nanofibers and Ag nanoparticles (AgNPs), and thermoplastic elastomers (TPE) are employed as the core and sheath, respectively. The in situ ultraviolet light reduction of Ag+ ensured AgNPs to maintain the interconnections between the BC nanofibers and form electron conductive networks (0.31 S m-1 ). Under applied strain, the BC nanofibers experience separation, bringing AMGF a high sensitivity (gauge factor 4.36). The concentration of free ions in the MOGs uniformly varies with applied deformation, endowing AMGF with high linearity and a goodness-of-fit of 0.98. The sheath TPE provided AMGF sensor with stable working life (>10 000 s). Furthermore, the AMGF sensors are demonstrated to monitor complex deformations of the dummy joints in real-time as a wearable sensor. Therefore, the fibrous hybrid conductive network fibers fabricated via the photo-spun reaction encapsulation strategy provide a new route for addressing the challenge of achieving both high sensitivity and high linearity.


Regulation of the murine TR2/HVEM gene expression by IRF.
TR2 (TNFR-related 2, HVEM, or TNFRSF-14), a member of the TNFR family, is involved in a number of immune responses. While TR2 is expressed on the surface of T cells during the resting state, little is known regarding how expression of the TR2 gene is regulated. To understand the mechanisms regulating the expression of TR2 in T cells, we analyzed the 5' flanking region of TR2. We identified an important region for the activity of the TR2 promoter using site directed mutagenesis. Using EMSA analysis, we found that IRF-2 was bound to the promoter region of the TR2 gene during the resting state of EL-4 T cells. Transfection of IRF-2 expression plasmid and of dominant negative IRF-2 mutant further confirmed our results. Together, these data demonstrate that IRF-2 is involved in the regulation of TR2 expression in EL-4 T cells.


Study protocol for a pragmatic cluster RCT on the effect and cost-effectiveness of Everyday Life Rehabilitation versus treatment as usual for persons with severe psychiatric disability living in sheltered or supported housing facilities.
People with severe psychiatric disabilities and impaired autonomy, living in sheltered or supported housing facilities, often lead sedentary, solitary lives indoors and have significantly poorer health than others in the population. Meaningful everyday activities are important for the recovery towards an enrichening, agentic, social, and hopeful everyday life. The Everyday Life Rehabilitation (ELR) model-a person-centred activity- and recovery-oriented intervention-has shown positive outcomes in feasibility studies, and thus a randomised controlled trial (RCT) is required to establish the effectiveness of ELR, along with calculations of cost-effectiveness. The ELR-RCT is a pragmatic, two-parallel-armed cluster RCT evaluating the effect and cost-effectiveness of using ELR from two measurement points over 6 months (pre-post intervention) and in three waves over 3 years. The primary outcome is recovering quality of life (ReQoL) at 6 months, and the secondary outcome is self-perceived recovery and daily functioning (RAS-DS) at 6 months. Additionally, Goal Attainment Scaling (GAS) will be used for the intervention group. Power analysis has been conducted for primary outcome measure. The first wave will include an internal pilot, to be evaluated after 6 months, used as basis for decisions on updating the required sample size and any other need for adaptations before continuing with the full-scale RCT in the second and third wave. All municipalities within a geographic area in northern Sweden, with a minimum of one sheltered or supported housing facility for people with severe psychiatric or neuropsychiatric disability, including access to occupational therapy, will be enrolled. Participants will be block-randomised to receive ELR plus treatment as usual (TAU) or TAU alone for a control period. The control group will thereafter receive delayed ELR. Occupational therapists and housing staff will receive an educational package, manuals, and tools, as well as reflections with colleagues during the intervention period. Housing managers will receive questions for monthly follow-up and coaching with staff. This is a protocol for both an internal pilot and full trial of the first RCT study using the ELR intervention model in sheltered or supported housing facilities, evaluating the effects together with cost-effectiveness. ClinicalTrials.gov NCT05056415. Registered on 24 September 2021.


Should ultrasound-guided needle fenestration be considered as a treatment option for recalcitrant patellar tendinopathy? A retrospective study of 47 cases.
To report the retrospective results of ultrasound-guided needle fenestration for the treatment of recalcitrant patellar tendinopathy. Retrospective follow-up study. University outpatient sports medicine clinic. Forty-seven patellar tendons in 32 patients (26 men and 6 women; mean age, 26 years) with recalcitrant patellar tendinopathy. Diagnosis made via history, physical examination, and sonographic examination. Ultrasound-guided needle fenestration after failure of conservative management. Pre-treatment and 4-week clinical follow-up determination of functional activity score. Phone follow-up determination of best achievable level of activity and satisfaction score of the procedure. Average time to follow-up was 45 months. Seventy-two percent of patients reported excellent or good results when questioned regarding return to activity. Twenty-eight percent of patients were unable to return to their desired activity level. Six patients subsequently underwent surgical treatment. One athlete underwent surgery to repair a patellar tendon rupture that occurred 6 weeks after the procedure. Eighty-one percent of patients reported excellent or good satisfaction scores. Ultrasound-guided needle fenestration warrants further investigation for the treatment of recalcitrant patellar tendinopathy.