Outcomes following adolescent athlete proximal hamstring apophyseal avulsion bone fragment excision and direct tendon-ischial tuberosity reattachment.
Apophyseal proximal hamstring bone avulsion is uncommon, occurring in adolescents following sudden forceful contraction of the musculotendinous unit. It can be severely disabling, preventing return to sport. This study assessed outcome following avulsed bone excision and direct hamstring tendon-ischial tuberosity reattachment using bone anchors. Validated hamstring-specific Sydney hamstring orthopaedic research evaluation PROMs were prospectively collected from consecutively treated athletes (7 elite and 11 recreational) by a single surgeon over 13 years. Outcomes at 1-year and final follow-up for primary acute surgery at less than 3 months after injury (group 1), primary chronic surgery at more than 3 months after established nonunion (group 2) and revision following failed screw fixation (group 3) were analyzed with sport participation and level at 1 year. Sixteen primary and two revision procedures were analyzed. Mean injury age was 14.6 years (SD, 1.8). Combined primary mean injury scores improved from 11.89 (SD, 7.32) to 33.31 (SD, 2.30) and showed mean 1 year and final follow-up scores within 0.3-6.1% of preinjury values. Pronounced improvement occurred from injured scores for groups 1 versus 2, respectively at 1 year by 247.7% versus 59.0% and at final follow-up by 251.0% versus 64.1%, for groups 1 versus 2, respectively. Final outcome scores of group 3 were high. All cases returned to preinjury sport level by 1 year and indicated satisfaction to repeat treatment. No significant complications occurred. As the largest series to assess outcomes following this surgical technique, success is highlighted by high score improvements close to preinjury values and return to preinjury sport level.


Fluoropolymer coated Dacron or polytetrafluoroethylene for femoropopliteal bypass grafting: a multicentre trial.
This trial was designed to compare graft patency between expanded polytetrafluoroethylene (PTFE) and fluoro-polymer coated Dacron for femoropopliteal bypass in patients in whom saphenous vein was unavailable. A multicentre prospective trial randomized 129 patients (74 men, 55 women) who underwent femoropopliteal bypass using either a PTFE or fluoropolymer coated Dacron graft. The indication for operation was disabling claudication in 68 (52.7%) and critical limb ischaemia in 61 (47.3%) patients. Distal anastomosis was above the knee in 76 (58.9%) and below the knee in 53 (41.1%) patients. Primary patency at 6, 12 and 24 months was 71%, 56% and 47% for PTFE and 50%, 36% and 36% for fluoropolymer coated Dacron (P = 0.002), respectively. Secondary patency at 6, 12 and 24 months was 77%, 60% and 48% for PTFE and 66%, 49% and 46% for fluoropolymer coated Dacron (P = 0.13), respectively. The superior primary patency of PTFE over fluoropolymer coated Dacron was most evident in patients with poor prognostic indicators for graft survival: critical limb ischaemia (P = 0.001); below-knee anastomosis (P = 0.01); and smaller (6 mm) diameter grafts (P = 0.002). Graft thrombosis developed in the first month in 22 of 61 (36%) patients receiving fluoropolymer coated grafts compared to six of 68 (8.8%) patients receiving PTFE, which accounts for the difference in primary patency. Successful thrombectomy in 10 of the 22 fluoropolymer coated grafts resulted in similar secondary patency. Polytetrafluoroethylene has superior primary patency and similar secondary patency to fluoropolymer coated Dacron. These results support the preferential use of PTFE in patients with critical limb ischaemia, especially when a below-knee distal anastomosis and smaller diameter graft is required.


Are only a few hours adequate for hospitalisation following mini-incision open appendectomy in paediatric patients?
A very short hospital length of stay following an open appendectomy in children with acute simple appendicitis has never been mentioned yet in the literature. The authors reviewed the outcome of these paediatric patients who were treated with the open technique. In this analytical cohort observational study, we retrospectively reviewed the medical records of the 115 consecutive patients who underwent open appendectomy from June 2017 to July 2021. There were 84 patients whose appendices were inflammatory or suppurative and appendectomies were done only through McBurney's point. Of these, the average age was 9.11 ± 2.67 years. The mean length of the incision was 1.95 ± 0.48 cm. Nearly one-third (25/85) were discharged within 3 h following surgery. Of the remaining cases, nine patients were discharged within the same day. There were increased percentages of patients who were eligible for early discharge in each consecutive year. The idea of immediate discharge within 3 h seems to be feasible for children with acute simple appendicitis who were treated with open appendectomy. We believe that the practice will be widely acknowledged and proceed to reduce the resources and the expenses in the hospital.


Facile N-Alkylation/N'-Arylation Process: A Direct Approach to Aromatic Aminoalkyl Amines.
An intriguing C-N transformation involving a catalyst-free N-alkylation/N'-arylation process in a multicomponent reaction with secondary amines, cyclic tertiary amines and electron-deficient aryl halides has been described. In this case, the N-alkylation of secondary amines, utilizing cyclic tertiary amines as alkyl group sources, is enabled by a facile C-N cleavage. Such an operationally simple method could facilitate access to aromatic aminoalkyl amines, nitrogen-containing bioactive molecules, in good to excellent yields.


In situ gene expression analysis of cancer using laser capture microdissection, microarrays and real time quantitative PCR.
The simultaneous development of laser capture microdissection (LCM) and high-throughput mRNA analysis platforms has provided a significant technological advance in the world of cancer biology. The combination of such technologies provides a unique and powerful opportunity to directly assess the in situ molecular genetic events that are associated with initiation and progression of human malignancies. Despite these technological advances, the integration of LCM with high-throughput gene expression analysis has been met with various challenges. The goal of this review is to highlight some of the obstacles that we have faced and continue to face as we try to optimally apply LCM to in situ gene expression analysis.


The mutational spectrum of holoprosencephaly-associated changes within the SHH gene in humans predicts loss-of-function through either key structural alterations of the ligand or its altered synthesis.
Mutations within either the SHH gene or its related pathway components are the most common, and best understood, pathogenetic changes observed in holoprosencephaly patients; this fact is consistent with the essential functions of this gene during forebrain development and patterning. Here we summarize the nature and types of deleterious sequence alterations among over one hundred distinct mutations in the SHH gene (64 novel mutations) and compare these to over a dozen mutations in disease-related Hedgehog family members IHH and DHH. This combined structural analysis suggests that dysfunction of Hedgehog signaling in human forebrain development can occur through truncations or major structural changes to the signaling domain, SHH-N, as well as due to defects in the processing of the mature ligand from its pre-pro-precursor or defective post-translation bi-lipid modifications with palmitate and cholesterol.


Overbite and overjet correction in a Class II, division 1 sample treated with Edgewise therapy.
The purpose of this study was to compare the effect of overjet and overbite correction in non-extraction and extraction therapy in a sample of Class II malocclusions treated with the Edgewise appliance. The subjects were 20 children treated without extraction and 20 children treated with extraction of the four first premolars. During the post-treatment period a relapse of overjet and overbite occurred in both groups. However, there was a beneficial net effect of overjet and overbite correction in both groups with no significant difference between the two groups. The study showed that mandibular intercanine width, space conditions in the lower jaw and mandibular incisor position were important factors in treatment planning.


Histaminergic modulation of stress-induced analgesia and cognitive dysfunction.
Physiological stress is known to produce analgesia and memory disruption. A large body of evidence favors the nonopiate mediation of stress-induced analgesia. It is suggested that brain histamine mediates nonopiate analgesia and participates in learning and memory in rodents. Histamine is released during stress, although the nature of histaminergic involvement in stress response is not clearly defined. Therefore, we studied the effect of L-histidine and histamine-receptor antagonists on antinociception and impaired retention induced by immobilization stress. In the present study, immobilization stress produced a naloxone-resistant analgesia that was potentiated by L-histidine and antagonized by pretreatment with the histamine receptor antagonists chlorpheniramine and cimetidine. L-histidine attenuated the memory disruption induced by immobilization stress, which was significantly reversed by chlorpheniramine but not by cimetidine. Thus the involvement of the central histaminergic system, through histamine H1- and H2-receptors, may be speculated in analgesia and cognitive deficit induced by immobilization stress.


Cross-linking of gelatin capsules and its relevance to their in vitro-in vivo performance.
The present review deals with the chemistry of gelatin cross-linking under conditions that are relevant to pharmaceutical situations. Mechanistic rationalizations are offered to explain gelatin cross-linking under "stress" conditions. These include elevated temperature and high humidity conditions. In addition, the chemical interactions between gelatin and aldehydes, such as formaldehyde and other formulation excipients, are discussed. The literature on the in vitro and in vivo dissolution and bioavailability of a drug from stressed gelatin capsules and gelatin-coated tablets is reviewed. Cross-linking phenomena, occurring in stressed hard gelatin capsules and gelatin-coated tablets, could cause considerable changes in the in vitro dissolution profiles of drugs. However, in a few cases, the bioavailability of the drug from the stressed capsules is not significantly altered when compared to that obtained from freshly packed capsules. It is concluded that, as with other drug-delivery systems, careful attention should be paid to the purity and chemical reactivity of all excipients that are to be encapsulated in a gelatin shell. It is suggested that in vitro dissolution tests of hard gelatin-containing dosage forms be conducted in two stages, one in a dissolution medium without enzymes and secondly in dissolution media containing enzymes (pepsin at pH 1.2 or pancreatin at pH 7.2, representing gastric and intestinal media, respectively) prior to in vivo evaluation. Such in vitro tests may constitute a better indication of the in vivo behavior of gelatin-encapsulated formulations. Furthermore, testing for contamination with formaldehyde as well as low molecular weight aldehydes should be a standard part of excipient evaluation procedures.


Trends in Quick-Service Restaurants near Public Schools in the United States: Differences by Community, School, and Student Characteristics.
More than one-third of children and adolescents consume foods from quick-service restaurants (QSRs) daily, which is associated with an increased risk of diet-related adverse health conditions. To examine trends in the proximity of top-selling QSR chains to all public schools across the United States between 2006 and 2018 by community-, school-, and student-level characteristics. This longitudinal study examined changes in the number QSRs between the 2006-2007 and 2017-2018 school years using data from National Center for Education Statistics, Infogroup US Historical Business Data, and the US Department of Agriculture's Economic Research Service. A mixed-model analysis of variance using census tract as a random effect and accounting for repeated measures by school was used to examine the proximity of QSRs near schools. Models adjusted for demographic characteristics and census tract population density. Data were analyzed in 2021. During 2006, 9% of schools had QSRs within 400 m, and 25% of schools in the most populated areas had at least one QSR within 400 m. There were more QSRs near schools with a high percentage of poverty (12%), and near schools with high school students with the highest population of Black or African American (16%) and Hispanic or Latino (18%) students. By 2018, the percent of all public schools within 400 m of QSRs increased to 12%. The increase over time was greater near schools with a high percentage of poverty (16%) and near schools with high school students with the highest population of Black or African American students (22%) and Hispanic or Latino (23%) students. This is the first nationwide study to examine trends in QSR proximity to all public schools. QSRs were most likely to be located near schools with high school students, near schools with a high percentage of poverty, and near schools with a higher proportion of racial and ethnic minority students. Over time, there were greater increases in QSRs near these schools which may have important implications for children's health and diet-related disparities.


Equivalence of conventional and sustained release oral dosage formulations of acetazolamide in primary open angle glaucoma.
1. Outpatients with primary open angle glaucoma uncontrolled on single topical therapy with either pilocarpine or timolol were recruited for a stratified double dummy cross over trial. Once or twice daily sustained release acetazolamide (SRA) was compared with an identical regimen of conventional tablets (CA). 2. During the run in period the patients received 500 mg SRA once or twice daily as needed to control intraocular pressure (IOP). The dose was thereafter kept constant and patients were allocated randomly to 4 weeks treatment with CA followed by 4 weeks SRA or vice versa. IOP and venous plasma concentrations of acetazolamide were measured at weekly intervals. At the end of each 4 week course, patients were admitted for a 24 h profile of IOP and drug concentration measurements. 3. Thirty-five patients were recruited, but eleven were withdrawn during the run in period largely because of adverse effects; these became less troublesome when it was decided to give the once daily dose at 22.00 h. Four were withdrawn during the cross over, two because of inadequate IOP control. Twenty completed the trial. 4. The morning plasma concentration of acetazolamide measured each week showed no tendency to accumulation during the study. The mean swing (maximum minus minimum) in plasma acetazolamide concentration during the 24 h profile was less (P less than 0.005) with the SR formulation (11.6 +/- 4.9; mg l-1) +/- s.d.) than with the conventional (15.5 +/- 4.7) but the mean concentrations over the 24 h profile were indistinguishable (P greater than 0.05; 9.7 +/- 3.8 and 8.6 +/- 2.8 respectively). 5. Satisfactory control of IOP (no more than one reading above 22 mmHg) was maintained despite the changes in formulation in all but two of the patients who entered the cross over study. No close relationship between IOP and plasma concentration of acetazolamide was found. The 24 h IOP profiles whilst receiving each of the formulations were indistinguishable; thus the smoothing of the plasma drug concentration profile achieved by the SR formulation did not reduce the amplitude of swings in IOP. Similarly, no difference was observed between the formulations with respect to adverse effects. 6. It is concluded that the SR and conventional formulations were equivalent with respect to mean plasma acetazolamide concentration, IOP control and adverse effects. The SR formulation did not show practical advantages over the conventional formulation which was equally effective even with dosage intervals of 12 or 24 h.


Hepatoprotective effect of Herpetospermum caudigerum Wall. on carbon tetrachloride-induced hepatic fibrosis in rats.
Tibetan medicine Herpetospermum caudigerum Wall. (HCW) has long been employed to treat hepatitis, inflammatory diseases and jaundice according to the records of "The Four Medical Tantras" in China. This study was investigated to explore the protective effects of HCW on hepatic fibrosis and the possible mechanism in a rat model. Hepatic fibrosis was established by intragastric administration of 3 ml/kg carbon tetrachloride (CCl4 ) twice a week for 6 weeks. CCl4 -treated rats were received HCW (1 and 3 g/kg/d) and silymarin (0.1 g/kg/d) from 3 to 6 weeks. The results showed that HCW could significantly decrease the levels of AST, ALT, HA, LN, PCIII, Col IV, TNF-α, IL-1β and IL-6. Moreover, HCW could effectively inhibit collagen deposition and reduce the pathological damage. Analysis experiments finally exhibited that HCW was able to markedly inhibit hepatic fibrosis by modulating the expressions of NF-κB p65, IκBα, Samd3 and TGF-β1 proteins. Therefore, our results suggest that HCW has hepatoprotective activity against CCl4 -induced hepatic fibrosis in rats by regulating the inflammatory responses.


Activity of a Synthetic Peptide Targeting MgtC on Pseudomonas aeruginosa Intramacrophage Survival and Biofilm Formation.
Antivirulence strategies aim to target pathogenicity factors while bypassing the pressure on the bacterium to develop resistance. The MgtC membrane protein has been proposed as an attractive target that is involved in the ability of several major bacterial pathogens, including Pseudomonas aeruginosa, to survive inside macrophages. In liquid culture, P. aeruginosa MgtC acts negatively on biofilm formation. However, a putative link between these two functions of MgtC in P. aeruginosa has not been experimentally addressed. In the present study, we first investigated the contribution of exopolysaccharides (EPS) in the intramacrophage survival defect and biofilm increase of mgtC mutant. Within infected macrophages, expression of EPS genes psl and alg was increased in a P. aeruginosa mgtC mutant strain comparatively to wild-type strain. However, the intramacrophage survival defect of mgtC mutant was not rescued upon introduction of psl or alg mutation, suggesting that MgtC intramacrophage role is unrelated to EPS production, whereas the increased biofilm formation of mgtC mutant was partially suppressed by introduction of psl mutation. We aimed to develop an antivirulence strategy targeting MgtC, by taking advantage of a natural antagonistic peptide, MgtR. Heterologous expression of mgtR in P. aeruginosa PAO1 was shown to reduce its ability to survive within macrophages. We investigated for the first time the biological effect of a synthetic MgtR peptide on P. aeruginosa. Exogenously added synthetic MgtR peptide lowered the intramacrophage survival of wild-type P. aeruginosa PAO1, thus mimicking the phenotype of an mgtC mutant as well as the effect of endogenously produced MgtR peptide. In correlation with this finding, addition of MgtR peptide to bacterial culture strongly reduced MgtC protein level, without reducing bacterial growth or viability, thus differing from classical antimicrobial peptides. On the other hand, the addition of exogenous MgtR peptide did not affect significantly biofilm formation, indicating an action toward EPS-independent phenotype rather than EPS-related phenotype. Cumulatively, our results show an antivirulence action of synthetic MgtR peptide, which may be more potent against acute infection, and provide a proof of concept for further exploitation of anti-Pseudomonas strategies.


Determination of an optimal dose of medetomidine-ketamine-buprenorphine for anaesthesia in the Cape ground squirrel (Xerus inauris).
The optimal dose of medetomidine-ketamine-buprenorphine was determined in 25 Cape ground squirrels (Xerus inauris) undergoing surgical implantation of a temperature logger into the abdominal cavity. At the end of anaesthesia, the squirrels were given atipamezole intramuscularly to reverse the effects of medetomidine. The mean dose of medetomidine was 67.6 +/- 9.2microg/kg, ketamine 13.6 +/- 1.9 mg/kg and buprenorphine 0.5 +/- 0.06 microg/kg. Induction time was 3.1 +/- 1.4 min. This produced surgical anaesthesia for 21 +/- 4.2 min. Atipamezole 232 +/- 92 microg/kg produced a rapid recovery. Squirrels were sternally recumbent in 3.5 +/- 2.2 min.


The effect of prophylactic antibiotics on febrile morbidity following cesarean section.
One hundred fifty patients undergoing cesarean section were evaluated prospectively for the effect of prophylactic antibiotics on postoperative morbidity. The postoperative infection rate was significantly reduced, being 30%, 16%, and 50% in the ampicillin, the cephalothin, and the control groups, respectively. The results are favorably compared with the results achieved in previously reported studies where the antibiotic treatment was started preoperatively. Our study confirms experimental studies that postoperative infection can be reduced by using prophylactic antibiotics in the immediate postoperative period. By this regimen, undesired placental transfer of the antibiotics to the fetus can be avoided.


Behavioral and clinical factors associated with self-reported abnormal Papanicolaou tests in rheumatoid arthritis.
Some evidence suggests that women with rheumatoid arthritis (RA) are at increased risk for the development of cervical cancer; however, it is unclear how this increase risk is conferred. We aimed to assess the factors related to abnormal Papanicolaou (Pap) tests in women with RA to determine whether they are similar to those reported for the general population. A structured questionnaire was mailed to 503 female patients from a longitudinal RA cohort. The survey included items on sociodemographic, behavioral, and gynecological factors. Univariate and multivariable logistic regression models examined the association of self-reported abnormal Pap results with a number of potential behavioral risk factors. The questionnaire response rate was 57.5% (n=289). Median age was 61 years and 97% had ≥1 Pap test previously. Twenty-nine percent of respondents reported a previous abnormal Pap result. In the multivariable logistic model adjusted for age, number of lifetime sexual partners, age at menarche, birth control use, and history of sexually transmitted disease (STD), ever using birth control (odds ratio [OR] 2.31, 95% confidence interval [CI] 1.18-4.52) and previous STD (OR 3.38, 95% CI 1.70-6.70) were associated with an increased risk of abnormal Pap result. Compared with either the state or national population, a greater proportion of the respondents was older, married, and previous smokers, and completed postsecondary education and obtained a Pap test. In this cross-sectional study, self-reported abnormal Pap results were associated with use of birth control and history of STD in RA patients.


Morphological studies on the venous drainage of the trachea in the neck of sheep.
Systemic venous drainage of the cervical portion of the trachea from the cricoid cartilage to the sternal notch was observed in 50 adult sheep. In all animals, the first five to six tracheal rings starting at the cricoid cartilage were drained by the thyroid veins (v. thyroideae) bilaterally to the external jugular veins (v. jugularis externa). A venous complex draining the remaining cervical portion of the trachea was observed only on the left side of the trachea. This complex drained to the cranial vena cava (vena cava cranialis). India ink or Evans blue dye were infused into small vessels draining this area for verification. Variations in this venous complex were classified into three types based upon length of trachea drained. Type I was found in 26%, type II found in 58%, and type III found in 16% of the sheep studied and drained 23 +/- 5%, 58 +/- 11% and 78 +/- 10% of the cervical portion of the trachea, respectively. Blood flow from this area of the trachea was 85 +/- 28 mL/min/100 g wet issue. This study identified and classified the venous drainage of the cervical portion of the trachea in sheep.


Longitudinal changes in tooth/single-implant relationship and bone topography: an 8-year retrospective analysis.
To evaluate longitudinal changes in tooth/implant relationship and bone topography at single implants with a microthreaded, conical marginal portion (Astra Tech ST® implants, Astra Tech AB, Mölndal, Sweden). Thirty-one subjects with single implant-supported restorations in the esthetic zone were included. Radiographs obtained at crown installation and 1, 5, and 8 years of follow-up were analyzed with regard to changes in (1) bone level at the implant and adjacent teeth and (2) vertical position of adjacent teeth relative to the single implant. The mean marginal bone loss amounted to 0.1 mm at both implants and adjacent teeth during the 8 years of follow-up. Regression analysis failed to identify significant explanatory factors for observed variance in bone level change at the adjacent tooth surfaces. Vertical change in position of the teeth relative to the implants was more frequent and significantly greater in incisor compared with premolar tooth region but not associated with gender or age. The marginal bone level at teeth adjacent to single implants with a microthreaded conical marginal part was not influenced by horizontal and vertical tooth-implant distances. Continuous eruption of adjacent teeth may result in infraocclusal positioning of a single-implant restoration.


Farnesyl transferase inhibitors in the treatment of breast cancer.
Until recently, the therapeutic treatment of breast cancer has been dominated by endocrine-based drugs (oestrogen receptor antagonists, aromatase inhibitors etc.) and conventional cytotoxics (doxorubicin, cyclophosphamide, 5-fluorouracil etc.). However, the advent of new generation signal transduction inhibitor drugs targeted against the molecular abnormalities of breast cancer (e.g., the antibody trastuzumab, directed against the cERBB2 receptor) has the promise of providing a new era of more tumour selective therapy. Inhibitors of the enzyme farnesyl transferase (FTIs) are now undergoing early-stage clinical trials, including in patients with advanced breast cancer. Although originally developed as inhibitors of RAS signal transduction pathways, it is now apparent that these drugs are better described as prenylation inhibitors; the addition of a 15-carbon prenyl or farnesyl moiety by farnesyl transferase being critical to the function of a number of proteins, including RAS. At least three FTIs are currently undergoing clinical evaluation; R115777 (tipifarnib, Zarnestra), SCH66336 (lonafarnib, Sarasar) and BMS-214662. In terms of their potential use in the chemotherapeutic treatment of advanced breast cancer, a Phase II trial of R115777 (using either continuous or intermittent twice-daily oral dosing) has demonstrated promising activity (approximately 10% partial response rate). Overall, however, the single agent activity of FTIs in various Phase II trials has been rather modest (as well as the above mentioned breast cancer trial, some responses have been seen in patients with acute and chronic myeloid leukaemias). The main dose-limiting toxicities that have been reported are myelosuppression and fatigue and neurotoxicity (with R115777). Two Phase III trials of R115777 in colorectal (versus placebo) and pancreatic (with gemcitabine versus placebo) cancer have failed to show a survival benefit. It is likely that the future clinical direction of FTIs will be as combination therapy, especially with the taxanes, where synergy has been seen in a variety of preclinical studies.


Evaluation of a transient noise reduction strategy for hearing AIDS.
Transient noise can be disruptive for people wearing hearing aids. Ideally, the transient noise should be detected and controlled by the signal processor without disrupting speech and other intended input signals. A technology for detecting and controlling transient noises in hearing aids was evaluated in this study. The purpose of this study was to evaluate the effectiveness of a transient noise reduction strategy on various transient noises and to determine whether the strategy has a negative impact on sound quality of intended speech inputs. This was a quasi-experimental study. The study involved 24 hearing aid users. Each participant was asked to rate the parameters of speech clarity, transient noise loudness, and overall impression for speech stimuli under the algorithm-on and algorithm-off conditions. During the evaluation, three types of stimuli were used: transient noises, speech, and background noises. The transient noises included "knife on a ceramic board," "mug on a tabletop," "office door slamming," "car door slamming," and "pen tapping on countertop." The speech sentences used for the test were presented by a male speaker in Mandarin. The background noises included "party noise" and "traffic noise." All of these sounds were combined into five listening situations: (1) speech only, (2) transient noise only, (3) speech and transient noise, (4) background noise and transient noise, and (5) speech and background noise and transient noise. There was no significant difference on the ratings of speech clarity between the algorithm-on and algorithm-off (t-test, p = 0.103). Further analysis revealed that speech clarity was significant better at 70 dB SLP than 55 dB SPL (p < 0.001). For transient noise loudness: under the algorithm-off condition, the percentages of subjects rating the transient noise to be somewhat soft, appropriate, somewhat loud, and too loud were 0.2, 47.1, 29.6, and 23.1%, respectively. The corresponding percentages under the algorithm-on were 3.0, 72.6, 22.9, and 1.4%, respectively. A significant difference on the ratings of the transient noise loudness was found between the algorithm-on and algorithm-off (t-test, p < 0.001). For overall impression for speech stimuli: under the algorithm-off condition, the percentage of subjects rating the algorithm to be not helpful at all, somewhat helpful, helpful, and very helpful for speech stimuli were 36.5, 20.8, 33.9, and 8.9%, respectively. Under the algorithm-on condition, the corresponding percentages were 35.0, 19.3, 30.7, and 15.0%, respectively. Statistical analysis revealed there was a significant difference on the ratings of overall impression on speech stimuli. The ratings under the algorithm-on condition were significantly more helpful for speech understanding than the ratings under algorithm-off (t-test, p < 0.001). The transient noise reduction strategy appropriately controlled the loudness for most of the transient noises and did not affect the sound quality, which could be beneficial to hearing aid wearers.


Oxime ester-enabled anti-Markovnikov hydrosilylation of alkenes.
An oxime ester-enabled anti-Markovnikov hydrosilylation of alkenes is developed. This protocol is operationally simple and atom economical. The reaction shows broad functional group tolerance, such as ketones, amides, esters, epoxides, alcohols and carboxylic acids. Mono-substituted and geminally substituted alkenes could be chemoselectively hydrosilylated.


A Normalization Circuit Underlying Coding of Spatial Attention in Primate Lateral Prefrontal Cortex.
Lateral prefrontal cortex (LPFC) neurons signal the allocation of voluntary attention; however, the neural computations underlying this function remain unknown. To investigate this, we recorded from neuronal ensembles in the LPFC of two Macaca fascicularis performing a visuospatial attention task. LPFC neural responses to a single stimulus were normalized when additional stimuli/distracters appeared across the visual field and were well-characterized by an averaging computation. Deploying attention toward an individual stimulus surrounded by distracters shifted neural activity from an averaging regime toward a regime similar to that when the attended stimulus was presented in isolation (winner-take-all; WTA). However, attentional modulation is both qualitatively and quantitatively dependent on a neuron's visuospatial tuning. Our results show that during attentive vision, LPFC neuronal ensemble activity can be robustly read out by downstream areas to generate motor commands, and/or fed back into sensory areas to filter out distracter signals in favor of target signals.


Evaluation of the utility of brain slice methods to study brain penetration.
The objective of this study was to evaluate the utility of brain tissue slices to determine the effect of plasma and brain tissue nonspecific binding on the brain-to-plasma ratio (K(p)). Mouse or rat brain slices (400 microm) were prepared using a McIlwain tissue chopper (Surrey, UK) and incubated with 1 microg/ml of compound at 37 degrees C either in a physiological buffer to determine the buffer-to-slice concentration ratio, i.e., unbound fraction in brain tissue (f(u,slice)), or in plasma to determine the slice-to-plasma concentration ratio (C(slice)/C(plasma)). The unbound fraction in plasma, f(u,plasma), was determined using equilibrium dialysis. In vitro-in vivo correlation of the brain-to-plasma ratio was examined for 13 and eight model compounds in mice and rats, respectively. C(slice)/C(plasma) and f(u,plasma)/f(u,slice) predicted the K(p) in rats, and C(slice)/C(plasma) predicted the K(p) in FVB mice for non-P-glycoprotein substrates within 3-fold but overpredicted K(p) for P-glycoprotein substrates by more than 3-fold. However, C(slice)/C(plasma) predicted the K(p) in mdr1a/1b knockout mice for both non-P-glycoprotein and P-glycoprotein substrates. Our present study demonstrates that a brain slice method can be used to differentiate whether a compound having a low K(p) is due to the effect of low nonspecific binding to brain tissue relative to plasma proteins or because of efflux transport at the blood-brain barrier.


Measuring the time course of selection during visual search.
In visual search tasks, observers can guide their attention towards items in the visual field that share features with the target item. In this series of studies, we examined the time course of guidance toward a subset of items that have the same color as the target item. Landolt Cs were placed on 16 colored disks. Fifteen distractor Cs had gaps facing up or down while one target C had a gap facing left or right. Observers searched for the target C and reported which side contained the gap as quickly as possible. In the absence of other information, observers must search at random through the Cs. However, during the trial, the disks changed colors. Twelve disks were now of one color and four disks were of another color. Observers knew that the target C would always be in the smaller color set. The experimental question was how quickly observers could guide their attention to the smaller color set. Results indicate that observers could not make instantaneous use of color information to guide the search, even when they knew which two colors would be appearing on every trial. In each study, it took participants 200-300 ms to fully utilize the color information once presented. Control studies replicated the finding with more saturated colors and with colored C stimuli (rather than Cs on colored disks). We conclude that segregation of a display by color for the purposes of guidance takes 200-300 ms to fully develop.


ATP produces vasodilation via P1 purinoceptors and vasoconstriction via P2 purinoceptors in the isolated rabbit central ear artery.
P1 and P2 purinoceptors mediating mechanical responses in isolated rabbit ear artery were studied by comparing responses to adenosine triphosphate (ATP), alpha, beta-methylene ATP, and adenosine, both when endothelial cells were intact and when they had been removed by mechanical rubbing (as confirmed by histochemical staining and near abolition of relaxation to acetylcholine). alpha, beta-Methylene ATP and ATP (but not adenosine or acetylcholine) contracted preparations at resting tone. alpha, beta-Methylene ATP was significantly more potent as a contractile agent than ATP. Neither was significantly affected by removal of the endothelium. Acetylcholine, ATP, and adenosine relaxed arteries whose tone had been raised by 10(-6) M histamine. Removal of the endothelium virtually abolished relaxations to acetylcholine and significantly decreased those to adenosine and ATP. All relaxations to adenosine and ATP were significantly antagonised by 8-phenyltheophylline, a potent P1 purinoceptor antagonist. alpha, beta-Methylene ATP further contracted the high-tone preparation and was again unaffected by removal of the endothelium. These results confirm that endothelial cells can mediate vasodilation. They also show that adenosine (and ATP) can elicit vasodilation via P1 purinoceptors both on the endothelial cells and on the smooth muscle of the isolated rabbit central ear artery. P2 purinoceptors, however, appear to be located on the smooth muscle only and mediate vasoconstriction.


D2 dopamine receptors in calf globus pallidus: agonist high- and low-affinity sites not regulated by guanine nucleotide.
By use of the radioligand [3H]spiroperidol, D2 3,4-dihydroxyphenylethylamine (dopamine) receptor binding characteristics were studied in calf globus pallidus and compared with those of neostriatum. Antagonist competition curves were monophasic and revealed similar affinities for neostriatum and globus pallidus, suggesting a uniform receptor population with one affinity state for antagonists. In both regions, competition curves with the agonist dopamine were biphasic, distinguishing a high- and low-agonist-affinity state. In neostriatum and globus pallidus, respectively, 45% and 19% of [3H]spiroperidol binding was displaced with high affinity and the remainder with low affinity. In neostriatum, the addition of 0.4 mM GTP resulted in a partial conversion from high- to low-affinity state with a remaining high-affinity component of 15%. In globus pallidus, dopamine binding was not altered by GTP. The capability of GTP to modulate agonist binding to D2 receptors appears to be dependent on their neuroanatomical localization.


Somatostatin analogue-induced pancreatic exocrine insufficiency in patients with neuroendocrine tumors: results of a prospective observational study.
Patients with advanced well-differentiated neuroendocrine tumours (Wd-NETs) are commonly treated with somatostatin analogues (SSAs). Some patients may develop SSA-related side effects such as pancreatic exocrine insufficiency (PEI). In this prospective, observational study, the frequency of SSA-induced PEI in 50 sequential patients with advanced Wd-NETs treated with SSAs was investigated. Toxicity was assessed monthly and faecal elastase-1 (FE1) and quality of life (QoL) were assessed 3-monthly. The median age was 65.8 years, 58% were male and the majority (92%) of patients had metastatic disease; patients received 4-weekly long acting octreotide (60%) or lanreotide (40%). Twelve patients (24%) developed SSA-related PEI after a median of 2.9 months from SSA initiation; FE1 was a reliable screening tool for PEI, especially in symptomatic (abdominal bloating, flatulence and/or diarrhea) patients (risk ratio 8.25 (95% confidence interval 1.15-59.01)). Most of these patients (11/12; 92%) required PERT. Other SSA-related adverse events (any grade) included flatulence (50%), abdominal pain (32%), diarrhoea (30%) and fatigue (20%). Development of PEI did not significantly worsen overall QoL, however gastrointestinal symptoms and diarrhoea were increased. This study demonstrated that PEI occurs at a higher rate than previously reported; clinicians need to diagnose and treat this SSA-related adverse-event which occurs in 1 in 4 patients with Wd-NETs treated with SSAs. Screening with FE1 in symtomatic patients is recommend.


[The apothicary of the "Maison Royale de Saint-Cyr"].
The "Maison Royale de Saint-Cyr", a royal school for education of poor noble officer's girls, founded by Louis XIV and Mme de Maintenon and working from 1686 to the French Revolution, had an apothicary run by nuns. Its inventory has reached us and its fully and distinct contents well call to mind a 18th century's pharmacy with a large variety of tools for pharmaceutical and chemical preparations, set of furnitures and library. In the garden, a place, carefully cultivated, was reserved to medicinal plants for supply of the apothicary.


The clavicle: normal and abnormal.
The clavicle is an unusual long bone with many unique embryologic features. It is often involved in congenital and acquired disorders. Traumatic, inflammatory, neoplastic, metabolic and many other miscellaneous lesions may also affect the bone. Because of its ligamentous attachments and the presence of articulations at both ends, the clavicle can also be involved in arthritic diseases. This article illustrates the radiographic manifestations of many of the disorders of the clavicle that are commonly encountered in clinical practice.


O3-Induced Leaf Senescence in Tomato Plants Is Ethylene Signaling-Dependent and Enhances the Population Abundance of Bemisia tabaci.
Elevated ozone (O3) can alter the phenotypes of host plants particularly in induction of leaf senescence, but few reports examine the involvement of phytohormone in O3-induced changes in host phenotypes that influence the foraging quality for insects. Here, we used an ethylene (ET) receptor mutant Nr and its wild-type to determine the function of the ET signaling pathway in O3-induced leaf senescence, and bottom-up effects on the performance of Bemisia tabaci in field open-top chambers (OTCs). Our results showed that elevated O3 reduced photosynthetic efficiency and chlorophyll content and induced leaf senescence of plant regardless of plant genotype. Leaf senescence in Nr plants was alleviated relative to wild-type under elevated O3. Further analyses of foliar quality showed that elevated O3 had little effect on phytohormone-mediated defenses, but significantly increased the concentration of amino acids in two plant genotypes. Furthermore, Nr plants had lower amino acid content relative to wild-type under elevated O3. These results provided an explanation of O3-induced increase in abundance of B. tabaci. We concluded that O3-induced senescence of plant was ET signal-dependent, and positive effects of O3-induced leaf senescence on the performance of B. tabaci largely resulted from changes of nutritional quality of host plants.


Interferon (IFN)-λ Takes the Helm: Immunomodulatory Roles of Type III IFNs.
Type III interferons (IFNs) (or IFN-λ) are the latest addition to the IFN family. Even though they share little protein homology with type I IFN, both exhibit remarkable functional similarities: each can be induced in response to viral infections, and both lead to Janus kinases (JAK) and signal transducer and activator of transcription (STAT) activation. The JAK/STAT pathway induces antiviral responses and IFN-stimulated gene transcription. However, despite the similarities in their effector functions with type I IFNs, IFN-λ also has a non-redundant role in protecting barrier organs: epithelial cells preferentially produce IFN-λ rather than type I IFNs; and interferon lambda receptor 1 (IFNLR1), the specific receptor for IFN-λ, is highly expressed on cells of epithelial lineage. Thus far, IFN-λ has been considered mainly as an epithelial cytokine, which restricts viral replication in epithelial cells and constitutes an added layer of protection at mucosal sites. However, it is now increasingly recognized that IFNLR1 is expressed broadly, and that immune cells such as neutrophils and dendritic cells also respond to IFN-λ. Moreover, in many in vivo models, IFN-λ modulates immune cell functions and thereby configures itself less as a cytokine that is only specific to the epithelium, and more as a cytokine that directly controls the inflammatory response at mucosal sites. Here, we critically review the recent literature on immune modulatory roles for IFN-λ, and distinguish between the direct and indirect effects of this IFN on immune cell functions in different inflammatory settings.


Coil embolization for distal left main aneurysm: a new approach to coronary artery aneurysm treatment.
Coronary artery aneurysm is an uncommon disease, whose natural history and therapeutic approach are still controversial: medical therapy, surgical revascularization with or without aneurysm ligation or excision, and endovascular exclusion with membrane covered stents are all accepted and viable options, according to anatomic characteristics. Intracranial aneurysms are adequately treated by means of coil embolization, an option that, to our knowledge, has never been tested in coronary interventions. We report the first case of a coronary aneurysm involving the distal left main and the proximal left anterior descending artery treated with "stent-assisted" coil embolization.


The solid-state photo-CIDNP effect and its analytical application : photo-CIDNP MAS NMR to study radical pairs.
Photochemically induced dynamic nuclear polarization (photo-CIDNP) is an effect that produces non-Boltzmann nuclear spin polarization which can be observed as modification of signal intensity in NMR spectroscopy. The effect is well known in liquid-state NMR where it is explained most generally by the classical radical pair mechanism (RPM). In the solid-state, other mechanisms are operative in the spin-dynamics of radical pairs such as three-spin mixing (TSM) and differential decay (DD). Initially the solid-state photo-CIDNP effect has been solely observed on natural photosynthetic reaction centers (RCs). Therefore the analytical capacity of the method has been explored in experiments on reaction centers (RCs) of the purple bacterium of Rhodobacter (R.) sphaeroides. Here we will provide an account on phenomenology, theory, and analytical capacity of the solid-state photo-CIDNP effect.


Stress Perceived by University Health Sciences Students, 1 Year after COVID-19 Pandemic.
Today's COVID-19 situation can affect university Health Sciences students' psychological health. This study aimed to analyze the stress caused by the impact of the COVID-19 pandemic on Health Sciences students from the University of Zaragoza (Spain) almost 1 year after the pandemic began. This cross-sectional descriptive study was conducted with a sample of 252 university students who completed a self-administered online questionnaire. It evaluated the impact of perceived stress with a modified scale (PSS-10-C), and assessed anxiety and depression on the Goldberg scale. Students presented stress (13.1%), anxiety (71.4%) and depression (81%). Females (81.7%) and the third-year Occupational Therapy students (p = 0.010) reported perceived stress. Nursing students perceived less stress (OR: 0.148; 95% CI: 0.026 to 0.842). University students developed stress and anxiety due to COVID-19 almost 1 year after the pandemic began. Psychological support measures for these groups should be prioritized.


Fatigue in amyotrophic lateral sclerosis: frequency and associated factors.
We aimed to quantify fatigue frequency and evolution in amyotrophic lateral sclerosis (ALS), and to correlate fatigue with factors such as age, sex, educational level, disease duration, functionality, quality of life, dyspnoea, depression and sleepiness. Sixty ALS patients (test group: TG) selected by El Escorial criteria and 60 normal individuals (control group: CG) matched according to sex and age, were followed every three months, during 9 months, by means of self-report scales: Fatigue Assessment Instrument (Fatigue Severity Scale plus three qualitative subscales); ALS Functional Rating Scale; McGill Quality of Life Questionnaire; dyspnoea analogical scale; Beck Depression Inventory and Epworth Sleepiness Scale. Fatigue was reported by 83% of TG (median: 3.6, interquartile range 1.5-5.4), compared with 20% of CG (median: 1, 1-1), and was significantly greater in the TG (p<0.001, Mann-Whitney test). Fatigue severity increased by the ninth month of the study (p=0.0008, Friedman, Müller-Dunn post test). There was no correlation between fatigue and other parameters, except for an inverse correlation with age at disease onset (p=0.0395, Spearman rank correlation). In conclusion, fatigue was frequent in ALS, greater in the youngest patients and worsened during follow-up. Possibly, ALS related fatigue is an independent factor, which deserves individualized approach and treatment.


Associations between Pretreatment Body Composition Features and Clinical Outcomes among Patients with Metastatic Clear Cell Renal Cell Carcinoma Treated with Immune Checkpoint Blockade.
High body mass index (BMI) may lead to improved immune-checkpoint blockade (ICB) outcomes in metastatic clear cell renal cell carcinoma (mccRCC). However, BMI is a crude body size measure. We investigated BMI and radiographically assessed body composition (BC) parameters association with mccRCC ICB outcomes. Retrospective study of ICB-treated patients with mccRCC. BMI and BC variables [skeletal muscle index (SMI) and multiple adiposity indexes] were determined using pretreatment CT scans. We examined the associations between BMI and BC variables with ICB outcomes. Therapeutic responses per RECIST v1.1 were determined. We compared whole-transcriptomic patterns with BC variables in a separate cohort of 62 primary tumor samples. 205 patients with mccRCC were included in the cohort (74% were male, 71% were overweight/obese, and 53% were classified as low SMI). High-BMI patients experienced longer overall survival (OS) than normal-weight patients [unadjusted HR, 0.66; 95% confidence interval (CI), 0.45-0.97; P = 0.035]. The only BC variable associated with OS was SMI [unadjusted HR comparing low vs. high SMI 1.65 (95% CI: 1.13-2.43); P = 0.009]. However, this OS association became nonsignificant after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium score and line of therapy. No OS association was seen for adiposity and no BC variable was associated with progression-free survival or radiological responses. Tumors from patients with low SMI displayed increased angiogenic, inflammatory, and myeloid signals. Our findings highlight the relevance of skeletal muscle in the BMI paradox. Future studies should investigate if addressing low skeletal muscle in metastatic patients treated with ICB can improve survival.


Dietary intake and use of dietary supplements in relation to demographic variables among pregnant Finnish women.
Proper nutrition during pregnancy may be important for maternal health and fetal growth and development. In Finland, targeted recommendations are given to guide pregnant women in their food choice and dietary supplement use so that they may obtain adequate nutritional status and meet the increased need for nutrients. The aims of the present study were to examine food choices, nutrient intake and dietary supplement use of pregnant Finnish women in association with demographic variables. One thousand and seventy-five families were invited to a birth cohort study during 1998-9. Mothers of 797 newborns completed a validated 181-item food-frequency questionnaire from which the food and nutrient intakes were calculated. The information about supplement use was collected concerning the whole pregnancy. The results of the present study suggest that healthy food choices are rather common among pregnant Finnish women and the choices are positively correlated with age and education. Nutrient supplements were used by 85 % of the women. Supplements were favoured by the older and well-educated women and by those who had normal weight before pregnancy. Of the women in the present study, 31 % received vitamin A-containing supplements, although it is not recommended during pregnancy. Taking food and supplementation into account, the intake of vitamin D did not meet the dietary recommendation and folic acid intake was below recommendation in 44 % of the women. Therefore there seemed to be unnecessary nutrient supplementation and at the same time lack of relevant supplementation among these pregnant women.


Maternal and offspring dopamine D4 receptor genotypes interact to influence juvenile impulsivity in vervet monkeys.
The merging of psychological and genetic methodologies has led to an increasing appreciation of environmental moderators of the relationships between genotype and phenotype. Here we used a nonhuman-primate model to study the moderating effect of the mother's genotype on the association of a dopamine D4 receptor (DRD4) gene polymorphism with juvenile impulsivity, assessed in a standardized social-challenge test. The results showed that juvenile carriers of the rare 5-repeat variant of the exon III 48-base-pair repeat polymorphism scored significantly higher in social impulsivity than juveniles homozygous for the common 6-repeat allele. In addition, juvenile genotype interacted with maternal genotype to influence impulsivity, with the highest rates of impulsivity found in variant offspring with variant mothers. These results highlight the importance of considering the genotype of the parents in studies of early experience and vulnerability genes for impulsivity-related traits.


Promotion of Physical Activity Among Mexican-Origin Women in Texas and South Carolina: An Examination of Social, Cultural, Economic, and Environmental Factors.
Interventions to improve physical activity levels among Latinos must take into consideration the social, cultural, economic, and environmental contexts of Latino communities. We report findings of formative assessments related to Mexican-origin women's levels of readiness, willingness, and ability to participate in regular leisure time physical activity in two diverse locations, the Texas Lower Rio Grande Valley and the South Carolina Midlands. The ENLACE project employed a Community-Based Participatory Research approach. Formative assessment activities focused on identification of community assets and resources and exploration of community members' experiences, opinions, values, preferences, and perceived needs related to physical activity. Data sources included windshield tours, walkability assessments of local neighborhoods; community inventory exercises, focus groups, and individual interviews. Barriers to regular physical activity included the dominance of work and family responsibilities, social norms, lack of social support, social isolation, environmental constraints, economics, and low levels of personal knowledge and motivation.


Robotic devices in surgery.
Robotic devices are defined wich can be used as an aid to surgery. A classification system is proposed that reflects the manner of use and the safety of the systems. Typical benefits and problems of using robots are discussed, and a number of applications are reviewed. These cover "autonomous" systems, that involve no intervention from the surgeon; "hands-on" systems, that require the direct involvement of the surgeon; and "Master/Slave" (or Telemanipulator) systems, that are somewhere between these two and involve some degree of indirect surgeon activity. A number of predictions for the future of medical robotics are provided.


Environmental isolation of Cryptococcus gattii VGII from indoor dust from typical wooden houses in the deep Amazonas of the Rio Negro basin.
Cryptococcosis is a human fungal infection of significant mortality and morbidity, especially in the meningoencephalitis form. Cryptococcosis is distributed worldwide and its agents, C. neoformans and C. gattii, present eight major molecular types-VNI-VNIV and VGI-VGIV respectively. The primary cryptococcosis caused by molecular type VGII (serotype B, MAT alpha) prevails in immunocompetent patients in the North and Northeast of Brazil, revealing an endemic regional pattern to this molecular type. Since 1999, C. gattii VGII has been involved in an ongoing outbreak in Canada, and is expanding to the Northwest of the United States, two temperate regions. Exposure to propagules dispersed in the environment, related to various organic substrates, mainly decomposing wood in and around dwellings, initiates the infection process. The present study investigated the presence of the agents of cryptococcosis in dust from dwellings in the upper Rio Negro, municipality of Santa Isabel do Rio Negro in Amazonas state. Indoor dust was collected from 51 houses, diluted and plated on bird seed agar. Dark brown colonies were identified phenotypically, and genotypically by URA5 restriction fragment length polymorphism analysis and multilocus sequence typing (MLST). The mating type was identified using pheromone-specific primers. Three of the 51 houses were positive for C. gattii molecular type VGII, MATα and MATa, showing a high prevalence of this agent. MLST studies identified eight subtypes, VGIIb (ST7), VGIIa (ST20), (ST5) and 5 new subtypes unique to the region. For the first time in the state of Amazonas, C. gattii VGII MATα and MATa were isolated from the environment and correlates with endemic cryptococcosis in this state. This is the first description of MLST subtypes on environmental isolates in the Brazilian Amazon, indicating domiciliary dust as a potential source for human infection with different subtypes of C. gattii VGII MATα and MATa.


Novel useful markers for follow-up of necrotizing enterocolitis: endocan and interleukin-33.
Objectives: To ascertain the diagnostic value of endocan and interleukin (IL)-33 in infants with necrotizing enterocolitis (NEC) and to compare their effectiveness with C-reactive protein (CRP) and interleukin-6 (IL-6).Methods: Eighty-four preterm infants including control (n = 42) and NEC (n = 42) were eligible. Blood samples were obtained from infants in the NEC for the assessment of CRP, IL-6, endocan, and IL-33 serum levels at the time of diagnosis (first day), at the third and seventh days of NEC. Endocan, IL-33, CRP, and IL-6 serum levels were measured at the 14th day of life in the control group.Results: Serum levels of endocan, IL-33, CRP, and IL-6 were significantly higher in the NEC group compared to the control group at the first, third, and seventh days (p < .05). IL-33 and endocan levels continued to rise in the consequent days in patients with stage III NEC (p < .05). Serum endocan and IL-33 levels gradually increased in patients who underwent surgery (p < .05). Serum endocan levels were higher in patients with stage III NEC than those in the stage II NEC at the diagnosis.Conclusions: Serum levels of IL-33 and endocan can be used as markers in the diagnosis and follow-up of NEC.


Stepped-plate ultrasonic transducer used as a source of harmonic radiation force optimized by genetic algorithm.
Circular stepped-plates are often chosen to generate continuous waves in air due to their transmission efficiency, directive radiation patterns and capability to generate high-intensity airwave emission. Such features can be suitable for an acoustic radiator intended for the generation of harmonic radiation force, if the narrow bandwidth of the piezoelectric power transducer is not an obstacle to the application. This force has been used as the excitation source in noncontact modal analysis of mechanical devices, since it offers some advantages over the traditional impact method and the use of shakers. In this study, a directional stepped-plate ultrasonic device driven by a bolt-clamped Langevin-type transducer is used to excite the first flexural mode of a clamped-free beam by means of harmonic radiation force. The harmonic component was generated using an amplitude-modulated electrical input signal. The radiator design was done by solving a parametric optimization problem of finding a plate with the desired vibrational behavior using the genetic algorithm. Finite element analysis was used to obtain the dynamic behavior of the device and the airwave propagation was modeled using linear acoustic theory. Modal and harmonic analyses were conducted to obtain some of the electroacoustic parameters of the transducer. The acoustic field generated by the prototype is estimated by solving the Rayleigh integral and the obtained results are compared to experimental measurements.


HIV type 1 integrase polymorphisms in treatment-naive and treatment-experienced HIV type 1-infected patients in Thailand where HIV type 1 subtype A/E predominates.
Integrase inhibitor (INI) is a novel antiretroviral drug recommended for both treatment-naive and treatment-experienced HIV-1-infected patients. Limited data are available on INI resistance in Thailand, where HIV-1 subtype A/E predominates. We aimed to investigate INI resistance-associated mutations (RAMs) among treatment-naive patients and patients who experienced treatment failure with NNRTI-based or PI-based antiretroviral therapy (ART) in Thailand. One hundred and eight plasma samples of 58 treatment-naive and 50 treatment-experienced HIV-1-infected individuals were collected. The HIV-1 integrase coding region was sequenced. Polymorphisms were compared between subtype A/E and B circulating in Thailand and between treatment-naive and treatment-experienced groups. Resulting amino acids were interpreted for drug resistance according to Stanford algorithms. Ninety-seven samples were HIV-1 subtype A/E, 10 were subtype B, and one was subtype C. Age, gender, and CD4 cell counts were similar between treatment-naive and treatment-experienced groups, while the treatment-failure group showed a statistically significant longer awareness time of HIV-1 infection and lower viral load than the treatment-naive group. Major INI-RAM was not found in this study, but some minor INI-RAMs, such asV54I, L68I, L74M, T97A, and S230N, were found. Comparing INI-RAMs between subtype A/E and B, the prevalence of V54I and V72I was higher in subtype B than subtype E, while V201I was found in all sequences of subtype A/E. In subtype A/E, integrase polymorphisms were not different between treatment-naive and treatment-experienced groups. However, the number of amino acid substitutions was significantly higher in the treatment-experienced group (p=0.009). One NNRTI-based ART-treated patient was found to have potential low-level INI-RAMs. INI-RAMs are rare in both treatment-naive and treatment-experienced patients in Thailand. This suggested that INI should be active in patients who are naive to INI in Thailand.


Intriguing Periprosthetic Fracture of Hip Stem and Proximal Femoral Replacement.
Lateral femoral prosthesis perforation is an uncommon periprosthetic fracture. Periprosthetic fractures may be fixed with open reduction and internal fixation, or with revision arthroplasty, depending on the type of fracture, the condition of the host bone in the proximal femur, the stability of the implant, and occasionally the medical co-morbidities of the patient. Proximal femoral replacement is a complex and challenging procedure but provides a better chance of early mobilisation. We describe a case of treating a 71-year-old woman who presented with an unusual type of periprosthetic fracture, treated with a revision arthroplasty procedure using a proximal femur replacement.


Indocyanine green fluorescence imaging for resection of pulmonary metastasis of hepatocellular carcinoma.
Indocyanine green (ICG) accumulates in hepatocellular carcinoma (HCC), and tumor fluorescence can be observed under irradiation with near infrared light (NIR). This study investigated the clinical utility of ICG fluorescence imaging during resection of pulmonary metastases of HCC. From April 2010 to June 2018, six patients with suspected pulmonary metastasis of HCC were enrolled prospectively. Prior to surgery, all patients underwent the ICG hepatic function test following intravenous administration of ICG (0.5 mg/kg body weight). During surgery, metastatic HCC was identified by observation of ICG fluorescence, allowing assessment of the surgical margin. Tumor fluorescence was also evaluated on cut sections. A total of 11 metastatic HCCs were resected in six patients at nine operations. Eight lesions were removed by wedge resection and 3 lesions were managed by lobectomy. During surgery, tumor fluorescence could be confirmed through the visceral pleura in 6 out of 7 lesions treated by wedge resection, while NIR irradiation was difficult for 1 lesion. For these 6 lesions, the median distance from the tumor to the visceral pleura and the median surgical margin were 0 mm (range, 0-2 mm) and 14 mm (range, 11-17 mm), respectively. When cut sections were examined, all tumors emitted fluorescence. All lesions were histologically confirmed to be metastatic HCC. In patients with pulmonary metastasis of HCC, ICG fluorescence imaging is useful for identifying the tumor and securing its margin when the lesion is peripheral and wedge resection is planned.


Therapeutic Targeting of NF-κB in Acute Lung Injury: A Double-Edged Sword.
Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a devastating disease that can be caused by a variety of conditions including pneumonia, sepsis, trauma, and most recently, COVID-19. Although our understanding of the mechanisms of ALI/ARDS pathogenesis and resolution has considerably increased in recent years, the mortality rate remains unacceptably high (~40%), primarily due to the lack of effective therapies for ALI/ARDS. Dysregulated inflammation, as characterized by massive infiltration of polymorphonuclear leukocytes (PMNs) into the airspace and the associated damage of the capillary-alveolar barrier leading to pulmonary edema and hypoxemia, is a major hallmark of ALI/ARDS. Endothelial cells (ECs), the inner lining of blood vessels, are important cellular orchestrators of PMN infiltration in the lung. Nuclear factor-kappa B (NF-κB) plays an essential role in rendering the endothelium permissive for PMN adhesion and transmigration to reach the inflammatory site. Thus, targeting NF-κB in the endothelium provides an attractive approach to mitigate PMN-mediated vascular injury, not only in ALI/ARDS, but in other inflammatory diseases as well in which EC dysfunction is a major pathogenic mechanism. This review discusses the role and regulation of NF-κB in the context of EC inflammation and evaluates the potential and problems of targeting it as a therapy for ALI/ARDS.


Characterization of Bombyx mori nucleopolyhedrovirus Bm17.
Open reading frame17 (Bm17) of Bombyx mori nucleopolyhedrovirus is a highly conserved gene in lepidopteran nucleopolyhedroviruses, suggesting that it performs an important role in the virus life cycle whose function is unknown. In this report, we describe the characterization of Bm17. Reversed transcriptive-PCR (RT-PCR) and Western blot analysis demonstrated that Bm17 was expressed as a late gen. Immunofluorescence analysis by confocal microscopy showed that BM17 protein was localized on cytoplasm and nucleus of infected cells. These results show that BM17 was a late protein localized in cytoplasm and nucleus.


A hitchhiker's guide to the cullin ubiquitin ligases: SCF and its kin.
The SCF (Skp1-Cullin-F-box) E3 ubiquitin ligase family was discovered through genetic requirements for cell cycle progression in budding yeast. In these multisubunit enzymes, an invariant core complex, composed of the Skp1 linker protein, the Cdc53/Cul1 scaffold protein and the Rbx1/Roc1/Hrt1 RING domain protein, engages one of a suite of substrate adaptors called F-box proteins that in turn recruit substrates for ubiquitination by an associated E2 enzyme. The cullin-RING domain-adaptor architecture has diversified through evolution, such that in total many hundreds of distinct SCF and SCF-like complexes enable degradation of myriad substrates. Substrate recognition by adaptors often depends on posttranslational modification of the substrate, which thus places substrate stability under dynamic regulation by intracellular signaling events. SCF complexes control cell proliferation through degradation of critical regulators such as cyclins, CDK inhibitors and transcription factors. A plethora of other processes in development and disease are controlled by other SCF-like complexes, including those based on Cul2-SOCS-box adaptor protein and Cul3-BTB domain adaptor protein combinations. Recent structural insights into SCF-like complexes have begun to illuminate aspects of substrate recognition and catalytic reaction mechanisms.


Oncolytic viruses for induction of anti-tumor immunity.
Oncolytic virotherapy is an evolving but, as yet, unrealized treatment option for cancer. This approach harnesses the cancer-restricted replicative activity of engineered viruses to achieve tumor cell kill. Tumors that are resistant to chemotherapy or radiotherapy can be susceptible to viral oncolysis because of distinct cell kill mechanisms. There is now compelling evidence that collateral induction of anti-tumor immune responses contributes substantially to viral antitumor activities. In addition to the expected anti-viral immune clearance, the "danger" signal created by virus-infected cells can generate immune co-stimulation known to override immune suppression and reverse tolerance within the tumor microenvironment. Our recent findings indicate that immune activation augments the clinical outcomes of oncolytic virotherapy. Strikingly similar and robust clinical response rates ( > 25%) were observed among advanced cancer patients following intratumoral treatments with adenoviral (AdΔ24) and herpes simplex (JS1/34.5-/47) constructs armed with an integrated granulocyte-macrophage colony-stimulating factor (GMCSF) payload. Both agents produced regressions in injected as well as distant, uninjected lesions, demonstrating systemic effectiveness. We discuss the innate and adaptive immune activating events that may contribute to these clinical outcomes, and examine systemic delivery strategies to tilt the immunological balance from viral clearance to tumor elimination.


HLA-B44-directed cytotoxic T cells associated with acute graft-versus-host disease following unrelated bone marrow transplantation.
We describe the recipient of a marrow graft from an HLA-serologically identical unrelated donor from whom highly potent host-reactive CTL of donor origin were isolated in association with acute GVHD. Extensive sequence and biochemical analysis of the HLA complex of this donor and recipient revealed several disparities in class I and class II HLA with the potential to be recognized by T cells from the donor or the host. The donor-derived CTL exclusively recognized a class I HLA difference associated with HLA-B44. Nucleotide sequencing of donor and recipient cells revealed that the patient possessed the HLA-B*4402 allele recognized by IEF as B44.2 while the donor possessed HLA-B*4403 (IEF variant B44.1). These alleles differ at one amino acid residue located at position 156 in the alpha 2 domain. The donor-derived CTL were shown to be specific for B44.2 by blocking studies and by the lysis of five different B44.2+ unrelated cell lines, two of which were confirmed by sequencing to be homozygous for B*4402. A host-specific difference involving a HLA-DRB1 allele was not recognized by the CTL, neither did HLA differences unique to the donor HLA-B*4403 and HLA-DQ8 elicit a host response. These data show that certain HLA disparities may be tolerated at the same time that other disparities elicit a potent immunologic response. The chemical nature of the difference, its structural impact, as well as the conditions of transplant appear to influence the type of response which occurs.


Effective oral combination metronomic chemotherapy with low toxicity for the management of castration-resistant prostate cancer.
Prostate cancer (PC) was previously believed to be a chemoresistant disease. In recent years taxane-based chemotherapy has been shown to prolong survival in patients with castration-resistant prostate cancer (CRPC). It remains to be shown, however, which type of chemotherapy provides the most beneficial effect with the least amount of side effects. Seventeen patients with chemonaive CRPC were enrolled in a pilot study evaluating an orally administered chemo-hormonal treatment regimen using a weekly sequential combination called KEES; consisting of ketoconazole in combination with cyclophosphamide or etoposide in combination with estramustine administered on alternate weeks. Prednisone was administered throughout the treatment period. Prostate-specific antigen (PSA) response and acute and chronic toxicities were evaluated. Seventeen patients with CRPC were treated; eleven patients demonstrated a median reduction in PSA of 87% (range 26-99%). Ten (59%) patients responded with a decrease in PSA >50%. Thrombocytopenia and anaemia were the most common side effects. One study fatality was reported, however, it was unclear whether this was treatment related. In conclusion, KEES may be a promising option for patients with CRPC, resulting in a clear reduction in PSA with limited toxicity. Further clinical evaluation of this metronomic chemohormonal combination is underway.


Survival models in health economic evaluations: balancing fit and parsimony to improve prediction.
Health economic decision models compare costs and health effects of different interventions over the long term and usually incorporate survival data. Since survival is often extrapolated beyond the range of the data, inaccurate model specification can result in very different policy decisions. However, in this area, flexible survival models are rarely considered, and model uncertainty is rarely accounted for. In this article, various survival distributions are applied in a decision model for oral cancer screening. Flexible parametric models are compared with Bayesian semiparametric models, in which the baseline hazard can be made arbitrarily complex while still enabling survival to be extrapolated. A fully Bayesian framework is used for all models so that uncertainties can be easily incorporated in estimates of long-term costs and effects. The fit and predictive ability of both parametric and semiparametric models are compared using the deviance information criterion in order to account for model uncertainty in the cost-effectiveness analysis. Under the Bayesian semiparametric models, some smoothing of the hazard function is required to obtain adequate predictive ability and avoid sensitivity to the choice of prior. We determine that one flexible parametric survival model fits substantially better than the others considered in the oral cancer example.


A herpes simplex virus infection secondary to acupuncture and cupping.
Acupuncture and cupping have a public reputation as being safe even though these practices can lead to complications such as trauma or infection. We report here on a case of herpes simplex virus (HSV) infection secondary to acupuncture and cupping in a 56-year-old woman. The patient, who had a history of acupuncture and cupping on her left forearm for treating her myalgia, developed painful papules. Histologically, the biopsy specimen showed characteristic ballooning degeneration and inclusion bodies in the epidermis and mid-dermis. These clinical and histological findings were consistent with the diagnosis of HSV infection.


Binding of 125I-labeled endotoxin to bovine, canine, and equine platelets and endotoxin-induced agglutination of canine platelets.
Endotoxin from Escherichia coli O127:B8, Salmonella abortus-equi and S minnesota induced clumping of some canine platelets (PLT) at a final endotoxin concentration of 1 microgram/ml. Endotoxin-induced clumping of canine PLT was independent of PLT energy-requiring processes, because clumping was observed with canine PLT incubated with 2-deoxy-D-glucose and antimycin A. The PLT responded to adenosine diphosphate before, but not after, incubation with the metabolic inhibitors. Endotoxin induced a slight and inconsistant clumping of bovine and equine PLT at high (mg/ml) endotoxin concentration. High-affinity binding sites could not be demonstrated on canine, bovine, and equine PLT, using 125I-labeled E coli O127:B8 endotoxin. Nonspecific binding was observed and appeared to be due primarily to an extraneous coat on the PLT surface that was removed by gel filtration. The endotoxin that was bound to PLT did not appear to modify PLT function. An attempt to identify plasma proteins that bound physiologically relevant amounts of endotoxin was not successful. The significance of the endotoxin-induced clumping or lack of it on the pathophysiology of endotoxemia is discussed.


Poor growth performance associated with hypocupremia in Hawaiian feedlot cattle.
Poor feedlot performance in native Hawaiian feedlot cattle was investigated. Cattle were first noticed to be affected 40 to 60 days after arrival at the feedlot, as judged by their retarded growth, when compared with penmates. Marked hypocupremia was detected in all 10 cattle examined, irrespective of time in the feedlot. Clinical signs and upper digestive tract lesions in 8 of the 10 cattle suggested secondary involvement of bovine papular stomatitis. The poor performance was attributed primarily to the hypocupremia, as a result of molybdenum-accentuated copper deficiency in forage on the ranch of origin.


Structure-aided optimization of 3-O-β-chacotriosyl ursolic acid as novel H5N1 entry inhibitors with high selective index.
Currently, entry inhibitors contribute immensely in developing a new generation of anti-influenza virus drugs. Our earlier studies have identified that 3-O-β-chacotriosyl ursolic acid (1) could inhibit H5N1 pseudovirus by targeting hemagglutinin (HA). In the present study, a series of C-28 modified pentacyclic triterpene saponins via conjugation with a series of amide derivatives were synthesized and their antiviral activities against influenza A/Duck/Guangdong/99 virus (H5N1) in MDCK cells were evaluated. The SARs analysis of these compounds revealed that introduction of certain amide structures at the 17-COOH of ursolic acid could significantly enhance both their antiviral activity and selective index. This study indicated that the attachment of the methoxy group or Cl atom to the phenyl ring at the ortho- or para-position was crucial to improve inhibitory activity. Mechanism studies demonstrated that these title triterpenoids could bind tightly to the viral envelope HA to block the attachment of viruses to host cells, which was consistent with docking studies.


Low intensity resistance exercise for breast cancer patients with arm lymphedema with or without compression sleeve.
Clinical trials of the effect of physical exercise on breast cancer related arm lymphedema (ALE) are very rare. The aim of this study was to examine if controlled low intensity arm exercises with weights, with or without a compression sleeve, influence breast cancer related ALE. Thirty-one breast cancer treated patients with small or moderate ALE were included in the study. A specifically designed arm exercise program was performed with or without compression sleeve on different days and in a randomized order. Measurements were performed before, directly after and 24 hours after the exercise intervention, with water displacement method and multiple frequency bioelectrical impedance analysis (n=10) for volume of the arms and Borg's scale for perceived exertion during training. There was an increase of total arm volume of the lymphedema arm immediately after the exercise intervention for both with and without sleeve conditions (p < 0.01). At 24 hours, no volume increase was found compared to pre-exercise and both groups showed tendency towards reduced lymphedema relative volume (p < 0.05). The patient's rating of perceived exertion was low regardless of whether a sleeve was worn, but was significantly higher when exercising with the sleeve. We conclude that low intensity exercises can be performed by patients with arm lymphedema without risk of worsening the edema. Exercises without the sleeve may be of benefit provided compression sleeve is worn regularly.


Alcohol dehydrogenase and hydrogenase transcript fluctuations during a day-night cycle in Chlamydomonas reinhardtii: the role of anoxia.
• The unicellular green alga Chlamydomonas reinhardtii contains two iron (Fe)-hydrogenases which are responsible for hydrogen production under anoxia. In the present work the patterns of expression of alcohol dehydrogenase, a typical anaerobic gene in plants, of the hydrogenases genes (HYD1, HYD2) and of the genes responsible for their maturation (HYDEF, HYDG), were analysed. • The expression patterns were analysed by real-time reverse-transcription polymerase chain reaction in Chlamydomonas cultures during the day-night cycle, as well as in response to oxygen availability. • The results indicated that ADH1, HYD1, HYD2, HYDEF and HYDG were expressed following precise day-night fluctuations. ADH1 and HYD2 were modulated by the day-night cycle. Low oxygen plays an important role for the induction of HYD1, HYDEF and HYDG, while ADH1 and HYD2 expression was relatively insensitive to oxygen availability. • The regulation of the anaerobic gene expression in Chlamydomonas is only partly explained by responses to anoxia. The cell cycle and light-dark cycles are equally important elements in the regulatory network modulating the anaerobic response in Chlamydomonas.


Is There a Spatial Relationship between Urban Landscape Pattern and Habitat Quality? Implication for Landscape Planning of the Yellow River Basin.
The extent to which landscape spatial patterns can impact the dynamics and distribution of biodiversity is a key geography and ecology issue. However, few previous studies have quantitatively analyzed the spatial relationship between the landscape pattern and habitat quality from a simulation perspective. In this study, the landscape pattern in 2031 was simulated using a patch-generating simulation (PLUS) model for the Yellow River Basin. Then, the landscape pattern index and habitat quality from 2005 to 2031 were evaluated using the Fragstats 4.2 and the Integrated Valuation of Ecosystem Services and Tradeoffs (InVEST) model. Furthermore, we analyzed the spatial distribution characteristics and spatial spillover effects of habitat quality using spatial autocorrelation analysis. Finally, the spatial association between the landscape pattern index and habitat quality was quantitatively revealed based on a spatial lag model. The simulation results showed that: (1) from 2005 to 2031, the landscape of the Yellow River Basin would be dominated by grassland and unused land, and the areas of construction land and water body will increase significantly, while the area of grassland will decrease; (2) patch density (PD) and Shannon's diversity index (SHDI) show significant increases, while edge density (ED), landscape shape index (LSI), mean patch area (AREA_MN), and contagion index (CONTAG) decrease; (3) from 2005 to 2031, habitat quality would decrease. The high-value areas of habitat quality are mainly distributed in the upper reaches of the Yellow River Basin, and the low-value areas are distributed in the lower reaches. Meanwhile, both habitat quality and its change rate present positive spatial autocorrelation; and (4) the spatial relationships of habitat quality with PD and COHESION are negative, while ED and LSI have positive impacts on habitat quality. Specifically, landscape fragmentation caused by high PD has a dominant negative influence on habitat quality. Therefore, this study can help decision makers manage future landscape patterns and develop ecological conservation policy in the Yellow River Basin.


Hereditary hemorrhagic telangiectasia: multi-detector row helical CT assessment of hepatic involvement.
To describe findings obtained with multi-detector row helical computed tomography (CT) of the liver in patients with hereditary hemorrhagic telangiectasia. Multiphasic multi-detector row helical CT was performed in 70 consecutive patients (29 females and 41 males; mean age, 48.5 years; age range, 15-75 years): 64 considered to have hereditary hemorrhagic telangiectasia and six suspected of having the disease. Scanning delay was achieved by using a test bolus of contrast medium to obtain early arterial phase, late arterial phase, and portal venous phase images. Multiplanar and angiographic reconstructions were then generated. The presence of shunts, hepatic perfusion disorders, telangiectases, other vascular lesions, indirect signs of portal hypertension, and vascular anatomic variants were evaluated by two radiologists in consensus. Fifty-two of 70 (74%) patients had hepatic vascular abnormalities. Only four of 52 (8%) patients were symptomatic. Arterioportal shunts were present in 27 of 52 (52%) patients, arteriosystemic shunts in eight of 52 (15%), and both shunt types in 17 of 52 (33%). In 34 of 52 (65%) patients, parenchymal perfusion disorders were detected. Telangiectases were found in 33 of 52 (63%) patients. Large confluent vascular masses were identified in 13 of 52 (25%) patients. In 31 of 52 (60%) patients, indirect CT signs of portal hypertension were detected, but only one had clinical signs of this condition. Vascular anatomic variants were detected in seven patients (13%). Multi-detector row helical CT and reconstructions depict the complex hepatic vascular alterations typical of hereditary hemorrhagic telangiectasia.


Comparative Study of Clinical and Dermoscopic Features in Nail Psoriasis.
Nail changes have been reported in approximately 40% of psoriasis patients. Occasionally nail psoriasis may be the sole finding or the first presentation of the disease. Assessment of the nail changes associated with psoriasis can be done clinically, ultrasonographically, and most recently using a dermoscope. The aim of this study is to assess the dermoscopic features in nails of psoriasis as well as to compare the dermoscopic with the clinical findings. This study has also assessed the correlation between disease duration and the severity of skin and nail involvement. A total of 50 patients with psoriatic nail changes were recruited in the study. The psoriasis area severity index (PASI) was used to assess the severity of the disease. The nail psoriasis severity index (NAPSI) was used to determine the severity of nail involvement. The patient's nails were examined both clinically and dermoscopically. Pitting was the commonest feature (84%) noted both clinically and dermoscopically. A statistically significant higher NAPSI score (P < 0.05) was obtained by a dermoscope than by clinical examination. Salmon patch and splinter hemorrhage were better visualized using a dermoscope than by clinical evaluation (P < 0.05). The duration of the disease had a strong positive correlation (R = 0.901) with the duration of nail involvement whereas there was a weak correlation between the duration of the disease and the clinical NAPSI (R = 0.23) and dermoscopic NAPSI (R = 0.28). A weak positive correlation (R = 0.3) was noted between the PASI and NAPSI scores. Dermoscopy of nails proved to be an efficient, supportive, easy, noninvasive method that provides a better insight into the subtle nail changes in psoriatic patients, which may have been missed clinically.


Using the topology of metabolic networks to predict viability of mutant strains.
Understanding the relationships between the structure (topology) and function of biological networks is a central question of systems biology. The idea that topology is a major determinant of systems function has become an attractive and highly disputed hypothesis. Although structural analysis of interaction networks demonstrates a correlation between the topological properties of a node (protein, gene) in the network and its functional essentiality, the analysis of metabolic networks fails to find such correlations. In contrast, approaches utilizing both the topology and biochemical parameters of metabolic networks, e.g., flux balance analysis, are more successful in predicting phenotypes of knockout strains. We reconcile these seemingly conflicting results by showing that the topology of the metabolic networks of both Escherichia coli and Saccharomyces cerevisiae are, in fact, sufficient to predict the viability of knockout strains with accuracy comparable to flux balance analysis on large, unbiased mutant data sets. This surprising result is obtained by introducing a novel topology-based measure of network transport: synthetic accessibility. We also show that other popular topology-based characteristics such as node degree, graph diameter, and node usage (betweenness) fail to predict the viability of E. coli mutant strains. The success of synthetic accessibility demonstrates its ability to capture the essential properties of the metabolic network, such as the branching of chemical reactions and the directed transport of material from inputs to outputs. Our results strongly support a link between the topology and function of biological networks and, in agreement with recent genetic studies, emphasize the minimal role of flux rerouting in providing robustness of mutant strains.


The potential of photon-counting CT for quantitative contrast-enhanced imaging in radiotherapy.
The aim of this study is to use a simulation environment to evaluate the potential of using photon-counting CT (PCCT) against dual-energy CT (DECT) in the context of quantitative contrast-enhanced CT for radiotherapy. An adaptation of Bayesian eigentissue decomposition by Lalonde et al (2017 Med. Phys. 44 5293-302) that incorporates the estimation of contrast agent fractions and virtual non-contrast (VNC) parameters is proposed, and its performance is validated against conventional maximum likelihood material decomposition methods for single and multiple contrast agents. PCCT and DECT are compared using two simulation frameworks: one including ideal CT numbers with image-based Gaussian noise and another defined as a virtual patient with projection-based Poisson noise and beam hardening artifacts, with both scenarios considering spectral distortion for PCCT. The modalities are compared for their accuracy in estimating four key physical parameters: (1) the contrast agent fraction, as well as VNC parameters relevant to radiotherapy such as the (2) electron density, (3) proton stopping power and (4) photon linear attenuation coefficient. Considering both simulation frameworks, a reduction of root mean square (RMS) errors with PCCT is noted for all physical parameters evaluated, with the exception of the error on the contrast agent fraction being about constant through modalities in the virtual patient. Notably, for the virtual patient, RMS errors on VNC electron density and stopping power are respectively reduced from 2.0% to 1.4% and 2.7% to 1.4% when going from DECT to PCCT with four energy bins. The increase in accuracy is comparable to the differences between contrast-enhanced and non-contrast DECT. This study suggests that in a realistic simulation environment, the overall accuracy of radiotherapy-related parameters can be increased when using PCCT with four energy bins instead of DECT. This confirms the potential of PCCT to provide robust and quantitative tissue parameters for contrast-enhanced CT required in radiotherapy applications.


Frequency of going outdoors as a good predictors for incident disability of physical function as well as disability recovery in community-dwelling older adults in rural Japan.
The clinico-epidemiologic relevance of the reduction in the frequency of going outdoors in older adults has not been well characterized. This study examined whether the frequency of going outdoors has predictive values for incident physical disability and recovery among community-dwelling elderly. One thousand, two hundred and sixty-seven persons aged 65+ years who lived in a rural community in Niigata, Japan, and participated in the baseline survey were assessed again 2 years later in terms of mobility, and instrumental and basic activities of daily living (IADL and BADL). We compared the incident disability and recovery at follow-up among three subgroups classified by the baseline frequency of going outdoors: once a day or more often, once per 2-3 days, and once a week or less often. Multivariate analyses tested associations between the frequency of going outdoors and functional transition, independent of potential confounders. A lower frequency of going outdoors at baseline was associated with a greater incident disability, and a lower recovery at the two-year follow-up. Even after adjustment, the effects of going outdoors remained significant. Adjusted risks of incident mobility and IADL disabilities were significantly higher (odds ratio[OR]=4.02, 95% confidence interval [CI]: 1.77-9.14 and OR=2.65, 95% CI: 1.06-6.58), respectively, and recovery from mobility disability was significantly lower (OR=0.29, 95% CI: 0.08-0.99) for "once a week or less often" subgroup compared with "once a day or more often" subgroup. The frequency of going outdoors is a good predictor for incident physical disability and recovery among community-living elderly. Public health nurses and clinicians should pay more attention how often their senior clients usually go outdoors.


Pigment Epithelium-Derived Factor (PEDF) Expression Induced by EGFRvIII Promotes Self-renewal and Tumor Progression of Glioma Stem Cells.
Epidermal growth factor receptor variant III (EGFRvIII) has been associated with glioma stemness, but the direct molecular mechanism linking the two is largely unknown. Here, we show that EGFRvIII induces the expression and secretion of pigment epithelium-derived factor (PEDF) via activation of signal transducer and activator of transcription 3 (STAT3), thereby promoting self-renewal and tumor progression of glioma stem cells (GSCs). Mechanistically, PEDF sustained GSC self-renewal by Notch1 cleavage, and the generated intracellular domain of Notch1 (NICD) induced the expression of Sox2 through interaction with its promoter region. Furthermore, a subpopulation with high levels of PEDF was capable of infiltration along corpus callosum. Inhibition of PEDF diminished GSC self-renewal and increased survival of orthotopic tumor-bearing mice. Together, these data indicate the novel role of PEDF as a key regulator of GSC and suggest clinical implications.


Comparison of Survival Outcomes in Early Stage Invasive Adenocarcinoma with Squamous Cell Carcinoma of the Uterine Cervix.
Invasive adenocarcinoma (AC) is the second most common carcinoma of the uterine cervix; however, it is not clear whether this histologic type influences survival outcomes. To evaluate the survival outcomes of patients with invasive AC compared to those with squamous cell carcinoma (SCC) in early stage cervical cancer following radical hysterectomy. A historical cohort study was conducted of 316 Thai women with cervical cancer clinical stage IA2-IIA (120 AC and 196 SCC) who underwent radical hysterectomy from January 1 to December 31, 2000. With a median follow-up of 65.23 months, the estimated 5-year recurrence-free survival (RFS) and overall survival (OS) for patients with AC did not significantly differ from those with SCC (90.3% vs. 93.1%, p = 0.301 and 90.9% vs. 93.5%, p = 0.342 respectively). Using Cox regression analysis, cervical stroma invasion (CSI) and lymphovascular space invasion (LVSI) were the significant prognostic factors for RFS, whereas CSI was the only significant prognostic factor for OS. Women with AC who had two prognostic factors showed significantly lower 5-year RFS than those with SCC (69.5% vs. 86.3%, p = 0.035). Survival and recurrence were not different for surgically treated cervical cancer in women with early stage AC or SCC.


Associations between co-exposure to multiple metals and renal function: a cross-sectional study in Guangxi, China.
The association between co-exposure to multiple metals and renal function is poorly understood. We aimed to evaluate the individual and joint effects of metal exposure on renal function in this study. We performed a cross-sectional study including 5828 participants in Guangxi, China, in 2019. Urine concentrations of 17 metals were detected by inductively coupled plasma mass spectrometry (ICP-MS). Logistic regression model and restricted cubic spline (RCS) were applied to investigate the association of individual metal exposure with renal dysfunction. Weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) were used to assess the co-exposure effects of the metals. Participants with the highest quartile of urinary Cu were at 1.84-fold (95% confidence interval (CI): 1.20-2.87) increased risk of renal dysfunction compared with the lowest quartile. The highest quartiles of urinary Sr, Cs, V, Ba, and Se were associated with 0.27-fold (95% CI: 0.17-0.43), 0.33 (95% CI: 0.19-0.53), 0.41 (95% CI: 0.25-0.65), 0.58 (95% CI: 0.36-0.90), and 0.33 (95% CI: 0.19-0.56) decreased risk of renal dysfunction compared with their lowest quartile, respectively. Furthermore, urinary Ba and Cu were non-linearly correlated with renal dysfunction. The WQS analysis showed that mixed metal exposure was inversely associated with renal dysfunction (OR = 0.47, 95% CI: 0.35-0.62), and Sr accounted for the largest weight (52.2%), followed by Cs (32.3%) in the association. Moreover, we observed a potential interaction between Cu, Cs, and Ba for renal dysfunction in BKMR model. Exposure to Se, Sr, Cs, V, and Ba is associated with decreased risk of renal dysfunction, whereas an increased risk is associated with Cu exposure. Co-exposure to these metals is negatively associated with renal dysfunction, and Sr and Cs are the main contributors to the associations.


Electronically conductive phospho-olivines as lithium storage electrodes.
Lithium transition metal phosphates have become of great interest as storage cathodes for rechargeable lithium batteries because of their high energy density, low raw materials cost, environmental friendliness and safety. Their key limitation has been extremely low electronic conductivity, until now believed to be intrinsic to this family of compounds. Here we show that controlled cation non-stoichiometry combined with solid-solution doping by metals supervalent to Li+ increases the electronic conductivity of LiFePO4 by a factor of approximately 10(8). The resulting materials show near-theoretical energy density at low charge/discharge rates, and retain significant capacity with little polarization at rates as high as 6,000 mA x g(-1). In a conventional cell design, they may allow development of lithium batteries with the highest power density yet.