Discovery of potential anti-SARS-CoV-2 drugs based on large-scale screening in vitro and effect evaluation in vivo.
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global crisis. Clinical candidates with high efficacy, ready availability, and that do not develop resistance are in urgent need. Despite that screening to repurpose clinically approved drugs has provided a variety of hits shown to be effective against SARS-CoV-2 infection in cell culture, there are few confirmed antiviral candidates in vivo. In this study, 94 compounds showing high antiviral activity against SARS-CoV-2 in Vero E6 cells were identified from 2,580 FDA-approved small-molecule drugs. Among them, 24 compounds with low cytotoxicity were selected, and of these, 17 compounds also effectively suppressed SARS-CoV-2 infection in HeLa cells transduced with human ACE2. Six compounds disturb multiple processes of the SARS-CoV-2 life cycle. Their prophylactic efficacies were determined in vivo using Syrian hamsters challenged with SARS-CoV-2 infection. Seven compounds reduced weight loss and promoted weight regain of hamsters infected not only with the original strain but also the D614G variant. Except for cisatracurium, six compounds reduced hamster pulmonary viral load, and IL-6 and TNF-α mRNA when assayed at 4 d postinfection. In particular, sertraline, salinomycin, and gilteritinib showed similar protective effects as remdesivir in vivo and did not induce antiviral drug resistance after 10 serial passages of SARS-CoV-2 in vitro, suggesting promising application for COVID-19 treatment.


Ephedrine enhances HIV-1 reactivation from latency through elevating tumor necrosis factor receptor II (TNFRII) expression.
HIV-1 persists during antiretroviral therapy (ART) due to long-lived and proliferating latently-infected host cells, with the outcome being an incomplete cure. The latently-infected cells, or reservoir cells, are transcriptionally absent and invisible to the immune response. Elimination of latency is one strategy in activating virus production, making it visible to immune clearance. We previously showed that Ephedrae herba reactivated HIV-1 from latency. In this study, we used ephedrine, a major component of Ephedra herba, to reactivate HIV-1 from latency. The results showed that ephedrine enhances HIV-1 reactivation in the presence of TNFα. Combination treatment demonstrates a synergistic effect of HIV-1 reactivation compared to TNFα alone. Ephedrine treatment shows a higher TNFRII expression level, which is related to increased HIV-1 reactivation. However, the mechanism of ephedrine in HIV-1 reactivation is still unclear, and may be related to TNFRII receptor expression. Our results indicate that ephedrine enhances HIV-1 reactivation from latency in combination with TNFα treatment. This new reagent could be a promising latency reversal agent (LRA).


The p53 codon 72 variation is associated with the age of onset of hereditary non-polyposis colorectal cancer (HNPCC).
The polymorphic variants at codon 72 of the p53 gene were shown to be functionally distinct in vitro, whereby the arginine (arg) variant induces apoptosis more efficiently than the proline (pro) variant. From the evidence that the DNA mismatch repair system and p53 interact to maintain genomic integrity, we hypothesized that the codon 72 variation may influence the age of onset of disease in HNPCC patients. We tested 538 patients for p53 codon 72 variants, including 167 unrelated patients with pathogenic germline mutations in MSH2 or MLH1 and colorectal carcinoma as first tumour, 126 patients with sporadic microsatellite stable colorectal cancers, and 245 healthy controls. The median age of onset was 41, 36, and 32 years for MSH2 or MLH1 mutation carriers with arg/arg, arg/pro, and pro/pro genotypes, respectively. The log rank test revealed significant differences in the age of onset between arg/arg and pro/pro individuals (p = 0.0002) and in arg/pro versus arg/arg and pro/pro individuals (p = 0.0026 and p = 0.0217, respectively). A Cox regression model indicated an additive mode of inheritance. No significant differences in age of onset were observed among different genotype carriers with microsatellite stable tumours. Our results suggest that p53 codon 72 genotypes are associated with the age of onset of colorectal carcinoma in a mismatch repair deficient background in a dose dependent manner. These findings may be relevant for preventive strategies in HNPCC.


Meta-analysis about efficacy of anti-resorptive drugs in post-menopausal osteoporosis.
The purpose of this study was to compare the effect of three groups of anti-resorptive drugs in post-menopausal osteoporosis. We collected data covering the period between 1983 and 1995, by first using MEDLINE. References retrieved were scanned further to identify additional papers. Only randomized studies evaluating bone mass by means of dual-photon or dual energy densitometry over a period of 1 year were accepted. Studies were arranged into three drug groups. We used densitometry results after 1 year in all treatment or control groups. Factors which might interfere with the results were recorded for subsequent separate analysis. The MEDLINE search identified almost 25,000 studies. On reading the abstracts, 275 trials appeared to be controlled trials and original copies were retrieved for detailed analysis. A total of 31 articles which satisfied the inclusion criteria were identified. The first meta-analysis included studies which compared oestrogens and placebo, and the global effect-size was 0.54 (95% CI 0.34, 0.73). The second meta-analysis compared calcitonins with placebo and produced an effect-size of 0.41 (95% CI 0.21, 0.61) The third analysis compared bisphosphonates and placebo and showed an effect-size of 0.87 (95% CI 0.68, 1.07). Only oestrogen dose affected the results found. Bisphosphonates had the greatest effect on bone mass in post-menopausal osteoporosis.


Long head of the biceps pathology as a cause of anterior shoulder pain after shoulder arthroplasty.
The use of shoulder arthroplasty has been increasing over the last decade, with nearly 20,000 shoulder arthroplasties being performed each year. Although many patients have excellent results, there exists a subset of patients in whom anterior catching shoulder pain develops after arthroplasty. The purpose of this study was to examine this group of patients and explore treatment options and outcomes for this condition. We undertook a review of 8 shoulders in 7 patients who were treated for anterior shoulder pain radiating into the biceps muscle after shoulder arthroplasty. Three patients had a hemiarthroplasty for fracture, and five had a total shoulder arthroplasty. All patients had anterior shoulder pain with physical examination findings consistent with biceps tendon pathology. Definitive diagnosis and treatment consisted of either arthroscopy, in 7 of 8 shoulders, or an open procedure, in 1 of 8 shoulders. The range of motion improved in all shoulders. The hemiarthroplasty group showed an increase in flexion of 36 degrees (range, 68 degrees -104 degrees ), external rotation of 23 degrees (range, 11 degrees -34 degrees ), and internal rotation to L4. The total shoulder group demonstrated an increase in flexion of 50 degrees (range, 66 degrees -166 degrees ), external rotation of 27 degrees (range, 22 degrees -39 degrees ), and internal rotation to L3. The Hospital for Special Surgery score improved in all shoulders, with all patients being satisfied with their final outcome. Pain scores improved from a mean of 6.9 (range, 4-9) preoperatively to 1.4 (range, 0.5-2) postoperatively on a scale of 1 to 10, with 10 indicating the most pain. The role of the biceps tendon in the pathology of anterior shoulder pain after shoulder arthroplasty appears to be consistent with fibrosis and inflammation. Initial results, achieved with arthroscopic debridement or tenodesis, were encouraging.


Toxicity of magnesium pulses to tropical freshwater species and the development of a duration-based water quality guideline.
Six freshwater species (Chlorella sp., Lemna aequinoctialis, Amerianna cumingi, Hydra viridissima, Moinodaphnia macleayi, and Mogurnda mogurnda) were exposed to 4-h, 8-h, and 24-h Mg pulses in natural creek water. Magnesium toxicity to all species increased with exposure duration; however, the extent of increase and the nature of the relationship differed greatly between species. Based on median inhibitory concentrations (IC50s), and compared with continuous exposure data from a previous study, the increase in toxicity with increasing exposure duration from 4 h to continuous (72-144 h) ranged from approximately 2-fold for Chlorella sp. and H. viridissima to greater than 40-fold for A. cumingi. Moreover, the form of the relationship between Mg toxicity and duration ranged from linear or near-linear to exponential for different species. The life-stage at which M. macleayi was exposed was important, with cladocerans pulsed at the onset of reproductive maturity being approximately 4 times more sensitive (based on IC50s) than younger than 6-h-old neonates. Species sensitivity distributions were constructed for the 4-h, 8-h, and 24-h pulse durations, from which 99% species protection guideline values (95% confidence limits [CLs]) of 94 (6.4-1360) mg/L, 14 (0.5-384) mg/L, and 8.0 (0.5-144) mg/L Mg, respectively, were derived. These values were plotted against exposure duration (h) and polynomial interpolation used to derive a guideline value for any pulse duration within the range assessed.


CRISPR/Cas9-mediated editing of Δ5 and Δ6 desaturases impairs Δ8-desaturation and docosahexaenoic acid synthesis in Atlantic salmon (Salmo salar L.).
The in vivo functions of Atlantic salmon fatty acyl desaturases (fads2), Δ6fads2-a, Δ6fads2-b, Δ6fads2-c and Δ5fads2 in long chain polyunsaturated fatty acid (LC-PUFA) synthesis in salmon and fish in general remains to be elucidated. Here, we investigate in vivo functions and in vivo functional redundancy of salmon fads2 using two CRISPR-mediated partial knockout salmon, Δ6abc/5Mt with mutations in Δ6fads2-a, Δ6fads2-b, Δ6fads2-c and Δ5fads2, and Δ6bcMt with mutations in Δ6fads2-b and Δ6fads2-c. F0 fish displaying high degree of gene editing (50-100%) were fed low LC-PUFA and high LC-PUFA diets, the former containing reduced levels of eicosapentaenoic (20:5n-3) and docosahexaenoic (22:6n-3) acids but higher content of linoleic (18:2n-6) and alpha-linolenic (18:3n-3) acids, and the latter containing high levels of 20:5n-3 and 22:6n-3 but reduced compositions of 18:2n-6 and 18:3n-3. The Δ6abc/5Mt showed reduced 22:6n-3 levels and accumulated Δ6-desaturation substrates (18:2n-6, 18:3n-3) and Δ5-desaturation substrate (20:4n-3), demonstrating impaired 22:6n-3 synthesis compared to wildtypes (WT). Δ6bcMt showed no effect on Δ6-desaturation compared to WT, suggesting Δ6 Fads2-a as having the predominant Δ6-desaturation activity in salmon, at least in the tissues analyzed. Both Δ6abc/5Mt and Δ6bcMt demonstrated significant accumulation of Δ8-desaturation substrates (20:2n-6, 20:3n-3) when fed low LC-PUFA diet. Additionally, Δ6abc/5Mt demonstrated significant upregulation of the lipogenic transcription regulator, sterol regulatory element binding protein-1 (srebp-1) in liver and pyloric caeca under reduced dietary LC-PUFA. Our data suggest a combined effect of endogenous LC-PUFA synthesis and dietary LC-PUFA levels on srebp-1 expression which ultimately affects LC-PUFA synthesis in salmon. Our data also suggest Δ8-desaturation activities for salmon Δ6 Fads2 enzymes.


Mitral annular disjunction in advanced myxomatous mitral valve disease: echocardiographic detection and surgical correction.
Mitral annular disjunction is a structural abnormality of the mitral annulus fibrosus described by pathologists in association with mitral leaflet prolapse and defined as a separation between the atrial wall-mitral valve (MV) junction and the left ventricular attachment allowing for hypermobility of the MV apparatus. The transesophageal echocardiographic characteristics of this abnormality have not been previously described. In patients undergoing MV repair for myxomatous MV degeneration and evaluated using a standardized transesophageal echocardiographic protocol, annular disjunction (mean value 10 +/- 3 mm) was seen at the base of the posterior leaflet in 98% of patients with advanced, and in 9% of patients with mild/moderate MV degeneration. There was a significant correlation between the magnitude of disjunction and the number of segments with prolapse/flail (r = 0.397, P = .001). We found annular disjunction to be a common component of MV apparatus in advanced MV degeneration. Its recognition on transesophageal echocardiography is important to facilitate optimal MV repair. The modification of the repair technique allows surgical correction of the annular disjunction, which seems to optimize long-term results in these challenging cases.


Felbamate-induced apoptosis of hematopoietic cells is mediated by redox-sensitive and redox-independent pathways.
Felbamate (FBM; 2-phenyl-1,3-propanediol dicarbamate) is an approved antiepileptic drug shown to be effective in a variety of seizure disorders refractory to other treatments. However, its use has been restricted because of association with occurrence of rare cases of aplastic anemia and hepatic failure. Since it was shown that FBM metabolism requires glutathione (GSH), we used two experimental protocols to determine if the effects of specific metabolites were sensitive to redox pathways. FBM and its metabolite W873 (2-phenyl-1,3-propanediol monocarbamate), at 0.1 mg/ml, induced increased apoptosis of bone marrow cells from B10.AKM mice as compared with B10.BR mice. Study of the effects of the drug on human promonocytic cell line U937 cells showed that FBM and the metabolite W2986 [2-(4-hydroxyphenyl)-1,3 propanediol dicarbamate], at higher concentrations (0.5 mg/ml), induced apoptosis in this cell line. We also observed that while FBM and its metabolites induced increased apoptosis of B cells with reduced intracellular GSH levels, addition of exogenous GSH decreased apoptosis induced by W873 but did not significantly affect apoptosis induced by FBM or W2986. Our results suggest that, at concentrations used during the present investigations, FBM metabolites induce apoptosis via redox-sensitive and redox-independent pathways.


Multi-scale hybrid spherical graphite composites: a light weight thermal interface material with high thermal conductivity and simple processing technology.
In consideration of low density and high intrinsic thermal conductivity, spherical graphite powders can act as promising fillers for light weight thermal interface materials. Herein, spherical artificial graphite derived composites exhibit a similar thermal conductivity and significantly reduced bulk density compared with traditional Al2O3-derived composites. Further, based on the particle packing theory, an innovatively optimized calculation method has been proposed by introducing the quadratic programming method into the traditional calculation method to acquire the optimum formulation of multi-scale spherical graphite particles. The thermal conductivity of the optimum formulation-derived composites attains 1.994 W m-1 K-1, which is 1.72 times higher than that of the single particle size-derived composites (1.156 W m-1 K-1), accompanied by a low density of 1.812 g cm-3 vs. the 2.31 g cm-3 of the traditional Al2O3-derived composites. Besides, the relationships between the tap density of the graphite powders, thermal conductivity and maximum filling content of the composites are creatively established, which are available for predicting the thermal conductivities of composites by simply testing the tap density of the fillers. This present work provides an instructional strategy to optimize spherical filler particles for thermal management of electronic devices.


Plasma miRNA Levels for Predicting Therapeutic Response to Neoadjuvant Treatment in HER2-positive Breast Cancer: Results from the NeoALTTO Trial.
To investigate the potential of circulating-miRNAs (ct-miRNA) as noninvasive biomarkers to predict the efficacy of single/dual HER2-targeted therapy in the NeoALTTO study. Patients with plasma samples at baseline (T0) and/or after 2 weeks (T1) of treatment were randomized into training (n = 183) and testing (n = 246) sets. RT-PCR-based high-throughput miRNA profiling was employed in the training set. After normalization, ct-miRNAs associated with pathologic complete response (pCR) were identified by univariate analysis. Multivariate logistic regression models were implemented to generate treatment-specific signatures at T0 and T1, which were evaluated by RT-PCR in the testing set. Event-free survival (EFS) according to ct-miRNA signatures was estimated by Kaplan-Meier method and Cox regression model. In the training set, starting from 51 ct-miRNAs associated with pCR, six signatures with statistically significant predictive capability in terms of area under the ROC curve (AUC) were identified. Four signatures were confirmed in the testing set: lapatinib at T0 and T1 [AUC 0.86; 95% confidence interval (CI), 0.73-0.98 and 0.71 (0.55-0.86)], respectively; trastuzumab at T1 (0.81; 0.70-0.92); lapatinib + trastuzumab at T1 (0.67; 0.51-0.83). These signatures were confirmed predictive after adjusting for known variables, including estrogen receptor status. ct-miRNA signatures failed to correlate with EFS. However, the levels of ct-miR-140-5p, included in the trastuzumab signature, were associated with EFS (HR 0.43; 95% CI, 0.22-0.84). ct-miRNAs discriminate patients with and without pCR after neoadjuvant lapatinib- and/or trastuzumab-based therapy. ct-miRNAs at week two could be valuable to identify patients responsive to trastuzumab, to avoid unnecessary combination with other anti-HER2 agents, and finally to assist deescalating treatment strategies.


The wide variation of definitions of genetic testing in international recommendations, guidelines and reports.
In spite of being very commonly used, the term genetic testing is debatable and used with several meanings. The diversity of existing definitions is confusing for scientists, clinicians and other professionals, health authorities, legislators and regulating agencies and the civil society in general, particularly when genetic testing is the object of guidelines or legal documents. This work compares definitions of genetic testing found in recommendations, guidelines and reports from international institutions, policy makers and professional organizations, but also in documents from other stakeholders in the field, as the pharmaceutical industry, insurers, ethics bodies, patient organizations or human-rights associations. A systematic review of these documents confirmed the extreme variability existing in the concepts and the ambiguous or equivocal use of the term. Some definitions (narrower) focus on methodologies or the material analysed, while others (broader) are information- or context-based. Its scope may range from being synonymous of just DNA analysis, to any test that yields genetic data. Genetic testing and genetic information, which may be derived from a range of medical exams or even family history, are often used interchangeably. Genetic testing and genetic screening are sometimes confused. Human molecular genetics (a discipline) is not always distinguished from molecular biology (a tool). Professional background, geographical context and purpose of the organizations may influence scope and usage. A common consensus definition does not exist. Nevertheless, a clear set of precise definitions may help creating a common language among geneticists and other health professionals. Moreover, a clear context-dependent, operative definition should always be given.


Comparable detection of nasopharyngeal swabs and induced sputum specimens for viral nucleic acid detection of suspected novel coronavirus (SARS-Cov-2) patients in Fayoum governorate, Egypt.
The most commonly utilized samples for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR) are nasopharyngeal swabs (NPS) and oropharyngeal swabs. However, there are some drawbacks. For SARS-CoV-2 detection, induced sputum might be analyzed and may be equivalent to pharyngeal swabs. This study was done to assess the potential superiority of induced sputum over NPS for SARS-CoV-2 detection. Sixty symptomatic COVID-19 patients who attended Fayoum University Hospitals in Fayoum Governorate, Egypt, were included in this cross-sectional descriptive study. Paired NPS and induced sputum samples were collected from each subject on the third and tenth days after symptoms began for RT-qPCR SARS-COV2 diagnosis. At day 3, 52 (86.7%) of NPS and 48 (80.00%) of induced sputum specimens had positive RT-qPCR results with a significant statistical difference (P = 0.001). At day 10, 41 induced sputum samples (68.3%) were negative, while 19 (31.7%) were positive. Only three (5.0%) of the 19 positive induced sputum samples tested positive for NPS. NPS samples had a higher viral load than induced sputum samples at day 3 [25 (41.7%) vs. 23 (38.3%)]. At day 10, induced sputum samples had a higher viral load than NPS [9 (15.0%) vs. 6 (10.0%)]. A statistically significant positive correlation between the viral load value of the NPS and the induced sputum sample at day 3 (r = 0.497, p = 0.00) denoting similarity in the results of the two types of samples. By ROC analysis, the highest area under the curve for the overall CT value of the induced sputum was (0.604), with a statistically significant difference (p value = 0.0418). In the early stages of the disease, induced sputum and NPS tests had comparable results, but NPS yielded more false negative results later in the disease course than an induced sputum sample, which yielded higher sample positivity and viral load than NPS. Furthermore, induced sputum collection is a straightforward, non-invasive, and risk-free method. As a result, induced sputum could be useful for COVID-19 confirmation in patients with radiologically or epidemiologically suspected COVID-19 who have a negative NPS or in difficult-to-diagnose COVID-19 patients.


Outcomes of Hospitalizations for Cardiogenic Shock at Left Ventricular Assist Device Versus Non-Left Ventricular Assist Device Centers.
Background Cardiogenic shock (CS) is a complex syndrome associated with high morbidity and mortality. In recent years, many US hospitals have formed multidisciplinary shock teams capable of rapid diagnosis and triage. Because of preexisting collaborative systems of care, hospitals with left ventricular assist device (LVAD) programs may also represent "centers of excellence" for CS care. However, the outcomes of patients with CS at LVAD centers have not been previously evaluated. Methods and Results Patients with CS were identified in the 2012 to 2014 National Inpatient Sample. Clinical characteristics, revascularization rates, and use of mechanical circulatory support were analyzed in LVAD versus non-LVAD centers. The association between hospital type and in-hospital mortality was examined using multivariable logistic regression models. Of 272 075 hospitalizations, 26.0% were in LVAD centers. CS attributable to causes other than acute myocardial infarction represented most cases. In-hospital mortality was lower in LVAD centers (38.9% versus 43.3%; P<0.001). In multivariable analysis, the odds of mortality remained significantly lower for hospitalizations in LVAD centers (odds ratio, 0.89; P<0.001). In patients with CS secondary to acute myocardial infarction, revascularization rates were similar between LVAD and non-LVAD centers. The use of intra-aortic balloon pump (18.7% versus 18.8%) and Impella/TandemHeart (2.6% versus 1.9%) was similar between hospital types, whereas extracorporeal membrane oxygenation was used more frequently in LVAD centers (4.3% versus 0.2%; P<0.001). Conclusions Risk-adjusted mortality was lower in patients with CS who were hospitalized at LVAD centers. These centers likely represent specialized, shock team capable institutions across the country that may be best suited to manage patients with CS.


Suppression of beta-adrenergic responsiveness of L-type Ca2+ current by IL-1beta in rat ventricular myocytes.
The possible mechanism by which interleukin-1beta (IL-1beta) affects beta-adrenergic responsiveness of L-type Ca2+ current (ICa,L) was examined in adult rat ventricular myocytes by use of whole cell patch-clamp techniques. In the presence of isoproterenol (Iso), exposure for 3 min to IL-1beta suppressed the Iso-activated ICa,L. In the presence of IL-1beta, the response of ICa,L to Iso was decreased, and the EC50 for Iso stimulation was increased. However, IL-1beta had no effect on [3H]CGP-12177 binding, displacement of [3H]CGP-12177 binding by Iso, or on basal and Iso-enhanced cAMP content. When ICa,L was activated by extracellular application of forskolin or 8-(4-chlorophenylthio)-cAMP, a membrane-permeable cAMP analog, or by intracellular dialysis with cAMP, IL-1beta had little effect on ICa,L. In contrast, in the presence of cAMP, IL-1beta still suppressed the Iso-enhanced ICa,L. These results show that the IL-1beta-induced decrease in beta-adrenergic responsiveness of ICa,L does not result from inhibition of beta-adrenoceptor binding, adenylyl cyclase activity, or cAMP-mediated pathways, suggesting a cAMP-independent mechanism.


Neoseiulus californicus (Acari: Phytoseiidae) as a potential control agent of Tetranychus urticae (Acari: Tetranychidae): effect of pest/predator ratio on pest abundance on strawberry.
Neoseiulus californicus (McGregor) is a promising agent for successful Tetranychus urticae Koch control through conservation techniques, in strawberry crops in La Plata (Buenos Aires, Argentina). In prey-predator interaction, initial relative densities have an important effect on system dynamics. The economic threshold level (ETL) used for this pest in the present study was 50 active mites per leaflet. In our laboratory experiments, initial T. urticae to N. californicus ratio had a significant effect on the population abundance of T. urticae at a 7-day period. When pest/predator ratio was 5/1 (at initial pest densities from 5 to 15 females/leaflet) the final number of active T. urticae/leaflet was significantly lower than the ETL, while at 20 females/leaflet this number did not differ from the ETL. At 7.5/1 ratio, the final number of active T. urticae/leaflet, at initial pest densities from 5 to 15 females/leaflet, reached the ETL without surpassing it. At 10/1 and 15/1 ratios, pest densities exceeded the ETL only at 15 initial T. urticae/leaflet. Most greenhouse and field observations were consistent with the predictions of a graphical model based on experimental results. This predator was very effective in limiting pest densities at a 7-day period and within the range of pest-predator ratios and absolute densities used in this study. Conservation of N. californicus promoting favorable pest/predator ratios may result in early control of T. urticae.


Thermophilic biodesulfurization and its application in oil desulfurization.
To reduce the harm caused to the environment by fuel combustion and meet the increasingly stringent emission standards, the sulfur content of fuels should be reduced. Dibenzothiophene, benzothiophene, and their derivatives are sulfur-containing components of fuels that are difficult to desulfurize and can therefore cause great environmental damage. Biodesulfurization is a desulfurization method that has the advantage of being able to remove dibenzothiophene and its derivatives removed easily under conditions that are relatively mild when compared with hydrodesulfurization. This paper introduces the advantages of thermophilic biodesulfurization compared with mesophilic biodesulfurization; analyzes the desulfurization mechanism, including the desulfurization pathways and enzymic systems of desulfurization bacteria; and discusses the application of biodesulfurization in oil desulfurization. The main problems existing in biodesulfurization and possible solutions are also analyzed in this paper. Biological desulfurization is a promising method for desulfurization; accordingly, more studies investigating biodesulfurization of actual oil are needed to enable the industrialized application of biodesulfurization.


The ubiquitination of rag A GTPase by RNF152 negatively regulates mTORC1 activation.
mTORC1 is essential for regulating cell growth and metabolism in response to various environmental stimuli. Heterodimeric Rag GTPases are required for amino-acid-mediated mTORC1 activation at the lysosome. However, the mechanism by which amino acids regulate Rag activation remains not fully understood. Here, we identified the lysosome-anchored E3 ubiquitin ligase RNF152 as an essential negative regulator of the mTORC1 pathway by targeting RagA for K63-linked ubiquitination. RNF152 interacts with and ubiquitinates RagA in an amino-acid-sensitive manner. The mutation of RagA ubiquitination sites abolishes this effect of RNF152 and enhances the RagA-mediated activation of mTORC1. Ubiquitination by RNF152 generates an anchor on RagA to recruit its inhibitor GATOR1, a GAP complex for Rag GTPases. RNF152 knockout results in the hyperactivation of mTORC1 and protects cells from amino-acid-starvation-induced autophagy. Thus, this study reveals a mechanism for regulation of mTORC1 signaling by RNF152-mediated K63-linked polyubiquitination of RagA.


Traumatic dental injuries in high school athletes in the United States of America from 2005 to 2020.
Participation in sports activities is a source of dental injury. Despite recommendations for the use of mouthguards, athletes underutilize them. The aim of this study was to provide estimates of dental injuries, the mechanism of injuries and the utilization of mouthguards in high school sports. This study was a secondary analysis of an existing dataset of a convenience sample of the National High School Sports-Related Injury Surveillance Study. Data of athletic exposures, dental injuries, mouthguard usage, and mechanism of injury from the 2005/2006 to the 2019/2020 academic years were analyzed. During the study period, there were 459 dental injuries in 49,987,927 athletic exposures resulting in a dental injury rate of 0.9 per 100,000 athletic exposures (AE). Slightly more than half of the traumatic dental injuries were sustained during competition (n = 256; 55.8%) and the rest (n = 200; 43.6%) were sustained during practice. The rate of dental injury in competition was 3.6 times higher than the rate in practice (RR: 3.6, 95% CI: 3.0-4.4). Dental injuries comprised 0.4% of the total 108,574 injuries sustained by athletes. Among girls' sports, field hockey had the highest rate (3.5 per 100,000 AE) and among boys' sports, basketball (2.4 per 100,000 AE) had the highest rate of dental injury. The most common mechanism of injury was contact with another player (276; 60.4%) followed by contact with apparatus (146; 31.9%). In the majority of dental injuries (308; 75.1%), the athlete was not wearing a mouthguard when the dental injury was sustained. Dental injuries were a small proportion of all injuries sustained by high school athletes. The majority of dental injuries were sustained when the athlete was not wearing a mouthguard.


A Fluorescent Polymer Probe with High Selectivity toward Vascular Endothelial Cells for and beyond Noninvasive Two-Photon Intravital Imaging of Brain Vasculature.
A chromophore-engineering strategy that relies on the introduction of a ground-state distortion in a quadrupolar chromophore was used to obtain a quasi-quadrupolar chromophore with red emission and large two-photon absorption (2PA) cross-section in polar solvents. This molecule was functionalized with water-solubilizing polymer chains. It constitutes not only a remarkable contrast agent for intravital two-photon microscopy of the functional cerebral vasculature in a minimally invasive configuration but presents intriguing endothelial staining ability that makes it a valuable probe for premortem histological staining.


Boron trifluoride etherate on silica-A modified Lewis acid reagent (VII). Antitumor activity of cannabigerol against human oral epitheloid carcinoma cells.
Geraniol (1), olivetol (2), cannabinoids (3 and 4) and 5-fluorouracil (5) were tested for their growth inhibitory effects against human oral epitheloid carcinoma cell lines (KB) and NIH 3T3 fibroblasts using two different 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and sulforhodamine B protein (SRB) assay. Cannabigerol (3) exhibited the highest growth-inhibitory activity against the cancer cell lines.


Prevention and Treatment of Flatulence From a Traditional Persian Medicine Perspective.
The feeling of abdominal fullness, bloating, and movement of gas in the abdomen is a very uncomfortable sensation termed flatulence. Since flatulence is one of the most common gastrointestinal symptoms that is bothersome to patients, it is important to identify effective methods to resolve this issue. In modern medicine, management of flatulence is often not satisfactory. On the other hand, traditional systems of medicine can be considered good potential sources to find new approaches for preventing and treating flatulence. The aim of this study is to review flatulence treatments from a traditional Persian medicine (TPM) viewpoint. In this study, the reasons for flatulence and methods for its prevention and treatment are reviewed in traditional Persian medicine (TPM) texts and then related with evidence from modern medicine by searching in databases, including PubMed, Scopus, Google Scholar, and IranMedex. From a traditional Persian scholar viewpoint, one of the most important causes of flatulence is an incorrect manner of eating; valuable advice to correct bad eating habits will be illustrated. In addition, traditional practitioners describe some herbs and vegetables as well as herbal compounds that are effective food additives to relieve flatulence. The anti-flatulent effect of most of these herbs has been experimentally verified using modern medicine. Attention to TPM can lead to the identification of new preventive and curative approaches to avoid and treat flatulence. In addition, Persian viewpoints from the medieval era regarding flatulence are historically important.


Radical vitrectomy and silicone-oil injection in the treatment of proliferative vitreoretinopathy following retinal detachment.
Eighteen consecutive patients with proliferative vitreoretinopathy following retinal detachment were treated with radical pars-plana vitrectomy and silicone oil injection. At least 6 months follow-up demonstrated fully attached retinas in 12 patients, partly attached retinas in 3 patients and primary failure in 3 patients. The visual fields revealed serious defects in 50% of those patients with attached retinas. The expected complications such as cataract (100%), glaucoma, corneal decompensation and subretinal oil were seen as well, but the complication rate is expected to diminish with newer surgical techniques.


Jail suicides by hanging. An epidemiological review and recommendations for prevention.
This article reviews 17 cases of jail suicide occurring in Oklahoma in calendar years 1981 through 1983. Significant variables are reviewed, and recommendations for prevention are presented.


Characterization of the recombinant Brettanomyces anomalus β-glucosidase and its potential for bioflavouring.
Plant materials used in the food industry contain up to five times more aromas bound to glucose (glucosides) than free, unbound aromas, making these bound aromas an unused flavouring potential. The aim of this study was to identify and purify a novel β-glucosidase from Brettanomyces yeasts that are capable of releasing bound aromas present in various food products. We screened 428 different yeast strains for β-glucosidase activity and are the first to sequence the whole genome of two Brettanomyces yeasts (Brettanomyces anomalus and Brettanomyces bruxellensis) with exceptionally high β-glucosidase activity. Heterologous expression and purification of the identified B. anomalus β-glucosidase showed that it has an optimal activity at a higher pH (5·75) and lower temperature (37°C) than commercial β-glucosidases. Adding this B. anomalus β-glucosidase to cherry beers and forest fruit milks resulted in increased amounts of benzyl alcohol, eugenol, linalool and methyl salicylate compared to Aspergillus niger and Almond glucosidase. The newly identified B. anomalus β-glucosidase offers new possibilities for food bioflavouring. This study is the first to sequence the B. anomalus genome and to identify the β-glucosidase-encoding genes of two Brettanomyces species, and reports a new bioflavouring enzyme.


Physicochemical, biochemical and microbiological changes of jeotgal-like fermented Chinook salmon (Oncorhynchus tshawytscha) roe.
A jeotgal-like product was processed from Chinook salmon (Oncorrhynchus tshawytscha) roe. Physicochemical, biochemical, and microbiological compositions were studied during 30 days of fermentation. Fermentation decreased water activity (aw) and pH value. Total bacterial and LAB counts (log CFU/g) increased up to 12 days of processing and then no further changes occurred. Saturated fatty acids (SFA) decreased (p < 0.05), monounsaturated fatty acids (MUFA) did not change (p > 0.05), whereas fermentation time improved polyunsaturated fatty acids (PUFA) content significantly (p < 0.05). Astaxanthin, lutein and phospholipids (PC, LPC, PE, LPE and LPS) concentrations were found to increase, while cholesterol and tocopherol contents were decreased at the end of the fermentation (p < 0.05). This study indicates that the nutritional value of salmon roe can be enhanced by fermentation.


Randomized, double-blind, placebo-controlled, crossover trial of oral doxycycline for epistaxis in hereditary hemorrhagic telangiectasia.
Vascular malformations in hereditary hemorrhagic telangiectasia (HHT) lead to chronic recurrent bleeding, hemorrhage, stroke, heart failure, and liver disease. There is great interest in identifying novel therapies for epistaxis in HHT given its associated morbidity and impact on quality of life. We aimed to measure the effectiveness of oral doxycycline for the treatment of epistaxis and explore mechanisms of action on angiogenic, inflammatory and pathway markers in HHT using a randomized controlled trial. 13 HHT patients with epistaxis were recruited from the Toronto HHT Center at St. Michael's Hospital. Recruitment was stopped early due to COVID-19-related limitations. The study duration was 24 months. Patients were randomly assigned to the treatment-first or placebo-first study arm. We compared the change in weekly epistaxis duration and frequency, biomarkers, blood measurements, and intravenous iron infusion and blood transfusion requirements between treatment and placebo. There was no significant difference in the change in weekly epistaxis duration (p = 0.136) or frequency (p = 0.261) between treatment and placebo. There was no significant difference in the levels of MMP-9, VEGF, ANG-2, IL-6 or ENG with treatment. Hemoglobin levels were significantly higher (p = 0.0499) during treatment. Ferritin levels were not significantly different between treatment and placebo. There was no significant difference in RBC transfusions between treatment periods (p = 0.299). Overall, our study did not demonstrate effectiveness of doxycycline as a treatment for epistaxis in patients with HHT, though the study was underpowered. Secondary analyses provided new observations which may help guide future trials in HHT. Trial Registration ClinicalTrials.gov, NCT03397004. Registered 11 January 2018 - Prospectively registered, https://clinicaltrials.gov/ct2/show/NCT03397004.


Correction to: CompNet: a GUI based tool for comparison of multiple biological interaction networks.
Following publication of the original article [1], the authors requested to update a link in the article. There was a server update and the hosted applications needed to move to a new web location.


Immediate commencement of amino acid supplementation in preterm infants: effect on serum amino acid concentrations and protein kinetics on the first day of life.
To determine whether the general reluctance to begin amino acid administration to preterm infants from birth onward might lead to loss of lean body mass and impairment of growth, we measured amino acid levels and protein kinetics in 18 preterm infants. Nine infants received amino acids (1.15 +/- 0.06 gm.kg-1.day-1) and glucose (6.05 +/- 1.58 gm.kg-1.day-1), whereas the other nine infants received only glucose (6.48 +/- 1.30 gm.kg-1.day-1) from birth onward. Protein kinetics on the first postnatal day were measured with a stable isotope dilution technique with [1-13C]leucine as a tracer. No statistically significant differences were noted in blood pH, base excess, urea concentration, or glucose levels. Both total amino acid concentration and total essential amino acid concentration were significantly lower and were below the reference range in the nonsupplemented group. Plasma amino acid levels of five essential amino acids (methionine, cystine, isoleucine, leucine, arginine) were below the reference range in the nonsupplemented group, whereas only cystine was below the reference range in the supplemented group. Nitrogen retention was improved significantly by the administration of amino acids (-110 +/- 44 mg nitrogen per kilogram per day in the glucose-only group vs +10 +/- 127 mg nitrogen per kilogram per day in the group given glucose and amino acids; p = 0.001); leucine oxidation was not significantly increased in the supplemented group (41 +/- 13 mumol.kg-1.hr-1 vs 46 +/- 16 mumol.kg-1.hr-1). Leucine balance also improved significantly (-41 +/- 13 mumol.kg-1.hr-1 vs -8 +/- 16 mumol.kg-1.hr-1; p = 0.01) because of a combination of an increased amount of leucine being used for protein synthesis and a lower amount of leucine coming from protein breakdown. Plasma cystine concentration, the only amino acid below the reference range in the supplemented group, was highly predictive for protein synthesis in that group. We conclude that the administration of amino acids to preterm infants from birth onward seems safe and prevents the loss of protein mass.


Inhibitory corticotropin-releasing factor neurons in the dorsomedial prefrontal cortex promote stress-resilient behavior in male rodents.
Adaptive behavior in response to adverse experiences facilitates faster recovery and less time spent engaging in maladaptive behaviors that contribute to psychopathology, including anxiety, depression, and posttraumatic stress disorder. Dysregulation of activity in the prefrontal cortex (PFC) has been implicated in these disorders, with stress further exacerbating these negative effects. Corticotropin-releasing factor is an important regulator of the stress-response system and may have a differential involvement in individuals who are especially susceptible to negative stress-related outcomes. A recent study by Chen et al. (Chen P, Lou S, Huang ZH, Wang Z, Shan QH, Wang Y, Yang Y, Li X, Gong H, Jin Y, Zhang Z, Zhou Z. Neuron 106: 301-315, 2020) has identified a novel subtype of GABAergic CRF interneurons in the dorsomedial PFC that, upon activation, can promote active responses and resilient behavior in response to stress.


Role of miRNAs in hypoxia-related disorders.
Hypoxia is a complex pathophysiological condition. The physiological and molecular responses to this stress have been extensively studied. However, the management of its ill effects still poses a challenge to clinicians. MicroRNAs (miRNAs) are short non-coding RNA molecules that control post-transcriptional gene expression. The regulatory role of miRNAs in hypoxic environments has been studied in many hypoxia-related disorders, however a comprehensive compilation and analysis of all data and the significance of miRNAs in hypoxia adaption is still lacking. This review summarizes the miRNAs related to various hypoxia-related disorders and highlights the computational approaches to study them. This would help in designing novel strategies toward efficient management of hypoxia-related disorders.


Simple flow injection colorimetric system for determination of paraquat in natural water.
A simple and low cost flow injection colorimetric system has been developed for determination of paraquat in natural water. The developed method is based on the reduction of paraquat by using sodium dithionite as a reducing agent in an alkaline medium to produce a blue free radical ion that can be detected by a simple light emitting diode-light dependent resistor (LED-LDR) colorimeter. The standard or sample solution was injected via a set of 3-way solenoid valves into a water carrier stream and flowed to merge with reagent to generate a colored product which is proportional to the concentration of paraquat ion in the solution. Under the optimum condition of the system, i.e., mixing coil length 30 cm, flow rate 2.0 mL min(-1), sample volume 100 μL, concentrations of dithionite 0.1% (w/v) and sodium hydroxide 0.06 mol L(-1), a linear calibration graph in the range of 0.2-10.0 mg L(-1) with a correlation coefficient of 0.9996, and a limit of detection of 0.15 mg L(-1) were achieved. Relative standard deviation for 9 replicate injections of 1 mg L(-1) paraquat is 3.7%. A sample throughput of 40 injections h(-1) was achieved. The limit of detection can be improved by off-line preconcentration of paraquat employing a column packed with Dowex 50WX8-100 (H) cation exchange resin and eluted with 10% (w/v) ammonium chloride in ammonium buffer solution pH 10. The eluting solution was then injected into the FI system for paraquat determination. The proposed system did not suffer from interferences of some possible ions in natural water and other herbicides. Recoveries obtained by spiking 0.5 and 5.0 mg L(-1) paraquat standard into water samples were in the range of 104-110% and 101-105%, respectively. The developed system can be conveniently applied for screening of paraquat contaminated in natural water.


Levels and profiles of perfluorinated alkyl acids in liver tissues of birds with different habitat types and trophic levels from an urbanized coastal region of South Korea.
Contamination status and characteristics of perfluorinated alkyl acids (PFAAs) including perfluorinated carboxylic acids (PFCAs) and perfluorinated sulfonic acids (PFSAs) was examined using liver tissue of birds - black-tailed gulls (Larus crassirostris), domestic pigeons (Columba livia var. domestica), pacific loons (Gavia pacifica), herons (Ardea cinerea), and egrets (Egretta garzetta and Ardea alba) - with different trophic levels, habitat types and migratory behaviors from an industrialized coastal region of South Korea. A wide range of PFAAs (1.09 ng/g to 1060 ng/g; median = 52.6 ng/g) were detected in bird livers from the Korean coasts with high detection frequency. Accumulation features of PFAAs in birds indicated that primarily trophic position and secondly habitat type influence the levels and composition of PFAAs, e.g., relatively high PFAA levels and high composition of odd-numbered long carbon chain PFCAs (perfluoroundecanoic acid (PFUnDA) and perfluorotridecanoic acid (PFTriDA)) and PFOS in higher trophic and marine birds. The prevalence of long carbon chain (≥14) PFCAs likely implies a wide use of fluorotelomer-based substances in Korea. Interspecies comparison in the accumulation profile of persistent organic pollutants (including polychlorinated biphenyls (PCBs), organochlorine pesticides, polybrominated diphenylethers (PBDEs), and PFAAs) reveals relatively high load of PFAAs in inland (pigeons) and estuarine (egrets/herons) species compared to marine bird species, indicating wide use of PFAAs in the terrestrial environment.


"V-Reverse" Suturing Technique for Tunnel Soft Tissue Graft and Flap Stabilization: Technique Illustration.
In periodontal and peri-implant plastic procedures, proper stabilization of the graft and the flap plays a crucial role in the outcomes. While the coronally advanced flap allows for better access with the possibility of suturing the graft to the periosteum and the de-epithelialized papillae, there is little evidence regarding what is the best approach in stabilizing the graft and the flap when performing the tunnel techniques (TUN). The purpose of this technical note is to describe a new suturing technique "V-reverse" for stabilization of the graft and the flap during a TUN procedure. The V-reverse suturing technique was used to enhance the stabilization of the graft and the flap during root coverage procedures, papilla augmentation, and immediate implant placement. Other advantages of this technique include reduced flap and graft micromotion; simple, easy, and fast procedure; and high patient compliance. The present article describes three main clinical scenarios in which V-reverse suturing technique is used to stabilize TUN + connective tissue graft for root coverage procedures, papilla augmentation, and immediate implant placement.


H.M. revisited: relations between language comprehension, memory, and the hippocampal system.
Three studies tested the claim that H.M. exhibits a "pure memory deficit" that has left his ability to comprehend language unimpaired relative to memory-normal controls. In Study 1, H.M. and memory-normal controls of comparable intelligence, education, and age indicated whether sentences were ambiguous or unambiguous, and H. M. detected ambiguities significantly less often than controls. In Study 2, participants identified the two meanings of visually presented sentences that they knew were ambiguous, and relative to controls, H.M. rarely discovered the ambiguities without help and had difficulty understanding the first meanings, experimenter requests, and his own output. Study 3 replicated these results and showed that they were not due to brain damage per se or to cohort effects: Unlike H.M., a patient with bilateral frontal lobe damage detected the ambiguities as readily as young and same-cohort older controls. These results bear on two general classes of theories in use within a wide range of neurosciences and cognitive sciences: The data favor "distributed-memory theories" that ascribe H.M.'s deficit to semantic-level binding processes that are inherent to both language comprehension and memory, over "stages-of-processing theories," where H.M.'s defective storage processes have no effect on language comprehension.


Aluminum adjuvants of vaccines injected into the muscle: Normal fate, pathology and associated disease.
Aluminum oxyhydroxide (Alhydrogel(®)) is a nano-crystalline compound forming aggregates that has been introduced in vaccine for its immunologic adjuvant effect in 1926. It is the most commonly used adjuvant in human and veterinary vaccines but mechanisms by which it stimulates immune responses remain ill-defined. Although generally well tolerated on the short term, it has been suspected to occasionally cause delayed neurologic problems in susceptible individuals. In particular, the long-term persistence of aluminic granuloma also termed macrophagic myofasciitis is associated with chronic arthromyalgias and fatigue and cognitive dysfunction. Safety concerns largely depend on the long biopersistence time inherent to this adjuvant, which may be related to its quick withdrawal from the interstitial fluid by avid cellular uptake; and the capacity of adjuvant particles to migrate and slowly accumulate in lymphoid organs and the brain, a phenomenon documented in animal models and resulting from MCP1/CCL2-dependant translocation of adjuvant-loaded monocyte-lineage cells (Trojan horse phenomenon). These novel insights strongly suggest that serious re-evaluation of long-term aluminum adjuvant phamacokinetics and safety should be carried out.


Lipid profiles and their potential inflammatory effects in anti-N-methyl-D-aspartate receptor encephalitis.
Growing evidence suggests an association between dyslipidemia and autoimmune diseases. This study aimed to perform a preliminary analysis to investigate the role of lipid profiles in anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis and to preliminarily explore the potential inflammatory effects of lipids on this disease by analyzing the association of lipid profiles with different inflammatory markers. This retrospective study consisted of 40 anti-NMDAR encephalitis patients and 74 healthy controls. Serum lipid profiles and different inflammatory markers were analyzed upon admission and at each follow-up. Lipid profiles were compared among subgroups of patients, which were divided according to clinical characteristics. Correlations between lipid profiles and different inflammatory markers were assessed. The results showed that lipid profiles were abnormal and were correlated with both disease severity and prognosis in patients with anti-NMDAR encephalitis. Correlations between lipid profiles and different inflammatory markers were observed. After 12 months of treatment, inflammatory markers changed with lipid profiles, and these changes were significantly correlated. Lipid profiles are associated with pathogenesis and progression of anti-NMDAR encephalitis, and they are significantly correlated with different inflammatory markers, suggesting that the association of lipids with the disease might be influenced by the inflammatory response.


Assessment of municipal solid waste settlement models based on field-scale data analysis.
An evaluation of municipal solid waste (MSW) settlement model performance and applicability was conducted based on analysis of two field-scale datasets: (1) Yolo and (2) Deer Track Bioreactor Experiment (DTBE). Twelve MSW settlement models were considered that included a range of compression behavior (i.e., immediate compression, mechanical creep, and biocompression) and range of total (2-22) and optimized (2-7) model parameters. A multi-layer immediate settlement analysis developed for Yolo provides a framework to estimate initial waste thickness and waste thickness at the end-of-immediate compression. Model application to the Yolo test cells (conventional and bioreactor landfills) via least squares optimization yielded high coefficient of determinations for all settlement models (R(2)>0.83). However, empirical models (i.e., power creep, logarithmic, and hyperbolic models) are not recommended for use in MSW settlement modeling due to potential non-representative long-term MSW behavior, limited physical significance of model parameters, and required settlement data for model parameterization. Settlement models that combine mechanical creep and biocompression into a single mathematical function constrain time-dependent settlement to a single process with finite magnitude, which limits model applicability. Overall, all models evaluated that couple multiple compression processes (immediate, creep, and biocompression) provided accurate representations of both Yolo and DTBE datasets. A model presented in Gourc et al. (2010) included the lowest number of total and optimized model parameters and yielded high statistical performance for all model applications (R(2)⩾0.97).


Evaluation of a standardized protocol using lepirudin or argatroban for heparin-induced thrombocytopenia.
To evaluate the effectiveness of our institutions heparin-induced thrombocytopenia (HIT) protocol in achieving a therapeutic activated partial thromboplastin time (aPTT) and to evaluate patient outcomes related to bleeding and thrombotic events before and after protocol implementation. Retrospective, single-center, pre- and post- assessment of a protocol previously approved at our institution. 400-bed community hospital serving surrounding rural populations with emphasis in cardiothoracic surgery. Retrospective chart review based on drug charge data identified 29 patients that received either argatroban or lepirudin for greater than 24 hours. Nineteen patients received either argatroban or lepirudin prior to HIT-protocol implementation, while the remaining ten received either drug after the HIT protocol was implemented. Implementation of HIT protocol occurred in March 2009. Patients were divided into pre-protocol and post-protocol groups. Primary outcome was to evaluate the number of therapeutic, subtherapeutic, and supratherapeutic aPTTs between two groups. In the pre-protocol group, aPTTs were therapeutic, subtherapeutic, and supratherapeutic 48.5% (164/338), 14.2% (48/338), and 37.2% (126/338) of the time, respectively. Meanwhile aPTTs in the post-protocol group were therapeutic, subtherapeutic, and supratherapeutic 46.6% (89/191), 22% (42/191), and 31.4% (60/191) of the time, respectively. The number of subtherapeutic aPTTs was statistically higher in the post-protocol group compared to the pre-protocol group. Secondary endpoints included the number of bleeding events and number of thrombotic events. None of the secondary endpoints reached statistical significance. Time to therapeutic aPTT was also evaluated: in the pre-protocol group median time (range) was 15 hours (2-108.6) compared to 8.1 hours (2.3-94.2) in the post-protocol group. Adoption and implementation of HIT protocol at our institution resulted in significantly more subtherapeutic aPTTs as compared to time prior to protocol. Although not statistically significant, the time required to obtain therapeutic aPTT was reduced by almost 50% after protocol implementation, which could be of clinical importance. Larger studies are needed to continue to assess if standardized protocols are effective in treatment of HIT.


Undertreatment of osteoporosis following hip fracture: a retrospective, observational study in Singapore.
Undertreatment of osteoporosis after hip fracture increases the risk of death, disability, recurrent osteoporotic fractures, and financial burden. Only half were compliant with osteoporosis medications. Elderly patients were less persistent and compliant to treatment. Denosumab was associated with a higher proportion of days covered by osteoporosis medications than oral bisphosphonates. The aim of this study was to identify factors that contributed to the initiation of osteoporosis medications following hip fracture as well as the compliance and persistence to osteoporosis medications. Clinical data of 532 patients older than 50 years old admitted for surgical fixation of hip fractures were reviewed. Three hundred forty-seven had sufficient data for analysis after excluding patients with non-fragility fractures. Prescription for any osteoporosis medication in the year following hip fracture as well as compliance to treatment was evaluated. Only 40.3% of patients were prescribed with osteoporosis medication within 1 year post-hip fracture. Females (p = 0.020) performing dual-energy x-ray absorptiometry scan (p < 0.001) and 25 hydroxyvitamin D levels testing post-hip fracture (p < 0.027) were independent determinants of increased likelihood of being prescribed with osteoporosis medication. Patients with proportion of days covered (PDC) ≥ 0.8 (or 80% of days covered in a year) were defined as compliant. Overall, only 49.7% of the patients were compliant with osteoporosis medications. Elderly patients aged 70-79 years (p = 0.002) and males (p = 0.017) were less persistent with osteoporosis treatment when compared with patients aged < 69 years and females. The compliance was poorer in patients aged 70-79 years (p = 0.026) as compared with those under 69 years of age. Statistically significant difference (p = 0.032) was observed between mean PDC of oral bisphosphonates (0.66) and denosumab (0.83). Only 39.3% of patients were persistent with treatment at 1 year. Our findings demonstrate the urgent need to increase awareness through a structured protocol of osteoporosis treatment. A multi-disciplinary Fracture Liaison Service should be set up to ensure compliance to osteoporosis medication post-hip fracture.


Quantitative assessment of Gd-DTPA contrast agent from signal enhancement: an in-vitro study.
Quantitative determination of in-vivo gadolinium diethylenetriamine-pentaacid (Gd-DTPA) concentration is attractive in various studies involving perfusion, tracer kinetics and permeability constants. Using a 1.5 T clinical system and a 7 T small-bore system, we evaluated a method for absolute determination of Gd-DTPA concentrations in plasma solutions. Different solutions of Gd-DTPA and (99m)Tc-DTPA were mixed in human plasma and concentrations in the range of 0-5.0 mmol/l (1.5 T system) or 0-3.0 mmol/l (7 T system) of Gd-DTPA were divided into thirteen tubes. All MRI measurements were carried out using conventional sequences (SE, FLASH and GRASS). The MR measured intensity was converted to Gd-DTPA concentration by mathematical interpretation of the sequences. All MRI sequences showed, that the measured concentrations of Gd-DTPA revealed a slight non-linear difference compared with the calculated Gd-DTPA concentrations determined by the plasma (99m)Tc-DTPA using gamma counting. This non-linearity was most pronounced at high Gd-DTPA concentrations, suggesting that the discrepancy could be a result of an increased plasma relaxivity at higher concentrations. Adjustment of measured Gd-DTPA concentration was therefore performed using a selected power function, A[Gd-DTPA](a), which yielded the best linear relationship. Regression analysis showed that the scaling constant (A) varied from 0.11 to 97.45 and the power constant (a) varied from 0.83 to 1.6. Based on these constants, the MRI measured concentrations of Gd-DTPA did not differ from the calculated concentrations of Gd-DTPA obtained from reference measurements of (99m)Tc-DTPA. In the 1.5 T system, a linear relationship (r(2) > or = 0.95) was demonstrated in the range of 0-5.0 mmol/l Gd-DTPA, and in the 7 T system, a linear relationship (r(2) > or = 0.92) was demonstrated in the range of 0-3.0 mmol/l Gd-DTPA. Additionally, the effect of signal-to-noise on measured concentrations of Gd-DTPA was simulated using MR data of the mixed solutions of Gd-DTPA in plasma and the analytical expression of the pulse sequences. The simulations showed that the concentrations were most sensitive to noise in the GRASS sequence. In conclusion, this study demonstrates a novel approach to quantify accurately the Gd-DTPA concentration directly from MRI signal data using different routine sequences.


Participation of Escherichia coli K-12 groE gene products in the synthesis of cellular DNA and RNA.
Cells having the temperature-sensitive mutation groES131(Ts) were isolated from Escherichia coli K-12 strain C600T by thymineless death selection at 44 degrees C. This conditionally expressed mutation affected both cellular DNA and RNA syntheses at nonpermissive temperature, in addition to rendering cells unable to propagate phage lambda at permissive temperature.


EPA's requirements for dermal irritation and sensitization testing.
This paper presents an overview of EPA guidelines for dermal irritation and sensitization testing (part of Subdivision F Guidelines) for the registration of pesticide products [Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)]. In addition, these data and others may be needed for chemicals submitted for the Premanufacture Notification or testing under Section 4 of the Toxic Substances Control Act (TSCA). The EPA periodically reviews its recommended test procedures and revises them when indicated scientifically.


[How T lymphocytes coordinate rheumatic inflammation].
Helper T (Th) cells play a decisive role in triggering and maintaining chronic rheumatic inflammation. Via secretion of proinflammatory cytokines and expression of costimulatory cell surface molecules, Th lymphocytes coordinate the recruitment and activation of effector cells, which are ultimately responsible for the immunopathology and tissue destruction. However, therapeutic approaches aimed at eliminating Th cells were unsuccessful due to their lack of selectivity. At the German Rheumatism Research Center (Deutsches Rheuma-Forschungszentrum, DRFZ), we are working to improve the understanding of the Th cells involved in chronic inflammatory reactions. Based on this understanding, our aim is to develop novel treatment strategies that selectively target the pathogenic Th lymphocytes causing rheumatic inflammation. The current article summarizes the DRFZ's research activities on this subject.


Comparison of percutaneous endoscopic lumbar discectomy versus open lumbar microdiscectomy for lumbar disc herniation: A meta-analysis.
The purpose of the study is to perform a systematic review and meta-analysis to evaluate the clinical results of percutaneous endoscopic lumbar discectomy (PELD) and open lumbar microdiscectomy (OLM) for the treatment of lumbar disc herniation (LDH). Randomized controlled trials or non-randomized controlled trials published from the time when databases were built to March 2016 that compared the clinical effectiveness of PELD and OLM surgical approaches for the treatment of LDH were acquired by a comprehensive search in four electronic databases (PubMed, EMBASE, Web of Science and Cochrane library). A total of 7 studies (1389 patients) were included in this systematic review and meta-analysis. Pooled mean differences (MD) and odds ratios (OR) and with 95% CIs were calculated for the outcomes. The results showed that there were no statistically between the PELD group and OLM group in terms of preoperative VAS-BP score (WMD = 0.03; 95% CI: -0.99 to 1.05; P = 0.95), postoperative VAS-BP score (WMD = -0.56; 95% CI: -1.43 to 0.31; P = 0.21), postoperative ODI (WMD = -0.98; 95% CI: -4.96 to 3.00; P = 0.63), complication rate (OR = 1.79; 95% CI: 0.95 to 3.37; P = 0.07) or reoperation rate (OR = 1.44; 95% CI: 0.94 to 2.20; P = 0.09). PELD group was associated with shorter operation time (WMD = -12.83; 95% CI: -24.79 to -0.87; P = 0.04) and hospital stay (WMD = -5.49; 95% CI: -8.63 to -2.35; P = 0.0006). The existing evidence indicate that no superiority exists between the two surgical approaches for the treatment of LDH in terms of functional outcome, complication rate and reoperation rate, in spite of that PELD surgical group can achieve shorter operation time and hospital stay than OLM surgical group.


Carbon bowl-confined subnanometric palladium-gold clusters for formic acid dehydrogenation and hexavalent chromium reduction.
Formic acid (FA), a high-value product of CO2 hydrogenation and biomass conversion, is considered a promising liquid organic hydrogen carrier for its high hydrogen content, easy accessibility, and relative stability. The development of an efficient heterogeneous catalyst toward FA dehydrogenation and Cr(VI) reduction by FA is needed to boost its sluggish kinetics but still remains a challenge. Herein, uniformly dispersed subnanometric PdAu alloy clusters (i.e., 0.9 nm) were successfully prepared and confined by amine-functionalized carbon bowls (ACB). By virtue of the tiny size and abundant active sites of PdAu clusters, the promotional effect of surface amine groups, and electronic interaction between subnanometric PdAu clusters and support, this as-prepared PdAu/ACB catalyst exhibits superior catalytic property for additive-free FA dehydrogenation (turnover frequency, 10597 h-1 at 323 K) and Cr(VI) reduction (rate constant, 0.47 min-1 at 298 K) under mild conditions, higher than most of the catalysts reported so far. This study offers insight into the design of efficient and durable catalysts for various catalytic applications in energy and environment.


Extravascular lung water in acute respiratory distress syndrome: potential clinical value, assumptions and limitations.
Extravascular lung water has been proposed as a marker of disease severity, response to treatment and mortality in patients with acute respiratory distress syndrome. Here, we discuss its potential value and limitations in clinical practice.


Age and oxidative stress regulate Nrf2 homeostasis in human articular chondrocytes.
The purpose of this study was to investigate the effect of age and oxidative stress on regulation of nuclear factor erythroid-2-related factor 2 (Nrf2) in young, old, and osteoarthritic (OA) human articular chondrocytes. Levels of Nrf2 in primary human chondrocytes isolated from young, old, and OA donors were measured by immunoblotting, qPCR, and immunohistochemistry. Effects on levels of Nrf2, antioxidant proteins regulated by Nrf2, as well as p65, and the anabolic response to insulin-like growth factor-1 (IGF-1) were evaluated after induction of oxidative stress with menadione, Nrf2 knockdown with siRNA, and/or Nrf2 activation with RTA-408. Nrf2 protein levels were significantly lower in older adult chondrocytes (∼0.59 fold; p = 0.034) and OA chondrocytes (∼0.50 fold; p = 0.016) compared to younger cells. Menadione significantly increased Nrf2 protein levels in young chondrocytes by just under four-fold without changes in old chondrocytes. Nrf2 knockdown and activation differentially regulated levels of anti-oxidant proteins including sulfiredoxin and NAD(P)H quinone dehydrogenase 1. Nrf2 activation with RTA-408 also decreased basal p65 phosphorylation, increased aggrecan and type II collagen gene expression, and increased production of proteoglycans in OA chondrocytes treated with IGF-1. Targeted therapeutic strategies aimed at maintaining Nrf2 activity could be useful in maintaining chondrocyte homeostasis through maintenance of intracellular antioxidant function and redox balance.


Pathogenicity of Listeria monocytogenes Scott A after oral and oculonasal challenges of day-old turkey poults.
Listeria monocytogenes is a ubiquitous, environmental pathogen that has contaminated poultry ready-to-eat products resulting in large-scale recalls. Research is needed to determine the source of product and processing plant contamination with L. monocytogenes. The purpose of this study was to compare the oral and oculonasal routes of infection on the pathogenicity of L. monocytogenes in turkey poults under different housing conditions. One-day-old turkey poults were challenged by either route with the Scott A strain of L. monocytogenes and placed either in paper-lined battery-brooder cages for 1 wk or in floor pens on fresh pine-shaving litter. On day 7, birds challenged in battery cages were transferred to floor pens. Challenge by the oculonasal route resulted in higher mortality (P = 0.05) and lower body weights (P < 0.0001) compared with both nonchallenged controls and those challenged by the oral route. Birds contained in battery cages for 1 wk had higher mortality (P = 0.002) and higher body weights (P < 0.0001) compared with floor-pen-reared birds. Using direct plating, the challenge strain was isolated from the gall bladder, brain, and knee joint of only one dead poult challenged by the oculonasal route. These results suggest that day-old turkey poults may be more susceptible to an oculonasal challenge with L. monocytogenes than to an oral challenge and that containment in battery cages for the first week increased contact exposure to the challenge.


Health economic evidence for the use of molecular biomarker tests in hematological malignancies: A systematic review.
Molecular biomarker tests can inform the clinical management of genomic heterogeneous hematological malignancies, yet their availability in routine care largely depends on the supporting health economic evidence. This study aims to systematically review the economic evidence for recent molecular biomarker tests in hematological malignancies. We conducted a systematic search in five electronic databases for studies published between January 2010 and October 2020. Publications were independently screened by two reviewers. Clinical study characteristics, economic methodology, and results were extracted, and reporting quality was assessed. Fourteen studies were identified, of which half (n = 7; 50%) were full economic evaluations examining both health and economic outcomes. Studies were predominantly conducted in a first-line treatment setting (n = 7; 50%) and adopted a non-lifetime time horizon to measure health outcomes and costs (n = 7; 50%). Five studies reported that companion diagnostics for associated therapies were likely cost-effective for acute myeloid leukemia, chronic myeloid leukemia, diffuse large B-cell lymphoma, and multiple myeloma. Four studies suggested molecular biomarker tests for treatment monitoring in chronic myeloid leukemia were likely cost-saving. Although there is initial confirmation of the promising health economic results, the present research for molecular biomarker tests in hematological malignancies is sparse with many applications of technological advances yet to be evaluated.


Genome-wide identification of WD40 superfamily in Cerasus humilis and functional characteristics of ChTTG1.
The WD40 superfamily plays an important role in a wide range of developmental and physiological processes. It is a large gene family in eukaryotes. Unfortunately, the research on the WD40 superfamily genes in Cerasus humilis has not been reported. 198 ChWD40s were identified and analyzed in the present study, along with evolutionary relationships, gene structure, chromosome distribution, and collinearity. Then, 5 pairs of tandem duplication and 17 pairs of segmental duplication were found. Based on RNA-Seq data analysis, we screened 31 candidate genes whose expression was up-regulated during the four developmental stages of fruit peel. In addition, we also demonstrated that ChWD40-140, namely ChTTG1, located in the nucleus, cytoplasm, and cytomembrane, has transcriptional activation activity and can form homodimers. ChTTG1 is involved in anthocyanin biosynthesis through heterologous overexpression in Arabidopsis. These research results provide a reference for a comprehensive analysis of the functions of WD40 in the future.


Inverse relationship between a genetic risk score of 31 BMI loci and weight change before and after reaching middle age.
Genome-wide-association studies have identified numerous body mass index (BMI)-associated variants, but it is unclear how these relate to weight gain in adults at different ages. We examined the association of a genetic risk score (GRS), consisting of 31 BMI-associated variants, with an annual weight change (AWC) and a substantial weight gain (SWG) of 10% by comparing self-reported weight at 20 years (y) with baseline weight (mean: 58 y; s.d.: 8 y) in 21407 participants from the Malmö Diet and Cancer Study (MDCS), and comparing baseline weight to weight at follow-up (mean: 73 y; s.d.: 6 y) among 2673 participants. Association between GRS and AWG and SWG was replicated in 4327 GLACIER (Gene x Lifestyle interactions And Complex traits Involved in Elevated disease Risk) participants (mean: 45 y; s.d.: 7 y) with 10 y follow-up. Cohort-specific results were pooled by fixed-effect meta-analyses. In MDCS, the GRS was associated with increased AWC (β: 0.003; s.e: 0.01; P: 7 × 10(-8)) and increased odds for SWG (odds ratio (OR) 1.01 (95% confidence interval (CI): 1.00, 1.02); P: 0.013) per risk-allele from age 20y, but unexpectedly with decreased AWC (β: -0.006; s.e: 0.002; P: 0.009) and decreased odds for SWG OR 0.96 (95% CI: 0.93, 0.98); P: 0.001) between baseline and follow-up. Effect estimates from age 20 y to baseline differed significantly from those from baseline to follow-up (P: 0.0002 for AWC and P: 0.0001 for SWG). Similar to MDCS, the GRS was associated with decreased odds for SWG OR 0.98 (95% CI: 0.96, 1.00); P: 0.029) from baseline to follow-up in GLACIER. In meta-analyses (n=7000), the GRS was associated with decreased AWC (β: -0.005; s.e.m. 0.002; P: 0.002) and decreased odds for SWG OR 0.97 (95% CI: 0.96, 0.99); P: 0.001) per risk-allele. Our results provide convincing evidence for a paradoxical inversed relationship between a high number of BMI-associated risk-alleles and less weight gain during and after middle-age, in contrast to the expected increased weight gain seen in younger age.


Psychosocial stress and well-being in patients presenting with acute myocardial infarction in a tertiary care center.
Psychosocial factors such as stress have been previously implicated as a risk factor for cardiovascular diseases (CVDs). There is little evidence regarding the prevalence of stress among patients with acute myocardial infarction (AMI). A total of 903 patients with AMI enrolled in the North Indian ST-Segment Elevation Myocardial Infarction (NORIN-STEMI) registry were included in this study. Perceived stress in these subjects was evaluated using the Perceived Stress Scale-10 questionnaire while the World health Organization (WHO-5) Well-being Index was used to evaluate psychological well-being. All these patients were followed up for one month and major adverse cardiac events (MACE) were determined. A majority of patients with AMI had either severe (478 [52.9%]) or moderate stress (347 [38.4%]) while low stress levels were observed in 78 [8.6%] patients. Additionally, most of the patients with AMI (478 [53%]) had WHO-5 well-being index <50%. Subjects with severe stress were younger (50.86 ± 13.31; P < 0.0001), more likely to be males (403 [84.30%]; P = 0.027), were less likely to have optimal level of physical activity (P < 0.0001) and had lower WHO-5 well-being score (45.54 ± 1.94%; P < 0.0001) as compared to those with low and moderate stress levels. On 30-days follow-up, subjects with moderate/severe stress had higher MACE however, the difference was non-significant (2.1% vs 1.04%; P = 0.42). A high prevalence of perceived stress and low well-being index was observed in patients presenting with AMI in India.


MicroRNAs as important players in regulating cancer through PTEN/PI3K/AKT signalling pathways.
Cancer being the leading cause of mortality has become a great threat worldwide. Current cancer therapeutics lack specificity and have side effects due to a lack of understanding of the molecular mechanisms and signalling pathways involved in carcinogenesis. In recent years, researchers have been focusing on several signalling pathways to pave the way for novel therapeutics. The PTEN/PI3K/AKT pathway is one of the important pathways involved in cell proliferation and apoptosis, leading to tumour growth. In addition, the PTEN/PI3K/AKT axis has several downstream pathways that could lead to tumour malignancy, metastasis and chemoresistance. On the other hand, microRNAs (miRNAs) are important regulators of various genes leading to disease pathogenesis. Hence studies of the role of miRNAs in regulating the PTEN/PI3K/AKT axis could lead to the development of novel therapeutics for cancer. Thus, in this review, we have focused on various miRNAs involved in the carcinogenesis of various cancer via the PTEN/PI3K/AKT axis.


Capture methods in five subspecies of free-ranging bighorn sheep: an evaluation of drop-net, drive-net, chemical immobilization and the net-gun.
Six hundred thirty-four bighorn sheep (Ovis canadensis) were captured in the western United States between 1980 and 1986, using four different methods: drop-net (n = 158), drive-net (n = 249), chemical immobilization (n = 90) and net-gun (n = 137). The net-gun was found to have considerable advantages over the use of ground nets and chemical immobilization methods for capturing bighorn sheep. Evaluation of specific outcome categories for individual sheep, including normal, compromised (stress-induced), mortality from capture myopathy (CM), and accidental mortality, revealed significant differences in these rates between capture groups (P less than 0.05). The use of the net-gun resulted in the lowest proportion of compromised sheep at 11% (15/137), had no CM mortality, and resulted in a 2% (2/137) accidental mortality. The use of drop-nets resulted in 15% compromised sheep (24/158), a CM mortality rate of 2% (3/158), and an accidental mortality rate of 1% (2/158). A similar proportion of sheep were compromised with the drive-nets (16%, 39/249). This method also had the highest CM mortality rate at 3% (7/249), and an accidental mortality rate of less than 1% (2/249). Chemical immobilization resulted in the most compromised sheep at 19% (17/90), had a CM mortality rate of 2% (2/90), and caused the most accidental deaths at 6% (5/90). Drop-nets and drive-nets were comparable when combining total mortality with rates for compromised bighorn sheep, 18% and 19%, respectively (29/158 and 48/249). Chemical immobilization had the highest combined measure of risk at 27% (24/90) and net-gun lowest at 12% (17/137).(ABSTRACT TRUNCATED AT 250 WORDS)


The Recruitment Experience of a Randomized Clinical Trial to Aid Young Adult Smokers to Stop Smoking without Weight Gain with Interactive Technology.
Multiple recruitment strategies are often needed to recruit an adequate number of participants, especially hard to reach groups. Technology-based recruitment methods hold promise as a more robust form of reaching and enrolling historically hard to reach young adults. The TARGIT study is a randomized two-arm clinical trial in young adults using interactive technology testing an efficacious proactive telephone Quitline versus the Quitline plus a behavioral weight management intervention focusing on smoking cessation and weight change. All randomized participants in the TARGIT study were required to be a young adult smoker (18-35 years), who reported smoking at least 10 cigarettes per day, had a BMI < 40 kg/m2, and were willing to stop smoking and not gain weight. Traditional recruitment methods were compared to technology-based strategies using standard descriptive statistics based on counts and proportions to describe the recruitment process from initial pre-screening (PS) to randomization into TARGIT. Participants at PS were majority Black (59.80%), female (52.66%), normal or over weight (combined 62.42%), 29.5 years old, and smoked 18.4 cigarettes per day. There were differences in men and women with respect to reasons for ineligibility during PS (p < 0.001; ignoring gender specific pregnancy-related ineligibility). TARGIT experienced a disproportionate loss of minorities during recruitment as well as a prolonged recruitment period due to either study ineligibility or not completing screening activities. Recruitment into longer term behavioral change intervention trials can be challenging and multiple methods are often required to recruit hard to reach groups.


Genotypic antiretroviral resistance testing for human immunodeficiency virus type 1 integrase inhibitors by use of the TruGene sequencing system.
A sequencing assay for detection of mutations conferring resistance to human immunodeficiency virus type 1 (HIV-1) integrase inhibitors raltegravir and elvitegravir was developed using the automated TruGene sequencing system. The assay returned clear sequencing results for samples with >or=500 RNA copies/ml for mutation detection and HIV-1 subtyping across a spectrum of HIV-1 subtypes.


Comparison between traditional laboratory tests, permeability measurements and CT-based fluid flow modelling for cultural heritage applications.
In this paper, we examine the possibility to use on-site permeability measurements for cultural heritage applications as an alternative for traditional laboratory tests such as determination of the capillary absorption coefficient. These on-site measurements, performed with a portable air permeameter, were correlated with the pore network properties of eight sandstones and one granular limestone that are discussed in this paper. The network properties of the 9 materials tested in this study were obtained from micro-computed tomography (μCT) and compared to measurements and calculations of permeability and the capillary absorption rate of the stones under investigation, in order to find the correlation between pore network characteristics and fluid management characteristics of these sandstones. Results show a good correlation between capillary absorption, permeability and network properties, opening the possibility of using on-site permeability measurements as a standard method in cultural heritage applications.


Efficacy of weekly paclitaxel for the treatment of advanced ovarian cancer: A protocol for systematic review and meta-analysis.
This study aims to assess the efficacy and safety of weekly paclitaxel (WP) for the treatment of advanced ovarian cancer (AOC). This study will systematically search bibliographic databases (MEDLINE, EMBASE, Cochrane Library, Web of Science, CINAHL, PSYCINFO, Allied and Complementary Medicine Database, CNKI, WANGFANG, and Chinese Biomedical Literature Database) and other literature sources from inception to the March 1, 2020 without language and publication time limitations. Two authors will independently complete all literature selection, data collection, and study quality evaluation. Any disagreements will be solved by a third author through discussion. We will analyze data by RevMan V.5.3 software. This study will systematically generate a comprehensive summary on the efficacy and safety of WP for the treatment of AOC. This study may provide beneficial evidence of WP for the treatment of AOC. INPLASY202040193.


Morpholin-2-yl-phosphinic acids are potent GABA(B) receptor antagonists in rat brain.
The pharmacological properties of morpholin-2-yl-phosphinic acids were evaluated on GABA(B) receptors. In rat neocortical slices maintained in Mg2+-free Krebs medium, baclofen, a GABA(B) receptor agonist, produced a concentration-dependent depression of the frequency of spontaneous discharges with an EC50 of 14 +/- 5.5 microM, which was antagonised reversibly by the morpholin-2-yl-phosphinic derivatives. The order of potency was 3-[(3S,6R)-6-[(cyclohexylmethyl)hydroxyphosphinoylmethyl- morpholin-3-yl]benzoic acid (CGP 76290A) (pA2 = 7.1 +/- 0.05) > its enantiomer 3-[(3R,6S)-6-[(cyclohexylmethyl)hydroxyphosphinoylmethyl]-++ +morpholin-3-yl]benzoic acid (CGP 76291A) (pA2 = 6.8 +/- 0.1) > cyclohexylmethyl-[(2R',5S')-5-(3-nitrophenyl)-morpholin-2-++ +ylmethyl]phosphinic acid (CGP 71978) (pA2 = 6.5 +/- 0.05) > cyclohexylmethyl-[(2R,5S)-5-phenyl-morpholin-2-ylmethyl++ +]phosphinic acid (CGP 71980) (pA2 = 6.3 +/- 0.15) > its enantiomer cyclohexylmethyl-[(2S,5R)-5-phenyl-morpholin-2-ylmethyl++ +]phosphinic acid (CGP 71979) (pA2 = 5.8 +/- 0.1). An open chain analogue of CGP 76290A, CGP 56999A (3-[1(R)-[(3-cyclohexylmethyl-hydroxyphosphinoyl)-2(S)-hydro xypropyl-amino]-ethyl]benzoic acid lithium salt) gave a pA2 of 6.6 +/- 0.2. In GABA(B) receptor binding assays, CGP 71982 (the racemic mixture of CGP 76290A and CGP 76291A), CGP 76290A, CGP 76291A, CGP 71978, CGP 71980 and CGP 71979 had IC50 values against [3H]CGP 27492 binding of 8, 1.85, 69, 124, 326 and 1460 nM, respectively. In electrically-evoked [3H]GABA release from rat cortical slices, CGP 71982, CGP 71978, CGP 71980 and its enantiomer CGP 71979, antagonised GABA(B) autoreceptors with EC150 values of 2.5, 33, 181 and 474 nM, respectively. These compounds form a novel class of potent GABA(B) receptor antagonists.


Effects of Condensed Tannins on Bacterial and Fungal Communities during Aerobic Exposure of Sainfoin Silage.
Sainfoin is a forage legume that is widely distributed around the world and is beneficial for animals owing to the characteristics of its condensed tannins (CTs), which, from certain plants, can prolong the aerobic stability of silage. The present study investigated whether sainfoin CTs can prolong aerobic stability by adding polyethylene glycol (PEG) to inactivate CT activity in the silage system. The results showed that aerobic stability increased under the PEG treatment (p < 0.05). Ammonia nitrogen (0.71 g/kg DM vs. 0.94 g/kg DM; p < 0.05) was higher in the PEG-treated group compared with the control after 3 d of aerobic exposure. BA was detected only in the PEG-treated group upon aerobic exposure. Yeasts were more abundant in the control compared with the PEG-treated group after 7 d of aerobic exposure, after which the relative abundance of Lactobacillus was lower in the PEG-treated group (65.01% vs. 75.01% in the control; p < 0.05), while the relative abundance of Pediococcus was higher in the PEG-treated group compared with the control (10.9% vs. 4.49%, respectively; p < 0.05).The relative abundances of Apiotrichum and Aspergillus were lower in the control than in the PEG-treated group after 7 d of aerobic exposure. The results suggested that sainfoin CTs decreased aerobic stability, but could inhibit certain bacteria and fungi, such as Pediococcus and Apiotrichum, and preserve the protein content during the aerobic exposure of silage.


Effect of Graphic Warning Labels on Cigarette Pack-Hiding Behavior Among Smokers: The CASA Randomized Clinical Trial.
The inclusion of graphic warning labels (GWLs) on cigarette packs is recommended for tobacco control but has not yet been implemented in the US. It is unknown whether and to what extent the inclusion of GWLs on cigarette packs affects smokers' willingness to display the packs in public. To determine whether the inclusion of GWLs on cigarette packs affects pack-hiding behavior among smokers in social settings. This community-based randomized clinical trial assessed smokers' real-world experience of using cigarettes repackaged to include GWLs (GWL packs) compared with standard US packs and blank packs over a 3-month intervention period with 12 months of follow-up between September 6, 2016, and December 3, 2019. The study included 357 participants aged 21 to 65 years from San Diego County, California, who smoked 5 or more cigarettes per day, were not actively planning to quit smoking, were not pregnant, and had no unstable medical conditions. Participants purchased and received cigarette packs through the study website. During the 1-month run-in period, participants received their usual US cigarette packs. During the 3-month intervention period, participants were randomized to receive GWL packs (study-manufactured packs with 3 rotating images under license from the Commonwealth of Australia; GWL pack group), blank packs (study-manufactured packs devoid of industry marketing imagery; blank pack group), or standard US packs (US pack group). Pack hiding was queried daily (with participants reporting behavior within the last 4 hours) and weekly via interactive text messages during the 1-month run-in and intervention periods. Self-reported smoking behavior was biochemically validated. Among 357 enrolled participants, the mean (SD) age was 39.3 (11.8) years; 195 participants (54.6%) were female, 40 (11.2%) were Hispanic, 243 (68.1%) were non-Hispanic White, and 74 (20.7%) were of other non-Hispanic races (including American Indian or Alaska Native, Asian or Pacific Islander, Black or African American, or multiracial). A total of 18 987 cigarette packs were purchased and delivered during the run-in and intervention periods. Daily querying showed that the inclusion of GWLs on cigarette packs increased the percentage of smokers who hid their packs at least some of the time from 41.3% (95% CI, 39.6%-43.0%) during the run-in period to 57.1% (95% CI, 55.9%-58.1%) by the end of the intervention period. In the postintervention period, returning to standard US packs reduced pack-hiding behavior to the levels observed during the run-in period. Pack hiding remained at run-in levels for both the blank pack group (35.2%; 95% CI, 33.6%-36.8%) and the US pack group (41.4%; 95% CI, 39.7%-43.1%]) throughout the study. Although even participants in the GWL group with the lowest prestudy tendency to conceal score (ie, 1) had a mean (SE) probability of pack hiding during the intervention of 0.84 (0.02), this group's probability of pack hiding decreased to a mean (SE) of 0.43 (0.03) after intervention. When social reactions to packs were queried at the end of the study, the modal response from participants in the GWL pack group was observers' aversive reactions to the packs, whereas the modal response from participants in the blank pack group was observers' positive interest in the study. Neither smoking prevalence nor consumption differed by group at any point in the study. In this randomized clinical trial, receiving cigarettes in GWL packs vs blank packs increased pack-hiding behavior in social settings, which may be associated with aversive reactions from observers. However, 12-month smoking behavior did not change. ClinicalTrials.gov Identifier: NCT02676193.


Integration of Postoperative Radiation Therapy with Cyclin-Dependent Kinase (CDK) Inhibitors.
Sequential use of radiation therapy before cyclin-dependent kinase (CDK) inhibitors in women with early breast cancer seems reasonable and with a low toxicity rate. This study aimed to evaluate the possible interaction between RT and CDK inhibitors in the adjuvant setting for patients with positive hormone receptors and HER-2 negative, investigating toxicity and the treatment sequencing. CDK inhibitors have been studied in patients with localized breast cancer and can improve invasive disease-free survival outcomes. Regarding the time of RT, all trials used CDK inhibitors after the RT. Interruptions in the CDK inhibitors were performed in 27.1% in Pallas, 17.5% in Penelope-B, and 16.6% in Monarch-E trials due to adverse events. Data from the Natalee trial are still not reported. The main adverse event grade III was neutropenia, with good resolution of the symptoms over time. CDK inhibitors applied sequentially and after RT postoperative showed a low profile of acute toxicity and suitable oncological outcomes.


The adoption of eating behaviors conducive to weight loss.
Given the plethora of eating behavior techniques that obese individuals might adopt for weight loss, it is not likely that they could, or would be willing to, adopt all of them. Therefore, the purpose of this study was to identify the specific eating behaviors conducive to weight loss adopted during the behavioral treatment of obesity, and to distinguish those that were deemed beneficial from the ones that were not. Fifty obese (BMI 32+/-4 kg/m(2), mean+/-SD), postmenopausal women (60+/-6 years old) participated in a 6-month behavior modification, dietary, low-intensity walking weight loss program. For analysis, they were divided into two groups: "no weight loss" (<or=5 kg, n=18) versus "weight loss" (>5 kg, n=32). At pre- and posttreatment women completed the Eating Behavior Inventory (EBI) that measures specific strategies conducive to weight loss. Women who lost weight increased their total eating behavior score by 20% (p<0.001) and improved the adoption of 14 eating behaviors, which was more than twice that of the non-weight losers. Topping the list of most strongly adopted behaviors were carefully watching and recording the type and quantity of food consumed. Maintaining a weight graph and weighing daily also were important to these women. Neither group of women adopted potentially helpful eating behaviors such as leaving food uneaten, refusing food offered by others, or shopping from a list. In studies of obesity treatment, attendance at class sessions is one marker of program adherence. More definitively, implementing the EBI in clinical and research obesity treatment programs will provide its leaders with insight into whether participants adopt, ignore, or fight the essential behaviors that will facilitate success toward their personal weight loss goals.


Attempted treatment of factor H deficiency by liver transplantation.
Complement factor H (FH) deficiency is one of the causes of atypical hemolytic uremic syndrome (HUS). Most patients with FH deficiency associated HUS progress to end-stage renal disease despite plasma therapy. Moreover, the disease invariably recurs in the graft kidney and causes graft failure. We confirmed FH deficiency in a 30-month-old boy with recurrent HUS of 2 years duration, and attempted an auxiliary partial orthotopic liver transplantation (APOLT) to overcome the sustained intractable dependency on plasma therapy. APOLT restored the plasma FH level, without HUS recurrence, for 7 months. However, thereafter he suffered from serious infectious complications associated with immunosuppression and finally died 11 months after APOLT. In conclusion, although APOLT showed clinical and laboratory improvement for some period in this patient, the final fatal outcome suggests that liver transplantation should be cautiously applied to patients with HUS associated with FH deficiency.


Shorter survival rate in varus-aligned knees after total knee arthroplasty.
One long-held tenet of total knee arthroplasty (TKA) is that post-operative neutral limb alignment promotes implant durability. Recently, the concept of generic safe zone (0° ± 3°) has been challenged. This meta-analysis aimed to evaluate whether neutral alignment was superior to malalignment in long-term survival of TKAs. The MEDLINE, Embase, Cochrane Library, China National Knowledge Infrastructure, Wan Fang Chinese Periodical, Google and reference lists of all the included studies were searched. Of the 1512 studies initially identified, ten met the eligibility criteria, including eight case-control studies and two cohort trials. Relative risks of implant failure were compared between post-operative neutrally aligned and malaligned knees. Post-operative malalignment showed higher failure rate of knee implants compared with neutral alignment (95 % CI 1.00-1.88, P = 0.05). Failure rate in knees with varus alignment was significantly higher than with neutral alignment (95 % CI 1.07-2.55, P = 0.02). There was no significant difference in the likelihood of implant failure between knees with valgus and neutral alignment (95 % CI 0.78-2.41, n.s.). No significant difference of failure rate was noted between neutral alignment and malalignment for fixed-bearing prothesis (95 % CI 0.94-1.95, n.s.) or rotating-platform prothesis (95 % CI 0.75-2.73, n.s.). There was no significant difference of failure rate between knees with neutral alignment and malalignment for studies with a mean follow-up of more than 10 years (95 % CI 0.81-2.01, n.s.) or studies using long-leg weight-bearing radiographs (95 % CI 0.79-1.79, n.s.). Post-operative varus alignment results in shorter survival rate after TKA. Not only neutral limb alignment but also the valgus alignment promotes implant durability. Neutral or valgus alignment rather than varus alignment is essential to achieve long-term survival of TKAs and patient satisfaction. III.