Airborne Nanoparticle Release and Toxicological Risk from Metal-Oxide-Coated Textiles: Toward a Multiscale Safe-by-Design Approach.
Nano metal oxides have been proposed as alternatives to silver (Ag) nanoparticles (NPs) for antibacterial coatings. Here, cotton and polyester-cotton fabrics were sonochemically coated with zinc oxide (ZnO) and copper oxide (CuO) NPs. By varying the reaction solvent (water or ethanol), NPs with different sizes and shapes were synthesized. The cytotoxic and pro-inflammatory effects of studied NPs were investigated in vitro in human alveolar epithelial A549 and macrophage-like THP1 cells. To understand the potential respiratory impact of the NPs, the coated textiles were subjected to the abrasion tests, and the released airborne particles were measured. A very small amount of the studied metal oxides NPs was released from abrasion of the textiles coated by the ethanol-based sonochemical process. The release from the water-based coating was comparably higher. Lung and immune cells viability decreased after 24 h of exposure only at the highest studied NPs concentration (100 μg/mL). Different from the ZnO NPs, both formulations of CuO NPs induced IL-8 release in the lung epithelial cells already at subtoxic concentrations (1-10 μg/mL) but not in immune cells. All of the studied NPs did not induce IL-6 release by the lung and immune cells. Calculations revealed that the exposures of the NPs to human lung due to the abrasion of the textiles were lower or comparable to the minimum doses in the cell viability tests (0.1 μg/mL), at which acute cytotoxicity was not observed. The results alleviate the concerns regarding the potential risk of these metal oxide NPs in their applications for the textile coating and provide insight for the safe-by-design approach.


Type 1 Conventional CD103+ Dendritic Cells Control Effector CD8+ T Cell Migration, Survival, and Memory Responses During Influenza Infection.
Type 1 conventional CD103+ dendritic cells (cDC1) contribute significantly to the cytotoxic T lymphocyte (CTL) response during influenza virus infection; however, the mechanisms by which cDC1s promote CTL recruitment and viral clearance are unclear. We demonstrate that cDC1 ablation leads to a deficient influenza-specific primary CD8+ T cell response alongside severe pulmonary inflammation, intensifying susceptibility to infection. The diminished pulmonary CTL population is not only a consequence of reduced priming in the lymph node (LN), but also of dysregulated CD8+ T cell egression from the LN and reduced CD8+ T cell viability in the lungs. cDC1s promote S1PR expression on CTLs, a key chemokine receptor facilitating CTL LN egress, and express high levels of the T cell survival cytokine, IL-15, to support CTL viability at the site of infection. Moreover, cDC1 ablation leads to severe impairment of CD8+ T cell memory recall and cross-reactive protection, suggesting that cDC1 are not only involved in primary T cell activation, but also in supporting the development of effective memory CD8+ T cell precursors. Our findings demonstrate a previously unappreciated and multifaceted role of CD103+ DCs in controlling pulmonary T cell-mediated immune responses.


Multiscale coherence regularization reconstruction using a nonlocal operator for fast variable-density spiral imaging.
Nonlinear reconstruction can suppress pseudo-incoherent aliasing artifacts from variable-density spiral (VDS) trajectories when interleaves are undersampled for acquisition acceleration during MR imaging. However, large-scale aliasing artifact suppression often conflicts with fine-scale structure preservation and may cause deterioration of image quality in the reconstructed images. To address this issue, a sequential, multiscale coherence regularization algorithm using a nonlocal operator (mCORNOL) is proposed. mCORNOL is formed by exploiting the scale-control capacity of nonlocal operators in image structure measurement. By changing the scale of the structure measurement, the smoothing constraint scales can be adjusted. Starting with a large value, mCORNOL gradually reduces the smoothing constraint scale until it reaches the same level as the noise. Therefore, the large-scale smoothing constraint dominates the first few iterations of the reconstruction and removes aliasing artifacts as well as fine structures. In the following iterations, the smoothing constraint is restricted to a smaller and smaller scale, so the fidelity term progressively dominates and restores lost structures. Thus, aliasing artifact removal and structure preservation can be decoupled and achieved sequentially, which alleviates the conflicts between them. Numerical simulation and in vivo experiment results demonstrate the superiority of mCORNOL for aliasing artifact suppression and image structure preservation at high reduction factors, compared to SENSE, Total Variation and the original CORNOL reconstruction. mCORNOL reconstruction provides an effective way to improve image quality for undersampled VDS acquisitions.


Effects of glucosamine sulfate on intracellular UDP-hexosamine and UDP-glucuronic acid levels in bovine primary chondrocytes.
To analyze the effects of exogenously added glucose (Glc), glucosamine (GlcN) and glucosamine sulfate (GS) on the intracellular UDP-hexoses (UDP-Hex), UDP-N-acetylhexosamines (UDP-HexN) and UDP-glucuronic acid (UDP-GlcA) levels in bovine primary chondrocytes. Chondrocytes were incubated with different concentrations of Glc, GlcN and GS either in high- or low-glucose DMEM for up to 120min to analyze the intracellular levels of UDP-Hex, UDP-GlcA and UDP-HexN by a reversed-phase high-performance liquid chromatography-electrospray ionization mass spectrometry analysis. Glycosaminoglycan (GAG) synthesis rate and aggrecan mRNA expression levels were quantified using (35)S-sulfate incorporation assay and quantitative real-time RT-PCR, respectively. The cells were cultivated for 2 days or 8 days before UDP-sugar analysis. Levels of UDP-HexN and UDP-GlcA were unchanged at 10microM concentration of GS in low-glucose DMEM, while addition of 1mM GlcN or GS in low-glucose DMEM for 10min increased UDP-HexN level. The highest intracellular level of UDP-HexN was reached at 30min after addition of 1mM GS to the cells. The intracellular contents of UDP-HexN and UDP-GlcA related to UDP-Hex were higher after prolonged cultivation of chondrocytes for 8 days compared with 2-day-old cultures. Aggrecan mRNA expression and GAG synthesis remained at control level after the cells were treated with 10, 100microM or 1mM of GS for 24h. Physiologically relevant level of GS could not increase the intracellular UDP-HexN and UDP-GlcA levels in bovine primary chondrocyte, while longer-time culture itself appeared to increase the intracellular UDP-HexN and UDP-GlcA levels.


Impairment of 40-km time-trial performance but not peak power output with external iliac kinking: a case study in a world-class cyclist.
Iliac blood-flow restrictions causing painful and "powerless" legs are often attributed to overtraining and may develop for some time before being correctly diagnosed. In the current study, differences between actual performance parameters and performance parameters predicted from the Lamberts and Lambert Submaximal Cycle Test (LSCT) were studied in a world-class cyclist with bilateral kinking of the external iliac artery before and after surgery. Two performance-testing sessions, including a peak-power-output (PPO) test and a 40-km time trial (TT) were conducted before surgery, while 1 testing session was conducted after the surgery. Actual vs LSCT-predicted performance parameters in the world-class cyclists were compared with 82 symptom-free trained to elite male cyclists. No differences were found between actual and LSCT-predicted PPO before and after surgical intervention. However, there were differences between actual and LSCT-predicted 40-km TT time in the tests performed before the surgery (2:51and 2:55 min:s, respectively). These differences were no longer apparent in the postsurgery 40-km TT (2 s). This finding suggests that iliac blood-flow restrictions seem to mainly impair endurance performance rather than peak cycling performance. A standard PPO test without brachial ankle blood-pressure measurements might not be able to reflect iliac blood-flow restrictions. Differences between actual and LSCT-predicted 40-km TT time may assist in earlier referral to a cardiovascular specialist and result in earlier detection of iliac blood-flow restrictions.


Chondroitin sulfates affect the formation of the segmental motor nerves in zebrafish embryos.
Chondroitin sulfates have been implicated in the promotion and in the inhibition of axon growth. In the zebrafish embryo, chondroitin sulfates are present at the interface of the somites and the notochord where spinal motor axons extend ventrally to establish the midsegmental ventral motor nerves. Injection of chondroitinase ABC prior to motor axon outgrowth effectively removed all chondroitin sulfate immunoreactivity and induced abnormal axonal outgrowth in many (39%) of the ventral motor nerves. The most common abnormality was the formation of side branches, approximately half of which extended posteriorly, the others anteriorly. The effect was specific to the removal of chondroitin sulfates, since injections of vehicle solution or of heparinase III did not affect the ventral motor nerves. Electron microscopic examination demonstrated that the injections caused no damage to spinal cord, somite, and notochord. This suggests that chondroitin sulfates normally constrain the outgrowth of the ventral motor nerves. Consistent with this hypothesis, injections of soluble chondroitin sulfates, either as a mixture or individually, led to truncated or missing ventral motor nerves. Truncations were most frequent after injection of chondroitin sulfate-B (up to 23%) while chondroitin sulfate-A had a lesser, and chondroitin sulfate-C no apparent, effect.


The Dopaminergic Midbrain Mediates an Effect of Average Reward on Pavlovian Vigor.
Dopamine plays a key role in motivation. Phasic dopamine response reflects a reinforcement prediction error (RPE), whereas tonic dopamine activity is postulated to represent an average reward that mediates motivational vigor. However, it has been hard to find evidence concerning the neural encoding of average reward that is uncorrupted by influences of RPEs. We circumvented this difficulty in a novel visual search task where we measured participants' button pressing vigor in a context where information (underlying an RPE) about future average reward was provided well before the average reward itself. Despite no instrumental consequence, participants' pressing force increased for greater current average reward, consistent with a form of Pavlovian effect on motivational vigor. We recorded participants' brain activity during task performance with fMRI. Greater average reward was associated with enhanced activity in dopaminergic midbrain to a degree that correlated with the relationship between average reward and pressing vigor. Interestingly, an opposite pattern was observed in subgenual cingulate cortex, a region implicated in negative mood and motivational inhibition. These findings highlight a crucial role for dopaminergic midbrain in representing aspects of average reward and motivational vigor.


[The effect of gravity on linear blood flow velocity in different parts of the venous system in humans].
Effects of gravity on linear blood velocity in jugular, femoral and popliteal veins were examined in 45 healthy male and female subjects. The zero-g effects were simulated by putting the subjects in the recumbent position, and the gravity effects were provoked by active orthostasis. Blood velocity was measured with CW Doppler (4 MHz). No difference was determined in velocity of the blood flow along the veins in recumbent subjects. In the head-up position, blood flow was significantly increased in the jugular vein and decreased in the leg veins. In several instances, brief contraction of the crus muscles caused a noticeable rise in the peak velocity along the femoral vein. In the head-up position this hemodynamic effect of the crus pump was much more pronounced.


Sustained release of mitomycin-C from poly(DL-lactide) /poly(DL-lactide-co-glycolide) films.
Mitomycin-C (MMC)-loaded poly(DL-lactide) (PLA)/poly(DL-lactide-co-glycolide) (PLGA) films which have different drug loading capacities and thicknesses were prepared by a solvent-evaporation technique. Degradation and release studies were conducted at 37 degrees C in pH 7.4 phosphate buffered saline. The results showed that both the rate and the percentage of released MMC increased as the glycolide content in the copolymer increased from 10 to 30% (w/w) and the drug load increased from 0.5 to 2 mg MMC per 300 mg of polymer. In contrast, they decreased depending upon increasing film thickness from 80 to 300 microm and polymer molecular weight. It was found that the drug release mechanism is diffusion-controlled according to a non-Fickian diffusion mechanism.


Knowledge and Attitudes of Undergraduate Dental, Allied Oral Health and Nursing Students Towards Patients with Alzheimer's Disease.
Purpose Alzheimer's disease (AD) is an age-related illness that is becoming increasingly more prevalent in the United States. The purpose of this pilot study was to assess dental, allied oral health, and nursing students' perceived knowledge, comfort, and attitudes for individuals with AD.Methods A total of 851 students from a university dental and nursing school were invited to participate in this cross-sectional study. A 48-item survey comprising of demographic questions, the Alzheimer's Disease Knowledge Scale (ADKS) and the Dementia Attitudes Scale (DAS) was disseminated via an electronic survey platform. Responses were summarized as means and standard deviations or counts and rates. Comparisons of survey responses by program type and exposure to AD, age group, and prior degree were performed using the chi-square test for association and analysis of variance.Results The response rate was 33.2%. Nursing students demonstrated the highest level of knowledge on AD with mean score of 25.26 (SD 2.87), followed by dental (M=23.4, SD 3.26) and allied oral health students (M=22.10, SD 2.98). Overall, students demonstrated perceived comfort in treating patients with AD and related dementias with mean scores in the "slightly agree" range. Nursing students demonstrated the highest level of perceived comfort (M=5.61, SD 0.71).Conclusions Nursing students demonstrated higher knowledge and more positive attitudes toward AD than dental and allied oral health students. There is a need for improved educational training and an expanded didactic curriculum to enhance knowledge for dental and allied oral health students. This pilot study provides a blueprint for replication on a national level.


Adjuvant therapy in neonatal sepsis to prevent mortality - A systematic review and network meta-analysis.
Despite appropriate antibiotic therapy, the risk of mortality in neonatal sepsis still remains high. We conducted a systematic review to comprehensively evaluate different adjuvant therapies in neonatal sepsis in a network meta-analysis. We included randomized controlled trials (RCTs) and quasi-RCTs that evaluated adjuvant therapies in neonatal sepsis. Neonates of all gestational and postnatal ages, who were diagnosed with sepsis based on blood culture or sepsis screen were included. We searched MEDLINE, CENTRAL, EMBASE and CINAHL until 12th April 2021 and reference lists. Data extraction and risk of bias assessment were performed in duplicate. A network meta-analysis with bayesian random-effects model was used for data synthesis. Certainty of evidence (CoE) was assessed using GRADE. We included 45 studies involving 6,566 neonates. Moderate CoE showed IVIG [Relative Risk (RR); 95% Credible Interval (CrI): 1.00; (0.67-1.53)] as an adjunctive therapy probably does not reduce all-cause mortality before discharge, compared to standard care. Melatonin [0.12 (0-0.08)] and granulocyte transfusion [0.39 (0.19-0.76)] may reduce mortality before discharge, but CoE is very low. The evidence is also very uncertain regarding other adjunctive therapies to reduce mortality before discharge. Pentoxifylline may decrease the duration of hospital stay [Mean difference; 95% CrI: -7.48 days (-14.50-0.37)], but CoE is very low. Given the biological plausibility for possible efficacy of these adjuvant therapies and that the CoE from the available trials is very low to low except for IVIG, we need large adequately powered RCTs to evaluate these therapies in sepsis in neonates.


Vaccines against atherosclerosis.
Atherosclerosis is the primary cause of acute myocardial infarction and stroke. It is well established that arterial inflammation in response to accumulation and oxidation of lipoproteins in the vascular wall is the major factor responsible for the development of atherosclerosis. During recent years, it has become apparent that this vascular inflammation is modulated by a complex array of autoimmune responses against modified self-antigens in the atherosclerotic plaque and that both protective and pathogenic immune responses become activated as part of the disease process. Studies of hypercholesterolemia-induced immune activation in mouse models of atherosclerosis have demonstrated that Th1 cells contribute to disease progression while regulatory T cells are protective. It has been suggested that antigen presentation of modified self-antigens in the inflammatory environment of atherosclerotic plaques favors generation of antigen-specific Th1 cells over that of regulatory T cells, resulting in a local loss of tolerance. This concept has stimulated the development of plaque-antigen tolerogenic vaccines to dampen plaque inflammation and disease progression. A first generation of atherosclerosis vaccines based on peptides derived from apoB100 and heat shock proteins have demonstrated promising results in animal studies and are now approaching clinical testing.


Improvement of the longitudinal vibration system for the hybrid transducer ultrasonic motor.
This paper presents a symmetric hybrid transducer ultrasonic motor designed to produce large longitudinal vibration stress in the rotor/stator contact interface for high-torque operation. The nodal plane of the longitudinal vibration mode was adjusted to match the rotor/stator contact interface, and the piezoelectric ceramic disks for the longitudinal vibration were installed at the nodal plane of the longitudinal vibration mode for effective excitation. An experimental motor, 20 mm in diameter, using the first torsional vibration mode and the second longitudinal vibration mode was manufactured. A maximum torque of 0.8 N.m was achieved in the prototype, an improvement over previous versions.


Atrioventricular Block: A Heralding Sign of Cardiac Allograft Rejection.
Heart transplantation is the treatment of choice for those with end-stage heart failure. However, despite improvements in immunosuppressive treatment, patients are at significant risk of allograft rejection, especially early after transplantation. Any changes in patient's heart condition including reduced left ventricular ejection fraction, arrhythmia and any types of blocks need attention. Herein we report on a 29-year-old man who underwent heart transplantation 5 years before due to dilated cardiomyopathy. He was on immunosuppressive therapy and was good until one week before his admission, when he felt palpitation. Electrocardiography during palpitation showed a second-degree AV-block with heart rate of 60 beats/min. Echocardiography showed good left ventricular systolic function with no regional wall motion abnormality. The patient referred for coronary angiography and endomyocardial biopsy. The angiography was normal. The biopsy showed rejection compatible with ISHLT grade 2R. After treating the patient with 1.5 g methylprednisolone, the symptoms relieved and the block resolved. Bradycardia and second-degree AV-block late after heart transplantation could be a sign of cardiac allograft rejection and need more evaluation, especially endomyocardial biopsy.


[Immunomodulatory effects of selank in patients with anxiety-asthenic disorders].
The purpose of this article was to study the immunotropic effects of the new neurotrophic heptapeptide selank. The experiments in vitro revealed that the drug in concentration 10-7 M completely suppressed gene expression by peripheral blood IL-6 of patients with depression but not of the healthy controls. At the same time, the significant increase (p<0,05) of IL-6 concentration was observed in the cell culture of peripheral blood of patients in the presence of selank. The changes of the Th1/Th2 cytokine balance in vivo were found in the serum of patients with generalized anxiety disorder and neurasthenia who received Selank during 14 days. The dynamics of these changes had the significant inverse correlation dependence. The cytokine regulating effects revealed in the study suggest that selank can be used as a novel immunomodulator in patients with anxiety-asthenic disorders. Additionally, the adaptogenic properties of selank may be beneficial to its use in elderly people and people exposed to environmental stressors for the prevention of infectious diseases.


Association of Uba6-Specific-E2 (USE1) With Lung Tumorigenesis.
The UBA6-specific E2 conjugating enzyme 1 (USE1) ubiquitin enzyme cascade is a poorly characterized arm of the ubiquitin-proteasome system. We investigated whether the UBA6-USE1 enzyme cascade plays a role in lung cancer tumorigenesis. USE1 expression was assessed in tumor-normal paired samples from 106 lung cancer patients by immunoblot. USE1 was stably overexpressed and knocked down in lung cancer cell lines to evaluate cell proliferation, colony formation, and invasion. Xenograft models were used to determine the effects of USE1 on tumor growth (n = 7). Proteomics analysis was used to identify proteins interacting with USE1. The USE1 gene was sequenced in lung cancer patients, and missense mutations of USE1 were generated to evaluate its function. All statistical tests were two-sided. USE1 proteins were frequently overexpressed in lung cancer patients (92.5%) Stable overexpression of USE1 increased cell proliferation ( P = .002), migration ( P < .001), and invasion ( P < .001), whereas knockdown of USE1 reduced cell proliferation ( P < .001), migration ( P = .003), and invasion in lung cancer cells and xenograft models ( P < .001). USE1 was found to have a conserved D-box domain, and the level of the protein was regulated by the anaphase-promoting complex. Several missense mutations in USE1 identified in patients prolong the stability of the protein. USE1 proteins are frequently overexpressed in lung cancer, and missense mutations in USE1 prolong the half-life of the protein, promoting tumor formation. Our findings reveal novel roles for USE1 in lung cancer and the possible use of USE1 as a novel biomarker and therapeutic target for lung cancer treatment.


Inhibition of DNA methylation by 5-aza-2'-deoxycytidine suppresses the growth of human tumor cell lines.
Alterations in DNA methylation patterns accompany the establishment of immortal cell lines. De novo methylation of CpG islands within the control regions of growth-regulatory genes may inactivate their transcription, giving cells selective growth advantages in culture. We exposed seven human tumor cell lines and two human fibroblast cell strains to the demethylating agent, 5-aza-2'-deoxycytidine (5-Aza-CdR), to determine whether the silencing of growth-regulatory genes by de novo methylation in immortalized cell lines could be reversed, possibly restoring growth control. After recovery from the immediate cytotoxic effects of 5-Aza-CdR, this agent suppressed cellular growth in all seven tumor lines but not in either fibroblast strain. Because alterations in the p16 (CDKN2/MTS1) cell cycle regulatory gene are associated with numerous cancers, we analyzed expression of this gene before and after 5-Aza-CdR treatment. The gene was reactivated by 5-Aza-CdR treatment in three of four tumor cell lines not expressing p16, whereas the fourth tumor line contained a p16 homozygous deletion. p16 was shown to be hypermethylated only in the cell lines and its up-regulation by 5-Aza-CdR was associated with demethylation of the p16 promoter. The remaining tumor lines expressed p16 at constant levels before and after 5-Aza-CdR treatment and showed minimal p16 promoter methylation, suggesting that other growth-regulatory genes may have been silenced by de novo methylation in these cells. p16 expression, cell growth inhibition, and G1 cell cycle arrest by 5-Aza-CdR in the T24 bladder tumor cell line were also heritable after prolonged passage in culture. Furthermore, a dormant p16 gene was reactivated in T24 cells growing in nu/nu rats, and 5-Aza-CdR treatment of T24 cells before inoculation into nu/nu mice decreased the rate of tumor growth. These results suggest that 5-Aza-CdR may slow the growth of tumor cells by reactivating growth-regulatory genes silenced by de novo methylation.


FUS ALS-causative mutations impair FUS autoregulation and splicing factor networks through intron retention.
Mutations in the RNA-binding protein FUS cause amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease. FUS plays a role in numerous aspects of RNA metabolism, including mRNA splicing. However, the impact of ALS-causative mutations on splicing has not been fully characterized, as most disease models have been based on overexpressing mutant FUS, which will alter RNA processing due to FUS autoregulation. We and others have recently created knockin models that overcome the overexpression problem, and have generated high depth RNA-sequencing on FUS mutants in parallel to FUS knockout, allowing us to compare mutation-induced changes to genuine loss of function. We find that FUS-ALS mutations induce a widespread loss of function on expression and splicing. Specifically, we find that mutant FUS directly alters intron retention levels in RNA-binding proteins. Moreover, we identify an intron retention event in FUS itself that is associated with its autoregulation. Altered FUS levels have been linked to disease, and we show here that this novel autoregulation mechanism is altered by FUS mutations. Crucially, we also observe this phenomenon in other genetic forms of ALS, including those caused by TDP-43, VCP and SOD1 mutations, supporting the concept that multiple ALS genes interact in a regulatory network.


GS28 Protects Neuronal Cell Death Induced by Hydrogen Peroxide under Glutathione-Depleted Condition.
Golgi SNAP receptor complex 1 (GS28) has been implicated in vesicular transport between intra-Golgi networks and between endoplasmic reticulum (ER) and Golgi. Additional role(s) of GS28 within cells have not been well characterized. We observed decreased expression of GS28 in rat ischemic hippocampus. In this study, we examined the role of GS28 and its molecular mechanisms in neuronal (SK-N-SH) cell death induced by hydrogen peroxide (H(2)O(2)). GS28 siRNA-transfected cells treated with H(2)O(2) showed a significant increase in cytotoxicity under glutathione (GSH)-depleted conditions after pretreatment with buthionine sulfoximine, which corresponded to an increase of intracellular reactive oxygen species (ROS) in the cells. Pretreatment of GS28 siRNA-transfected cells with p38 chemical inhibitor significantly inhibited cytotoxicity; we also observed that p38 was activated in the cells by immunoblot analysis. We confirmed the role of p38 MAPK in cotransfected cells with GS28 siRNA and p38 siRNA in the cell viability assay, flow cytometry, and immunoblot. Involvement of apoptotic or autophagic processes in the cells was not shown in the cell viability, flow cytometry, and immunoblot analyses. However, pretreatment of the cells with necrostatin-1 completely inhibited H(2)O(2)-induced cytotoxicity, ROS generation, and p38 activation, indicating that the cell death is necroptotic. Collectively these data imply that H(2)O(2) induces necroptotic cell death in the GS28 siRNA-transfected cells and that the necroptotic signals are mediated by sequential activations in RIP1/p38/ROS. Taken together, these results indicate that GS28 has a protective role in H(2)O(2)-induced necroptosis via inhibition of p38 MAPK in GSH-depleted neuronal cells.


Self-Supervised Video Representation Learning by Uncovering Spatio-Temporal Statistics.
This paper proposes a novel pretext task to address the self-supervised video representation learning problem. Specifically, given an unlabeled video clip, we compute a series of spatio-temporal statistical summaries, such as the spatial location and dominant direction of the largest motion, the spatial location and dominant color of the largest color diversity along the temporal axis, etc. Then a neural network is built and trained to yield the statistical summaries given the video frames as inputs. In order to alleviate the learning difficulty, we employ several spatial partitioning patterns to encode rough spatial locations instead of exact spatial Cartesian coordinates. Our approach is inspired by the observation that human visual system is sensitive to rapidly changing contents in the visual field, and only needs impressions about rough spatial locations to understand the visual contents. To validate the effectiveness of the proposed approach, we conduct extensive experiments with four 3D backbone networks, i.e., C3D, 3D-ResNet, R(2+1)D and S3D-G. The results show that our approach outperforms the existing approaches across these backbone networks on four downstream video analysis tasks including action recognition, video retrieval, dynamic scene recognition, and action similarity labeling. The source code is publicly available at: https://github.com/laura-wang/video_repres_sts.


Hepatotoxicity of thiazolidinediones.
Thiazolidinediones are insulin sensitisers now widely used for the treatment of Type 2 diabetes mellitus. The initial marketed drug in this class, troglitazone, was removed from the market worldwide after approximately 3 years of use due to rare but severe hepatotoxicity, which sometimes resulted in liver failure leading to the need for liver transplantation, or even death. The unpredictability of such liver toxicity made the use of troglitazone highly problematic. Fortunately, the two newer drugs in this class, rosiglitazone and pioglitazone, have a much larger margin of safety for liver toxicity. Very rare reports of liver toxicity, usually milder and reversible, have been seen with these drugs. Therefore, whilst pharmacovigilance for hepatotoxicity is probably still warranted, the practitioner and patient can be fairly confident that these drugs are safe from a liver standpoint. Finally, recent work would suggest that these agents may prove useful to reduce hepatic fat in patients with non-alcoholic steatohepatitis, and may possibly protect against adverse metabolic consequences and the ultimate development of cirrhosis in patients with fatty livers.


Tumors involving the skin of the upper extremity.
This review can only introduce the subject of tumors found involving the skin of the upper extremity. Many benign masses as well as some malignant tumors have to be considered when a patient calls to the physician's attention a lump, firm area, color change, ulcer, or other alteration in the skin. In response, the physician must have a high index of suspicion, take a careful history, and carry out a thorough examination in order to develop a safe approach. Thought has to be given to the complex anatomy of this area. Understanding of the pathophysiology of tumors and of possible later additional therapy is needed to plan an appropriate biopsy. In the brief discussions of treatment, the difficulty in choosing margins of resection and assessing the efficacy of lymph node dissection is mentioned. An open mind and assessment of future reports of studies in progress may be helpful. Whatever treatment is applied to the malignant tumors under consideration, it is my opinion that one must persist in this until one obtains tumor-free margins. The surgeon undertaking this responsibility must apply the same tumor techniques including operating room discipline that would be applied to any serious malignancy. Consultation and careful work with colleagues that are able to assess the potential for response to chemotherapy, immunotherapy, and/or radiotherapy, should be sought. Subtle hazards in our environment, such as changing risk of sun exposure, industrial chemicals, and irradiation should be pointed out to our patients. These are a challenge to the student of this subject, just as tobacco products are to those involved with malignancies of the head and neck, respiratory, and other systems. All of the previously mentioned methods must be used in the anatomically complex upper extremity to preserve function while ridding the patient of the burden of a disfiguring or painful benign process, or even a life-threatening malignancy.


Pre-hospital symptoms associated with acute bacterial meningitis differs between children and adults.
Community acquired bacterial meningitis (CABM) is a medical emergency requiring timely appropriate action. More knowledge about pre-hospital symptoms is needed. Retrospective observational study of pre-hospital management in patients with CABM between 2016 and 2021 admitted to a hospital in the Capital Region of Denmark. Reported symptoms were extracted from archived audio files of the initial phone call to emergency medical service. The majority of the 209 patients (82%) were adults. The most common symptoms were altered mental state (58%) and fever (57%), while neck stiffness was less common (9%). Children more often presented with fever, fatigue, rashes, and neck stiffness, while adults more often presented with altered mental state, and leg pain. Most patients (85%) reported at least 1 of the 3 symptoms in the classical triad of meningitis, while 3% reported all 3. Children more often presented at least 2 of 3 symptoms in the triad. One child (3%) and 7 adults (4%) received antibiotics pre-admission. Patients with CABM reported a variety of symptoms that differed significantly in children and adults. The classic triad was rare. Very few patients received antibiotics pre-admission. We suggest that questioning relevant symptoms should be done in febrile or mentally altered patients.


Randomized trial comparing in-situ radiofrequency ablation and Milligan-Morgan hemorrhoidectomy in prolapsing hemorrhoids.
The Milligan-Morgan (MM) operation is the most widely practiced procedure for prolapsed hemorrhoids. But it is also associated with a fair amount of postoperative pain, a long period of convalescence, and complications like bleeding and anal stenosis. The aim of this study was to evaluate the efficacy of in-situ radiofrequency ablation (RA) of hemorrhoids. During a 6-month period, 40 patients with grade 3 hemorrhoids were prospectively randomized for RA (21 patients) or MM hemorrhoidectomy (19 patients). Patients were evaluated for operative time, postoperative pain, time to return to work and occurrence of early and late complications. Duration of surgery was significantly higher in the MM group (p<0.0001). Postoperative hospitalization was longer in the MM group (p<0.001). The post defecation pain and pain at rest were much less in the RA group (p<0.001). Wound healing period (16.3 vs. 37.5 days) and time to return to work (7.3 vs. 18.3 days) were other significant findings. Early complications occurred more frequently in the MM group, but late complications like external skin tags [4 patients vs. 2 patients] and one asymptomatic recurrence was noted in the RA group. In-situ RA of prolapsing hemorrhoids is a quick and bloodless procedure. It is associated with significantly less postoperative pain, shorter hospital stay and early return to normal activity. It can be considered as an alternative to conventional hemorrhoidectomy.


Evaluating Patient, Family and Public Engagement in Health Services Improvement and System Redesign.
As efforts to actively involve patients, family members and the broader public in health service improvement and system redesign have grown, increasing attention has also been paid to evaluation of their engagement in the health system. We discuss key concepts and approaches related to evaluation, drawing particular attention to different and potentially competing goals, stakeholders and epistemological entry points. Evaluation itself can be supported by an increasing number of frameworks and tools, matched to the relevant purpose and approach. The patient engagement evaluation field faces several challenges, including the need for greater specification of both the form and the context of engagement, the need to balance the measurement imperative with the relational aspects of care and the need for supportive organizations with the capacity and commitment to undertake high-quality engagement and its evaluation.


Transmission mechanisms of an emerging insect-borne rickettsial pathogen.
Vector-borne pathogens must overcome arthropod infection and escape barriers (e.g. midgut and salivary glands) during the extrinsic incubation period (EIP) before subsequent transmission to another host. This particular timespan is undetermined for the etiological agent of flea-borne spotted fever (Rickettsia felis). Artificial acquisition of R. felis by blood-feeding cat fleas revealed dissemination to the salivary glands after seven days; however, this length of time is inconsistent with co-feeding studies that produced infectious cat fleas within 24 h of infection. In the current study, we demonstrated that an alternative mechanism is responsible for the early-phase transmission that typifies flea-borne R. felis spread. Co-feeding transmission bioassays were constructed to assess temporal dynamics of R. felis amongst cat fleas, including exposure time to produce infectious fleas and association time to transmit infection to naïve fleas. Additional experiments examined the proportion of R. felis-exposed cat fleas with contaminated mouthparts, as well as the likelihood for cat fleas to release R. felis from their mouthparts following exposure to an infectious bloodmeal. The potential for mechanical transmission of R. felis by co-feeding cat fleas was further examined using fluorescent latex beads, as opposed to a live pathogen, which would not require a biological mechanism to achieve transmission. Analyses revealed that R. felis-infected cat fleas were infectious to naïve fleas less than 24 h after exposure to the pathogen, but showed no rickettsial dissemination to the salivary glands during this early-phase transmission. Additionally, the current study revealed that R. felis-infected cat fleas must co-feed with naïve fleas for more than 12 h in order for early-phase transmission to occur. Further evidence supported that contaminated flea mouthparts may be the source of the bacteria transmitted early, and demonstrated that R. felis is released from the mouthparts during brief probing events. Moreover, the use of fluorescent latex beads supports the notion that early-phase transmission of R. felis is a mechanical mechanism. Determination of the transmission mechanisms utilized by R. felis is essential to fully understand the vulnerability of susceptible vertebrate hosts, including humans, to this pathogen.


Effects of intravascular contrast media on blood-brain barrier. Comparison between iothalamate, iohexol, iopentol and iodixanol.
The effects upon the rabbit blood-brain barrier after intracarotid injection of two non-ionic contrast media, iopentol (a monomer) and iodixanol (a dimer) were compared. Iothalamate and iohexol were used as reference substances. 99Tcm-DTPA, 125I-HSA and Trypsin blue were used as tracers in order to demonstrate various degrees of damage to the barrier. Injection of iothalamate led to large extravasation of 99Tcm-DTPA, 125I-HSA and Trypan blue which means severe damage of the blood-brain barrier. Injection of iopentol and iohexol resulted in some extravasation of all three tracers used, whereas injection of iodixanol only led to extravasation of the small molecule tracer 99Tcm-DTPA demonstrating minor changes of the barrier. At computed tomography of the brain with intravascular contrast medium enhancement it is safer to use iodixanol than iothalamate. Iodixanol is expected to cause even less adverse effects to the brain after intraarterial injection than iopentol and iohexol.


Decades of focus: grant making at the John A. Hartford Foundation.
Foundation grant making can play an important role in advancing the U.S. health agenda. However, given the scale of the health care system and the intractability of many of its problems, philanthropy must be guided by strategic thinking in pursuit of realistically achievable goals. This essay describes the grant-making process at one nationally oriented foundation as an example of how these challenges might be approached. We believe that greater clarity about this process can improve collaboration among foundations, help the public appreciate foundations' work, facilitate partnerships with grantees, and, most importantly, yield sustainable improvement in the problem being addressed.


Natronospira proteinivora gen. nov., sp. nov, an extremely salt-tolerant, alkaliphilic gammaproteobacterium from hypersaline soda lakes.
Brine samples from Kulunda Steppe soda lakes (Altai, Russia) were inoculated into a hypersaline alkaline mineral medium with β-keratin (chicken feather) as a substrate. The micro-organisms dominating the enrichment culture were isolated by limiting serial dilution on the same medium with casein as a substrate. The cells of strain BSker1T were motile, curved rods. The strain was an obligately aerobic heterotroph utilizing proteins and peptides as growth substrates. The isolate was an obligate alkaliphile with a pH range for growth from pH 8.5 to 10.25 (optimum at pH 9.5), and it was extremely salt tolerant, growing with between 1 and 4.5 M total Na+ (optimally at 2-2.5 M). BSker1T had a unique composition of polar lipid fatty acids, dominated by two C17 species. The membrane polar lipids included multiple unidentified phospholipids and two aminolipids. According to phylogenetic analysis of the 16S rRNA gene sequence, the isolate forms a novel branch within the family Ectothiorhodospiraceae (class Gammaproteobacteria) with the highest sequence similarity to the members of this family being 91 %. On the basis of distinct phenotypic and genotypic properties, strain BSker1T (=JCM 31341T=UNIQEM U1008T) is proposed to be classified as a representative of a novel genus and species, Natronospira proteinivora gen. nov., sp. nov.


Effectiveness of an oral health care training workshop for school teachers: a pilot study.
School teachers play key roles in imparting appropriate and up-to-date knowledge to pupils and students. However, most teachers in developing countries like Nigeria have poor knowledge and motivation about oral health which may be due to inadequate training in the area of oral health. This might be one of the reasons for the poor oral hygiene among them and their students. To evaluate the effectiveness of an oral health care training programme organized for teachers in Eruwa, Oyo state, Nigeria. An intervention study was conducted among 40 school teachers who attended a two day oral health training workshop at Eruwa, headquarters of Ibarapa East Local Government Area. Training methods included lectures and demonstrations on aetiology, clinical features, treatment and prevention of common oral diseases. Pre- and post- evaluation written tests were administered to the participants to assess the effectiveness of the training. The knowledge scores were rated as poor, fair and good knowledge scoring <50.0%, 50.0-60.0% and > 60.0% respectively. Frequencies, percentages and means of relevant variables were generated. Paired t-test was used to compare means at P<0.05. The mean age of the teachers was 40.13 ±7.24 years. There were 16 (40.0%) males and 24 (60.0%) females. Twenty (50.0%) of the participants had poor pre-training knowledge as compared to 7 (17.5%) after the training. Thirteen (32.5%) had fair pre-training knowledge as compared to 17 (42.5%) post training. Only (2.5%) of the participants had good pre-training knowledge as compared to 18 (45.0%) post training. The mean scores of the pre- and post-evaluation tests were 31.70 ±11.31 and 48.20 ±11.16 respectively. There was a statistically significant difference between the mean scores of the pre and post evaluations P<0.05. The training workshop improved the knowledge of school teachers regarding oral health.


Hepatocellular carcinoma and aflatoxin exposure in Zhuqing Village, Fusui County, People's Republic of China.
Hepatocellular carcinoma (HCC) is a common cause of cancer morbidity and mortality in Asia and Africa. Epidemiological studies have found that dietary exposure to aflatoxin B1 (AFB1) and chronic infection with hepatitis B virus are two major risk factors for HCC. We have collated the incidence and mortality data of malignant tumors from 1973 to 1999 in Zhuqing Village, Fusui County, an area with very high HCC rates, and found that this cancer accounted for 64% of the total cancer incidence. Dietary intake of AFB1 was monitored for 1 week in a study group consisting of 15 males and 14 females from different households in this village. Four of 29 participants (13.8%) and 3 of 15 (20%) male participants were hepatitis B virus surface antigen positive. AFB1 was detectable in 76.7% (23 of 30) of ground corn samples (range, 0.4-128.1 ppb), 66.7% (20 of 30) of cooking peanut oil samples (range, 0.1-52.5 ppb), and 23.3% (7 of 30) of rice samples (range, 0.3-2.0 ppb) collected from each household. Mean levels of serum AFB1-albumin adducts in this group were 1.24 +/- 0.31 pmol/mg of albumin at the beginning of the study and 1.21 +/- 0.19 pmol/mg of albumin at the end of the period. Urinary AFB1 metabolites were detectable in 88.9% (24 of 27) samples (range, 0.9-3569.7 ng/24-h urine). These data provide the exposure and disease risk information for establishing intervention studies to diminish the impact of aflatoxin exposure in this high-risk population.


What mental health nurses have to say about themselves: A discourse analysis.
Mental health nursing is largely invisible within public discourse. When mentioned at all in news media, it is usually a signifier of an occupation connoting where a nurse works. There is rarely a presumption of expertise in any sphere or articulation of a unique skill set or defining features which differentiate the mental health nurse from other nurses. This paper sought to examine the professional discourse around mental health nursing as inferred from a review of papers published in the International Journal of Mental Health Nursing in 2019. A discourse analysis of full-text papers (n = 117) was undertaken exploring references to mental health nurses or nursing and what this communicated about the field. The discourse clustered around three themes: The invisible or absent mental health nurse, ambiguous and blended identities, and a group of low attributed value and sophistication. There were few examples of authors presenting mental health nurses in a way which counters stereotypes of the dominant discourse about mental health nurses as a lesser skilled occupational group. Academics, editors, authors, and practitioners are urged to contribute to the construction of discourse around mental health nursing expertise which differentiates it from other branches of nursing and other distinctive disciplines.


Possible prognostic and therapeutic significance of c-Kit expression, mast cell count and microvessel density in renal cell carcinoma.
Renal cell carcinoma (RCC) is the most frequent renal tumor and its incidence is increasing worldwide. Tumor angiogenesis is known to play a crucial role in the etiopathogenesis of RCC and over the last few years an even deeper knowledge of its contribution in metastatic RCC development has led to the development of numerous molecular targeting agents (such as sunitinib, sorafenib, pazopanib, axitinib, tivozanib, and dovitinib). The above agents are principally directed against vascular endothelial growth factor receptor (VEGFR) members and also against c-Kit receptor (c-KitR). The role of c-kitR inhibition on clear cell RCC (ccRCC), the main RCC subtype, is less well established. Whether c-kitR activation through its ligand, stem cell factor (SCF) contributes significantly to the effects of tyrosine kinase inhibitors (TKIs) treatment remains to be established. It is important to underscore that the c-KitR is expressed on mast cells (MCs) and cancer cells. After an examination of the c-KitR/SCF pathway, we review here the principal studies that have evaluated c-Kit expression in RCC. Moreover, we summarize some investigations that have observed the distribution of MCs in primary renal cancer and in adjacent normal tissue with appropriate histological immunohistochemical techniques. We also focus on few studies that have evaluated the correlation between RCC proliferation, MC count and microvessel density (MVD), as hallmarks of tumor angiogenesis. Thus, the aim of this review of the literature is to clarify if c-KitR expression, MC count and MVD could have prognostic significance and the possible predictive therapeutic implications in RCC.


A public health collaboration for the surveillance of autism spectrum disorders.
Autism spectrum disorders (ASDs) represent a range of behavioural phenotypes defined by impaired development in social interaction, communication, imagination, and range of interests or behaviours. The aetiology and epidemiology of these serious developmental disabilities (DDs) are poorly understood. Estimates of the population prevalence of ASDs have varied widely within the US and abroad, with increasing estimates in most of the recent studies. In an effort to improve our understanding of the prevalence, population characteristics and public health impact of these conditions, the Centers for Disease Control and Prevention has funded a multi-site surveillance network for ASDs and other DDs that consists of programmes known as the Autism and Developmental Disabilities Monitoring (ADDM) network which conducts surveillance activities and the Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) which also conducts surveillance in addition to special research studies related to the ASDs. This collaboration will be referred to hereafter as the ADDM Network. The ADDM Network is implementing a multiple-source surveillance programme to determine population prevalence and characteristics of ASDs and other DDs. This paper describes the collaborative efforts and explains the methods in developing this coordinated public health surveillance network to provide an ongoing source of high-quality data on ASDs.


Intraperitoneal immunity and pneumoperitoneum.
Carbon dioxide (CO(2)) pneumoperitoneum has been implicated as a possible factor in depressed intraperitoneal immunity. Using in vitro functional assays, CO(2) has been shown to decrease the function of peritoneal macrophages harvested from insufflated mice. However, an effective in vivo assessment is lacking. Listeria monocytogenes (LM), an intracellular pathogen, has served as a well-established in vivo model to study cell-mediated immune responses in mice. This study examines the immune competence of mice based on their ability to clear intraperitoneally administered LM following CO(2) vs helium (He) insufflation. Eighty-five mice (C57Bl/6, males, 4-6 weeks old) were divided between the following four treatment groups: CO(2) insufflation, He insufflation, abdominal laparotomy (Lap), and control (anesthesia only). Immediately postoperatively, each group was inoculated percutaneously and intraperitoneally with a sublethal dose (.015 x 10(6) org) of virulent LM (EGD strain). Half of the animals were killed on postoperative day 3 and half on day 5. Spleens and livers (sites of bacterial predilection) were harvested, homogenized, and plated on TSB agar. The amount of bacteria (1 x 10(6) LM/spleen and liver) from each group was then compared. Statistical significance was set at p </= 0.05. Control animals had nominal bacteria on day 3 (0.016 x 10(6) LM/spleen and liver), and the bacterial burden remained low at day 5 (0.038 x 10(6) LM/spleen and liver) postchallenge. On day 3, the bacterial burden was significantly higher in the CO(2) group (5.46 x 10(6) LM/spleen and liver) as compared to He (0.093 x 10(6) LM/spleen and liver) and controls. The Lap group (3.44 x 10(6) LM/spleen and liver) had significantly more bacteria than the controls. There were no significant differences between any of the groups on day 5. In this animal model, CO(2) pneumoperitoneum impaired cell-mediated intraperitoneal immunity significantly more than He pneumoperitoneum and controls on day 3. Also on day 3, laparotomy caused impairment of intraperitoneal immunity when compared to controls. Finally, intraperitoneal immunosuppression resolved by day 5.


Strong structuration analysis of patterns of adherence to hypertension medication.
Achieving blood pressure control is among the highest priorities for reducing the burden of cardiovascular diseases globally. Control is poor in the Philippines, especially in socioeconomically marginalised communities. This paper explores long-term adherence to anti-hypertensive medication in these communities, identifying 4 distinct medication adherence patterns. We draw on Strong Structuration Theory to explore motivations of action for those who are consistently adherent, consistently non-adherent, and those who became more or less adherent over time. We employ longitudinal qualitative methods comprising repeat interviews and digital diaries collected over 12 months by 34 participants. Twelve participants were consistently adherent, 9 consistently non-adherent, 9 increasingly adherent, and 4 increasingly non-adherent. For the consistently adherent, positive views about prescribed medication and family support encouraged adherence. Conversely, negative views of medication and lack of family support were notable amongst the consistently non-adherent, along with resistance to accepting a 'sick' label. A shift toward positive views of medication was detected amongst those whose adherence improved, along with worsening health and increased family support. A decrease in financial resources drove some participants to become less adherent, especially if they already held negative views toward medication. This study sheds light on the variety of medication adherence patterns among poor people with hypertension in the Philippines, as well as the complex web of elements influencing their treatment choices. The results point to the potential for measures that address concerns about medicines and increase family support.


Ion allocation in two different salt-tolerant Mediterranean Medicago species.
The relationship between Na+, major cation concentrations and salt tolerance under long-term saline conditions of Medicago arborea and Medicago citrina was studied. Plants were grown in solution culture in 1, 50, 100, or 200 mmol/L NaCl for 30 days in a climate-controlled greenhouse. Stem and petiole growth was the most affected by salt in both species. Leaf growth was inhibited in M. arborea, with increased salt, while only the 200 mmol/L NaCl-treated M. citrina plants were significantly affected. Both species had the highest Na+ concentrations in the shoots, however, the allocation pattern was different; M. arborea showed the highest concentrations in the leaf blades, whereas M. citrina distributed the salt into the petioles. K+/Na+ ratio decreased with salt in both species; however, leaf K+ use efficiency (g leaf DW mg-1 leaf K+) was higher in M. citrina. The difference in Na+ allocation and cation concentrations found in these medic species and their importance is discussed in relation to their response to NaCl salinity.


Variability of the diagnosis of stroke by clinical judgement and by a scoring method.
Existing criteria for the diagnosis of acute cerebrovascular disease (stroke) have not been satisfactory in epidemiological studies. Variability of the diagnosis of stroke, which had not been studied before, was investigated in a WHO collaborative study. Intra-observer and inter-observer variation of the diagnosis of stroke was studied by means of 45 case reports drawn at random from among those included in the study. Diagnosis of stroke and of the type of stroke was made by clinical judgement and by a scoring method. The clinical diagnosis of stroke was more consistent and more comparable than the diagnosis of the type of stroke. Inter-observer agreement in clinical diagnosis was improved by using the score method.


fMRI evidence for the neural representation of faces.
fMRI (functional magnetic resonance imaging) studies on humans have shown a cortical area, the fusiform face area, that is specialized for face processing. An important question is how faces are represented within this area. This study provides direct evidence for a representation in which individual faces are encoded by their direction (facial identity) and distance (distinctiveness) from a prototypical (mean) face. When facial geometry (head shape, hair line, internal feature size and placement) was varied, the fMRI signal increased with increasing distance from the mean face. Furthermore, adaptation of the fMRI signal showed that the same neural population responds to faces falling along single identity axes within this space.


Smart Nanotherapeutic Targeting of Tumor Vasculature.
The past decades have witnessed the development of a field dedicated to targeting tumor vasculature for cancer therapy. In contrast to conventional chemotherapeutics that need to penetrate into tumor tissues for killing tumor cells, the agents targeting tumor vascular system have two major advantages: direct contact with vascular endothelial cells or the blood and less possibility to induce drug resistance because of high gene stability of endothelial cells. More specifically, various angiogenesis inhibitors (AIs) and vascular disrupting agents (VDAs) that block tumor blood supply to inhibit tumor progression, some of which have been applied clinically, have been described. However, off-target effects and high effective doses limit the utility of these formulations in cancer patients. Thus, new strategies with improved therapeutic efficacy and safety are needed for tumor vessel targeting therapy. With the burgeoning developments in nanotechnology, smart nanotherapeutics now offer unprecedented potential for targeting tumor vasculature. Based on specific structural and functional features of the tumor vasculature, a number of different nanoscale delivery systems have been proposed for cancer therapy. In this Account, we summarize several distinct strategies to modulate tumor vasculature with various smart nanotherapeutics for safe and effective tumor therapy developed by our research programs. Inspired by the blood coagulation cascade, we generated nanoparticle-mediated tumor vessel infarction strategies that selectively block tumor blood supply to starve the tumor to death. By specifically delivering thrombin loaded DNA nanorobots (Nanorobot-Th) into tumor vessels, an intratumoral thrombosis is triggered to induce vascular infarction and, ultimately, tumor necrosis. Mimicking the coagulation cascade, a smart polymeric nanogel achieves permanent and peripheral embolization of liver tumors. Considering the critical role of platelets in maintaining tumor vessel integrity, a hybrid (PLP-D-R) nanoparticle selectively depleting tumor-associated platelets (TAP) to boost tumor vessel permeability was developed for enhancing intratumoral drug accumulation. In addition, benefiting from a better understanding of the molecular and cellular underpinnings of vascular normalization, several tumor acidity responsive nanotherapeutics, encapsulating therapeutic peptides, and small interfering RNA were developed to correct the abnormal features of the tumor vasculature. This made the tumor vessels more efficient for drug delivery. While we are still exploring the mechanisms of action of these novel nanoformulations, we expect that the strategies summarized here will offer a promising platform to design effective next-generation nanotherapeutics against cancer and facilitate the clinical translation of smart nanotherapeutics that target tumor vasculature.


Advances in cardiac pacing: beyond the transvenous right ventricular apical lead.
While for decades right ventricular (RV) apical pacing has been the standard of care for patients requiring pacemaker or defibrillator lead placement, investigators have sought alternatives to achieve more physiologic electrical activation of the heart and reduce long-term pathologic effects of nonphysiologic apical pacing. These investigations have included attempts at identifying superior pacing sites within the right atrium and RV and development of new leads to enhance specificity of sensing and capture. This review focuses on recent advances in alternative sites for pacing and developments in novel pacing technology ranging from intramyocardial electrodes to leadless pacemakers. First, there have been several studies demonstrating potential benefits of site-specific pacing, including His bundle pacing and RV outflow tract pacing in potentially attenuating electromechanical dyssynchrony and long-term functional decline seen with RV apical pacing. Available options for lead placement have been enhanced by development of intramyocardial electrodes that may significantly reduce far-field oversensing and nonchamber specific capture. With development of intramyocardial electrodes, the potential for atrioventricular septal pacing has recently been described, making synchronous activation of both ventricles with a one-lead system possible without crossing the tricuspid valve and offering an alternative to modern cardiac resynchronization therapy (CRT). Finally, recent advances in leadless pacemaker systems using ultrasound or magnetic fields are briefly discussed. The results of these studies suggest that there may be options to the RV apex, made possible by novel lead and pacemaker technology. These advances can potentially aid in reducing long-term negative effects of chronic pacemaker therapy.


Aneurysm Growth After Endovascular Sealing of Abdominal Aortic Aneurysms (EVAS) with the Nellix Endoprosthesis.
The aim of this study was to measure the incidence of post endovascular aneurysm sealing (EVAS) abdominal aortic aneurysm (AAA) growth, and its association with stent migration, in a cohort of patients with differing compliance to old and new Instructions For Use (IFU). A retrospective single centre study was conducted to review the computed tomography (CT) and clinical data of elective, infrarenal EVAS cases, performed as a primary intervention, between December 2013 and March 2018. All included patients had a baseline post-operative CT scan at one month and at least one year follow up. The primary outcome measure was the incidence of AAA growth and its association with stent migration. AAA growth was defined as a ≥5% increase in aortic volume between the lowermost renal artery and the aortic bifurcation post EVAS at any time during follow up, in comparison to the baseline CT scan. Migration was defined according to the ESVS guidelines, as > 10 mm downward movement of either Nellix stent frame in the proximal zone. Seventy-six patients were eligible for inclusion in the study (mean age 76 ± 7.4 years; 58 men). AAA growth was identified in 50 of 76 patients (66%); adherence to IFU did not affect its incidence (mean growth within IFU-2016 compliant cohort vs. non-compliant: 16% vs. 13%, p = .33). Over time, the incidence of AAA growth increased, from 32% at one year to 100% at four years. AAA growth by volume was progressive (p < .001), as its extent increased over time. Migration was detected in 16 patients and there was a statistically significant association with AAA growth (13 patients displayed migration and AAA growth, p = .036). Patients treated with EVAS are prone to AAA growth, irrespective of whether their aortic anatomy is IFU compliant. AAA growth by volume is associated with stent migration. Clinicians should continue close surveillance post EVAS, regardless of whether patients are treated within IFU.


Genetic literacy and attitude towards genetic testing in patients with Parkinson's disease and their caregivers: A review of literature.
Genetic literacy refers to an individual's ability to understand the basics of genetic concepts and apply them to health-related decisions. The level of genetic literacy influences attitude towards genetic testing and is, in turn, influenced by several other factors. Clinicians must be aware of the genetic literacy of their patients and their caregivers before advising genetic testing and/or undertaking pre and post-test counseling. A systematic review of literature in PubMed was carried out using keywords "Genetic testing", "Genetic counseling", "Knowledge", "Attitude", "Parkinson's disease" in various combinations. Seven eligible studies with a total of 1837 individuals (patients with PD-1355 and patient caregivers-482) were identified. More than half the participants were well-versed in basic concepts of genetics (57.8%) and risks of inheriting PD (60.5%) while less than 10% were aware regarding the contribution of specific genes (e.g. LRRK2). Interest in diagnosis, treatment, prevention and facilitating PD research were central themes for positive attitude while apprehensions revolving around impact on employment and insurance and non-benefit were associated with negative attitudes. Possible associations included greater knowledge scores with positive attitudes towards genetic testing and older age for negative attitude towards testing. Insufficient data on attitudes toward prenatal testing, presymptomatic testing and clinicians' attitude toward testing was identified. Patients with PD and their caregivers are aware of the role of genetics in the etiopathogenesis of their disease, which contributes to their positive attitude towards testing. Further studies exploring negative attitudes towards testing will help overcome the hurdles in genetic testing and counseling in this cohort of patients.


Quantitative regional differences in corneal endothelial abnormalities in the central and peripheral zones in Fuchs' endothelial corneal dystrophy.
To quantitate the regional corneal differences in endothelial abnormalities in Fuchs' endothelial corneal dystrophy at multiple sites, including the peripheral zone. Forty-one eyes of 23 patients with Fuchs' endothelial corneal dystrophy were studied at Osaka University Hospital. The sizes of the areas of degeneration resulting from guttae were measured using a new noncontact specular microscope in the central cornea, the paracentral zone 0.6 mm from the center, and the peripheral zone 3.7 mm peripheral to the center. The percentages of the images covered by the abnormal areas were 71% ± 36% in the center, 68% ± 35% in the paracentral zone, and 33% ± 36% in the peripheral zone. The values in the peripheral zone were significantly (P < 0.001) smaller than in the center and paracentral zones. The percentage of the abnormal area in the peripheral zone was correlated significantly (P < 0.001, R(2) = 0.452) with the disease grade in advanced cases, whereas those in the center or paracentral zones were not. Among the areas of the peripheral zone, the abnormal inferotemporal areas were significantly (P < 0.001) larger than superonasally. In Fuchs' endothelial corneal dystrophy, the corneal endothelium is damaged more severely in the center and paracentral zones than in the peripheral zone, and peripheral measurement can objectively grade the disease. In the peripheral zones, the inferotemporal endothelium is damaged more severely. These findings might provide a new understanding of the disease mechanisms.


Oocyte recovery and fertilization rates in women at various times after the administration of hCG.
Volunteer women requesting laparoscopic sterilization were subjected to a fixed schedule of ovulation induction and oocyte recovery. Follicle aspiration was carried out in four groups: those to whom hCG was not administered and 12, 24 or 36 h respectively after the administration of hCG. For each group oocytes were cultured in vitro for 42 h, 30 h, 18 h and 6 h respectively, before insemination with donor spermatozoa. Oocyte recovery rates improved with longer hCG-to-recovery intervals (36% with no hCG to 81% 36 h after hCG). Although there was a slight reduction in fertilization rates when oocytes were not exposed to hCG in the follicle, normal cleavage was noted in more than 50% of oocytes in all four groups. It therefore appears that the final maturation stages of the human oocyte are not dependent on the midcycle gonadotrophin surge, provided the oocyte is matured in vitro before insemination. However, it was also evident that the fertilization rates were reduced when oocytes were removed from less mature follicles, as reflected by high androstenedione/oestradiol ratios.


A risk-based approach to development of ultrasound-based high-dose-rate prostate brachytherapy quality management.
The purpose of this study was to apply a risk-based approach to the development of a quality management (QM) program for ultrasound-based high-dose-rate (HDR) prostate brachytherapy (pBT) treatment planning and delivery. A QM program was developed by a multidisciplinary team, using both an in-house risk-and-benefit balance impact template (RABBIT) tool and a failure modes and effect analysis (FMEA). FMEA scores were determined by three physicists, one radiation therapist and two radiation oncologists who were familiar with the protocol. The QM program produced by both risk-based techniques was then compared and consolidated. The RABBIT tool identified 26 potential risks during the treatment planning and delivery process. During the FMEA, a total of 35 potential failure modes were identified from the seven major processes in ultrasound-based HDR pBT. For the 35 potential failure modes, risk priority number scores ranged from 14 to 267. The highest ranked failure mode was identified to be mislabeling/connection of the transfer tubes/catheters. From the risks analyses, a comprehensive QM program was developed. Both the RABBIT tool and process mapping and FMEA were shown to be valuable tools in developing a QM program for ultrasound-based HDR pBT treatments. A considerable number of the potential failure modes identified in both tools were related to human or procedural errors, highlighting the importance of checklists and protocols in delivering a safe and effective ultrasound-based HDR pBT treatment.


Structure-function relationship of Rous sarcoma virus leader RNA.
Cells infected by RSV synthesize viral 35S RNA as well as subgenomic 28S and 22S RNAs coding for the Env and Src genes respectively. In addition, at least the 5' 101 nucleotides of the leader are also conserved and we have shown previously that this sequence contains a strong ribosome binding site (J.-L. Darlix et al., J. Virol. 29, 597). We now report the RNA sequence of Rous Sarcoma virus (RSV) leader RNA and propose a folding of this 5' untranslated region which brings the Cap, the initiation codon for Gag and the strong ribosome binding site close to each other. We also show that ribosomes protect a sequence just upstream from initiator Aug of Gag in vitro, and believed to interact with part of the strong ribosome binding site according to the folding proposed for the leader RNA.


[Perinatal infection due to cytomegaloviruses in a public hospital of the municipality of São Paulo: a prospective study].
In order to demonstrate the occurrence of CMV perinatal infection in a middle socioeconomic class population, the authors conducted a 8-month prospective study in 37 children, not infected congenitally, born in a public hospital of São Paulo city, Prevalence of CMV-IgG antibodies in mothers, detected by immunoenzymatic assay (ELISA), was 92.7%. Survival analysis showed that the risk of acquiring CMV perinatal infection diagnosed by virus isolation in human fibroblasts was 30.9%. When the diagnostic method was detection of IgM class antibodies by indirect immunofluorescence the risk was 8.1% (p < 0.05). Milk samples inoculated in human fibroblasts failed to demonstrate the presence of virus. The infected children did not present any signal of disease in a 4-month follow-up.


Variability of apparent particle density of an urban aerosol.
The day to day and diurnal variation of apparent particle density was studied using highly time-resolved measurements of particle number distribution and fine-particle mass concentration. The study was conducted in Erfurt, Germany, from January 1, 1999, to November 22, 2000. A setup consisting of a differential mobility particle spectrometer and a laser aerosol spectrometer was used for particle number distribution measurements. PM2.5 particle mass was measured in parallel on an hourly basis using a tapered element oscillating microbalance (TEOM) and on daily base by using a Harvard marple impactor (HI). For the estimation of the mean apparent density of particles, number size distributions were converted into volume size distributions, assuming that the particles were spherically shaped. The volume size distributions were integrated over the range of 10 nm to 2.03 microm Stokes equivalent diameter to obtain volume concentrations. Mean apparent particle density was calculated as ratio of mass concentration and volume concentration. The mean apparent particle density, determined from HI and number size distribution on a daily basis was 1.6 +/- 0.5 g cm(-3). We found a strong day-to-day variation of apparent density ranging from 1.0 to 2.5 g cm(-3) (5th and 95th percentile). Furthermore, the apparent density showed pronounced diurnal pattern both in summer and in winter and also on weekdays and weekends. The apparent density was lowest in the morning and highest in the afternoon. The mean apparent density on an hourly basis was 1.4 +/- 0.5 and 1.5 +/- 0.5 g cm(-3) for PM2.5TEOM and corrected PM2.5TEOM using regression equation between daily mass concentration of HI and TEOM, respectively. The strong diurnal variation of apparent particle density was associated predominantly with the vertical temperature inversion and with traffic intensity. Thus, the apparent particle density depends on the physical particle properties and might be related to chemical composition of the sampled particle.


CD79 alpha expression in acute myeloid leukemia. High frequency of expression in acute promyelocytic leukemia.
CD79 alpha is a subunit of an intracytoplasmic protein reported to be specific for B lymphocytes, including immature B lineage cells. To evaluate expression of the CD79 alpha antigen in acute myeloid leukemia (AML), we studied forty-eight cases of AML by paraffin section immunohistochemistry. The cases included four MO, nine M1, nine M2, ten M3, ten M4, and six M5 AMLs using criteria of the French-American-British cooperative group. Eleven cases demonstrated cytoplasmic staining for the CD79 alpha antigen, including one M1, nine M3, and one M5 AML. These CD79 alpha-positive cases represented 5% of all non-promyelocytic AMLs and 90% of all acute promyelocytic leukemias studied. All acute promyelocytic leukemias had the characteristic t(15;17)(q24;q21), including two cases of the microgranular variant (M3v). No other B-lineage-associated antigens were found in the CD79 alpha-positive cases, with the exception of a subpopulation of CD19-positive leukemic cells in one patient. The two non-promyelocytic leukemias that expressed CD79 alpha had no evidence of t(15;17) and did not express any additional B-lineage-associated antigens that might suggest a mixed lineage proliferation. This study demonstrates that CD79 alpha expression in acute leukemia is not restricted to B-lineage acute lymphoblastic leukemias and that CD79 alpha expression is frequently associated with t(15;17) acute myeloid leukemia.


Post-lesion practice and amphetamine-facilitated recovery of beam-walking in the rat.
Treatment with amphetamine increases the rate of recovery of beam-walking in rats when administered after a unilateral suction-ablation lesion of the sensorimotor cortex. It is thought that amphetamine treatment must be combined with postlesion practice on the beam since confinement to prevent locomotion blocks amphetamine-facilitated recovery. However, rats which are confined are also isolated and not handled. In the present experiment, beam-walking recovery was compared among groups of rats which were treated with either amphetamine or saline and then either handled and allowed to walk in a home cage or given practice on the beam. Although amphetamine treatment and postlesion practice had independent beneficial effects on recovery, the group of rats given both treatments had the greatest improvement in beam-walking scores.


A Novel Navigation Device for Precise Percutaneous Placement of the Guidewire in Femoral Neck Fracture Cannulated Screw Fixation Surgery.
The accuracy of screw placement is a key factor for the stability of the cannulated screws used in the fixation of femoral neck fractures. In this study we designed a navigation device for ensuring the screw reaches the ideal position for optimal fixation. From March 2019 to September 2020, 66 patients with femoral neck fracture were enrolled and divided into 2 groups, one group was treated using the traditional free-hand cannulated screw fixation and the other using the new navigation device with assisted fixation. The effectiveness of the 2 methods was compared based on surgery duration, intraoperative bleeding, number of fluoroscopic examination and guidewire insertion attempts, screw parallelism, and effective fixation area. Fracture healing, complications and hip joint function were assessed after operation. The new navigation device reduced the duration of surgery without causing additional intraoperative bleeding, and significantly reduced number of fluoroscopy examination and guidewire insertion attempts (4.00±1.58 vs. 6.09±1.94 with traditional surgery). The accuracy of screw implantation was improved, as demonstrated by increased screw parallelism (0.71±0.57° vs. 1.66 ±1.01° with traditional surgery) and higher effective fixed area (64.88±10.52 vs. 58.61±9.19 mm2 with traditional surgery). In the postoperative follow-up, except for one case of femoral head necrosis and one case of bone nonunion in the traditional surgical group, the other patients showed fracture healing. There was no significant difference in hip joint function between the 2 groups. The new navigation device enables rapid and accurate guidewire positioning for cannulated screw fixation through simple operation procedures, resulting in good prospect for clinical transformation.


AlGaN/GaN heterostructures for non-invasive cell electrophysiological measurements.
Recently, the ability to create bio-semiconductor hybrid devices has gained much interest for cell activity analysis. AlGaN material system has been demonstrated to be a promising cell-based biosensing platform due to a combination of unique properties, such as chemical inertness, optical transparency and low signal to noise ratios. To investigate the potential application of hybrid cell-AlGaN/GaN field effect transistor for cell electrophysiological monitoring, saos-2 human osteoblast-like cells were cultured in high density in non-metallized gate area of a transparent AlGaN/GaN heterostructure field effect transistor. We implemented and characterized the transistor recording of extracellular voltage in the cell-chip junction using the FET chip. The effect of ion channel blocker TEA on transistor signal was explored in order to test the capability of this hybrid chip for in vitro drug screening bioassay. Finally, the effect of cell adhesion on transistor signal was also studied by applying the protein kinase inhibitor H-7.


Treatment and Outcome of Carbapenem-Resistant Gram-Negative Bacilli Blood-Stream Infections in a Tertiary Care Hospital.
Infections caused by carbapenem-resistant bacteria constitute a major challenge for current medical practice. To describe treatment and outcome of carbapenem-resistant Gram-negative bacilli (GNB) blood-stream infection (BSI) caused by these organisms at a tertiary care hospital in Mumbai. Carbapenem-resistant isolates from blood cultures were collected from January 2013 to April 2013. Identification and antimicrobial susceptibility testing were performed using Vitek 2 analyzer (Biomerieux Ltd.). Carbapenemase production was detected by modified Hodge's test (MHT). Patient's medical history, treatment and co-morbid conditions were noted. Outcomes of BSIs were evaluated. Forty-two isolates of carbapenem-resistant GNB isolated from BSIs were Enterobacteriaceae spp. (19), Acinetobacter baumannii (15), and Pseudomonas aeruginosa (8). Colistin had maximum in vitro activity with 97% against Enterobacteriaceae, 100% against Acinetobacter, and 100% activity against Pseudomonas aeruginosa isolates. Positivity of MHT was 92.9%. Outcome of colistin mono and combination therapy was comparable with 83% and 79%, respectively. Outcome of colistin and carbapenem combination therapy was found to be 100 percent. High incidences of bacteremia by carbapenem-resistant GNB including Enterobacteriaceae is a worrisome trend. Treatment options are compromised and only available option is colistin which has its own limitation. Colistin monotherapy may be non-inferior compared to combination therapy for treating BSIs caused by isolates with minimum inhibitory concentration (MIC) for colistin as ≤0.5 mg/l. Combined use of the colistin and carbapenem may provide good therapeutic options for BSI caused by carbapenem-resistant GNB and warrants further investigations.


Early sensory protection in reverse end-to-side neurorrhaphy to improve the functional recovery of chronically denervated muscle in rat: a pilot study.
Early innervation by sensory nerves has been proposed to prevent atrophy of chronically denervated muscle, but conventional end-to-end (ETE) neurorrhaphy has been demonstrated to have adverse effects on muscle contractile function. The aim of the present study was to investigate the potential for modified sensory nerve protection in reverse end-to-side (ETS) neurorrhaphy as a way of improving the functional recovery of denervated muscle. Four groups of rats underwent surgical denervation of the tibial nerve projecting to the right hindlimbs (Group 1, unprotected controls; Group 2, positive control [immediate repair without delayed denervation]; Group 3, ETS protected; and Group 4, ETE protected). The proximal and distal stumps of the tibial nerve were ligated in all animals except for those in the immediate-repair group. Other animals underwent denervation without sural nerve protection, or with ETE or ETS neurorrhaphy. The ETE- and ETS-protected and unprotected groups underwent an additional surgery in which the trimmed proximal and distal tibial nerve stumps were sutured together. After 3 months of recovery, the tibial function index was determined, and electrophysiological, histological, and morphometric parameters were assessed. Significant muscle atrophy was observed in the unprotected group, while a well-preserved ultrastructure was observed for the gastrocnemius muscle in the ETE- and ETS-protected groups. Enhanced recovery in the ETS-protected group was indicated by the tibial function index, motor nerve conduction velocity, muscle contractile force tests, and the histological results. In contrast, early sensory nerve protection in ETE neurorrhaphy impaired the recovery of the regenerated axons and diminished the contractile force of the denervated muscle. Early sensory protection in reverse ETS neurorrhaphy is an effective method for improving the functional recovery of chronically denervated muscle following peripheral nerve injury in rats.


Does gravitational pressure of blood hinder flow to the brain of the giraffe?
Vascular pressure consists of the sum of two pressures: (a) pressure developed by the pumping of the ventricles against the resistance of vessels, designated as viscous flow pressure, and (b) pressure caused by gravity, traditionally called hydrostatic, better described as gravitational pressure. In a conduit, both of these pressures must be overcome when a liquid is discharged to a higher level of gravitational potential energy. If a liquid is returned to its original level, gravity neither helps nor hinders flow because of the siphon effect. This circumstance prevails in the circulatory system. Hence, P1-P2 in the Poiseuille equation excludes gravitational pressure between those points. The long neck of the giraffe, therefore, poses no impediment to blood flow in the erect posture. The giraffe has a high aortic pressure. This is not for driving the blood to its head but is for minimizing the gravitational drop of intravascular pressure and collapse of the vessels. The cerebral circulation is protected by the cerebrospinal fluid which undergoes parallel changes in pressure with posture. Other vessels in the head are less protected by connective tissue, surrounding muscles and other structures. The high aortic pressure in the giraffe is probably caused by the high total peripheral resistance of the systemic circuit due to vascular adaptations related to the overall height of the animal.


Impaired tissue growth is mediated by checkpoint kinase 1 (CHK1) in the integrated stress response.
The integrated stress response (ISR) protects cells from numerous forms of stress and is involved in the growth of solid tumours; however, it is unclear how the ISR acts on cellular proliferation. We have developed a model of ISR signalling with which to study its effects on tissue growth. Overexpression of the ISR kinase PERK resulted in a striking atrophic eye phenotype in Drosophila melanogaster that could be rescued by co-expressing the eIF2alpha phosphatase GADD34. A genetic screen of 3000 transposon insertions identified grapes, the gene that encodes the Drosophila orthologue of checkpoint kinase 1 (CHK1). Knockdown of grapes by RNAi rescued eye development despite ongoing PERK activation. In mammalian cells, CHK1 was activated by agents that induce ER stress, which resulted in a G2 cell cycle delay. PERK was both necessary and sufficient for CHK1 activation. These findings indicate that non-genotoxic misfolded protein stress accesses DNA-damage-induced cell cycle checkpoints to couple the ISR to cell cycle arrest.


[Rheumatology in Russia in the early 21st century].
Rheumatoid arthritis (RA) is the most common immune inflammatory rheumatic disease. The paper gives the current data of Russian investigations into the early diagnosis of RA and into innovative approaches to its therapy.


A galactose-rich, cell-wall glycoprotein from styles of Nicotiana alata.
A basic, galactose-rich style glycoprotein (GaRSGP) encoded by a previously characterized style-specific cDNA (NaPRP4) has been isolated from the styles of Nicotiana alata and structurally characterized. The glycoprotein is associated with cell walls in the transmitting tract and is composed of approximately 25% (w/w) protein and 75% (w/w) carbohydrate. The purified glycoprotein appears as a smear of between 45-120 kDa on SDS-PAGE; the deglycosylated protein backbone has an apparent molecular weight of approximately 30 kDa. The glycoprotein is rich in the amino acids lysine, proline, and hydroxyproline and in the monosaccharides galactose and arabinose. It is one of only a few proline/hydroxyproline-rich glycoproteins (P/HRGPs) to be characterized both as a cDNA-clone and protein. Glycans are attached to the protein backbone through both O- and N-glycosidic linkages with the majority of the carbohydrate being O-linked and consisting of short, highly branched chains terminating primarily in galactose residues. A carbohydrate epitope(s) is found on both GaRSGP and another style-specific glycoprotein but not on glycoproteins from other tissues. This finding provides further evidence for the existence of a style-specific carbohydrate epitope(s) which may play a role in style function.


Intravenous bamlanivimab use associates with reduced hospitalization in high-risk patients with mild to moderate COVID-19.
BACKGROUNDClinical data to support the use of bamlanivimab for the treatment of outpatients with mild to moderate coronavirus disease-19 (COVID-19) are needed.METHODS2335 Patients who received single-dose bamlanivimab infusion between November 12, 2020, and February 17, 2021, were compared with a propensity-matched control of 2335 untreated patients with mild to moderate COVID-19 at Mayo Clinic facilities across 4 states. The primary outcome was the rate of hospitalization at days 14, 21, and 28.RESULTSThe median age of the population was 63 years; 47.3% of the bamlanivimab-treated cohort were 65 years or more; 49.3% were female and 50.7% were male. High-risk characteristics included hypertension (54.2%), BMI greater than or equal to 35 (32.4%), diabetes mellitus (26.5%), chronic lung disease (25.1%), malignancy (16.6%), and renal disease (14.5%). Patients who received bamlanivimab had lower all-cause hospitalization rates at days 14 (1.5% vs. 3.5%; risk ratio [RR], 0.41), 21 (1.9% vs. 3.9%; RR, 0.49), and 28 (2.5% vs. 3.9%; RR, 0.63). Secondary exploratory outcomes included lower intensive care unit (ICU) admission rates at days 14 (0.14% vs. 1%; RR, 0.14), 21 (0.25% vs.1%; RR, 0.25), and 28 (0.56% vs.1.1%; RR. 0.51) and lower all-cause mortality at days 14 (0% vs. 0.33%), 21 (0.05% vs. 0.4%; RR,0.13), and 28 (0.11% vs. 0.44%; RR, 0.26). Adverse events were uncommon with bamlanivimab, occurring in 19 of 2355 patients, and were most commonly fever (n = 6), nausea (n = 5), and lightheadedness (n = 3).CONCLUSIONSAmong high-risk patients with mild to moderate COVID-19, treatment with bamlanivimab was associated with a statistically significant lower rate of hospitalization, ICU admission, and mortality compared with usual care.FUNDINGMayo Clinic.


The amphiphilic nature of saponins and their effects on artificial and biological membranes and potential consequences for red blood and cancer cells.
Saponins, amphiphiles of natural origin with numerous biological activities, are widely used in the cosmetic and pharmaceutical industry. Some saponins exhibit relatively selective cytotoxic effects on cancer cells but the tendency of saponins to induce hemolysis limits their anticancer potential. This review focused on the effects of saponin activity on membranes and consequent implications for red blood and cancer cells. This activity seems to be strongly related to the amphiphilic character of saponins that gives them the ability to self-aggregate and interact with membrane components such as cholesterol and phospholipids. Membrane interactions of saponins with artificial membrane models, red blood and cancer cells are reviewed with respect to their molecular structures. The review considered the mechanisms of these membrane interactions and their consequences including the modulation of membrane dynamics, interaction with membrane rafts, and membrane lysis. We summarized current knowledge concerning the mechanisms involved in the interactions of saponins with membrane lipids and examined the structure activity relationship of saponins regarding hemolysis and cancer cell death. A critical analysis of these findings speculates on their potential to further develop new anticancer compounds.


Incidence of subsequent vertebral fracture after kyphoplasty.
A retrospective review of charts and radiographs of all consecutive patients who underwent kyphoplasty at the authors' center from the initial procedure in September 2000 to the end of the collection period in July 2002. The best available natural history data would suggest that after experiencing an osteoporotic vertebral compression fracture, patients have a 19% incidence of subsequent fracture in the following year when no surgical intervention is performed. When kyphoplasty is performed, there are conflicting data regarding the incidence of subsequent fracture, ranging anywhere from 3 to 29%. These fractures occur at adjacent levels between 30 and 90% of the time, with no clear explanation for the wide variation in the results of three different studies. There are biomechanical data to suggest that injection of cement does increase the stiffness of the treated vertebra and that this increases strain on adjacent vertebrae, especially in forward bending. A database was created containing patient age, gender, height, weight, medication history, comorbidities, fracture levels, and pain level before and after surgery. Subsequent fractures were confirmed with radiographs and MRI. Statistical analysis was performed. Thirty-eight patients (10 men and 28 women) were treated for 47 levels initially. L1 and L2 were the most common level of fracture managed initially. The gender, smoking and medication history, location of fracture, and number of fracture levels of the patients did not correlate with the risk of subsequent fracture. Over the follow-up period (average, 8 months), 10 patients sustained 17 subsequent fractures. Eight patients sustained fractures in the first 2 months after the index procedure, all with at least one fracture at an adjacent level. Of the 17 subsequent fractures, there were nine at the adjacent-above levels, four at adjacent-below levels, and four at remote levels. The remote fractures occurred at significantly greater time intervals after the index procedure (P < 0.001). This study demonstrated a higher rate of subsequent fracture after kyphoplasty compared with natural history data for untreated fractures. Most of these occurred at an adjacent level within 2 months of the index procedure. After this 2-month period, there were only occasional subsequent fractures, which occurred at remote levels. This confirms biomechanical studies showing that cement augmentation places additional stress on adjacent levels. Patients with an increase in back pain after kyphoplasty should be evaluated carefully for subsequent adjacent fractures, especially during the first 2 months after the index procedure.


Haptic-based neurorehabilitation in poststroke patients: a feasibility prospective multicentre trial for robotics hand rehabilitation.
Background. Haptic robots allow the exploitation of known motor learning mechanisms, representing a valuable option for motor treatment after stroke. The aim of this feasibility multicentre study was to test the clinical efficacy of a haptic prototype, for the recovery of hand function after stroke. Methods. A prospective pilot clinical trial was planned on 15 consecutive patients enrolled in 3 rehabilitation centre in Italy. All the framework features of the haptic robot (e.g., control loop, external communication, and graphic rendering for virtual reality) were implemented into a real-time MATLAB/Simulink environment, controlling a five-bar linkage able to provide forces up to 20 [N] at the end effector, used for finger and hand rehabilitation therapies. Clinical (i.e., Fugl-Meyer upper extremity scale; nine hold pegboard test) and kinematics (i.e., time; velocity; jerk metric; normalized jerk of standard movements) outcomes were assessed before and after treatment to detect changes in patients' motor performance. Reorganization of cortical activation was detected in one patient by fMRI. Results and Conclusions. All patients showed significant improvements in both clinical and kinematic outcomes. Additionally, fMRI results suggest that the proposed approach may promote a better cortical activation in the brain.


Toward structural dynamics: protein motions viewed by chemical shift modulations and direct detection of C'N multiple-quantum relaxation.
Multiple quantum relaxation in proteins reveals unexpected relationships between correlated or anti-correlated conformational backbone dynamics in alpha-helices or beta-sheets. The contributions of conformational exchange to the relaxation rates of C'N coherences (i.e., double- and zero-quantum coherences involving backbone carbonyl (13)C' and neighboring amide (15)N nuclei) depend on the kinetics of slow exchange processes, as well as on the populations of the conformations and chemical shift differences of (13)C' and (15)N nuclei. The relaxation rates of C'N coherences, which reflect concerted fluctuations due to slow chemical shift modulations (CSMs), were determined by direct (13)C detection in diamagnetic and paramagnetic proteins. In well-folded proteins such as lanthanide-substituted calbindin (CaLnCb), copper,zinc superoxide dismutase (Cu,Zn SOD), and matrix metalloproteinase (MMP12), slow conformational exchange occurs along the entire backbone. Our observations demonstrate that relaxation rates of C'N coherences arising from slow backbone dynamics have positive signs (characteristic of correlated fluctuations) in beta-sheets and negative signs (characteristic of anti-correlated fluctuations) in alpha-helices. This extends the prospects of structure-dynamics relationships to slow time scales that are relevant for protein function and enzymatic activity.


Compact optical function generator.
We demonstrate the use of a nonlinear photonic crystal to generate a harmonic comb and an ultrabroad-band acousto-optic modulator for the field amplitudes and phases of the comb to succeed in synthesizing femtosecond and subfemtosecond optical field waveforms. Nonsinusoidal fields of various shapes are synthesized and verified using shaper-assisted linear cross-correlation. The compact all-solid-state system could lead to the realization of a portable arbitrary optical waveform synthesizer that is analogous in many aspects to an RF function generator.