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Stimulation of the mesencephalic locomotor region elicits exaggerated sympathetic nerve and pressor responses in spontaneously hypertensive rats (SHR) as compared with normotensive Wistar-Kyoto rats (WKY). This suggests that central command or its influence on vasomotor centers is augmented in hypertension. The decerebrate animal model possesses an ability to evoke intermittent bouts of spontaneously occurring motor activity (SpMA) and generates cardiovascular responses associated with the SpMA. It remains unknown whether the changes in sympathetic nerve activity and hemodynamics during SpMA are altered by hypertension. To test the hypothesis that the responses in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) during SpMA are exaggerated with hypertension, this study aimed to compare the responses in decerebrate, paralyzed SHR, WKY, and normotensive Sprague-Dawley (SD) rats. In all strains, an abrupt increase in RSNA occurred in synchronization with tibial motor discharge (an index of motor activity) and was followed by rises in MAP and heart rate. The centrally evoked increase in RSNA and MAP during SpMA was much greater (306 ± 110%) in SHR than WKY (187 ± 146%) and SD (165 ± 44%). Although resting baroreflex-mediated changes in RSNA were not different across strains, mechanically or pharmacologically induced elevations in MAP attenuated or abolished the RSNA increase during SpMA in WKY and SD but had no effect in SHR. It is likely that the exaggerated sympathetic nerve and pressor responses during SpMA in SHR are induced along a central command pathway independent of the arterial baroreflex and/or result from central command-induced inhibition of the baroreflex.

Purpose of Review Bound to its high affinity receptor on mast cells and basophils, the IgE antibody molecule plays an integral role in the allergic reaction. Through interactions with the allergen, it provides the sensitivity and specificity parameters for cell activation and mediator release that produce allergic symptoms. Advancements in human hybridoma technologies allow for the generation and molecular definition of naturally occurring allergen-specific human IgE monoclonal antibodies. Recent Findings A high-resolution structure of dust mite allergen Der p 2 in complex with Fab of the human IgE mAb 2F10 was recently determined using X-ray crystallography. The structure reveals the fine molecular details of IgE 2F10 binding its 750 Å2 conformational epitope on Der p 2. Summary This review provides an overview of this major milestone in allergy, the first atomic resolution structure of an authentic human IgE epitope. The molecular insights that IgE epitopes provide will allow for structure-based design approaches to the development of novel diagnostics, antibody therapeutics, and immunotherapies.

Much of our understanding of the targets of IgE comes from studies of allergy, though little is known about the natural immunogenic targets seen after parasitic worm infections.We used human monoclonal antibodies (mAbs) for an unbiased and comprehensive characterization of the immunodominant antigens targeted by IgE in conditions like allergy or helminth infection that are associated with elevated levels of IgE.Using human hybridoma technology to immortalize IgE encoding B-cells from peripheral blood of subjects with filarial infections and elevated IgE, we generated naturally occurring human IgE mAbs. B-cell cultures were screened in an unbiased manner for IgE production without regard to specificity. Isolated IgE mAbs were then tested for binding to Brugia malayi somatic extracts using ImmunoCAP, immunoblot, and ELISA. Immunoprecipitation followed by mass spectrometry proteomics was used to identify helminth antigens that were then expressed in Escherichia coli for IgE binding characterization.We isolated 56 discrete IgE mAbs from 7 individuals with filarial infections. From these mAbs, we were able to definitively identify 19 filarial antigens. All IgE mAbs targeted filarial excreted/secretory proteins, including a family of previously uncharacterized proteins. Interestingly, the transthyretin-related antigens acted as the dominant inducer of the filaria-specific IgE antibody response. These filaria-specific IgE mAbs were potent inducers of anaphylaxis when passively administered to human FcεRI-expressing mice.We generated human hybridomas secreting naturally occurring helminth-specific IgE mAbs from filarial-infected subjects. This work provides much-needed insight into the ontogeny of helminth-induced immune response and IgE antibody response.

Decision making in clinical practice is only possible if we are able to understand the limits of our own knowledge and manage the associated uncertainty. Tolerance of ambiguity is therefore an important attribute for trainee pharmacists and medical students to develop. This study aimed to explore the impact of an interprofessional simulation on the tolerance of ambiguity of trainee pharmacists and medical students.Trainee pharmacists and final year medical students participated in interprofessional simulation in two regions of Scotland. Participants completed pre- and post-session tolerance of ambiguity questionnaires. Analysis included differences between the pre-session scores of the two groups; the trainee pharmacists' pre- and post-session scores; and the medical students' pre- and post-session scores.A total of 15 trainee pharmacists and 15 medical students participated. Baseline tolerance of ambiguity was slightly higher in medical students than trainee pharmacists (56.9 vs. 52.6), but the study was insufficiently powered to detect whether this was a true difference (P = .21). Trainee pharmacists showed a statistically significant increase in self-reported tolerance of ambiguity (52.6 to 60.8, P = .004), but medical students did not (56.9 to 63.8, P = .04).Trainee pharmacists' tolerance of ambiguity was improved following participation in an interprofessional simulation. Further research could establish whether the improvements differ between professional groups, and explore the reasons why tolerance of ambiguity may be affected by interprofessional simulation.

Importance Although the diagnosis of vitreoretinal lymphoma (VRL) can be challenging, early detection is critical for visual prognosis. Objective To analyze the spectrum of optical coherence tomography (OCT) findings in patients with biopsy-proven VRL and correlate these features with clinical parameters. Design Retrospective cross-sectional study Setting Multicenter chart review from 13 retina, uveitis and ocular oncology clinics worldwide over an 11-year period (2008-2019). Participants Patients with a diagnosis of biopsy-proven VRL imaged with OCT at presentation Exposure The ocular information, systemic information and multimodal retinal imaging findings were collected and studied. Main Outcome Measure Characteristics of VRL on OCT Results A total of 182 eyes of 115 patients (63 women, mean age 65 years) were included in this study. The disease was bilateral in 81 (70%) patients, and mean baseline visual acuity (VA) was 0.2±0.89 logMAR (Snellen equivalent of 20/32). At baseline, 38 patients (33%) presented with isolated ocular involvement, 54 (45%) with associated central nervous system (CNS) involvement and 11 (10%) with other systemic lymphomatous involvement and an additional 12 (10%) patients presented with both CNS and other systemic involvement. On OCT, tumor infiltration was identified in various retinal layers including lesions in the sub-retinal pigment epithelium (RPE) compartment (91% of eyes), the subretinal compartment (43% of eyes) and the intraretinal compartment (7% of eyes). Conclusions and Relevance OCT analysis of eyes with vitreoretinal lymphoma identified 3 main regions of retinal infiltration. Sub-RPE location, with or without subretinal infiltration, was the most common pattern of involvement whereas isolated intraretinal infiltration was the least common.

The stiffness and strength properties of freshly poured concrete develop over time as the concrete hardens due to curing. The monitoring of such properties therefore enables timely construction decisions such as formwork removal. Traditional point-in-time destructive tests can be cumbersome, while continuous non-destructive testing is desirable. Piezoelectric-based electromechanical impedance (EMI) and wave propagation (WP) techniques fall into the latter, and they have been verified for monitoring concrete properties during curing in the laboratory. This paper reports the first field application of the EMI and WP techniques for monitoring concrete curing, where smart aggregate (SA) sensors are embedded into concrete pour strips of a multi-storey residential building during construction. For comparison and verification purposes, destructive compression and non-destructive ultrasonic pulse velocity (UPV) tests were conducted. Results obtained from both EMI and WP techniques were consistent and repeatable. They were also comparable to the UPV result, and they showed a close correlation to the compressive strength tests. The current study has also revealed that the electrical signatures acquired from the EMI and WP techniques have a linear relationship. EMI-based and WP-based semi-analytical models (and their derivations) that can quantify the compressive strength and modulus of elasticity of concrete at various curing durations are also presented. This reported study ultimately demonstrates the applicability and practical application of the EMI and WP techniques for real-time measurements, bridging the gap between laboratory-based studies and field applications.

The sialic acid-binding immunoglobulin type lectins (Siglecs) are expressed predominantly on white blood cells and participate in immune cell recognition of self. Most Siglecs contain cytoplasmic inhibitory immunoreceptor tyrosine-based inhibitory motifs (ITIMs) characteristic of inhibitory checkpoint co-receptors that suppress cell signaling when they are recruited to the immunological synapse of an activating receptor. Antibodies to activatory receptors typically activate immune cells by ligating the receptors on the cell surface. Here we report that the conjugationof high affinity ligands of Siglecs to anti-bodies targeting activatory immune receptors can suppress receptor mediated activation of immune cells. Indeed, B cell activation by antibodies to the B cell receptor (BCR) IgD is dramatically suppressed by conjugation of anti-IgD with high affinity ligands of a B cell Siglec CD22/Siglec-2. Similarly, degranulation of mast cells induced by antibodies to IgE, which ligate the IgE/FcεR1 receptor complex, is suppressed by conjugation of anti-IgE to high affinity ligands of a mast cell Siglec, CD33/Siglec-3 (CD33L). Moreover, the anti-IgE-CD33L suppresses anti-IgE mediated systemic anaphylaxis of sensitized humanized mice, and prevents anaphylaxis upon subsequent challenge with anti-IgE. The results demonstrate that attachment of ligands of inhibitory Siglecs to anti-receptor antibodies can suppress activation of immune cells and modulate unwanted immune responses.

A venous thromboembolism (VTE) event occurred in a female astronaut during long-duration spaceflight. Multiple factors may have contributed to this risk, including the use of combined (progestin + estrogen) oral contraceptives (cOC). Biochemistry data from 65 astronauts were evaluated for associations with cOC use and with sex. The female astronauts who used cOCs had lower concentrations of serum albumin and higher concentrations of transferrin, a protein involved in the clotting cascade, than the male astronauts and the female astronauts who were not taking cOCs (P < 0.001). The women who used cOCs had higher serum concentrations of the acute phase reactant ceruloplasmin and cortisol during flight (P < 0.001) than the men and the women who were not taking cOCs; they also had higher calculated whole blood viscosity than women not taking cOCs (P < 0.001). Lower circulating concentrations of albumin, higher concentrations of transferrin, and elevated markers of inflammation all could contribute to an increased risk of VTE during spaceflight. These changes, in association with a higher blood viscosity, can directly affect endothelial glycocalyx integrity and hypercoagulability status, both of which contribute to VTE risk in terrestrial populations. NEW & NOTEWORTHY We report here evidence of an association between oral contraceptive use and serum albumin, among other factors, which potentially increase the risk of venous thromboembolism in astronauts. These findings highlight potential risks to astronaut health while providing potential alternative countermeasures for decreasing VTE risk during spaceflight. These findings also highlight an underrecognized potential mechanism for hypoalbuminemia to increase VTE risk in terrestrial populations.

Following the outbreak and subsequent pandemic of coronavirus disease 2019 (COVID-19), clinical diagnostic laboratories worldwide sought accurate and reliable testing methodologies. However, many laboratories were and still are hindered by a number of factors, including an unprecedented demand for testing, reagent and laboratory supply shortages and availability of qualified staff. To respond to these concerns, two separate laboratory-developed tests were validated for detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using two different specimen types. In addition, these assays target different genomic regions of SARS-CoV-2, allowing for viral detection and mitigating genetic variation. Lower limit of detection and clinical evaluation studies showed detection of SARS-CoV-2 at 500 cp/mL with nasopharyngeal and saliva samples. These multiplexed RT-qPCR assays, although based on modified CDC, New York State Department of Health, and World Health Organization Emergency Use Authorization tests, allow for higher throughput and rapid turnaround time, benefiting patients, clinicians, and communities as a whole. These cost-effective tests also use readily obtainable reagents, circumventing commercial assay supply chain issues. The laboratory-developed tests described here have improved patient care and are highly adaptable should the need arise at other clinical diagnostic laboratories. Furthermore, the foundation and design of these assays may be modified in the future for detection of COVID-19 variants or other RNA-based viral detection tests.

Phalaena militta Stoll, [1781], currently in the combination Thyrgis militta, is transferred to the new combination Calodesma militta. Phalaena militta is the type species of Thyrgis Walker, 1854, and so Thyrgis is a junior synonym of Calodesma Hübner, [1820]. The reinstated genus Seileria Dognin, 1923 is the next available name for the genus previously known as Thyrgis, and the remaining eight species and their subspecies currently in Thyrgis are transferred to new combinations as species of Seileria: S. angustifascia (Hering, 1925), S. basipunctata (Hering, 1926), S. constrictifascia (Dognin, 1919), S. flavonigra (Dognin, 1910), S. investigatorum (Toulgoët, 1988), S. marginata (Butler, 1875), S. meres (Druce, 1911), S. phlegon (Druce, 1885), S. phlegon ruscia (Druce, 1895), S. tenuifascia (Hering, 1930) and S. tenuifascia daguana (Hering, 1930). Eucyanoides Toulgoët, 1988, currently a synonym of Thyrgis, is made a new subjective synonym of Seileria. Based on DNA barcodes, we recognise three very similar, sexually dimorphic and in two cases polymorphic South American species of Calodesma with some phenotypes in common but very similar male genitalia: C. militta (BOLD:AAK1660), C. sp. cf. collaris (BOLD:ABZ2392) and C. pseudocollaris Cock new species (BOLD:AEI2170). Calodesma militta is widespread in South America, with two male morphs (collaris and dioptis) and two female morphs with variable markings (white and orange morphs). Centronia plorator Kaye, [1923] and Thyrgis lacryma Dognin, 1919 are variants of the white female morph and are new synonyms of Calodesma militta. A third female morph with red markings was not sequenced and could not be allocated to a species. Calodesma sp. cf. collaris (BOLD:ABZ2392) occurs in southern South America with both male morphs but only a white female morph. Calodesma pseudocollaris new species (BOLD:AEI2170) is only known from Trinidad, with one male morph (collaris) and the white female morph. Although more than ten morphs relating to this complex have been described as species, they cannot be synonymised without more data on distribution of the different species or DNA barcodes from the type specimens. Collated life history information indicates species of this group are split between Malpighiaceae feeders and Bromeliaceae feeders, but more work is needed to define these differences. The morphism patterns observed are discussed in terms of Müllerian mimicry and mimicry rings, and we suggest that in Trinidad (and elsewhere) there is a loose mimicry ring of diurnal black species with white spots or transparent patches on the wings which are most conspicuous and frequently observed when feeding on white Asteraceae flowers.

Skeletal muscle reflexes play a crucial role in determining the magnitude of the cardiovascular response to exercise. However, evidence supporting an association between the magnitude of the pressor response and velocity of muscle deformation has remained to be elucidated. Thus, we investigated the impact of different muscle deformation rates on the neural discharge of muscle afferents as well as pressor and sympathetic responses in Sprague-Dawley rats. In an ex vivo muscle-nerve preparation, action potentials elicited by sinusoidal mechanical stimuli (137 mN) at different frequencies (0.01, 0.05, 0.1, 0.2, and 0.25 Hz) were recorded in mechanosensitive group III and IV fibers. The afferent response magnitude to sine-wave stimulation significantly varied at different frequencies (ANOVA, P=0.025). Specifically, as compared to 0.01 Hz (0.83±0.96 spikes/s), the response magnitudes were significantly greater at 0.20 Hz (4.07±5.04 spikes/s, P=0.031) and 0.25 Hz (4.91±5.30 spikes/s, P=0.014). In an in vivo decerebrated rat preparation, renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to passive stretch (1kg) of hindlimb skeletal muscle at different velocities of loading (slow, medium, fast) was measured. Pressor responses to passive stretch were significantly associated with velocity of muscle deformation (ANOVA, P

Sup. Figure 1. MHH-ES-1 and RD-ES are triploid for chromosome 10. Sup. Figure 2. PTEN copy number variation in primary Ewing sarcoma. Sup. Figure 3. PTEN immunofluoresence is concordant with immunoblotting. Sup Figure 4. Immunofluoresence and immunohistochemical staining are highly concordant. Sup. Figure 5. Quantification of Cytoplasmic PTEN. Sup. Figure 6. IGF-1 sensitivity is not influence by the presence of PTEN. Sup. Figure 7. Expression of PTEN increases cleaved PARP. Sup. Figure 8. PTEN expression reduces the autophagy-mediated viability effects of temsirolimus.

Recent evidence implicates the insulin-like growth factor (IGF) pathway in development of Ewing sarcoma, a highly malignant bone and soft-tissue tumor that primarily affects children and young adults. Despite promising results from preclinical studies of therapies that target this pathway, early-phase clinical trials have shown that a significant fraction of patients do not benefit, suggesting that cellular factors determine tumor sensitivity. Using FAIRE-seq, a chromosomal deletion of the PTEN locus in a Ewing sarcoma cell line was identified. In primary tumors, PTEN deficiency was observed in a large subset of cases, although not mediated by large chromosomal deletions. PTEN loss resulted in hyperactivation of the AKT signaling pathway. PTEN rescue led to decreased proliferation, inhibition of colony formation, and increased apoptosis. Strikingly, PTEN loss decreased sensitivity to IGF1R inhibitors but increased responsiveness to temsirolimus, a potent mTOR inhibitor, as marked by induction of autophagy. These results suggest that PTEN is lost in a significant fraction of primary tumors, and this deficiency may have therapeutic consequences by concurrently attenuating responsiveness to IGF1R inhibition while increasing activity of mTOR inhibitors. The identification of PTEN status in the tumors of patients with recurrent disease could help guide the selection of therapies.Implications: PTEN status in Ewing sarcoma affects cellular responses to IGFI and mTOR-directed therapy, thus justifying its consideration as a biomarker in future clinical trials. Mol Cancer Res; 12(11); 1610–20. ©2014 AACR.

PDF file - 339K, Flow cytometry histograms of serial levels of p-ERK and p-mTOR in patient samples.

Purpose: The clinical relevance of targeting the RAS/RAF/MEK/ERK pathway, activated in 70% to 80% of patients with acute myelogenous leukemia (AML), is unknown.Experimental Design: Selumetinib is an oral small-molecule inhibitor of MAP–ERK kinase (MEK)-1/2. Forty-seven patients with relapsed/refractory AML or 60 years old or more with untreated AML were enrolled on a phase II study. Patients were stratified by FLT3 ITD mutation status. The primary endpoint was response rate (complete, partial, and minor). Leukemia cells were analyzed for extracellular signal—regulated kinase (ERK) and mTOR phosphorylation.Results: Common drug-related toxicities were grade 1–2 diarrhea, fatigue, nausea, vomiting, and skin rash. In the FLT3 wild-type cohort, six of 36 (17%) patients had a response [one partial response, three minor responses, two unconfirmed minor responses (uMR)]. No patient with FLT3 ITD responded. NRAS and KRAS mutations were detected in 7% and 2% of patients, respectively. The sole patient with KRAS mutation had uMR with hematologic improvement in platelets. Baseline p-ERK activation was observed in 85% of patients analyzed but did not correlate with a response. A single-nucleotide polymorphism (SNP) rs3733542 in exon 18 of the KIT gene was detected in significantly higher number of patients with response/stable disease compared with nonresponders (60% vs. 23%; P = 0.027).Conclusions: Selumetinib is associated with modest single-agent antileukemic activity in advanced AML. However, given its favorable toxicity profile, combination with drugs that target other signaling pathways in AML should be considered. The potential association of SNP rs3733542 in exon 18 of the KIT gene with antileukemic activity of selumetinib is intriguing, but will require validation in larger trials. Clin Cancer Res; 20(2); 490–8. ©2013 AACR.

PDF file - 50K, Primers for KIT gene mutation testing.

In 2017, the study, Vision Impairment and Intracranial Pressure and Psychological Envihab Research, dubbed VaPER, was conducted in the:envihab facility in Cologne, Germany to determine whether 30 days of bed rest at 6° head down tilt in an increased ambient CO2 (hypercapnic) environment contributes to the deterioration of ocular anatomy and to changes in musculoskeletal, nutritional, hematological, immunological, behavioral, and balance functions. A set of international standard measures were used to evaluate bone, muscle, and nutritional status, and to assess the function of the cardiovascular, sensorimotor, visual, and immune systems, and psychological state. Strict 6° head-down tilt bed rest in an elevated ambient CO2 environment induced mild immunological dysregulation. After bed rest, selenium, urinary iodine, and folate status were lower in the subjects of the VaPER study than they were in subjects of previous bed rest studies of similar duration, which likely reflects regional differences in diet and nutritional status. Bed rest induced optic disc edema in 5 of the 11 subjects. Interestingly, the subjects who were diagnosed with optic disc edema, as determined by fundoscopy imaging, also tended to exhibit higher body temperature and overall higher levels of anxiety and insomnia during bed rest.

This paper presents the results of an experimental study on a full-scale precast concrete frame reinforced with glass fibre reinforced polymer (GFRP) bars that was tested to failure under lateral cyclic loading. Within the frame four different pocket connections are tested that will lead to accelerated construction. Traditionally, a pocket connection is comprised of a column that is extended into a recessed portion of the connecting beam and the pocket is filled with grout to create a moment-resisting connection. In order to accelerate the construction process, quicker setting epoxy resin was used in place of grout. The results show that while the epoxy resin could significantly accelerate and simplify the construction procedure due to its workability in addition to its high early strength and non-shrinkable properties, its thickness and low modulus of elasticity significantly affected the performance of the pocket joint. The test frame showed a flag-shaped hysteretic behaviour with narrow loops and small residual displacement thus illustrating desirable frame self-centring behaviour. This self-centring behaviour was due to rocking of the column in the pocket connection. The frame displaced with a large displacement ductility of approximately 7.0, however, the level of energy dissipation and damping ratio was very low when compared with conventional concrete structures. This experimental study shows that pocket connections can be used for GFRP reinforced precast concrete elements, however, they should be designed carefully to account for the lower stiffness of GFRP reinforcement. Also, to avoid premature failure and achieve a higher capacity of the pocket connections, the material used in the pocket to fill the gap between column and beam is recommended to have higher strength and elastic modulus compared to the surrounding precast concrete. Refereed/Peer-reviewed

Peanut-induced allergy is an immunoglobulin E (IgE)–mediated type I hypersensitivity reaction that manifests symptoms ranging from local edema to life-threatening anaphylaxis. Although there are treatments for symptoms in patients with allergies resulting from allergen exposure, there are few preventive therapies other than strict dietary avoidance or oral immunotherapy, neither of which are successful in all patients. We have previously designed a covalent heterobivalent inhibitor (cHBI) that binds in an allergen-specific manner as a preventive for allergic reactions. Building on previous in vitro testing, here, we developed a humanized mouse model to test cHBI efficacy in vivo. Nonobese diabetic–severe combined immunodeficient γc-deficient mice expressing transgenes for human stem cell factor, granulocyte-macrophage colony-stimulating factor, and interleukin-3 developed mature functional human mast cells in multiple tissues and displayed robust anaphylactic reactions when passively sensitized with patient-derived IgE monoclonal antibodies specific for peanut Arachis hypogaea 2 (Ara h 2). The allergic response in humanized mice was IgE dose dependent and was mediated by human mast cells. Using this humanized mouse model, we showed that cHBI prevented allergic reactions for more than 2 weeks when administered before allergen exposure. cHBI also prevented fatal anaphylaxis and attenuated allergic reactions when administered shortly after the onset of symptoms. cHBI impaired mast cell degranulation in vivo in an allergen-specific manner. cHBI rescued the mice from lethal anaphylactic responses during oral Ara h 2 allergen–induced anaphylaxis. Together, these findings suggest that cHBI has the potential to be an effective preventative for peanut-specific allergic responses in patients.

Astronauts on the International Space Station are exposed to levels of atmospheric carbon dioxide (CO2) above typical terrestrial levels. We explored the possibility that increased levels of ambient CO2 further stimulate bone resorption during bed rest. We report here data from 2 ground-based spaceflight analog studies in which 12 male and 7 female subjects were placed in a strict 6° head-down tilt (HDT) position for either 30 days at 0.5% ambient CO2 or 60 days with nominal environmental exposure to CO2. Bone mineral density (BMD) and bone mineral content (BMC) were determined using dual-energy X-ray absorptiometry (DXA). Blood and urine were collected before and after HDT for biochemical analysis. No change was detected in either BMD or BMC, as expected given the study duration. Bone resorption markers increased after bed rest as expected; however, elevated CO2 had no additive effect. Elevated CO2 did not affect concentrations of minerals in serum and urine. Serum parathyroid hormone and 1,25-dihydroxyvitamin D were both reduced after bed rest, likely secondary to calcium efflux from bone. In summary, exposure to 0.5% CO2 for 30 days did not exacerbate the typical bone resorption response observed after HDT bed rest. Furthermore, results from these strict HDT studies were similar to data from previous bed rest studies, confirming that strict 30–60 days of HDT can be used to evaluate changes in bone metabolism. This is valuable in the continuing effort to develop and refine efficacious countermeasure protocols to mitigate bone loss during spaceflight in low-Earth orbit and beyond.

Long-duration spaceflight impacts human physiology, including well documented immune system dysregulation. The space food system has the potential to serve as a countermeasure to maladaptive physiological changes during spaceflight. However, the relationship between dietary requirements, the food system, and spaceflight adaptation requires further investigation to adequately define countermeasures and prioritize resources on future spaceflight missions. We evaluated the impact of an enhanced spaceflight diet, with increased quantity and variety of fruits, vegetables, fish, and other foods rich in flavonoids and omega-3 fatty acids, compared to a standard spaceflight diet on multiple health and performance outcomes in 16 subjects over four 45-day closed chamber missions in the NASA Human Exploration Research Analog (HERA). Subjects consuming the enhanced spaceflight diet had lower cholesterol levels, lower stress (i.e. cortisol levels), better cognitive speed, accuracy, and attention, and a more stable microbiome and metatranscriptome than subjects consuming the standard diet. Although no substantial changes were observed in the immune response, there were also no immune challenges, such as illness or infection, so the full benefits of the diet may not have been apparent in these analog missions. These results indicate that a spaceflight diet rich in fruits, vegetables, and omega-3 fatty acids produces significant health and performance benefits even over short durations. Further investigation is required to fully develop dietary countermeasures to physiological decrements observed during spaceflight. These results will have implications for food resource prioritization on spaceflight missions.

In this article, a flexible power-efficient video memory is presented that can dynamically adjust the strength of error correction code (ECC), thereby enabling power-quality tradeoff based on application requirements. Specifically, we utilize the bit significance characteristics of video data to develop a low-cost parity storage scheme that supports both hamming code-74 (ECC74) and hamming code-1511 (ECC1511). Based on this, we propose a flexible memory with three dynamic power-quality adaptation schemes (i.e., ECC74, ECC1511, and no ECC) to meet different video application requirements. Our simulation results in 45-nm CMOS technology show that the proposed memory can enable up to 35.37% power savings without a noticeable degradation in video quality, as compared to the conventional design. We also design an integrated ECC encoder/decoder that handles both ECC74 and ECC1511, which reduces area overhead. To evaluate the effectiveness of the proposed technique, we further develop a system-level video storage embedded test platform based on a commercial 65-nm SRAM chip, which shows that the proposed technique results in significant supply voltage reduction without noticeable video quality degradation.

Anterior cerebral artery blood velocity and vascular conductance index along with prefrontal oxygenated-hemoglobin concentration all increased at the onset of finger tapping, peaking immediately after tapping onset, as long as tapping was arbitrarily started. Positive cross correlation and linear regression between the increases in ACABV and prefrontal Oxy-Hb were significant in 67%–75% of subjects. Active vasodilatation of the ACA vascular bed occurs with arbitrary tapping onset and contributes to increased ACABV and prefrontal oxygenation.

Spaceflight entails a variety of environmental and psychological stressors that may have long-term physiological and genomic consequences. Metabolomics, an approach that investigates the terminal metabolites of complex physiological alterations, takes into account the dynamic state of the human body and allows the identification and quantification of down-stream metabolic outputs linked to up-stream physiological and genomic regulation by stress. Employing a metabolomics-based approach, this study investigated the longitudinal metabolic perturbations of male (n=40) and female (n=11) astronauts on 4-6-month missions to the International Space Station. Proton nuclear magnetic resonance (1H-NMR) spectroscopy followed by univariate, multivariate and machine learning analyses were used on blood serum to examine sex-specific metabolic changes at various time points throughout the astronauts’ missions, and the metabolic effects of long-duration space travel. Space travel generated sex-specific changes in energy metabolism, bone mineral and muscle regulation, immunity, and macromolecule maintenance and synthesis. Additionally, metabolic signatures suggest differential metabolic responses especially during the recovery period, with females requiring more time to adjust to return to Earth. These findings provide insight into the perturbations in glucose and amino acid metabolism and macromolecule biosynthesis that result from the stressors of long-duration spaceflight. Metabolomic biomarkers may provide a viable approach to predicting and diagnosing health risks associated with prolonged space travel and other physiological challenges on Earth.

Bound to its high affinity receptor on mast cells and basophils, the IgE antibody molecule plays an integral role in the allergic reaction. Through interactions with the allergen, it provides the sensitivity and specificity parameters for cell activation and mediator release that produce allergic symptoms. Advancements in human hybridoma technologies allow for the generation and molecular definition of naturally occurring allergen-specific human IgE monoclonal antibodies.A high-resolution structure of dust mite allergen Der p 2 in complex with Fab of the human IgE mAb 2F10 was recently determined using X-ray crystallography. The structure reveals the fine molecular details of IgE 2F10 binding its 750 Å

Members of clinical teams can hold stereotyped views of one another that can form barriers to interprofessional cohesion and collaboration. Interprofessional education (IPE) is often championed as a way of teaching individuals to be better team players through the adoption of collaborative attitudes and behaviours. However, the potentially detrimental effects of IPE are not well understood. This study used the social identity approach (SIA) as a lens to explore the impact of interprofessional simulation on the identities and professional relationships of trainee pharmacists and medical students. Across three different locations in Scotland, trainee pharmacists were paired with medical students to participate in immersive simulation scenarios with post-scenario debriefs. Participants were individually interviewed shortly after their simulation session, using a semi-structured interview schedule based on SIA. Transcripts were analysed using template analysis, with sub-categorizations of SIA forming the initial coding template. Twenty-five interviews were undertaken across both groups. The interprofessional simulation session effectively challenged pre-existing stereotypes. For the trainee pharmacists, the alteration of self-stereotypes influenced motivation through self-enhancement and, in turn, altered group norms via the promotion of genuine collaboration and joint decision-making. However, social comparisons focussed on status remained prominent. This study has shown that interprofessional simulation can effectively challenge and alter stereotypes (including self-stereotypes), but social comparisons may be less easy to overcome in this context. As it continues to be embedded within healthcare education, the limitations of IPE must be better understood to ensure that the potential value of such opportunities is maximized.

Clinical guidelines recommend office blood pressures (BP) to be taken in a seated position. However, the accuracy of standing BP measurements for diagnosing hypertension (HTN) has not been investigated. We assessed BP in both seated and standing positions in 125 healthy adults not on anti-HTN medications. HTN was defined by 24-hour ambulatory SBP/DBP of ≥ 125/75 mmHg. Area under receiver operator characteristic curve (AUROC) was calculated to determine accuracy of seated and standing BP in diagnosing HTN. Bayes factor (BF) was used to assess the significance of the difference between AUROC of seated and standing BP. Sensitivity and specificity of standing BP in diagnosing HTN was derived using cut-off points derived from Youden’s Index. Our cohort’s mean age was 49 ± 17 years, with 62% female (77 of 125), and 24% Black (30 of 125). Prevalence of HTN was 33.6% (42 of 125). Sensitivity and specificity of seated SBP was 43% and 92%, respectively. Optimal cutoffs selected by Youden’s index for standing SBP/DBP was 124/81 mmHg. Sensitivity and specificity of standing SBP was 74% and 65%, respectively. The AUROC of standing SBP was significantly higher than seated SBP (BF =11.8), when HTN was defined as 24-Hr SBP ≥ 125 mmHg (Fig 1). Similarly, when HTN was defined as 24-Hr DBP ≥ 75 mmHg or daytime DBP ≥ 80 mmHg, the AUROC of standing DBP was higher than seated DBP (all BF >3). The addition of standing to seated BP improved HTN detection than seated BP alone based on 24-Hr SBP/DBP ≥ 125/75 mmHg or daytime SBP/DBP ≥ 130/80 mmHg (all BF >3). In conclusion, standing office BPs both alone and in combination with seated BPs, outperformed seated BPs in diagnosing hypertension in untreated adults.

BackgroundGiven rising costs and changing payment models, healthcare organisations are increasingly focused on value and efficiency. The goal of our study was to develop survey items to assess clinician and staff perspectives about the extent to which the organisational culture in hospitals and medical offices supports value and efficiency.MethodsDevelopment began with a literature review and interviews with experts and clinicians and staff from hospitals and medical offices. We identified key areas of value and efficiency culture, drafted survey items and conducted cognitive testing. Using purposive sampling to select sites, the 36-item surveys were pilot tested in 47 hospitals and 96 medical offices. Psychometric analysis was conducted on data from 3951 hospital respondents (42% response) and 1458 medical office respondents (63% response).ResultsFactor loadings, multilevel confirmatory factor analysis model fit and reliability estimates were acceptable for the 13 items grouped into 4 composite measures: Empowerment to Improve Efficiency (3 items), Efficiency and Waste Reduction (3 items), Patient Centeredness and Efficiency (3 items) and Management Support for Improving Efficiency and Reducing Waste (4 items). All composite measures were significantly intercorrelated and related to the four Overall Ratings of Healthcare Quality, indicating adequate conceptual convergence among the measures. Eight items assessing Experiences With Activities to Improve Efficiency were also included.ConclusionWe developed psychometrically sound survey items measuring value and efficiency culture. When added to the Agency for Healthcare Research and Quality Surveys on Patient Safety Culture, the item sets extend those surveys by assessing additional dimensions of organisational culture that affect care delivery. Healthcare organisations can use these item sets to assess how well their organisational culture supports value and efficiency and identify areas for improvement.

INTRODUCTION: For over 50 yr, investigators have studied the physiological adaptations of the human system during short- and long-duration spaceflight exposures. Much of the knowledge gained in developing health countermeasures for astronauts onboard the International Space Station demonstrate terrestrial applications. To date, a systematic process for translating these space applications to terrestrial human health has yet to be defined.METHODS: In the summer of 2017, a team of 38 international scientists launched the Bellagio ll Summit Initiative. The goals of the Summit were: 1) To identify space medicine findings and countermeasures with highest probability for future terrestrial applications; and 2) To develop a roadmap for translation of these countermeasures to future terrestrial application. The team reviewed public domain literature, NASA databases, and evidence books within the framework of the five-stage National Institutes of Health (NIH) translation science model, and the NASA two-stage translation model. Teams then analyzed and discussed interdisciplinary findings to determine the most significant evidence-based countermeasures sufficiently developed for terrestrial application.RESULTS: Teams identified published human spaceflight research and applied translational science models to define mature products for terrestrial clinical practice.CONCLUSIONS: The Bellagio ll Summit identified a snapshot of space medicine research and mature science with the highest probability of translation and developed a Roadmap of terrestrial application from space medicine-derived countermeasures. These evidence-based findings can provide guidance regarding the terrestrial applications of best practices, countermeasures, and clinical protocols currently used in spaceflight.Sides MB, Johnston SL III, Sirek A, Lee PH, Blue RS, Antonsen EL, Basner M, Douglas GL, Epstein A, Flynn-Evans EE, Gallagher MB, Hayes J, Lee SMC, Lockley SW, Monseur B, Nelson NG, Sargsyan A, Smith SM, Stenger MB, Stepanek J, Zwart SR; Bellagio II Team. Bellagio II report: terrestrial applications of space medicine research. Aerosp Med Hum Perform. 2021; 92(8):650669.

This paper describes an iterative hybrid (additive + subtractive) manufacturing approach for a titanium alloy (Ti6Al4V) part using a laser hotwire directed energy deposition system (LHWDED) and a traditional four-axis milling machine tool. The term iterative hybrid manufacturing is used to described hybrid manufacturing where the additive and subtractive operations occur in multiple stages rather than sequentially. It is currently common to produce an entire part by sequential hybrid manufacturing by additively manufacturing (AM) an entire preform geometry that then requires post processing by another machine tool to create final part features. By contrast, a part produced by iterative hybrid manufacturing (IHM) does not produce the entire preform geometry in a single AM process. Instead, a portion of the entire preform geometry is manufactured by an AM process, then that portion is transferred to another machine tool which creates features in that portion, and then that machined portion is transferred back to the AM machine to complete another AM process. There is no limit to the number of iterations that an IHM process can have. IHM offers several advantages over sequential hybrid manufacturing such as the use of shorter and stiffer subtractive tooling, better access to part geometries that require subtractive processes, and the separation of the AM heat source from the subtractive machine tool. A titanium alloy demonstration part was successfully manufactured by IHM with three iterations using a shared pallet system between the AM machine tool and the subtractive machine tool. 1

This paper describes a time-domain simulation for predicting surface finish in modulated tool path (MTP) turning, which uses sinusoidal axis motions in the feed direction to produce discontinuous chips for ductile workpiece materials. The simulation includes: the low frequency and low amplitude tool oscillation in the feed direction; the time-varying chip thickness, cutting force, and tool displacement; and the plastic side flow effect used to calibrate the effective tool nose radius. Comparisons between predicted and measured surface profiles are presented for turning a 6061-T6 aluminum cylinder as a function of the MTP oscillation frequency and amplitude with discontinuous chip formation.

The Lodging Shared Economy (LSE) has recently become a dominant force in the lodging industry. Airbnb is a well-known example of LSE and has become a favorite for business and leisure travelers. Ho...

Ibrutinib has superior progression-free survival compared with bendamustine plus rituximab (BR) in older CLL patients, however, differences in treatment duration, six monthly BR cycles versus continuous ibrutinib, complicate adverse event (AE) comparisons. We introduce the AE burden score (AEsc) to compare AEs, calculated for each patient by summing over products of reporting period length and grade for each all-cause grade 1-4 AE and dividing by the length of time over which AEs are assessed. A total of 176 patients received BR and 361 ibrutinib alone or with six cycles of rituximab. At 38 months median follow-up, 64% remained on ibrutinib. Median AEsc was higher with BR versus ibrutinib in the first six cycles (7.2 versus 4.9, p < 0.0001). Within ibrutinib arms, median AEsc decreased significantly to 3.7 after six cycles (p < 0.0001). 10% and 14% of BR and ibrutinib patients discontinued treatment for AEs. In ibrutinib arms, cumulative incidence of grade 3 or higher atrial fibrillation, hypertension, and infection (AEs of clinical interest) at 12 months was 4.5%, 17.5%, and 12.8%, respectively, and increased more slowly thereafter to 7.7%, 25.4%, and 20.5% at 36 months. Analytical tools including the AEsc and cumulative incidence of AEs can help to better characterize AE burden over time. ClinicalTrials.gov identifier: NCT01886872.

Edge artificial intelligence (AI) achieves real-time local data analysis for IoT systems, enabling low-power and high-speed operation, but comes with privacy-preserving requirements. The memristor-based computing system is a promising solution for edge AI, but it needs a low-cost privacy protection mechanism due to limited resources. In this article, we propose a noise distribution normalization (NDN) method to add Gaussian distributed noise through hardware implementation, thereby achieving differential privacy in edge AI. Instead of using traditional algorithmic noise-insertion methods, we take advantage of inherent cycle-to-cycle variations of memristors during the weight-update process as the noise source, which does not incur extra software or hardware overhead. In one case study, the proposed method realizes ultralow-cost differentially private stochastic gradient descent (DP-SGD) for edge AI in IoT systems, achieving a 3.5%–15.5% average recognition accuracy improvement under different noise levels, as compared with a baseline mechanism.

International audience; Background Immobilization and related oxidative stress are associated with bone loss. Antioxidants like polyphenols, omega-3 fatty acids, vitamins, and micronutrients may mitigate these negative effects on bone metabolism through scavenging of free radicals. Objectives We hypothesized that antioxidant supplementation during 60 days of 6° head-down tilt bed rest (HDBR) would reduce bone resorption and increase bone formation compared to nonsupplemented controls. Methods This exploratory randomized, controlled, single-blind intervention study conducted in a parallel design included 20 healthy male volunteers (age, 34 ± 8 years; weight, 74 ± 6 kg). The study consisted of a 14-day adaptation phase [baseline data collection (BDC)], followed by 60 days of HDBR and a 14-day recovery period (R). In the antioxidant group, volunteers received an antioxidant cocktail (741 mg/d polyphenols, 2.1 g/d omega-3 fatty acids, 168 mg/d vitamin E, and 80 μg/d selenium) with their daily meals. In the control group, volunteers received no supplement. Based on their body weight, all volunteers received an individually tailored and strictly controlled diet, consistent with DRIs. We analyzed biomarkers of calcium homeostasis, bone formation, and bone resorption during BDC, HDBR, and R, as well as for 30 days after the end of HDBR. Data were analyzed by linear mixed models. Results The antioxidant supplement did not affect serum calcium, parathyroid hormone, urinary C-telopeptide of type I collagen (CTX), urinary N-telopeptide of type I collagen, serum β–C-telopeptide of type I collagen (β-CTX), bone alkaline phosphatase, aminoterminal propeptide of type I collagen, osteocalcin, or urinary calcium excretion. In both groups, typical bed rest–related changes were observed. Conclusions Supplementation of an antioxidant cocktail to a diet matching the DRIs did not affect bone resorption or formation during 60 days of HDBR in healthy young men. This trial was registered at clinicaltrials.gov as NCT03594799.

Cast iron and steel weldments are the most common machine tool base elements. However, both construction methods have associated disadvantages for domestic machine tool manufacturers. This paper documents the investigation of an alternative method for machine tool base production using concrete to fill an additively manufactured polymer mold, where the motion components are attached to the concrete base after the initial concrete curing. Modal testing results for a three-axis, vertical spindle prototype indicate high damping and stiffness can be achieved using the concrete base construction. Advantages are reduced cost and lead time compared to traditional methods.

This study examined psychological distress among students at a predominantly-minority college, attitudes toward seeking help, and utilization of college counseling services. Demographic variables and associations between 8 problem areas (depression, generalized anxiety, social anxiety, academic stress, eating concerns, family distress, hostility, substance use) were explored.Participants were 347 students at a large public university.In 2016-2017, students completed a Web-based questionnaire providing information about their mental health, attitudes toward seeking help, and utilization of counseling services.Psychological distress was significantly higher for LGBQT, Muslim and female students and lower for Christian affiliated and religious students. LGBQT students were less likely to seek psychological help than other students. Utilization of college counseling did not differ by race or gender.Administrators at PMCs must increase their efforts to disseminate information about mental health services and reduce barriers to seeking help, particularly for LGBQT, female and Muslim students.