A Curcumin Analog, GO-Y078, Effectively Inhibits Angiogenesis through Actin Disorganization.
The inhibition of angiogenesis is a theoretically ideal chemotherapy for cancer, but there remains room for improvement. Most inhibitors of angiogenesis approved to date target vascular endothelial growth factors (VEGFs); however, VEGFs are only one of the many classes of participant in tumor angiogenesis. Because tumor angiogenesis is orchestrated by many components, including growth factors, signal transducers, and effectors, its regulation exhibits redundancy. Curcumin can associate with many proteins, and it reportedly inhibits tumor angiogenesis. We investigated the ability of a new curcumin analog, GO-Y078, to inhibit tumor angiogenesis. GO-Y078 inhibited human umbilical vascular endothelial cell sprouting. GO-Y078 also induced complete anoikis in vascular endothelial cells. Moreover, GO-Y078 suppressed the migration and invasion of vascular endothelial cells into extracellular matrix proteins. However, expression analysis revealed that GO-Y078 did not suppress molecules involved in VEGF signaling. Rather, GOY078 induced actin disorganization, dissociation of vinculin from actin, and destruction of focal adhesion, resulting in the inhibition of vascular endothelial cell mobility. GO-Y078 also suppressed in-vivo vasculogenesis in Xenopus laevis tadpoles. Actin organization is a common effecter related to vascular endothelial cell mobility in angiogenesis. We demonstrated that GO-Y078 inhibits angiogenesis through actin disorganization.


Analysis of curing of a sustained release coating formulation by application of NIR spectroscopy to monitor changes physical-mechanical properties.
The focus of the study was to explore the physical-mechanical properties of curing films and use these properties as a reference for models that relate NIR spectra to the extent of curing. Cast films were cured at 40, 50, and 60°C from 1 to 48 h before being scanned on an NIR Spectrometer and analyzed for physical-mechanical properties using an Instron(®) material testing system. The studies show clear dependence of the physical-mechanical properties on the time and temperature used for curing. Principal component analysis (PCA) and parallel factor analysis (PARAFAC) were performed to investigate the effect of curing on the films. Both PCA and PARAFAC analysis of the NIR spectra showed that spectral features could be directly related to the changes associated with the triethyl citrate (TEC), which directly affected the physical-mechanical properties during curing. Partial least squares (PLS) models were developed that related NIR spectra to the physical-mechanical properties. The use of the Young's Modulus as a reference for NIRS model development resulted in good prediction and was determined to be the best reference for model development. This study demonstrated the NIRS could predict the Young's Modulus which may be used to indicate the extent of curing.


Association of the COVID-19 Pandemic With Adolescent and Young Adult Eating Disorder Care Volume.
The COVID-19 pandemic has affected youth mental health. Increases in site-specific eating disorder (ED) care have been documented; however, multisite studies demonstrating national trends are lacking. To compare the number of adolescent/young adult patients seeking inpatient and outpatient ED care before and after onset of the COVID-19 pandemic. Using an observational case series design, changes in volume in inpatient and outpatient ED-related care across 15 member sites (14 geographically diverse hospital-based adolescent medicine programs and 1 nonhospital-based ED program) of the US National Eating Disorder Quality Improvement Collaborative was examined. Sites reported monthly volumes of patients seeking inpatient and outpatient ED care between January 2018 and December 2021. Patient volumes pre- and postpandemic onset were compared separately for inpatient and outpatient settings. Demographic data such as race and ethnicity were not collected because this study used monthly summary data. Onset of the COVID-19 pandemic. Monthly number of patients seeking inpatient/outpatient ED-related care. Aggregate total inpatient ED admissions were 81 in January 2018 and 109 in February 2020. Aggregate total new outpatient assessments were 195 in January 2018 and 254 in February 2020. Before the COVID-19 pandemic, the relative number of pooled inpatient ED admissions were increasing over time by 0.7% per month (95% CI, 0.2%-1.3%). After onset of the pandemic, there was a significant increase in admissions over time of 7.2% per month (95% CI, 4.8%-9.7%) through April 2021, then a decrease of 3.6% per month (95% CI, -6.0% to -1.1%) through December 2021. Prepandemic, pooled data showed relative outpatient ED assessment volume was stable over time, with an immediate 39.7% decline (95% CI, -50.4% to -26.7%) in April 2020. Subsequently, new assessments increased by 8.1% (95% CI, 5.3%-11.1%) per month through April 2021, then decreased by 1.5% per month (95% CI, -3.6% to 0.7%) through December 2021. The nonhospital-based ED program did not demonstrate a significant increase in the absolute number of admissions after onset of the pandemic but did see a significant increase of 8.2 (95% CI, 6.2-10.2) additional inquiries for care per month in the first year after onset of the pandemic. In this study, there was a significant COVID-19 pandemic-related increase in both inpatient and outpatient volume of patients with EDs across sites, particularly in the first year of the pandemic. Given inadequate ED care availability prior to the pandemic, the increased postpandemic demand will likely outstrip available resources. Results highlight the need to address ED workforce and program capacity issues as well as improve ED prevention strategies.


Mutations of RPGR in X-linked retinitis pigmentosa (RP3).
Mutations in RPGR, retinitis pigmentosa GTPase regulator, are associated with RP3 type of X-linked retinitis pigmentosa, a severe, non-syndromic form of retinal degeneration. In the majority of subjects RPGR mutations are associated with a typical rod-cone degeneration, but in a small number, cone-rod dystrophy, deafness, and abnormalities in respiratory cilia have been noted. Alternative splicing of RPGR is complex in all species examined. In RP3 patients, mutations have been found in exons 1-14 and ORF15, thus delineating a transcript necessary for normal retinal function in humans. The great majority of mutations are predicted to result in premature termination of translation. These mutations are scattered over exons 1-14 and ORF15, while most missense mutations occur in a domain with homology to the protein RCC1, encoded by exons 1-10. Exon ORF15 is a "hot spot" for mutation, at least in the British population, in which it harbors 80% of the mutations found within a sample of 47 X-linked retinitis pigmentosa patients. Most RPGR mutations are unique to single families, which makes it difficult to demonstrate phenotype-genotype correlations.


The effect of concanavalin-A on the reaggregation of cells dissociated from Xenopus laevis early embryos.
The effects of concanavalin-A on the reaggregation and sorting of cells from Xenopus laevis early embryos have been studied. The results suggest that at high concentrations, concanavalin-A can prevent reaggregation.


Effectiveness of risk scoring systems in predicting endoscopic treatment in colonic diverticular bleeding.
The identification of stigmata of recent hemorrhage (SRH) in colonic diverticular bleeding (CDB) enables an endoscopic treatment and can improve the clinical outcome. However, SRH identification rate remains low. This study aims to investigate whether NOBLADS and Strate scoring systems are useful for predicting SRH identification rate of CDB pre-procedurally via colonoscopy. In this single-center retrospective observational study, 302 patients who experienced their first episode of CDB from April 2008 to March 2018 were included. Patients were classified into SRH-positive and SRH-negative groups. The primary outcome was SRH identification rate. The secondary outcomes were active bleeding in SRH and early rebleeding rates. The usefulness of the NOBLADS and Strate scores as predicted values of SRH identification was evaluated using the area under the receiver operating characteristic curve. There were 126 and 176 patients in the SRH-positive and SRH-negative groups, respectively. The area under the receiver operating characteristic curve for SRH identification using the NOBLADS score was 0.74 (95% confidence interval, 0.69-0.80) and that using the Strate score was 0.74 (95% confidence interval, 0.68-0.79). Active bleeding and early rebleeding rates increased according to each score. By setting the cut-off of the NOBLADS score to four points, treatment was possible in 70.2% (66/94) patients. Addition of extravasation at computed tomography to a NOBLADS score of ≧ 4 points allowed treatment of all patients (24/24). Severity scoring in acute lower gastrointestinal bleeding was effective for predicting SRH identification in CDB. We suggest that combination of these scorings and CT findings could offer a new therapeutic strategy.


The association of apolipoproteins with later-life all-cause and cardiovascular mortality: a population-based study stratified by age.
Midlife lipid levels are important predictors of cardiovascular diseases, yet their association with mortality in older adults is less clear. We aimed to (1) identify lipid profiles based on cholesterol, triglycerides, and apolipoproteins using cluster analysis, and (2) investigate how lipid profiles and lipid levels at different ages are associated with later-life all-cause and cardiovascular mortality. We used data from 98,270 individuals in the Swedish AMORIS cohort who had blood measurements between 1985-1996 and were followed until 2012. Over the follow-up (mean 18.0 years), 30,730 (31.3%) individuals died. Three lipid profiles were identified. Compared with reference profile, a high lipid profile (low ApoA-I and high total cholesterol (TC), triglycerides, ApoB, and ApoB/ApoA-I ratio) at ages 39-59 or 60-79 was associated with higher all-cause mortality. A high lipid profile at ≥ 80 years, however, did not confer higher mortality. For the specific markers, high TC (≥ 7.25 mmol/L) was associated with higher all-cause mortality in ages 39-59 but lower mortality in ages 60-79 and ≥ 80. Low ApoA-I (< 1.28 g/L) and high ApoB/ApoA-I ratio (≥ 1.18), on the other hand, were associated with higher cardiovascular mortality regardless of age at lipid measurement, highlighting their potential relevance for survival in both young and older individuals.


Influence of 12-O-tetradecanoylphorbol-13-acetate (TPA) on the susceptibility of K562 to natural cytotoxicity: evidence for clonal variation in differentiation-induced changes of lytic sensitivity.
The effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on the sensitivity to NK cell-mediated lysis of two cloned populations of K562 which exhibit marked and stable differences in their susceptibility to natural cytotoxicity has been examined. Culture in medium supplemented with TPA concentrations of l ng/ml or more invariably caused a decrease in the susceptibility of the sensitive clone E10/P2, whereas treatment of the relatively resistant clone F9/P2 with TPA under identical conditions caused a significant increase in susceptibility to natural cytotoxicity. In both cases the change in susceptibility occurred within 1 day of culture in TPA and was rapidly reversible following removal of the inducing agent. The changes in resistance to natural cytotoxicity induced by TPA were independent of variations in osmotic fragility and were not attributable to alterations in NK cell binding capacity as determined by cold competition analysis. In contrast to the effect of TPA, exposure of E10/P2 and F9/P2 to interferon (IFN) caused a reduction in sensitivity to natural cytotoxicity of both populations which was associated with a decreased capacity to compete for lysis of labelled target cells. These data suggest that the effects of differentiating agents on target susceptibility to NK cell lysis are variable and that responses to TPA are clonally distributed within cell populations.


Chemical properties and immunobiological activities of streptococcal lipoteichoic acids.
Lipoteichoic acids (LTAs) were chromatographically purified from crude phenol-water extract of whole cells of some streptococcal species, which included Streptococcus pyogenes Sv, Streptococcus mutans 6715, and Streptococcus sanguis ATCC 10556. Among these, special attention was paid to S. pyogenes LTA for analyses of chemical composition and biological activities. All LTA preparations contained equimolar amounts of glycerol and phosphorus. Chemical analyses showed that S. pyogenes LTA contained glycerophosphate, alanine, glucose, and fatty acids (as palmitic acid) at molar ratio of 1 : 0.1 : 0.1 : 0.25. The crude phenol-water extract and isolated LTA from S. pyogenes Sv were found to be mitogenic for spleen cells of BALB/c and BALB/c (nu/nu) mice, but not for thymus cells of BALB/c mice. The mitogenicity of deacylated LTA (dLTA) was significantly lower than that of LTA. It was also found that various LTA preparations possessed polyclonal B cell activation ability and adjuvant activity both in vivo and in vitro, as demonstrated by using hemolytic plaque assay. LTA, but not dLTA, induced macrophage activation which resulted in tumor cytotoxicity in mice. Limulus lysate activity of S. pyogenes LTA was approximately 1,000 fold lower than that of Escherichia coli lipopolysaccharide. These results indicate that streptococcal LTA possesses various immunobiological activities that modulate lymphoreticular system in vivo and in vitro.


Voltage-dependent anion channels (VDAC) in the plasma membrane play a critical role in apoptosis in differentiated hippocampal neurons but not in neural stem cells.
One of the earliest morphological changes occurring in apoptosis is cell shrinkage associated with an increased efflux of K(+) and Cl(-) ions. Block of K(+) or Cl(-) channels prevents cell shrinkage and death. Recently, we found evidences for the activation of a voltage-dependent anion channel in the plasma membrane (pl-VDAC) of a hippocampal cell line undergoing apoptosis. Nothing is known on pl-VDAC in apoptotic cell death of neural cells at different stages of differentiation. We have addressed this issue in primary cultures of differentiated hippocampal neurons and embryonic neural stem cells (NSCs). In control hippocampal neurons, pl-VDAC is closed but acts as an NADH-ferricyanide reductase, while in apoptotic neurons, pl-VDAC is opened and the enzymatic activity is increased. Anti-VDAC antibodies block pl-VDAC and prevent apoptosis, as well as the increase in enzymatic activity. Conversely, in NSCs, pl-VDAC is scarcely seen and there is no NADH-ferricyanide reductase activity. In agreement, anti-VDAC antibodies do not affect the apoptotic process. Instead, we find activation of a Na(+) channel that has low voltage dependency, a conductance of 26 pS, and is blocked by amiloride, which also prevents apoptosis. Thus, it appears that activation of pl-VDAC during apoptosis is a critical event in differentiated neurons, but not in NSCs.


Microbial growth and air pollution in carbonate rock weathering. Preliminary results of a in situ experimental study.
Preliminary results on limestone weathering caused by air pollution and microbial colonization are presented in this study. Outdoor exposure experimental assays were performed on Scaglia limestone samples. Samples were exposed in two areas in Perugia (Italy) that differ for degree of urban air pollution. At different times of exposure, ranging from 1 to 12 months, microbial contamination and textural modifications of sampled surfaces were evaluated by microbiological procedures, X-ray diffraction, and scanning electron microscopy. After one year of exposure a significant fungal colonization and the presence of weathering products (i.e. gypsum) were detected on sampled surfaces.


Disparities Between International Guidelines (AHA/ESC/ESVS/ESVM/SVS) Concerning Lower Extremity Arterial Disease: Consensus of the French Society of Vascular Medicine (SFMV) and the French Society for Vascular and Endovascular Surgery (SCVE).
Several international guidelines concerning lower extremity arterial disease (LEAD) have been published recently, in particular, by the American Heart Association the European Society of Cardiology/European Society for Vascular Surgery, the European Society for Vascular Medicine and the Society for Vascular Surgery. These guidelines differ in some respects and certain issues are not addressed. The objective of this consensus driven by the French Societies of vascular Medicine and surgery was to analyze the disparities between the different guidelines, as well as certain issues not covered, and develop proposals with regard to these points. The following fields of LEAD have been explored: 1) classifications, 2) clinical evaluation, 3) diagnostic criteria, 4) quantification of arterial stenosis using duplex ultrasound, 5) detection of asymptomatic multisite lesions, 6) screening for LEAD in the context of cardiac disease, 7) medical treatment, 8) supervised exercise therapy, 9) revascularization and revascularization of the internal artery stenosis, 10) management of chronic limb ischemia, 11) longitudinal follow-up, and 12) diet.


Development and economic trends in anticancer drugs licensed in the UK from 2015 to 2019.
Analysis of new anticancer drugs licensed in the UK found that 44 new therapies were approved from 2015 to 2019. No other 5-year period has produced as many new therapies. Most new drugs are kinase inhibitors (KIs, N=18) and monoclonal antibodies (mAbs, N=16) with only one classical cytotoxic chemotherapy (CC) licensed. The average median treatment duration has risen by 55 days to 318 days (263 days in 2010-2014). Drug costs have escalated; an average treatment course now costs £62 343, compared to £35 383 in 2010-2014. New drugs are delivering significant clinical benefits with longer treatment durations. However, the financial burden is greater, heralding economic challenges for healthcare providers.


Reversal to normal anatomy after failed gastric bypass: systematic review of indications, techniques, and outcomes.
Roux-en-Y gastric bypass (RYGB) is one of the most common and most effective procedures performed to combat obesity and obesity-related metabolic disease. In a small proportion of patients, however, complications may necessitate the attempted reversal of RYGB to normal anatomy. The indications for this procedure, as well as technique, complication rate, and success in resolving symptoms are not clearly defined. To assess current literature describing outcomes after reversal of RYGB. A systematic search of online databases was conducted. Two independent researchers identified and extracted data for studies describing outcomes after RYGB reversal surgery. Indications, techniques, and outcomes were compared, with results pooled where possible. Eight articles were included in the final data synthesis, incorporating data for 46 patients. Reversal was undertaken due to metabolic, physical, nutritional, or other complications. All successfully underwent RYGB reversal with no reported mortality. Surgical technique varied greatly across the included studies. Postoperative morbidity was high, with 42% suffering complications (56% of which were major). Symptom relief or improvement was achieved in 82% of cases. Reversal of RYGB may be undertaken for a variety of indications after RYGB. Though this may successfully eliminate or improve symptoms in a large proportion of patients, the risk of morbidity is high. Surgery should be undertaken after careful patient selection and in appropriately skilled centers only.


Single-shot 3D imaging techniques improve arterial spin labeling perfusion measurements.
Arterial spin labeling (ASL) can be used to measure perfusion without the use of contrast agents. Due to the small volume fraction of blood vessels compared to tissue in the human brain (typ. 3-5%) ASL techniques have an intrinsically low signal-to-noise ratio (SNR). In this publication, evidence is presented that the SNR can be improved by using arterial spin labeling in combination with single-shot 3D readout techniques. Specifically, a single-shot 3D-GRASE sequence is presented, which yields a 2.8-fold increase in SNR compared to 2D EPI at the same nominal resolution. Up to 18 slices can be acquired in 2 min with an SNR of 10 or more for gray matter perfusion. A method is proposed to increase the reliability of perfusion quantification using QUIPSS II derivates by acquiring low-resolution maps of the bolus arrival time, which allows differentiation between lack of perfusion and delayed arrival of the labeled blood. For arterial spin labeling, single-shot 3D imaging techniques are optimal in terms of efficiency and might prove beneficial to improve reliability of perfusion quantitation in a clinical setup.


Non-criteria antiphospholipid antibodies and pediatric rheumatic disease: a case series.
Non-criteria antiphospholipid antibodies (NC-aPL) are a relatively undefined subgroup of antiphospholipid antibodies (aPL). Knowledge about NC-aPL in adults is limited and even less is known in pediatric patients. Routine tests for antiphospholipid syndrome (APS)-a clinical state marked by the presence of aPL in association with vascular thrombosis-usually include lupus anticoagulant (LAC), anti-cardiolipin (aCL) and -beta-2 glycoprotein I (aβ2GPI). LAC is a functional screen for prothrombotic aPL, while the latter tests identify specific autoantibodies. Specific targets of NC-aPL include, but are not limited to, phosphatidylethanolamine, phosphatidylserine, and prothrombin. We present single-center data from eight pediatric patients with NC-aPL identified during a three-year period. All patients had presenting features raising suspicion for APS. Most patients were female with a primary rheumatic disease. One patient had a stroke. Another patient had alveolar hemorrhage and pulmonary hypertension. Raynaud's phenomenon, rashes involving distal extremities, and headaches were common. Most patients had a positive LAC, yet their routine aPL tests were negative, prompting testing for NC-aPL. Our findings suggest NC-aPL are associated with typical signs and symptoms of APS in pediatric patients. Pediatricians and pediatric subspecialists should consider NC-aPL when clinical suspicion is high and routine aPL tests are negative, particularly when LAC is positive. While guidelines for NC-aPL do not yet exist for children or adults, these autoantibodies have pathogenic potential. Actionable items could include evaluation for the presence of other (primary) rheumatic diseases, and consultation with hematologists and/or obstetricians regarding anticoagulation/platelet inhibition and thrombosis education. Future guidelines regarding NC-aPL will only be generated by gathering more data, ideally prospectively.


A humanized β2 integrin knockin mouse reveals localized intra- and extravascular neutrophil integrin activation in vivo.
β2 integrins are leukocyte-specific adhesion molecules that are essential for leukocyte recruitment. The lack of tools for reporting β2 integrin activation in mice hindered the study of β2 integrin-related immune responses in vivo. Here, we generated a humanized β2 integrin knockin mouse strain by targeting the human β2 integrin coding sequence into the mouse Itgb2 locus to enable imaging of β2 integrin activation using the KIM127 (extension) and mAb24 (high-affinity) reporter antibodies. Using a CXCL1-induced acute inflammation model, we show the local dynamics of β2 integrin activation in arresting neutrophils in vivo in venules of the mouse cremaster muscle. Activated integrins are highly concentrated in a small area at the rear of arresting neutrophils in vivo. In a high-dose lipopolysaccharide model, we find that β2 integrins are activated in association with elevated neutrophil adhesion in lung and liver. Thus, these mice enable studies of β2 integrin activation in vivo.


Evidence for an ethanol mediated disruption of hemostasis.
Male Sprague-Dawley rats were given 1 ml intraperitoneal (i.p.) injections of saline, 5, 10 or 20% ethanol once daily for 7 days. Clotting times were determined for the PT, APTT, FIB, and factors II, V, VII, VIII, X, and XII. The platelet count (PLT) and the hematocrit (HCT) were also determined. Besides a uniform statistically significant decrease in the platelet count, the clotting times for the coagulation factors were also influenced by the alcohol injected. The data tends to indicate that when the concentration of alcohol was greater, that more clotting times were influenced. Detailed analysis of the data in reference to the total clotting cascade tends to suggest that ethanol principally prolongs the clotting times of the intrinsic pathway, while the extrinsic pathway appears to be unaffected by the treatment, and the common pathway is normal to accelerated in clotting times. This suggests that hemostasis as a whole was not affected by the treatment, but specific portions of the clotting cascade were, and development of abnormal hemostasis due to ethanol might depend on which part of the pathway was activated.


Comparison of methods of alert acknowledgement by critical care clinicians in the ICU setting.
Electronic Health Record (EHR)-based sepsis alert systems have failed to demonstrate improvements in clinically meaningful endpoints. However, the effect of implementation barriers on the success of new sepsis alert systems is rarely explored. To test the hypothesis time to severe sepsis alert acknowledgement by critical care clinicians in the ICU setting would be reduced using an EHR-based alert acknowledgement system compared to a text paging-based system. In one arm of this simulation study, real alerts for patients in the medical ICU were delivered to critical care clinicians through the EHR. In the other arm, simulated alerts were delivered through text paging. The primary outcome was time to alert acknowledgement. The secondary outcomes were a structured, mixed quantitative/qualitative survey and informal group interview. The alert acknowledgement rate from the severe sepsis alert system was 3% (N = 148) and 51% (N = 156) from simulated severe sepsis alerts through traditional text paging. Time to alert acknowledgement from the severe sepsis alert system was median 274 min (N = 5) and median 2 min (N = 80) from text paging. The response rate from the EHR-based alert system was insufficient to compare primary measures. However, secondary measures revealed important barriers. Alert fatigue, interruption, human error, and information overload are barriers to alert and simulation studies in the ICU setting.


Silaborations of 1,3-enynes - substrate controlled allene/1,3-diene selectivity.
Silaboration of 1,3-enynes catalyzed by group 10 metal complexes affords 1,3-dienes with vinylborane and vinylsilane functions or 1,2-dienes with allylborane and vinylsilane functions. The type of product formed is determined by the size of the alkyne substituent.


Time series analysis of rhythmic bacterial resistance development to antibiotics.
The sensitivity data of Staphylococcus aureus and Escherichia coli to a large set of antibiotics have undergone time series procedures of analysis in order to highlight possibly periodical behavior in time. These oscillational patterns have been characterized through the use of FFT and cross-correlational and variance analysis and were proved to be species-specific and drug-independent. S. aureus was shown to have a large period of oscillation (40 months) when compared to E. coli (from 7 to 11 months). A perfect species distinction was only possible through cross correlation. These results may reflect the influence of the local environment, since this finding was not referred to in the literature.


The utility of bioimpedance analysis for monitoring the children with nutcracker syndrome.
We aimed to evaluate anthropometric and bioimpedance analysis (BIA) indices of children with nutcracker syndrome (NCS). Eighteen patients and 20 age-gender matched controls were enrolled. Weight, height, body mass index (BMI), mid-arm circumference (MAC), waist circumference (WC), waist/hip ratio measurements, and BIA results were assessed. Laboratory parameters and Doppler sonographic findings were recorded. The weight, BMI, MAC, WC, body fat z scores, and waist/hip ratio were significantly lower in patients than in controls (p < 0.05). Serum creatinine (Scr), albumin, HDL cholesterol, and urine protein (Up) were significantly increased in NCS patients compared to controls (p < 0.05). On multivariate analysis, body fat z score was independently related to Up and the degree of superior mesenteric artery (SMA) angle (beta = -0.965, p = 0.018 and beta = 0.841, p = 0.04, respectively). NCS might be considered in slim proteinuric patients with unproven etiology. Serial anthropometric measurements and BIA analysis would estimate the severity of entrapment in LRV. Long-term follow-up of Scr might be required in NCS. • Nutcracker syndrome (NCS) is very rare and characterized by the compression of LRV between aorta and SMA. What is new: • Patients with NCS have a slimmer body feature with lower anthropometric and BIA indices. • Fat percentage indicates the degree of LRV entrapment and amount of proteinuria in NCS.


Ultrasound stiffness and perfusion markers correlate with tumor volume responses to immunotherapy.
Immunotherapy has revolutionized the treatment of dozens of cancers and became a standard of care for some tumor types. However, the majority of patients do not benefit from current immunotherapeutics and many develop severe toxicities. Therefore, the identification of biomarkers to classify patients as likely responders or non-responders to immunotherapy is a timely task. Here, we test ultrasound imaging markers of tumor stiffness and perfusion. Ultrasound imaging is non-invasive and clinically available and can be used both for stiffness and perfusion evaluation. In this study, we employed syngeneic orthotopic models of two breast cancers, a fibrosarcoma and a melanoma, to demonstrate that ultrasound-derived measures of tumor stiffness and perfusion (i.e., blood volume) correlate with the efficacy of immune checkpoint inhibition (ICI) in terms of changes in primary tumor volume. To modulate tumor stiffness and perfusion and thus, get a range of therapeutic outcomes, we employed the mechanotherapeutic tranilast. Mechanotherapeutics combined with ICI are advancing through clinical trials, but biomarkers of response have not been tested until now. We found the existence of linear correlations between tumor stiffness and perfusion imaging biomarkers as well as strong linear correlations between the stiffness and perfusion markers with ICI efficacy on primary tumor growth rates. Our findings set the basis for ultrasound biomarkers predictive of ICI therapy in combination with mechanotherapeutics. STATEMENT OF SIGNIFICANCE: Hypothesis: Monitoring Tumor Microenvironment (TME) mechanical abnormalities can predict the efficacy of immune checkpoint inhibition and provide biomarkers predictive of response. Tumor stiffening and solid stress elevation are hallmarks of tumor patho-physiology in desmoplastic tumors. They induce hypo-perfusion and hypoxia by compressing tumor vessels, posing major barriers to immunotherapy. Mechanotherapeutics is a new class of drugs that target the TME to reduce stiffness and improve perfusion and oxygenation. In this study, we show that measures of stiffness and perfusion derived from ultrasound shear wave elastography and contrast enhanced ultrasound can provide biomarkers of tumor response.


D2 dopaminergic regulation of striatal preproenkephalin mRNA levels is mediated at least in part through cholinergic interneurons.
The effect of administration of the muscarinic antagonist scopolamine on the increase in striatal preproenkephalin (PPE) mRNA following a 6-hydroxydopamine (6-OHDA) lesion or chronic D2 dopamine (DA) antagonist treatment was examined by dot-blot hybridization. Administration of scopolamine dose-dependently attenuated the 6-OHDA lesion-induced increase in striatal PPE mRNA. Administration of the D2 DA antagonist eticlopride to naive rats increased striatal PPE mRNA in a dose- and time-dependent fashion. Chronic coadministration of scopolamine attenuated the eticlopride-induced increase in striatal PPE mRNA. Chronic administration of scopolamine alone did not alter striatal PPE mRNA levels. In contrast, chronic administration of eticlopride, scopolamine or the two combined decreased striatal preprotachykinin (PPT) mRNA to the same extent, suggesting that there was no direct interaction between D2 dopaminergic and cholinergic mechanisms in the regulation of striatal PPT mRNA. These data indicate that DA differentially regulates striatal PPE and PPT mRNA and suggest that dopaminergic regulation of striatal PPE mRNA is mediated in part through D2 DA effects on striatal cholinergic neurons.


Thyroid dysfunction in the era of precision medicine.
The launching of the Precision Medicine Initiative by the President of the United States in January 2015 was an invitation for all healthcare professionals to review their practice. This call should stimulate thyroidologists working in different areas (from basic research or epidemiology to the frontline of the clinical arena or to those designing public health programs) to be aware of this new outlook. The aim of the initiative is to eradicate imprecision in estimating the probability of a correct diagnosis, to be as sure as possible of the most effective treatment, and to maximize the chances of a successful outcome. This paper summarizes some of the current challenges faced by endocrinologists in the field of thyroid dysfunction, and illustrates how precision medicine may improve diagnosis and therapy in the future.


An interface to input analogue signals to a digital computer.
An electrical control unit is described which permits analogue signals from most sources to be made compatible with, and optimise the use of, an A/D converter. This circuitry enables the signal to be offset, relative to the electrical zero, and to be reset to zero using a push button. Extension of this unit has enabled mechanical movement, such as rotation of a shaft, to be measured. In order to make the most efficient use of the A/D converter the gain of the output can be varied.


Treatment and outcome in combined scapula and rib fractures: a retrospective study.
The primary aim was to describe the population characteristics of patients with combined scapula and rib fractures and outcomes associated with different treatment strategies. All adult (≥ 18 years) patients with concurrent ipsilateral scapula and rib fractures admitted to the study hospital between 1st January 2010 and 31st June 2021 were retrospectively reviewed. A total of 223 patients were admitted with concurrent ipsilateral rib and scapula fractures. A total of 160 patients (72%) were treated conservatively, 63 patients (28%) operatively. Among operatively treated patients, 32 (51%) underwent rib fixation (RF) only, 24 (38%) underwent scapula fixation (SF) only, and seven patients (11%) underwent combined fixation of scapula and ribs (SRF). In general, more severely injured patients were treated with more extensive surgery. RF patients had a median hospital length of stay of 16 days, the SF patients 11 days and SRF patients 18 days. There were no significant differences in complications (pneumonia, recurrent pneumothorax and revision surgery) between groups. Injury severity resulted in different treatment modalities. As a result, different patient characteristics between treatment groups were observed, which makes direct comparison between treatment modalities impossible. All treatment modalities seem feasible; however, the additional value of both rib and scapula fixation has yet to be proven in large multicentre studies.


Estrogen-dependent regulation of sodium/hydrogen exchanger-3 (NHE3) expression via estrogen receptor β in proximal colon of pregnant mice.
Although constipation is very common during pregnancy, the exact mechanism is unknown. We hypothesized that the involvement of estrogen receptor (ER) in the regulation of electrolyte transporter in the colon leads to constipation. In this study, the intestines of normal female ICR mouse and pregnant mice were examined for the expression of ERα and ERβ by immunohistochemistry and in situ hybridization. ERβ, but not ERα, was expressed in surface epithelial cells of the proximal, but not distal, colon on pregnancy days 10, 15, and 18, but not day 5, and the number of ERβ-positive cells increased significantly during pregnancy. Expression of NHE3, the gene that harbors estrogen response element, examined by immunohistochemistry and western blotting, was localized in the surface epithelial cells of the proximal colon and increased in parallel with ERβ expression. In ovariectomized mice, NHE3 expression was only marginal and was up-regulated after treatment with 17β-estradiol (E(2)), but not E(2) + ICI 182,780 (estrogen receptor antagonist). Moreover, knock-down of ERβ expression by electroporetically transfected siRNA resulted in a significant reduction of NHE3 expression. These results indicate that ERβ regulates the expression of NHE3 in the proximal colon of pregnant mice through estrogen action, suggesting the involvement of increased sodium absorption by up-regulated NHE3 in constipation during pregnancy.


Modifying matrix micro-environmental pH to achieve sustained drug release from highly laminating alginate matrices.
Lamination of alginate matrix tablet at acidic pH can compromise its function as a sustained release carrier. This phenomenon is associated with the conversion of sodium alginate to alginic acid. An innovative approach for controlling the release of a highly water-soluble drug from such matrices is presented in this paper. Inclusion of pH-modifiers was employed to raise the micro-environmental pH within matrices undergoing dissolution at gastric pH. The changes in micro-environmental pH of hydrating alginate matrices were visualized with the aid of a pH-indicator and subsequently quantified using image analysis. Transient elevation in micro-environmental pH impeded alginate protonation and minimized or prevented matrix lamination, contributing to preservation of drug diffusion barrier. Significant reduction in the rate of drug release at pH 1.2 was achieved in the presence of such additives. The action of pH-modifiers was synergistically enhanced in the presence of a carbon dioxide barrier formed by effervescing sodium bicarbonate, reducing drug release in the acidic medium from 60 to 20%. Further insight into the influence of lamination on drug release from alginate compacts was given.


Modifications to established fiber methods may be required to quantify cellulose from flow aids in grated Parmesan cheese.
Reliable detection and quantification of flow-aid concentrations in grated cheese is warranted for both quality assurance and to prevent fraud, yet no official method exists. This study evaluated enzymatic-gravimetric methods that quantify insoluble dietary fiber, as well as near-infrared spectroscopy (NIR), for their suitability to measure cellulose and flow-aid concentrations in ground Parmesan with known amounts of commercial flow-aid preparations. The range of flow-aid concentrations spanned 0 to 5.01 g/100 g of cheese, corresponding to 0 to 1.39 g/100 g of cellulose. Use of the total dietary fiber assay, with or without modifications, consistently overestimated flow-aid concentrations by formation of aggregates that were presumably difficult to digest. Increasing protease amounts reduced but did not eliminate this issue. In contrast, the integrated dietary fiber assay and NIR spectroscopy were suitable methods for quantification of cellulose and flow aid. However, analyzing control cheeses without flow aid proved difficult with both methods. For these samples, the integrated dietary fiber assay and NIR spectroscopy calibrated for cellulose gave higher than actual values with poor precision (0.50 ± 0.36 and 0.38 ± 0.22 g/100 g, respectively). However, NIR calibrations for flow aid (which also contained starch), instead of cellulose, specifically yielded more accurate results for samples with 0 g/100 g of flow aid (0.06 ± 0.14 g/100 g). In general, prediction of higher concentrations of flow aid via NIR spectroscopy had lower accuracy than with the integrated dietary fiber assay; however, results obtained via NIR spectroscopy had lower variability. The total dietary fiber assay always overestimated cellulose in ground Parmesan, and further modifications are necessary to obtain accurate results. Differences between the pH at which protein digestion occurs (lower for the integrated dietary fiber assay than the total dietary fiber assay) may have contributed to differences in results.


Behavioral response to antennal tactile stimulation in the field cricket Gryllus bimaculatus.
We examined behavioral responses of the field cricket Gryllus bimaculatus to tactile stimuli to the antennae. Three stimulants of similar shape and size but different textures were used: a tibia from the hunting spider Heteropoda venatoria (potential predator), a tibia from the orb-web spider Argiope bruennichi (less likely predator), and a glass rod. Each stimulus session comprised a first gentle contact and a second strong contact. The evoked behavioral responses were classified into four categories: aversion, aggression, antennal search, and no response. Regardless of the stimulants, the crickets exhibited antennal search and aversion most frequently in response to the first and second stimuli, respectively. The frequency of aversion was significantly higher to the tibia of H. venatoria than to other stimulants. The most striking observation was that aggressive responses were exclusive to the H. venatoria tibia. To specify the hair type that induced aggression, we manipulated two types of common hairs (bristle and fine) on the tibia of the predatory spider. When bristle hairs were removed from the H. venatoria tibia, aggression was significantly reduced. These results suggest that antennae can discriminate the tactile texture of external objects and elicit adaptive behavioral responses.


Regulatory role of membrane fluidity in gene expression and physiological functions.
Plants, algae, and photosynthetic bacteria experience frequent changes in environment. The ability to survive depends on their capacity to acclimate to such changes. In particular, fluctuations in temperature affect the fluidity of cytoplasmic and thylakoid membranes. The molecular mechanisms responsible for the perception of changes in membrane fluidity have not been fully characterized. However, the understanding of the functions of the individual genes for fatty acid desaturases in cyanobacteria and plants led to the directed mutagenesis of such genes that altered the membrane fluidity of cytoplasmic and thylakoid membranes. Characterization of the photosynthetic properties of the transformed cyanobacteria and higher plants revealed that lipid unsaturation is essential for protection of the photosynthetic machinery against environmental stresses, such as strong light, salt stress, and high and low temperatures. The unsaturation of fatty acids enhances the repair of the damaged photosystem II complex under stress conditions. In this review, we summarize the knowledge on the mechanisms that regulate membrane fluidity, on putative sensors that perceive changes in membrane fluidity, on genes that are involved in acclimation to new sets of environmental conditions, and on the influence of membrane properties on photosynthetic functions.


Stabilizing blood glucose with a novel medical expert system.
In health, metabolism is elegantly coordinated. Failure of an underlying process (as occurs in diabetes) disrupts the coordination and impacts on the global status of the affected individual. It takes a medical expert to intervene and restore order. Chaotic processes prevail at all times in biological systems and their behaviour in sickness degenerates between medical interventions. We have explored the use of an expert system to substitute for the physician between interventions and demonstrated its ability to maintain order and thus significantly improve control of blood glucose.


Kinetics of 57Co-bleomycin in sheep after intra-arterial injection in the head and neck region.
Intra-arterial (i.a.) chemotherapy for the treatment of head and neck tumors is performed on the basis of clinical reports. The hypothetical aim of i.a. chemotherapy is to achieve higher drug concentrations in the tumor than are achieved by systemic intravenous (i.v.) administration. Therefore, it is postulated that i.a. chemotherapy leads to an increased therapeutic effect at the tumor site and to a decrease in systemic drug toxicity. The lack of adequate animal experiments and the absence of prospective randomized clinical trials comparing i.a. with i.v. chemotherapy led to the present kinetic study, concerned with various modes of administration of bleomycin with the aim of achieving high cytotoxic concentrations at the required site. Radioactive bleomycin (57Co-bleomycin) was injected locally (buccal plane, group I), intra-arterially (transverse facial artery, group II; superficial temporal artery, group III; external carotid artery, group IV), and intravenously (saphenous vein, group V) in five sheep per group. Between 1 and 360 min after injection of radioactive bleomycin the urine and the systemic blood activities were determined, and the activities in the hypothetical tumor area (buccal plane) were measured continuously. The animals were killed 360 min after injection and the activities in the hypothetical tumor area, in the lymph nodes draining this area (submandibular, parotic, lateral pharyngeal) and in different tissues and organs were determined. For all groups, 70%-80% of the injected bleomycin was eliminated by the kidneys, without any significant differences among the five groups tested. The systemic blood activities measured at 5-min intervals exhibited no differences for the groups injected i.a. (II-IV) and i.v. (V). Only animals which received local injections (group I) showed lower activities for 60 min after injection as compared with the other four groups. The activities of radioactively labeled bleomycin in the hypothetical tumor area during the entire experiment (360 min) were again similar for the groups injected i.a. (II-IV) and those injected i.v. (V). However, only animals injected locally (group I) showed significantly increased activities. After the death of the animals there was again no significant difference between i.a. and i.v. administration. Only local injection led to significantly increased tissue activities. Similar results also obtained for the lymph nodes draining the hypothetical tumor area.(ABSTRACT TRUNCATED AT 400 WORDS)


Maternal inflammation modulates infant immune response patterns to viral lung challenge in a murine model.
Chorioamnionitis, an inflammatory gestational disorder, commonly precedes preterm delivery. Preterm infants may be at particular risk for inflammation-related morbidity related to infection, although the pathogenic mechanisms are unclear. We hypothesized that maternal inflammation modulates immune programming to drive postnatal inflammatory processes. We used a novel combined murine model to treat late gestation dams with low-dose lipopolysaccharide (LPS) and to secondarily challenge exposed neonates or weanlings with Sendai virus (SeV) lung infection. Multiple organs were analyzed to characterize age-specific postnatal immune and inflammatory responses. Maternal LPS treatment enhanced innate immune populations in the lungs, livers, and/or spleens of exposed neonates or weanlings. Secondary lung SeV infection variably affected neutrophil, macrophage, and dendritic cell proportions in multiple organs of exposed pups. Neonatal lung infection induced brain interleukin (IL)-4 expression, although this response was muted in LPS-exposed pups. Adaptive immune cells, including lung, lymph node, and thymic lymphocytes and lung CD4 cells expressing FoxP3, interferon (IFN)-γ, or IL-17, were variably prominent in LPS-exposed pups. Maternal inflammation modifies postnatal immunity and augments systemic inflammatory responses to viral lung infection in an age-specific manner. We speculate that inflammatory modulation of the developing immune system contributes to chronic morbidity and mortality in preterm infants.


Stressors in hospitalized patients and their associations with mental health outcomes: testing perceived social support and spiritual well-being as moderators.
Although hospitalization can be a burdensome experience for all patients, research into the sources of this distress and potential protective factors has so far been scattered, specifically among the broad hospitalized population across all disease types and inpatient units. The present study explores the frequency and nature of the foremost experienced hassles among a sample of Lebanese hospitalized patients, tracing their correlations with depression and anxiety while also investigating positive coping (i.e., perceived social support and spiritual well-being) as potential moderator of these relationships. A total of 452 Lebanese inpatients from all medical units filled a survey composed of a list of 38 stressors experienced during hospitalization and other measures assessing depression, anxiety, perceived social support, and spiritual well-being. Pain was the most common stressor experienced by the patients (88.9%), followed by the feeling of being overwhelmed (80.3%). When conducting a factor analysis, 18 stressors loaded on 4 distinct factors, hence yielding 4 main stressor groups (i.e., Illness Apprehension, Hopelessness/Uselessness, Social Isolation, and Spiritual Concerns). The multivariable analysis showed that increased illness apprehension (Beta = 0.69) and hopelessness (Beta = 1.37), being married (Beta = 1.17) or divorced (Beta = 1.38) compared to single, being admitted in a two-bed room compared to one-bed (Beta = 1.59), higher financial burden (Beta = 0.24), and lower socio-economic status (Beta = 1.60) were significantly associated with higher anxiety. Additionally, increased hopelessness (Beta = 0.82) and being married (Beta = 0.79) compared to single were significantly associated with higher depression. However, among patients experiencing high levels of stressors, those with high spiritual well-being and perceived social support had lower depressive/anxiety symptoms. Our study characterized the principal stressors encountered during hospitalization, underscoring their associations with Lebanese inpatients' mental health. On the other hand, as perceived social support and spiritual well-being acted as negative moderators of these associations, intervention programs aimed at enhancing such adaptive coping techniques are strongly called upon to palliate the psychological distress of patients in hospital settings.


Influence of freezing temperatures on a cactus, Coryphantha vivipara.
Coryphantha vivipara (Nutt.) Britton & Rose var. deserti (Engelm.) W.T. Marshall (Cactaceae) survived snow and tissue temperatures of-12°C in southern Nevada. However, the freezing point depression of the cell sap was only about 0.9°C. When the nocturnal air temperature in the laboratory was reduced from 10°C to-10°C for one night, the optimum temperature for CO2 uptake shifted from 10°C to 6°C and uptake was reduced 70%, but full recovery to the original values occurred in 4 days. Nocturnal temperatures of-15°C killed 2 out of 5 plants and-20°C killed 5 out of 5, as judged by lack of net CO2 uptake at night over a 2-month observation period. when the stems were cooled at 2° C/h, supercooling to about-6°C occurred followed by an exothermic reaction that presumably represented the freezing of extracellular water. When the subzero temperature was lowered further, no other exothermic reaction was observed and the cells became progressively dehydrated. Freezing-induced tissue death was ascribed to this cellular dehydration, which led to about 94% loss of intracellular water at-15°C. when the tissue temperature was lowered, the ability of chlorenchyma cells to plasmolyze and to take up a stain decreased, both being nearly 70% inhibited at-15°C and completely abolished at-20°C. Some cold-bardening occurred, since lowering the air temperature from 30° to-10°C in 10°C increments at weekly intervals caused the subzero temperature for 50% inhibition of staining to decrease from-10°C to-17°C. Extension of the range of C. vivipara to regions with wintertime freezing apparently reflects the tolerance of considerable freeze dehydration by its protoplasts.


T-cell analysis in identical twins reveals an impaired anti-follicular lymphoma immune response in the patient but not in the healthy twin.
In lymphomas an innate defect in the T-cell repertoire could account for the impaired tumour-specific immune response; alternatively, the tumour itself could exert an inhibitory effect on the immune system. To address this issue we analysed the T-cell responses against follicular lymphoma (FL) in identical twins as it can be postulated that their overall T-cell repertoire is identical. While differences between the T-cell response of the patient and the healthy twin would point to a tumour-induced T-cell unresponsiveness, impaired responses in both would point to a defective T-cell repertoire. We demonstrated an impaired tumour-specific proliferation (P = 0.035 and P = 0.013) and cytokine release (P = 0.004 and P = 0.0008) of both peripheral blood and tumour-derived T-cells, respectively, in the FL patient compared with the T-cell response of the healthy twin. Moreover, only syngeneic primed T cells were able to directly lyse unmodified FL cells of the patient. These data support previous findings in murine lymphomas and suggest that inhibitory mechanisms during tumour growth, rather than a defective T-cell repertoire, are responsible for the insufficient T-cell response in lymphoma.


Scintigraphy has the potential to replace thyroid stimulating hormone and ultrasonography in hyperthyroidism diagnosis.
The value of thyroid scintigraphy in hyperthyroidism diagnosis has long been the subject of debate. Unresolved issue is whether scintigraphy should be performed routinely, selectively, or for all hyperthyroidism patients. So, this study is concerned with the evaluation of thyroid scintigraphy for identifying hyperthyroidism in comparison with thyroid stimulating hormone (TSH) and ultrasound. This is cross sectional study including convenient patients sample (n = 50, 15 males and 35 females) aged (20-50 years) with primary hyperthyroidism and were attending endocrine clinics at King Faisal Specialist Hospital and Research Centre. All patients performed clinical investigations (TSH, ultrasound and thyroid scintigraphy). Among these patients, 96%, 48/50, had positive findings for hyperthyroidism with thyroid SC (95% CI; 96.0-99.5%); 84%, 42/50, had positive findings for hyperthyroidism by US (95% CI; 70.9-92.8%); and 56%, 28/50, had positive findings for hyperthyroidism by TSH measurement (95% CI; 41.3.0-70.0%). There was very good agreement between scintigraphy diagnosis and ultrasonography (kappa score = 0.812 (P < 0.0001), 95% CI (0.77-0.85). In many cases, scintigraphy provides considerably more functioning and anatomic details than ultrasound. In conclusion, these findings bring forth practical aspects of thyroid scintigraphy utilization for hyperthyroidism. By combining functional and anatomical information in one step, scintigraphy provides non-invasive, simple, fast and cost effective hyperthyroidism diagnostic method and has the potential to replace TSH and ultrasonography in hyperthyroidism investigation.


Cellular membrane contrast and contrast differentiation with osmium triazole and tetrazole complexes.
Addition of heterocyclic nitrogen compounds to the classical osmium tetroxide postfixation medium, applied after glutaraldehyde fixation, results in enhanced membrane contrast in ultrathin sections of liver tissue. The addition of similar compounds to potassium osmate solutions, results in contrast differences in some cellular membranes. The membranes of the rough endoplasmic reticulum, the nuclear envelope and the plasma membrane acquire contrast, while the mitochondrial membranes do not. The apolar regions of membranes are contrasted when osmium tetroxide is combined with heterocyclic nitrogen compounds, whereas the polar regions are contrasted by combinations of potassium osmate with these compounds. This polar membrane contrast is probably due to the presence of an amino-group in the heterocyclic nitrogen compounds. Compounds without the amino-group do not contrast membranes, although the glycogen is contrasted. X-ray microanalysis served to establish the relative osmium content in contrasted glycogen, and showed that such nitrogen compounds play a role in complexation of cations in aldehyde-fixed tissues. Electron spectroscopy for chemical analysis (ESCA) measurements of isolated muscle glycogen show that after treatment with various osmium tetroxide or potassium osmate solutions, hexavalent and quadrivalent osmium species are present in the glycogen. The presence of (heterocyclic) nitrogen compounds in such solutions stabilizes certain osmium valency species, and this may account for the contrast observed.


[Morphometric study of the ultrastructural organization of the endotheliocytes of blood capillaries in the iliac lymph nodes of pregnant rats].
The ultrastructure of blood capillary endotheliocytes of iliac lymph nodes during pregnancy was investigated in rats. It was found that changes in microcirculation during pregnancy are accompanied by the appearance of the adaptive changes at all levels of lymph node structural organization. They are: increased lumen of arterial and venous part of the capillaries, increased intermediate sinus volume, increased fenestration of both parts of capillaries, a sharp increase in the number of micropinocytous vesicles and activation of transendothelial channel formation.


Power tether for long duration multi-copter flight.
The possibilities and promises of unmanned aerial vehicles (UAVs) for smart agriculture, 5G cellular integration, package delivery, and persistent surveillance are but a few of the active drivers for advancing UAV technology and systems. The UAVs' dependence on battery power represents a key limitation for practical deployment. As every remote pilot understands, even a modest research payload can limit a UAV's endurance to under 20 min. When horizontal maneuverability is not required, a power tether from the ground can provide near infinite flight time. Commercial tethers exist but can be prohibitively expensive or underpowered for research payloads. This paper describes the detailed design, construction, and operation of a relatively inexpensive open-source alternative. The designed and prototyped tether system delivers 1 kW of power at the tether base which, on an efficient UAV, corresponds to a payload of approximately 4.75 kg. We discuss the tradeoffs, design choices, best practices, and customization options, and provide empirical data for characterizing the power-payload relationship. The power and payload are scalable thanks to the modular design and the tools presented in this paper. The very low cost compared to commercial heavy-lift tether systems and the open-source design enable reproducibility and widespread use for supporting research, development, and emerging services/applications.


The biology of Acanthamoeba keratitis.
Acanthamoeba keratitis (AK) is a rare protozoal infection of the cornea. At least eight species of Acanthamoeba are known to cause this sight-threatening disease of the ocular surface. Acanthamoeba spp. exist in a wide array of niches ranging from thermal springs to under ice and every conceivable habitat in between. Contact lens wear is the leading risk factor for AK and is practiced by over 30 million individuals in the United States, yet the incidence of AK is less than 33 cases per one million contact lens wearers. Serological studies have reported that 90%-100% of individuals with no history of AK possess antibodies specific for Acanthamoeba antigens indicating that exposure to this organism is commonplace, yet disease is remarkably rare. Animal studies have shed light on the pathobiology and immunobiology of AK and indicate that a constellation of factors including the ocular surface microbiome and the microbiome of Acanthamoeba itself contribute to the pathogenesis of AK. Interesting, secretory antibodies produced by the adaptive immune response can prevent the initiation of corneal infection, but once Acanthamoeba trophozoites breach the corneal epithelium the adaptive immune system is helpless in altering the course of AK. It has been almost 50 years since AK was first described, yet many questions remain unanswered about this curious and enigmatic disease of the ocular surface.


Genotype, phenotype and treatment outcomes of 17 Malaysian patients with infantile-onset Pompe disease and the identification of 3 novel GAA variants.
Pompe disease is a rare glycogen storage disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to glycogen deposition in multiple tissues. Infantile-onset Pompe disease (IOPD) patients present within the first year of life with profound hypotonia and hypertrophic cardiomyopathy. Treatment with enzyme replacement therapy (ERT) has significantly improved survival for this otherwise lethal disorder. This study aims to describe the clinical and molecular spectrum of Malaysian IOPD patients, and to analyze their long term treatment outcomes. Seventeen patients diagnosed with IOPD between 2000 and 2020 were included in this retrospective cohort study. Clinical and biochemical data were collated and analyzed using descriptive statistics. GAA enzyme levels were performed on dried blood spots. Molecular analysis of the GAA gene was performed by polymerase chain reaction and Sanger sequencing. Structural modelling was used to predict the effect of the novel mutations on enzyme structure. Our cohort had a median age of presentation of 3 months and median age of diagnosis of 6 months. Presenting features were hypertrophic cardiomyopathy (100%), respiratory insufficiency (94%), hypotonia (88%), failure to thrive (82%), feeding difficulties (76%), and hepatomegaly (76%). Fourteen different mutations in the GAA gene were identified, with three novel mutations, c.1552-14_1552-1del, exons 2-3 deletion and exons 6-10 deletion. The most common mutation identified was c.1935C > A p.(D645E), with an allele frequency of 33%. Sixteen patients received ERT at the median age of 7 months. Overall survival was 29%. Mean age of death was 17.5 months. Our longest surviving patient has atypical IOPD and is currently 20 years old. This is the first study to analyze the genotype and phenotype of Malaysian IOPD patients, and has identified the c.1935C > A p.(D645E) as the most common mutation. The three novel mutations reported in this study expands the mutation spectrum for IOPD. Our low survival rate underscores the importance of early diagnosis and treatment in achieving better treatment outcomes.


The Effect of Animal Welfare Training on the Knowledge and Attitudes of Abattoir Stakeholders in China.
Globally, China is one of the largest producers and exporters of meat, and animal welfare is an emerging focal issue for Chinese society and for primary producers. We assessed the effectiveness of a "train the trainer" program to increase awareness of animal welfare issues in stakeholders in the livestock industries of China. Chinese abattoir employees were trained in slaughter and transportation standards in either a classroom setting or using posted materials. They subsequently held training sessions within their own workplace and the participants were surveyed either before (n = 161) or after (n = 147) their training. The post-training group had more confidence to improve the welfare of animals in their care than the pre-training group (p = 0.03), and also scored better on the knowledge section of the survey (p = 0.006) only when the facilitator was trained in the classroom setting. The participants' knowledge of animal welfare was also affected by living area (p = 0.005) and education (p = 0.005). Participants with the least formal education (to middle school only) scored lower than all other participants. Female respondents reported more positive attitudes towards animal welfare than males (p = 0.009). These results indicate that training can effectively improve stakeholder knowledge on animal welfare during slaughter and transport, however, the mode of delivery has an important influence on learning success, and participant demographics, such as gender and education level, need to be considered when preparing training material.


Resection of colorectal liver metastases in the elderly: does age matter?
Despite the incidence of colorectal cancer increasing with age the proportion of patients undergoing surgery for colorectal liver metastases decreases dramatically in the elderly. Is this referral or selection bias justified? A prospective database of resection for colorectal liver metastases at a single centre was retrospectively analysed to compare the outcome in patients aged ≥75 years (group E) with those aged <75 years (group Y). Data were analysed using the Kaplan-Meier method with Cox regression modelling. Of 1443 resections, 151 (10.5%) in group E were compared with 1292 (89.5%) in group Y. The two groups were matched apart from higher American Society of Anesthesiology scores (P=0.001) and less use of chemotherapy (P=0.01) in the elderly. Perioperative morbidity and 90-day mortality were higher in the elderly compared with the younger group (32.5%vs 21.2%, P=0.02, and 7.3%vs 1.3%, P=0.001). In the last 5 years, mortality in the elderly improved and was no longer significantly different from that of the younger patients [n=2/76 (2.6%) vs n=9/559 (1.6%); P=0.063]. The 5-year survival was similar in groups E and Y for cancer-specific (41.4%vs 41.6%, P=0.917), overall (37.0%vs 38.2%) and median (44.1 months vs 43.6 months, P=0.697) survival respectively. In the elderly liver resection for metastatic disease can be performed with acceptable mortality and morbidity with as good a prospect of survival as for younger patients.


Pulsatile secretion of luteinizing hormone in agonadal men before and during testosterone replacement therapy.
We have reevaluated the question regarding the pulsatile pattern of LH secretion in agonadal men before and following testosterone replacement therapy. Five normal males were used as a reference group and four agonadal men were studied before and during replacement therapy with testosterone enanthate. All the subjects were sampled every 5 min for 12 h (08:00 to 20:00). Data were analyzed using the statistically based and validated pulse detection program DETECT. The normal subjects showed an LH pulse frequency of 10.2 +/- 1.7 peaks/12 h (mean +/- SEM) and a mean duration of 48.8 +/- 14 min, while in agonadal patients without testosterone replacement the frequency of LH peaks (27.5 +/- 2 peaks/12h) was significantly higher than for normal subjects (p less than 0.05), and the mean duration of peaks was lower than in controls (17.2 +/- 1.2 min; p less than 0.01). Following chronic testosterone enanthate replacement therapy (200 mg im every two weeks) these patients showed an increase in the duration and a significant reduction in the frequency of LH peaks (from 27.5 +/- 2 to 18.2 +/- 2.1 peaks/12 h; p less than 0.01) but pulse frequency remained significantly higher than for normal subjects (p less than 0.01). This finding is independent of the choice of p values for false positive detection rate (p = 0.01 or p = 0.005), but it does depend on sampling frequency and is influenced by large (four-fold) changes in the thresholds for peak detection. Using a "discrete deconvolution" technique we estimated the instantaneous secretory rate (ISR) for the two groups of patients. The results using ISR corroborated the findings obtained using analysis of observed plasma LH measurements. ISR computation also showed that the duration of the secretory events of the gonadotropes is significantly shorter (p less than 0.01) than the one estimated on plasma concentration, both in normal subjects and in agonadal patients before and during testosterone administration. LH pulse frequency observed in basal conditions in agonadal men was much higher than previously reported in primary testicular failure; during conventional testosterone replacement therapy LH pulse frequency of agonadal men was significantly reduced but still higher (p less than 0.01) than in normal men. This finding is probably related to the subnormal plasma levels of testosterone found in agonadal men during the replacement therapy; the analysis of data using a sampling interval of 10 min gave results similar to previous reports, confirming that the choice of sampling interval can markedly affect the evaluation of frequent LH pulsatile secretion.


Bovine protamine genes contain a single intron. The structures of the two alleles.
In a recent paper, we described the isolation of the first bovine protamine cDNA (BPK59), demonstrating that the gene was autosomal and single copy (Krawetz, S. A., Connor, W., and Dixon, G. H. (1987) DNA 6, 45-57). We have since utilized the BPK59 clone as a probe, to isolate both alleles of the protamine gene from a bovine genomic library constructed in Charon 28. The sequenced alleles are highly homologous and code for identical mRNAs. Unlike the trout protamine genes, the bovine gene is not contiguous as it possesses a single intron. This intron divides the highly variable mammalian carboxyl domain from the conserved protamine basic core. Three tandemly repeated CG-like ("enhancer") sequences upstream from the CAAT box have been identified, separated by a conserved spacer region. Their possible role in the transcription of this P1 gene is discussed. The bovine genome immediately surrounding (approximately equal to 20 kilobase pairs) the protamine gene has been mapped and reveals that the sequence flanking the 5' segment of the gene is unique, while the sequence flanking the 3' segment is repetitive.


The impact of distance traveled and rurality on the clinical course of head and neck cancer.
To explore the relationship between distance traveled and rurality to clinical timepoints and 2-year disease free survival (DFS) in newly diagnosed HNC patients. This study was conducted through retrospective analysis, with key independent variables including distance to academic medical center and rurality score. To better understand delays in care, the sample was divided into two groups based on an optimal treatment timeline. We then assessed for the impact of distance traveled. A higher proportion of patients in the optimal treatment timeline group resided in metropolitan areas, which also had a lower mean index of medically underserviced score. Patients in this group had a shorter duration from first presentation for HNC to presentation to an academic medical center and a shorter duration from referral to presentation. However, there was no significant difference in 2-year DFS between the groups. Those who lived closest to Upstate were more likely to identify as Black. Those who live in suburban communities around Upstate were most likely to initiate treatment within 1 month of presentation. Those who live farthest from Upstate were the least likely to have an HPV-negative cancer of the head and neck, and more likely to receive surgery as part of treatment and to receive a biopsy prior to presenting to Upstate. Despite differences in distance traveled and rurality between communities, there was no impact on 2-year DFS. Together, we suggest that these findings support that socioeconomic and patient factors, instead of travel distance alone, impact HNC workup patterns. Level III.


Mango seed causing acute large bowel obstruction in descending colon-world's first reported case.
Phytobezoars are a very rare cause of large bowel obstruction. Mango seeds as a phytobezoar causing large bowel obstruction have not been reported in the English literature. We present the case of a 69 years old female who presented to us with clinical and radiological signs of acute large bowel obstruction. On laparotomy, it was noted that mango seeds as a phytobezoar was responsible for the obstruction in the descending colon. Phytobezoars are a rare but known cause of small bowel obstruction. Large bowel obstruction is even rarer. The literature has documented a few cases of small bowel obstruction caused by mango seeds but none for large bowel obstruction. The most frequent reported sites of large bowel obstruction are the sigmoid colon and recto-sigmoid junction. However, phytobezoar causing descending colonic obstruction without any pre-existing underlying pathology has not been reported. The association of bezoar with acute large bowel obstruction is a very rare however; it must be entertained in the differential diagnosis of any large bowel obstruction. Early diagnosis and treatment can avoid lethal complications. Our case being the first case of mango seeds phytobezoar in descending colon with acute large bowel obstruction; signifies its importance for reporting in the English literature.


Toxicity and distribution of tetrodotoxin-producing bacteria in puffer fish Fugu rubripes collected from the Bohai Sea of China.
To investigate the relationship between the toxicity of puffer fish and the distribution of tetrodotoxin-producing bacteria in puffer fish Fugu rubripes collected from the Bohai Sea of China, bacteria were isolated from each organ (ovaries, livers, intestines and gallbladders) and screened for tetrodotoxin (TTX) production. 20 out of 36 isolated strains were found to produce TTX in vitro. In the organs of ovaries and livers whose toxicity is more potent than other organs, the number and toxicity of TTX-producing strains was greater than that of others. Most TTX-producing bacterial strains were identified as Bacillus spp. (19 strains) and Actinomycete spp. (1 strain) based on the morphological observation, physiological and biochemical characteristics and G+C content of DNA. The purified toxin was identified to be TTX by high performance liquid chromatography assay, thin-layer chromatography assay and electrospray ionization mass spectrometry analysis. Our results suggested that TTX-producing bacteria are closely related to the toxification of the puffer fish. More research is needed to elucidate the mechanism of TTX synthesis and the role of TTX in bacteria.


The road to bioabsorbable stents: reaching clinical reality?
This article provides an overview of the evolution of revascularization devices since Grüntzig's initial introduction of balloon angioplasty in 1977. In-stent restenosis (ISR) is the major shortcoming of conventional (permanent-implant) stent therapy; even with the innovation and promising benefits of drug-eluting stents, management of ISR is very difficult. ISR is mainly caused by the interaction between the blood and the stent surface and a permanent mechanical irritation of the vascular tissue. Thus stenting technology has moved toward the development of temporary implants composed of biocompatible materials which mechanically support the vessel during the period of high risk for recoil and then completely biodegrade in the long term. Preclinical and first clinical experiences with bioabsorbable magnesium stents are discussed.


The role of macrocyclic compounds in the extraction and possible separation of platinum and rhodium from chloride solutions.
Macrocyclic compounds (crown ethers), specifically 18-crown-6 (18-C-6), benzo-15-crown-5 (B-15-C-5), di-benzo-18-crown-6 (DB-18-C-6) and di-cyclohexano-18-crown-6 (DC-18C-6), are used as extractants as well as synergists with amine-group extractants. Platinum and rhodium belong to platinum-group metals (PGMs) and have very similar ionic radii and similar properties. The separation of PGMs is most useful for the preparation of functional materials. Macrocyclic compounds are tested for platinum and rhodium separation and are found to achieve marginal separation. Amines (used as extractants) are paired with macrocyclic compounds (used as synergists), and the separation factor between platinum and rhodium is increased with synergistic enhancement from a chloride solution. The present study discusses extraction chemistry, separation factors and the synergy between platinum and rhodium from chloride solutions. To ensure accurate data, the aqueous samples in this study are analyzed using an inductively coupled plasma optical emission spectrometer (ICP-OES).


Cytotoxicity of monoclonal antibodies to Trypanosoma brucei.
Monoclonal antibodies (McAbs) were raised against Metacyclic Variable Antigen Types (M-VATs) of the AnTAR 1 and ETAR 1 serodemes of Trypanosoma brucei. Two dominant M-VATs, one from each serodeme, were labelled by two of the McAbs using the indirect immunofluorescence technique. These McAbs were of the IgM class, and labelled exposed epitopes on living trypanosomes. They showed lytic activity in vitro towards their respective homologous VAT trypanosomes, both in the presence and absence of complement. In vivo, the McAbs promoted lysis and clearance of trypanosomes from the bloodstream of infected mice. Prevention of reinfection with trypanosomes expressing the same VAT was conferred by the McAbs.


EVESTA: Emergency VESTibular Algorithm and its impact on the acute management of benign paroxysmal positional vertigo.
To synthesise evidence-based research concerning the assessment and management of acute dizziness via construction of a comprehensive clinical algorithm. Assess its clinical impact with an aim to improve the acute management of benign paroxysmal positional vertigo (BPPV) within Wyong Public Hospital ED in four key recommendations. Current best practice models of care were synthesised into a single clinical, district-based peer-reviewed algorithm by a specialist focus group. An observational pre- and post-implementation study was completed to assess the impact of the algorithm on the management of BPPV. A total of 162 notes (pre [control] n = 87 and post [intervention] n = 75) met the inclusion criteria. Adherence to the BPPV clinical practice guidelines statements 1a, 3a, 4a and 6 were analysed for statistical difference in practice between the two groups. Following implementation of the Emergency VESTibular Algorithm (EVESTA), compliance showed a significant improvement in Hallpike-Dix performed by 27% (95% confidence interval [CI] 14-40%; defects pre-intervention 40%: post-intervention 13%) (P < 0.001), utilisation of neuroimaging reduced by 16% (95% CI 2-30%; 40%: 24%) (P < 0.05), repositioning techniques performed increased by 33% (95% CI 18-48%; 68%: 36%) (P < 0.001). Administration of vestibular suppressant medication reduced by 30% (95% CI 15-45%; 59%: 29%) (P < 0.001). An interrupted time series analysis confirmed significant change in BPPV admissions post-project -4.23% (95% CI -7.20, -1.27%) (P = 0.041). Diagnosis and management of acute dizziness is challenging within the ED. Synthesis of best practice into a clinical algorithm has improved the diagnosis and evidence-based treatment of BPPV. There is continued opportunity to improve the efficiency and effectiveness in the management of both central and peripheral acute dizziness within the ED.


Dedifferentiated chondrosarcoma of the larynx: Radiological, gross, microscopic and clinical features.
Laryngeal chondrosarcoma is an uncommon malignancy with a predilection for the cricoid cartilage of adult male patients. Although rare, identification of aggressive chondrosarcoma variants, such as dedifferentiated chondrosarcoma (DDCS) may influence preoperative patient counseling, definitive surgical management, potential implementation of post-operative adjuvant therapy and prognosis. Herein we describe clinical and imaging features of laryngeal DDCS, the unique perspective of fresh and formalin fixed macroscopic examination, a spectrum of histopathologic findings, and detail the full course of the patient's disease.


Primary phacoemulsification and aspiration combined with 25-gauge single-port vitrectomy for management of acute angle closure.
To describe a technique using phacoemulsification and aspiration (PEA) combined with 25-gauge single-port vitrectomy as a primary treatment for acute angle closure (AAC). Seventeen consecutive cases of AAC were treated with 1) transconjunctival limited single-port vitrectomy with a 25-gauge vitrector and 2) transcorneal PEA and cortex removal followed by implantation of foldable intraocular lenses (IOL). Intraocular pressure (IOP) control was achieved in all 17 eyes examined. Mean preoperative IOP was 51.8+/-13.1 mmHg, and mean IOP on postoperative day 1 was 18.3+/-8.5 mmHg. Additional anti-glaucoma surgery was necessary in one eye. IOL could not be implanted because of zonular dialysis in one eye. Postoperative complications were seen in three cases (one retinal hemorrhage and two papilledema). The PEA procedure is efficient as a primary treatment of AAC. Single-port vitrectomy with a 25-gauge vitrector facilitated PEA and IOL implantation.


Deciphering the role of Epstein-Barr virus in the pathogenesis of T and NK cell lymphoproliferations.
Epstein-Barr virus (EBV) is a highly successful herpesvirus, colonizing more than 90% of the adult human population worldwide, although it is also associated with various malignant diseases. Primary infection is usually clinically silent, and subsequent establishment of latency in the memory B lymphocyte compartment allows persistence of the virus in the infected host for life. EBV is so markedly B-lymphotropic when exposed to human lymphocytes in vitro that the association of EBV with rare but distinct types of T and NK cell lymphoproliferations was quite unexpected. Whilst relatively rare, these EBV-associated T and NK lymphoproliferations can be therapeutically challenging and prognosis for the majority of patients is dismal. In this review, we summarize the current knowledge on the role of EBV in the pathogenesis of these tumours, and the implications for treatment.


Mucous retention cyst of temporal bone: a mimic of cholesteatoma on DW-MRI.
Non-EPI DW imaging is increasingly being used as a sensitive sequence in detecting cholesteatomas especially if CT findings are not confirmatory. Cholesteatoma appears as a hyperintense focus on DWI. We present two cases of mucous retention cysts in the mastoid temporal bone/middle ear cavity, which present as hyperintense on non-EPI DWI and potentially may mimic cholesteatomas. Differentiating between the two conditions is important, as surgery can be avoided in mucous retention cysts. We have also discussed ways to differentiate between these two conditions on MRI. To our knowledge, this entity is not reported previously.


Normal Pressure Hydrocephalus Associated with Chronic Alpha Interferon Treatment: A Case Report.
Chronic a-interferon use has been reported to cause a variety of neurotoxic side effects. This case summary suggests the possibility of a new neurotoxic side effect of normal pressure hydrocephalus following chronic a-interferon use.


Use of Antimicrobial-Coated Catheters in Preventing Catheter-Associated Urinary Tract Infections and Bacteriuria: A Meta-Analysis for Clinicians.
Catheter-associated urinary tract infections comprise a significant burden to the health care system and are of major concern for indwelling catheter use. Catheter coatings have been studied for their potential to reduce risk of infection. The purpose of this meta-analysis is to determine the efficacy of coated catheters across clinical studies in preventing these common nosocomial infections. Searches were conducted on PubMed Central® and ScienceDirect using the terms "catheter," "urinary tract infection" and "coated" or "antimicrobial." Articles included were prospective randomized clinical studies of coated (experimental) vs uncoated (control) catheters published in English between the years 2000 and 2020. Results from included studies were analyzed using Fisher's exact test and conditional logistic regression. Fifteen studies met the inclusion criteria. Tested urinary catheter coatings include silver, silver salt, nitrofurazone and metal-alloy. Conditional logistic regression (p <0.001) shows statistically significant negative association between coated catheter use and the incidence of catheter-associated urinary tract infections. The odds ratio of 0.80 and 95% confidence interval (0.74, 0.88) support protective effect of catheter coatings. Meta-analysis demonstrates a negative association of coated catheter and incidence of catheter-associated urinary tract infections, supporting that antimicrobial catheter coatings decreases incidence of infection across studies. Further clinical research is recommended to determine the potential for catheter coating adoption in clinical practice to reduce catheter-associated urinary tract infection risk and incidence.


Neural circuitry: seeing the parts that make the picture.
What are the neural correlates of vision? A recent study on Drosophila has described the incredible neuronal diversity in the fly visual system, and traced the circuits that underlie color vision.


Gas6 in chronic liver disease-a novel blood-based biomarker for liver fibrosis.
The expression of the receptor tyrosine kinase Axl and its cleavage product soluble Axl (sAxl) is increased in liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). In this multicenter study, we evaluated the diagnostic value of Gas6, the high-affinity ligand of Axl, in patients with chronic liver disease. Levels of sAxl and Gas6, and their albumin (alb) ratios were analyzed in serum samples of patients with biopsy-proven liver fibrosis, end-stage liver disease, HCC, and healthy controls, and were compared to Fibrosis-4 (FIB-4), enhanced liver fibrosis (ELF™) test, Child-Pugh score (CPS), model of end-stage liver disease (MELD) score, hepatic venous pressure gradient, and α-fetoprotein, respectively. A total of 1111 patients (median age 57.8 y, 67.3% male) was analyzed. Gas6/alb showed high diagnostic accuracy for the detection of significant (≥F2: AUC 0.805) to advanced fibrosis (≥F3: AUC 0.818), and was superior to Fib-4 for the detection of cirrhosis (F4: AUC 0.897 vs. 0.878). In addition, Gas6/alb was highly predictive of liver disease severity (Odds ratios for CPS B/C, MELD ≥ 15, and clinically significant portal hypertension (CSPH) were 16.534, 10.258, and 12.115), and was associated with transplant-free survival (Hazard ratio 1.031). Although Gas6 and Gas6/alb showed high diagnostic accuracy for the detection of HCC in comparison to chronic liver disease patients without cirrhosis (AUC 0.852, 0.868), they failed to discriminate between HCC in cirrhosis versus cirrhosis only. In conclusion, Gas6/alb shows a high accuracy to detect significant to advanced fibrosis and cirrhosis, and predicts severity of liver disease including CSPH.


The Present Projects Past Behavior into the Future while the Past Projects Attitudes into the Future: How Verb Tense Moderates Predictors of Drinking Intentions.
Three studies examined how the use of the present versus the past tense in recalling a past experience influences behavioral intentions. Experiment 1 revealed a stronger influence of past behaviors on drinking intentions when participants self-reported an episode of excessive drinking using the present tense. Correspondingly, there was a stronger influence of attitudes towards excessive drinking when participants self-reported the episode in the past tense. Experiments 2 and 3 liked this effect to changes in construal level (Liberman, Trope, & Stephan, 2007; Trope & Liberman, 2003), with the present tense being similar to a concrete construal level and the past tense being similar to an abstract construal level.


Design and analysis of controlled trials in naturally clustered environments: implications for medical informatics.
In medical informatics research, study questions frequently involve individuals who are grouped into clusters. For example, an intervention may be aimed at a clinician (who treats a cluster of patients) with the intention of improving the health of individual patients. Correlation among individuals within a cluster can lead to incorrect estimates of the sample size required to detect an effect and inappropriate estimates of the confidence intervals and the statistical significance of the intervention effects. Contamination, which is the spread of the effect of an intervention or control treatment to the opposite group, often occurs between individuals within clusters. It leads to an attenuation of the effect of the intervention and reduced power to detect a difference. If individuals are randomized in a clinical trial (individual-randomized trial), then correlation must be taken into account in the analysis, and the sample size may need to be increased to compensate for contamination. Randomizing clusters rather than individuals (cluster-randomized trials) can eliminate contamination and may be preferred for logistical reasons. Cluster-randomized trials are generally less efficient than individual-randomized trials, so the tradeoffs must be assessed. Correlation must be taken into account in the analysis and in the sample-size calculations for cluster-randomized trials.


Repair of acute respiratory distress syndrome by stromal cell administration (REALIST): a structured study protocol for an open-label dose-escalation phase 1 trial followed by a randomised, triple-blind, allocation concealed, placebo-controlled phase 2 trial.
Mesenchymal stromal cells (MSCs) may be of benefit in ARDS due to immunomodulatory and reparative properties. This trial investigates a novel CD362 enriched umbilical cord derived MSC product (REALIST ORBCEL-C), produced to Good Manufacturing Practice standards, in patients with moderate to severe ARDS due to COVID-19 and ARDS due to other causes. Phase 1 is a multicentre open-label dose-escalation pilot trial. Patients will receive a single infusion of REALIST ORBCEL-C (100 × 106 cells, 200 × 106 cells or 400 × 106 cells) in a 3 + 3 design. Phase 2 is a multicentre randomised, triple blind, allocation concealed placebo-controlled trial. Two cohorts of patients, with ARDS due to COVID-19 or ARDS due to other causes, will be recruited and randomised 1:1 to receive either a single infusion of REALIST ORBCEL-C (400 × 106 cells or maximal tolerated dose in phase 1) or placebo. Planned recruitment to each cohort is 60 patients. The primary safety outcome is the incidence of serious adverse events. The primary efficacy outcome is oxygenation index at day 7. The trial will be reported according to the Consolidated Standards for Reporting Trials (CONSORT 2010) statement. The development and manufacture of an advanced therapy medicinal product to Good Manufacturing Practice standards within NHS infrastructure are discussed, including challenges encountered during the early stages of trial set up. The rationale to include a separate cohort of patients with ARDS due to COVID-19 in phase 2 of the trial is outlined. ClinicalTrials.gov NCT03042143. Registered on 3 February 2017. EudraCT Number 2017-000584-33.


Ten common questions (and their answers) on medical futility.
The term medical futility is frequently used when discussing complex clinical scenarios and throughout the medical, legal, and ethics literature. However, we propose that health care professionals and others often use this term inaccurately and imprecisely, without fully appreciating the powerful, often visceral, response that the term can evoke. This article introduces and answers 10 common questions regarding medical futility in an effort to define, clarify, and explore the implications of the term. We discuss multiple domains related to futility, including the biological, ethical, legal, societal, and financial considerations that have a bearing on definitions and actions. Finally, we encourage empathetic communication among clinicians, patients, and families and emphasize how dialogue that seeks an understanding of multiple points of view is critically important in preventing or attenuating conflict among the involved parties.


Two-dimensional profiling of carriers in terahertz quantum cascade lasers using calibrated scanning spreading resistance microscopy and scanning capacitance microscopy.
The distribution of charge carriers inside the active region of a terahertz (THz) quantum cascade laser (QCL) has been measured with scanning spreading resistance microscopy (SSRM) and scanning capacitance microscopy (SCM). Individual quantum well-barrier modules with a 35.7-nm single module thickness in the active region of the device have been resolved for the first time using high-resolution SSRM and SCM techniques at room temperature. SSRM and SCM measurements on the quantum well-barrier structure were calibrated utilizing known GaAs dopant staircase samples. Doping concentrations derived from SSRM and SCM measurements were found to be in quantitative agreement with the designed average doping values of the n-type active region in the terahertz quantum cascade laser. The secondary ion mass spectroscopy provides a partial picture of internal device parameters, and we have demonstrated with our results the efficacy of uniting calibrated SSRM and SCM to delineate quantitatively the transverse cross-sectional structure of complex two-dimensional terahertz quantum cascade laser devices.


Antimicrobial activities of twenty lysine-peptoid hybrids against clinically relevant bacteria and fungi.
This paper describes the antimicrobial activities of 20 lysine-peptoid hybrids against a selection of clinically relevant bacteria and fungi. Minimal inhibitory concentrations were determined against methicillin-susceptible Staphylococcus aureus (ATCC 29213), methicillin-resistant S. aureus (ATCC 33591), vancomycin-intermediate S. aureus (ATCC 700699 MU50), vancomycin-resistant Enterococcus faecium (ATCC 700221), Pseudomonas aeruginosa (ATCC 27853), Salmonella typhimurium (clinical isolate), Klebsiella pneumoniae (clinical isolate), amphotericin-B-resistant C. albicans (ATCC 200955) and Cryptococcus neoformans (clinical isolate). The lysine-peptoid hybrids proved to be active against all strains tested, except K. pneumoniae. For each susceptible strain, we identified at least 4 lysine-peptoid hybrids showing excellent activity. The most active compounds displayed minimal inhibitory concentrations ranging from < or =1.6 to 6.25 microM. This study demonstrates that lysine-peptoid hybrids show activity against drug-resistant pathogens.


Accuracy of the new ICD-9-CM code for "drip-and-ship" thrombolytic treatment in patients with ischemic stroke.
A new International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code, V45.88, was approved by the Centers for Medicare and Medicaid Services (CMS) on October 1, 2008. This code identifies patients in whom intravenous (IV) recombinant tissue plasminogen activator (rt-PA) is initiated in one hospital's emergency department, followed by transfer within 24 hours to a comprehensive stroke center, a paradigm commonly referred to as "drip-and-ship." This study assessed the use and accuracy of the new V45.88 code for identifying ischemic stroke patients who meet the criteria for drip-and-ship at 2 advanced certified primary stroke centers. Consecutive patients over a 12-month period were identified by primary ICD-9-CM diagnosis codes related to ischemic stroke. The accuracy of V45.88 code utilization using administrative data provided by Health Information Management Services was assessed through a comparison with data collected in prospective stroke registries maintained at each hospital by a trained abstractor. Out of a total of 428 patients discharged from both hospitals with a diagnosis of ischemic stroke, 37 patients were given ICD-9-CM code V45.88. The internally validated data from the prospective stroke database demonstrated that a total of 40 patients met the criteria for drip-and-ship. A concurrent comparison found that 92% (sensitivity) of the patients treated with drip-and-ship were coded with V45.88. None of the non-drip-and-ship stroke cases received the V45.88 code (100% specificity). The new ICD-9-CM code for drip-and-ship appears to have high specificity and sensitivity, allowing effective data collection by the CMS.


Fetal growth, glucose tolerance and plasma insulin concentration in rats given a marginal-zinc diet in the latter stages of pregnancy.
1. Wistar rats were fed on a control semi-synthetic diet throughout pregnancy, or a control diet in the first 2 weeks and a marginal-zinc diet in the 3rd week of pregnancy. On day 20, after an overnight fast, half the animals in each group were given glucose by gavage and the 0-30 min rise in blood glucose measured in tail blood. After 60 min blood was taken by cardiac puncture for glucose and insulin assay. Maternal pancreases were removed and the Zn contents measured. Fetuses from each litter were combined for wet/dry weights, protein and DNA determinations. 2. Plasma insulin concentration was higher, and glucose concentration and pancreatic Zn content lower, in pregnant v. non-pregnant animals of similar age, fed on the same diet. Pancreatic Zn content was lowest in the marginal-Zn group of pregnant rats. Fetuses from mothers fed on the marginal-Zn diet during the last week of pregnancy were slightly heavier than controls and had a significantly higher protein: DNA ratio. The 0-30 min rise in blood glucose was significantly greater in the marginal-Zn animals. 3. In a second experiment, pregnant rats were given similar diets to those used in the first study, but the marginal-Zn diet was given for a shorter period (days 15-19 of pregnancy). On day 19 the rats were meal-fed and on day 20, after an overnight fast, an oral glucose dose was administered. Tail-blood was taken at timed intervals up to 60 min post-dosing for glucose assay.(ABSTRACT TRUNCATED AT 250 WORDS)