Unwelcome prevalence of leishmaniasis with several other infectious diseases.
Co-infection among leishmaniasis and other infectious diseases is common among natural populations especially in the endemic areas of the disease. It depends on the environmental factors, vector availability, host-parasite interactions and above all geographical boundaries. Leishmaniasis being an immunosuppressive disease empowers the invading opportunistic infections to invade and successfully colonize. A variety of infections coexist with leishmaniasis like HIV, leprosy, tuberculosis, schistosomiasis etc. With the different pathology and immune status, co-infection in most cases leads to disease severity and increased mortality.Inevitably, co-infection increases the complexity and poses a threat in the cure and control programmes. This is the first review which highlights the existing co-infections of leishmaniasis with other infectious diseases. The review also focuses on the immunology of co-infections together, diagnosis and the treatment options available for treating such cases. With the changing environment and the overlapping endemic areas of leishmaniasis with other diseases, it becomes difficult to treat a disease without accurate diagnosis. Thus, the review insists on the need for more research on development of newer and differential diagnostic methods for co-infected individuals with theoverlapping symptoms.


[Allergic diseases in pregnancy. Overview of diagnosis and therapy].
Allergic diseases arising in pregnancy may pose a challenge. Skin test results may be influenced by hormonal factors and fetal risk due to the skin testing procedure cannot be excluded. Also, several anti-allergic drugs are not licensed or are even contraindicated in pregnancy. This paper reviews diagnostic and therapeutic procedures in pregnant women.


The image features of emotional faces that predict the initial eye movement to a face.
Emotional facial expressions are important visual communication signals that indicate a sender's intent and emotional state to an observer. As such, it is not surprising that reactions to different expressions are thought to be automatic and independent of awareness. What is surprising, is that studies show inconsistent results concerning such automatic reactions, particularly when using different face stimuli. We argue that automatic reactions to facial expressions can be better explained, and better understood, in terms of quantitative descriptions of their low-level image features rather than in terms of the emotional content (e.g. angry) of the expressions. Here, we focused on overall spatial frequency (SF) and localized Histograms of Oriented Gradients (HOG) features. We used machine learning classification to reveal the SF and HOG features that are sufficient for classification of the initial eye movement towards one out of two simultaneously presented faces. Interestingly, the identified features serve as better predictors than the emotional content of the expressions. We therefore propose that our modelling approach can further specify which visual features drive these and other behavioural effects related to emotional expressions, which can help solve the inconsistencies found in this line of research.


A novel multi-factor & multi-scale method for PM2.5 concentration forecasting.
In the era of big data, a variety of factors (particularly meteorological factors) have been applied to PM2.5 concentration prediction, revealing a clear discrepancy in timescale. To capture the complicated multi-scale relationship with PM2.5-related factors, a novel multi-factor & multi-scale method is proposed for PM2.5 forecasting. Three major steps are taken: (1) multi-factor analysis, to select predictive factors via statistical tests; (2) multi-scale analysis, to extract scale-aligned components via multivariate empirical mode decomposition; and (3) PM2.5 prediction, including individual prediction at each timescale and ensemble prediction across different timescales. The empirical study focuses on the PM2.5 of Cangzhou, which is one of the most air-polluted cities in China, and indicates that the proposed multi-factor & multi-scale learning paradigms statistically outperform their corresponding original techniques (without multi-factor and multi-scale analysis), semi-improved variants (with either multi-factor or multi-scale analysis), and similar counterparts (with other multi-scale analyses) in terms of prediction accuracy.


Effective remediation of low-concentration cadmium in groundwater using nano-scale magnesia.
Cadmium (Cd), one of the hazardous elements in groundwater, is a severe threat to human health and ecological systems even at low concentrations. This study explores the effectiveness of commercial and self-synthesized nano-scale magnesia (NMgO) for remediating low-concentration Cd in groundwater as well as their associated removal mechanisms. The sorption kinetic data for both NMgOs were well fitted to the pseudo-second-order model and the calculated q e values matched the experimental q e values for both commercial and self-synthesized NMgOs. The sorption equilibrium data for both NMgOs were well fitted to the Langmuir isotherm model, with the maximum Cd sorption capacity (q e) of 19.25 and 16.54 mg/g at an initial concentration range of 5-200 μg/L and a temperature of 25 °C, for commercial and self-synthesized NMgOs, respectively. The combined sorption kinetics and equilibrium data suggest that the sorption onto both NMgOs follows a monolayer chemisorption. The scanning electron microscope-energy dispersive X-ray (SEM-EDX), Fourier transform infrared spectroscopy (FTIR), and X-ray diffractometer (XRD) analyses show that the chemisorption of Cd onto commercial NMgO is due to the formation of Cd(OH)2, which precipitates on the sorbent surface. For the self-synthesized NMgO, it was demonstrated that the hydroxyl group plays a role in the chemisorption process and the amount of Cd sorbed on the sorbent was quantified. The results of batch experiments showed that both NMgOs removed Cd effectively, obtaining a removal efficiency of more than 99%, under different experimental conditions of pH, sorbent dosage, co-existing ions, and simulated groundwater. Results from both the sorption isotherm and desorption experiments indicated strong bonding between Cd and both NMgOs, suggesting that NMgOs are safe, effective, and practical sorbents to remediate Cd in groundwater.


The arterial supply of the eye of the yak (Bos Grunniens).
The heads and necks of 10 yaks were dissected to study the arterial supply to the eye of the yak in the Qinghai-Tibetan Plateau. The supply came from the internal ophthalmic, external eight ophthalmic, superficial temporal and malar arteries. The internal ophthalmic was one of sources of the posterior long ciliary artery. The external ophthalmic artery gave rise to branches to supply the dorsal oblique muscle and otherwise, and to take part in the formation of the ophthalmic rete mirabile. The ophthalmic rete mirabile gave off many branches to supply the rectus muscles of the eye and otherwise. The malar artery was one of the branches derived from the infraorbital artery, and its branches supplied the inferior, superior and third eyelids and otherwise. The superficial temporal artery detached off some branches to supply the lateral angle of the eye and otherwise, and anastomosed with the lacrimal artery of the ophthalmic rete mirabile.


Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles.
Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.


Surgical efficacy of carpal tunnel release for carpal tunnel syndrome in acromegaly: report of four patients.
Although carpal tunnel syndrome is frequent in acromegaly, few acromegalics will be encountered by most hand surgeons. This paper considers the treatment of four cases of acromegaly in whom carpal tunnel syndrome arose, to discuss aspects of management of carpal tunnel syndrome in this patient group.


First-pass contrast-enhanced inversion recovery and driven equilibrium fast GRE imaging studies: detection of acute myocardial ischemia.
The purpose of this study was (1) to monitor the dynamic effects of T1-enhancing and magnetic susceptibility contrast material on normal canine myocardium using inversion recovery (IR)- and driven equilibrium (DE)-prepared fast gradient-recalled echo (GRE) sequences and (2) to determine the relative value of T1-enhancing and magnetic susceptibility contrast material in detecting regions of ischemia in the same animal. Normal dogs (n = 5) and dogs with acute occlusion of the left anterior descending (LAD) coronary artery (n = 11) were studied using a 1.5-T MR imager. ECG-gated fast IR-prepared GRE images were acquired using TI/TR/TE of 700/7.0/2.9 msec and a flip angle of 7 degrees. Fast DE-prepared GRE images were obtained using a flip angle of 12 degrees and a DE delay/TR/TE of 60/10.2/4.2 msec. Sequential images were acquired to monitor transit of 0.05 mmol/kg gadodiamide injection and 0.2 and 0.4 mmol/kg sprodiamide injection. On slice-nonselective IR fast GRE images, gadodiamide caused significant enhancement of the normal myocardium and the left ventricular (LV) chamber blood. In dogs with LAD occlusion, the ischemic region was defined as an area of low signal intensity (SI). On DE-prepared GRE sequences, administration of sprodiamide resulted in a substantial decrease in signal from normal myocardium and LV chamber blood in normal dogs. In animals subjected to LAD occlusion, this contrast medium produced a transient decrease in SI from normal myocardium (P < .05) and no significant change in SI from ischemic myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)


Soluble and insoluble antigens of human spermatozoa.
Human spermatozoa separated from normal semen were washed with NaC1 (0.9%)and then were washed nine and 20 times with water. Soluble and insoluble fractions were thus obtained. Proteins, nucleoproteins, lipids, and carbohydrates were determined in both fractions. Different subproducts were obtained from the insoluble fraction, and analysis of diffusible proteins was made by disc electrophoresis. They were also used as antigens in immunoserologic reactions against anti-human seminal plasma, antihuman serum proteins, and anti-insoluble fraction of sperm cells. Aglycopeptide, isolated from human seminal plasma, was also employed as antigen against the antisera. The following results were observed: (1) the soluble fraction showed a high concentration of proteins and carbohydrates and a negligible amount of nucleic acid; (2) the insoluble fraction (nine times washed spermatozoa) had a high content of proteins, low concentration of carbohydrates, and no lipids; (3) cross reactions were observed by immunodiffusion test among spermatozoa washed nine times, spermatozoa washed 20 times, seminal plasma and soluble fraction against antiseminal plasma and anti-insoluble fraction SRM9, suggesting the presence of similar antigenic groups; and (4) immunoelectrophoresis showed three arcs for nine times washed speratozoa against anti-insoluble fraction and anti-seminal plasma.


Blend uniformity end-point determination using near-infrared spectroscopy and multivariate calibration.
A multivariate calibration approach using near-infrared (NIR) spectroscopy for determining blend uniformity end-point of a pharmaceutical solid dosage form containing 29.4% (w/w) drug load with three major excipients (crospovidone, lactose, and microcrystalline cellulose) is presented. A set of 21 off-line, static calibration samples were used to develop a multivariate partial least-squares (PLS) calibration model for on-line predictions of the API content during the blending process. The concentrations of the API and the three major excipients were varied randomly to minimize correlations between the components. A micro-electrical-mechanical-system (MEMS) based NIR spectrometer was used for this study. To minimize spectral differences between the static and dynamic measurement modes, the acquired NIR spectra were preprocessed using standard normal variate (SNV) followed by second derivative Savitsky-Golay using 21 points. The performance of the off-line PLS calibration model were evaluated in real-time on 67 production scale (750L bin size) blend experiments conducted over 3 years. The real-time API-NIR (%) predictions of all batches ranged from 93.7% to 104.8% with standard deviation ranging from 0.5% to 1.8%. These results showed the attainment of blend homogeneity and were confirmed with content uniformity by HPLC of respective manufactured tablets values ranging from 95.4% to 101.3% with standard deviation ranging from 0.5% to 2.1%. Furthermore, the performance of the PLS calibration model was evaluated against off-target batches manufactured with high and low amounts of water during the granulation phase of production. This approach affects the particle size and hence blending. All the off-target batches exhibited API-NIR (%) predictions of 94.6% to 103.5% with standard deviation ranging from 0.7% to 1.9%. Using off-target data, a systematic approach was developed to determine blend uniformity end-point. This was confirmed with 3 production scale batches whereby the blend uniformity end-point was determined using the PLS calibration model. Subsequently, the uniformity was also ascertained with conventional thief sampling followed by HPLC analysis and content uniformity by HPLC of the manufactured tablets.


The association between chiropractors' view of practice and patient encounter-level characteristics in Ontario, Canada: a cross-sectional study.
Chiropractors have diverse views of practice, but the impact on their patient profiles and treatment approaches remains unclear. We assessed the association between chiropractors' view of practice (unorthodox versus orthodox) and patient encounter-level characteristics among chiropractors who practice in Ontario, Canada. We conducted a cross-sectional study using Ontario Chiropractic Observation and Analysis STudy (O-COAST) data. In O-COAST, Ontario chiropractors were randomly recruited from a list of registered chiropractors in 2015 and recorded up to 100 consecutive patient encounters. We classified chiropractors' response regarding their views of practice as unorthodox when viewing "vertebral subluxation as an encumbrance to health that is corrected to benefit overall well-being"; other views were considered orthodox. Patient encounter-level characteristics included: (1) non-musculoskeletal reason-for-encounter; (2) subluxation as diagnosis; (3) duration of encounter (log-transformed for modeling); (4) unimodal manipulative treatment; and (5) patient health characteristics (good health status, some activity limitations). We conducted multilevel logistic regression to assess the association between view of practice and aforementioned characteristics, accounting for potential confounders and clustering of encounters within chiropractors. The multilevel models had two levels (level 1-patient encounter level; level 2-chiropractor level), with level 1 patient encounters nested within level 2 chiropractors. We included 40 chiropractors (mean age = 43.4 years, SD = 11.5) and 3,378 chiropractor-patient encounters. The 2,332 unique patients identified had a mean age of 48.5 years (SD = 18.5). Chiropractors with unorthodox views had higher odds of having patients with a non-musculoskeletal reason-for-encounter (adjusted odds ratio (aOR) 16.5, 95% CI 3.2-84.0) and subluxation as diagnosis (aOR 63.0, 95% CI 4.2-949.1). Encounters of chiropractors with unorthodox views were 0.6 times shorter than those with orthodox views (95% CI 0.4-0.9). Chiropractor level explained 32%, 75%, and 49% of the variability in non-musculoskeletal reason-for-encounter, subluxation as diagnosis, and encounter duration, respectively. We observed no association between unorthodox view and unimodal manipulative treatment or patient health characteristics. Chiropractors' unorthodox view of practice was associated with treating non-musculoskeletal conditions, subluxation as diagnosis, and shorter duration of encounter. Chiropractor level explained a high proportion of variability in these outcomes. Findings have implications for understanding chiropractic practice and informing interprofessional collaboration.


Oral contraceptives in premenstrual syndrome: a randomized comparison of triphasic and monophasic preparations.
Thirty-seven women with cyclical mood changes, either only in the premenstrual phase ('pure PMS') or during the entire cycle with premenstrual aggravation ('PMA'), were recruited to participate in a randomized study investigating the effect of three different oral contraceptives (OCs) on mood symptoms; 32 out of the 37 women completed the study. The monophasic ethinylestradiol (EE)/desogestrel (DSG) OC was compared, in a single (doctor)-blind cross-over design, with a monophasic and a triphasic levonorgestrel (LNG)-containing combined OC. The women kept a record of their symptoms and complaints by noting daily ratings using a validated visual analogue scale. One pretreatment cycle was followed by four treatment cycles, two cycles on each OC. All OCs had a beneficial effect on the PMS symptoms compared to the pre-treatment period. There were no changes between consecutive cycles. Cyclical symptom changes were noted during all OC treatment. The monophasic desogestrel pill provoked less changes in mood parameters than the monophasic and triphasic levonorgestrel OCs. However, physical complaints were less frequently reported during the use of the triphasic preparation as compared to the monophasic desogestrel preparation. Women with 'pure' PMS (premenstrual syndrome) were more consistent in their reactions on OCs compared to women with PMA.


NLRs in immune privileged sites.
Innate immune receptors such as the nucleotide-binding domain, leucine-rich repeat-containing (NBD-LRR) receptors, referred to as NLRs, are known to serve as a critical component of host defense. However, their participation in inflammatory responses within immune privileged sites such as the brain and eye is less understood. The potential importance of NLRs in regulation of inflammation within these particular sites is further underscored by their association with autoinflammatory disorders, wherein localized inflammation can occur within the brain or eye as neuroinflammation or uveitis, respectively. Many NLRs are expressed within the brain and eye and in this review, we discuss their roles in the inflammation of the central nervous system (CNS) and uveitis.


Amplification of AML1 gene is present in childhood acute lymphoblastic leukemia but not in adult, and is not associated with AML1 gene mutation.
The AML1/CBFA2/RUNX1 gene is the target of many recurrent translocations seen in different leukemia subtypes. The t(12;21)(p13;q22) is the most frequent translocation observed in childhood B acute lymphoblastic leukemia (ALL), occurring in 20% to 25% of cases. In adult ALL this rearrangement is scarce. Another route of AML1deregulation could be point mutations in the runt domain. We now report on AML1amplification in two cases of childhood ALL, found in a series of 107 consecutive children with B-lineage ALL analyzed by fluorescence in situ hybridization (FISH). A parallel analysis of 42 adult B-ALL failed to detect any AML1 rearrangement by FISH. The two patients with AML1 amplification were further analyzed using molecular techniques. SSCP analysis did not detect any mutation. Furthermore, direct sequencing of the cDNA did not reveal any mutation. In conclusion, AML1amplification seems to be observed only in childhood ALL and is not associated with AML1 gene mutation. Other mechanisms, such as gene dosage effects could be hypothesized.


The BMP-7-Smad1/5/8 pathway promotes kidney repair after obstruction induced renal injury.
Urinary tract obstruction causes hydroureteronephrosis and requires surgical intervention to prevent permanent renal injury. While many studies have focused on the development of renal injury, we examined the molecular mechanisms that promote renal recovery after correcting obstruction. A reversible murine model of ureteral obstruction was used to examine the bone morphogenic protein-7 and transforming growth factor-β signaling pathways during renal recovery after obstruction induced injury. Analysis was done using standard molecular techniques, including reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay, immunoblotting and co-immunoprecipitation. After correcting obstruction the up-regulation of bone morphogenic protein-7 inhibited the transforming growth factor-β dependent profibrotic pathways that are central to renal injury pathogenesis. The inhibitory effects of bone morphogenic protein-7 were mediated in part by the activation of its downstream target proteins, SMA and MAD related proteins 1, 5 and 8, which suppress the activity of transforming growth factor-β dependent Smad proteins and in turn inhibit the expression of transforming growth factor-β dependent genes. Activation of the bone morphogenic protein-7-Smad related protein 1/5/8 pathway during renal recovery promoted renal architecture restoration and fibrosis resolution in the kidney after correcting obstruction. Together these findings show that the bone morphogenic protein-7-Smad1/5/8 pathway promotes kidney repair after obstruction induced injury. Accordingly the pathway represents an important therapeutic target to stimulate this innate repair mechanisms of the kidney during treatment for obstruction induced renal injury.


cTAGE5 mediates collagen secretion through interaction with TANGO1 at endoplasmic reticulum exit sites.
Cutaneous T-cell lymphoma-associated antigen 5 (cTAGE5), an originally identified tumor antigen, is overexpressed in various cancer cell lines. The cDNA encodes an integral membrane protein containing two coiled-coil motifs and a proline-rich domain. We show that cTAGE5 specifically localizes to the endoplasmic reticulum (ER) exit sites. In addition, cTAGE5 forms a complex with TANGO1 (MIA3), a previously characterized cargo receptor for collagen VII, by the interaction of their coiled-coil motifs. Of interest, cTAGE5, as well as TANGO1, is capable of interacting with the inner-layer coatomer of COPII Sec23/24 complex through their C-terminal proline-rich domains and required for collagen VII secretion. We propose that cTAGE5 acts as a coreceptor of TANGO1 for collagen VII export from the ER.


Wing shape divergence between Rhodnius prolixus from Cojedes (Venezuela) and Rhodnius robustus from Mérida (Venezuela).
The existence of Rhodnius robustus as a species distinct from Rhodnius prolixus has long been the main epidemiological question about Chagas disease transmission in Venezuela and surrounding countries. These two taxa are morphologically and genetically very similar, but only R. prolixus is assumed to colonize houses and transmit Chagas disease to humans. R. robustus is assumed to be an exclusively sylvatic species, restricted to palm trees. If robustus and prolixus are actually the same species, the theoretical possibility exists of sylvatic specimens invading houses, even after insecticide application, and a control strategy similar to that of the successful Southern Cone Initiative against Triatoma infestans would be difficult to consider. Since no valid alternative control strategy exists, the answer to this biological question could be decisive about the future of vector control in this region. Although we believe genetic techniques are best suited to define species boundaries, we present here an example of the relevance of modern morphometrics in dealing with such an issue. Using both traditional and geometric morphometrics, we compared the wing size and shape in both sexes of these two taxa reared in the same laboratory for one generation. R. robustus specimens were collected from palm trees in the state of Mérida (Venezuela), and R. prolixus were collected from houses in the state of Cojedes (Venezuela). Our study provided no argument to question their specific status. Even after one generation of living in the same laboratory conditions, the two lines showed clear size differences, divergent allometric trends, and significant allometry-free differences in shape. These results suggest that R. robustus (Mérida, Venezuela) and R. prolixus (Cojedes, Venezuela) are distinct evolutionary units. Due to the epidemiological importance of this question, further studies in other geographic areas of Venezuela are required to accurately define the relationships of R. robustus and R. prolixus.


Early prediction of regional functional recovery in reperfused myocardium using single-injection resting quantitative electrocardiographic gated SPET.
By evaluating concordant or discordant perfusion and systolic wall thickening patterns, resting quantitative electrocardiographic (ECG) gated single-photon emission tomography (SPET) can identify various myocardial pathological conditions with different functional recovery after revascularisation therapy. However, no data are available on the ability of this methodology to predict regional functional recovery after primary percutaneous transluminal coronary angioplasty (PTCA). This study evaluated whether single-injection ECG gated SPET imaging performed at rest with 99mTc-tetrofosmin early after successful PTCA can predict recovery of regional wall motion. ECG gated SPET was performed 3 days and 3 weeks after successful PTCA in 26 patients. Regional functional parameters were automatically calculated with a 20-segment model on the day 3 image, and segments with perfusion/thickening mismatch were defined as showing preserved perfusion (>55% uptake on the end-diastolic image: mean-standard deviation of the normal value) without systolic wall thickening (mean-standard deviation of the normal value). On the third day, the regional wall motion score of 37 mismatched segments (3.8+/-2.1) was significantly lower than that of 41 matched normal segments (6.0+/-2.9), but was significantly higher than that of 108 matched abnormal segments (1.4+/-1.9, both P<0.01). At 3 weeks after acute MI, the regional wall motion score of mismatched segments (6.4+/-3.9) improved to the level of matched normal segments (7.1+/-3.0) and was significantly higher than that of matched abnormal segments (2.5+/-3.0, P<0.01). Absolute change in the regional wall motion score (3 days to 3 weeks) of mismatched segments (2.6+/-3.5) was significantly greater than that in the regional wall motion score of matched normal segments and matched abnormal segments (1.1+/-1.3 and 1.2+/-2.6, respectively, both P<0.05). Twenty-seven of 37 segments (73%) with perfusion/thickening mismatch showed significant improvement in regional wall motion, whereas improvement in regional wall motion was observed in 22 of 108 segments (20%) with matched abnormal segments and 6 of 41 segments (15%) with matched normal segments. Segments with perfusion/thickening mismatch had a significantly higher incidence of regional functional improvement than did matched abnormal or matched normal segments (chi2=42.3, P<0.01). Thus, by estimating both perfusion and wall thickening, single-injection resting ECG gated SPET imaging with 99mTc-tetrofosmin early after primary PTCA can predict recovery of regional wall motion after successful reperfusion.


Interfacial Super-Assembly of Ordered Mesoporous Carbon-Silica/AAO Hybrid Membrane with Enhanced Permselectivity for Temperature- and pH-Sensitive Smart Ion Transport.
Nanofluidic devices have been widely used for diode-like ion transport and salinity gradients energy conversion. Emerging reverse electrodialysis (RED) nanofluidic systems based on nanochannel membrane display great superiority in salinity gradient energy harvesting. However, the imbalance between permeability and selectivity limits their practical application. Here, a new mesoporous carbon-silica/anodized aluminum (MCS/AAO) nanofluidic device with enhanced permselectivity for temperature- and pH-regulated energy generation was obtained by interfacial super-assembly method. A maximum power density of 5.04 W m-2 is achieved, and a higher performance can be obtained by regulating temperature and pH. Theoretical calculations are further implemented to reveal the mechanism for ion rectification, ion selectivity and energy conversion. Results show that the MCS/AAO hybrid membrane has great superiority in diode-like ion transport, temperature- and pH-regulated salinity gradient energy conversion.


Plasmonic droplet screen for single-cell secretion analysis.
Single-cell secretion analysis technologies are needed to elucidate the heterogeneity of cellular functionalities. Although ligand binding assays in microwells provide a promising approach for measuring single-cell secretions, their throughput is limited. Recently, droplet assays have been developed for high-throughput single-cell screening. However, because washing steps are difficult to perform with droplets, there are still challenges in measuring secretions using droplet assays. In this study, a plasmonic droplet screen approach is developed for one-step washing-free multiplex detection of single-cell secretions. Individual cells are encapsulated with antibody-conjugated gold nanorods (AuNRs) in droplets to evaluate their secretion levels. The shift in the plasmon resonance peak reflects the amount of secreted protein without needing additional indicator and washing steps. The plasmonic signals from a continuous flow of single-cell droplets are collected by dark-field spectroscopy (∼100-150 cells min-1). This platform is tested by screening interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) secreted from suspended leukemia cells and adherent breast cancer cells. Overall, this novel strategy shows the potential and flexibility of high-efficiency multiplex single-cell secretion analysis.


Particle interactions in kaolinite suspensions and corresponding aggregate structures.
The surface charge densities of the silica face surface and the alumina face surface of kaolinite particles, recently determined from surface force measurements using atomic force microscopy, show a distinct dependence on the pH of the system. The silica face was found to be negatively charged at pH>4, whereas the alumina face surface was found to be positively charged at pH<6, and negatively charged at pH>8. The surface charge densities of the silica face and the alumina face were utilized in this study to determine the interaction energies between different surfaces of kaolinite particles. Results indicate that the silica face-alumina face interaction is dominant for kaolinite particle aggregation at low pH. This face-face association increases the stacking of kaolinite layers, and thereby promotes the edge-face (edge-silica face and edge-alumina face) and face-face (silica face-alumina face) associations with increasing pH, and hence the maximum shear-yield stress at pH 5-5.5. With further increase in pH, the face-face and edge-face association decreases due to increasing surface charge density on the silica face and the edge surfaces, and decreasing surface charge density on the alumina face. At high pH, all kaolinite surfaces become negatively charged, kaolinite particles are dispersed, and the suspension is stabilized. The face-face association at low pH has been confirmed from cryo-SEM images of kaolinite aggregates taken from suspension which show that the particles are mostly organized in a face-face and edge-face manner. At higher pH conditions, the cryo-SEM images of the kaolinite aggregates reveal a lower degree of consolidation and the edge-edge association is evident.


Cytokine concentrations in the cerebrospinal fluid of great danes with cervical spondylomyelopathy.
Chronic inflammation is involved in the pathogenesis of human cervical spondylotic myelopathy and could also play a role in cervical spondylomyelopathy (CSM) in dogs. That cerebrospinal fluid (CSF) cytokine concentrations would differ between clinically normal (control) and CSM-affected Great Danes (GDs), with affected GDs showing higher levels of inflammatory cytokines, such as interleukin (IL)-6 and monocyte chemoattractant protein-1/chemokine ligand 2 (MCP-1/CCL2). Client-owned GDs: 15 control, 15 CSM-affected. Prospective study. Dogs underwent cervical vertebral column magnetic resonance imaging and collection of CSF from the cerebellomedullary cistern. Cytokine concentrations were measured using a commercially available canine multiplex immunoassay. Cytokine concentrations were compared between groups. Associations with the administration of anti-inflammatory medications, disease duration and severity, severity of spinal cord (SC) compression, and SC signal changes were investigated in affected GDs. Affected GDs had significantly lower MCP-1/CCL2 (mean 138.03 pg/mL, 95% confidence interval [CI] = 114.85-161.20) than control GDs (212.89 pg/mL, 95% CI = 165.68-260.11, P = .028). In affected GDs, MCP-1/CCL2 concentrations correlated inversely with the severity of SC compression. There were no associations with administration of anti-inflammatory medications, disease duration, or disease severity. IL-6 concentrations were significantly higher (2.20 pg/mL, 95% CI = 1.92-2.47, P < .001) in GDs with SC signal changes. Lower MCP-1/CCL2 in CSM-affected GDs might compromise clearance of axonal and myelin debris, delay axon regeneration, and affect recovery. Higher IL-6 in CSM-affected GDs with SC signal changes suggests more severe inflammation in this group.


Treatment of trilateral retinoblastoma with vincristine and cyclophosphamide.
Current therapy for patients with trilateral retinoblastoma, consisting primarily of surgical intervention and radiotherapy, has resulted in no long-term survivors. The use of adjuvant chemotherapy has not improved this outcome. After observing a tumor response to cyclophosphamide in a patient with suprasellar retinoblastoma, we treated a subsequent patient with trilateral retinoblastoma with both vincristine and cyclophosphamide. Objective tumor regression resulted. Although the tumor ultimately progressed in both patients, these findings suggest that vincristine and cyclophosphamide are active in patients with intracranial (trilateral) retinoblastoma.


Evaluation of biomolecular interactions and cytotoxic activity of organometallic binuclear Ru(II) complexes of ferrocenyl thiosemicarbazones.
Four new ferrocenyl substituted thiosemicarbazone ligands (L1-L4) and their corresponding binuclear ruthenium(II) arene complexes of the general type [(η6-p cym)(L)Ru(μ-im)Ru(L)(η6-p-cym)]Cl (C1-C4) and [(η6-p cym)(L)Ru(μ-azpy)Ru(L)(η6-p-cym)]Cl2 (C5-C8) (cym = cymene, im = imidazole, azpy = 4,4'-azopyridine) have been synthesized and characterized. The structures of the complexes were established through DFT calculations and geometry optimization. The interactions of the binuclear complexes with DNA were investigated by absorption, emission and viscosity studies which indicated that the complexes bind to DNA via intercalation. Meanwhile, the interaction of complexes with the protein, bovine serum albumin (BSA), has also been studied using fluorescence emission spectroscopy. The experimental results show that the binuclear complexes exhibit good binding propensities to BSA. The complexes can quench the intrinsic fluorescence of BSA remarkably through a static or dynamic quenching process. In addition, the in vitro cytotoxicity of complexes C1-C8 against HeLa cell line was assayed which showed lower IC50 values indicating their higher cytotoxicity and potency in killing the cancer cells at low concentrations.Communicated by Ramaswamy H. Sarma.


Accurate prediction of the properties of materials using the CAM-B3LYP density functional.
Density functionals with asymptotic corrections to the long-range potential provide entry-level methods for calculations on molecules that can sustain charge transfer, but similar applications in materials science are rare. We describe an implementation of the CAM-B3LYP range-separated functional within the Vienna Ab-initio Simulation Package (VASP) framework, together with its analytical functional derivatives. Results obtained for eight representative materials: aluminum, diamond, graphene, silicon, NaCl, MgO, 2D h-BN, and 3D h-BN, indicate that CAM-B3LYP predictions embody mean-absolute deviations (MAD) compared to HSE06 that are reduced by a factor of six for lattice parameters, four for quasiparticle band gaps, three for the lowest optical excitation energies, and six for exciton binding energies. Further, CAM-B3LYP appears competitive compared to ab initio G0 W0 and Bethe-Salpeter equation approaches. The CAM-B3LYP implementation in VASP was verified by comparison of optimized geometries and reaction energies for isolated molecules taken from the ACCDB database, evaluated in large periodic unit cells, to analogous results obtained using Gaussian basis sets. Using standard GW pseudopotentials and energy cutoffs for the plane-wave calculations and the aug-cc-pV5Z basis set for the atomic-basis ones, the MAD in energy for 1738 chemical reactions was 0.34 kcal mol-1 , while for 480 unique bond lengths this was 0.0036 Å; these values reduced to 0.28 kcal mol-1 (largest error 0.94 kcal mol-1 ) and 0.0009 Å by increasing the plane-wave cutoff energy to 850 eV.


Effect of experimental endotoxemia on thrombelastography parameters, secondary and tertiary hemostasis in dogs.
Thrombelastography (TEG) and indicators of secondary and tertiary hemostasis might be altered in dogs with endotoxemia. Endotoxemia influences measures of coagulation in dogs. Ten healthy cross-bred dogs. Prospective laboratory study between controls (n = 5) receiving 0.9% saline IV and the study group (n = 5) treated with low-dose lipopolysaccharide (0.02 mg/kg IV). Physical examination and sampling for measurement of leukocytes, platelets, and coagulation variables were performed at time points 0, 1, 4, and 24 hours. Coagulation variables included kaolin-activated TEG, 1-stage prothrombin time (OSPT), activated partial thromboplastin time (aPTT), fibrinogen, factor VIII, antithrombin, protein C, protein S, activated protein C (APC)-ratio calculated from aPTT with and without presence of APC), and D-Dimers. Endotoxemia-induced clinical signs included lethargy (n = 5/5), diarrhea (n = 4/5), emesis (n = 4/5), and abdominal pain (2/5). After 1 hour there was severe leukopenia (2.5 ± 0.7 × 10(9)/L; mean ± SD, P < .0001) and a 2.2-fold increase in D-Dimers (0.81 ± 0.64 mg/L, P < .0001). After 4 hours there was hyperthermia (40.3 ± 0.4°C, P < .0001) and increases in OSPT (10.5 ± 2.7 seconds, P < .0001), aPTT (16.7 ± 5.2 seconds, P = 0.002). A significant decrease in fibrinogen (1.5 ± 1.0 g/L, P = 0.001), protein C (31 ± 33%, P < .0001), protein S (63 ± 47%, P < .0001), TEG α (58 ± 19, P = .007), and TEG maximal amplitude (50 ± 19 mm, P = .003) was seen compared with the controls. APC-ratio rose significantly (2.5 ± 0.2, P < .0001) without exceeding the reference interval (n = 4/5). D-Dimers are the earliest indicator for endotoxemia-associated coagulation abnormalities followed by decreased protein C concentration. APC-ratio and TEG were not good screening variables.


Integrated pest management.
Integrated pest management, in which the conventional pesticides are augmented by one or more nonchemical control practices, has been receiving renewed interest. What is new in this revitalization of an old technique is the careful and more knowledgeable application of a variety of control techniques.


Biotransformation of 17-alkylsteroids in the equine: gas chromatographic-mass spectral identification of ten intermediate metabolites of methyltestosterone.
The metabolism of the orally active anabolic steroid methyltestosterone in the equine was investigated by administration of the drug along with a tritiated radiolabel tracer. In this study some of the metabolites were identified and a radio immunoassay screen and immunoaffinity chromatography gel for methyltestosterone were also evaluated. Pathway intermediates, in particular the 17-methylandrostanediols, were studied to gain an insight into the most likely stereochemistry of the major metabolites. The predominant phase I biotransformations involve reduction of the A ring 3-oxo and 4-ene groups to yield predominantly 3 beta-hydroxy-5 alpha-androstane products and hydroxylation of the steroid nucleus at several positions. Epimerisation of the 17 alpha-methyl group also occurred. Ten steroids could be positively identified by comparison with authentic reference materials and many other triol, tetrol and pentols were also observed. Phase II metabolites and sulphate conjugates in particular, were common.


Central 6-hydroxydopamine lesions decrease mineralocorticoid, but not glucocorticoid receptor gene expression in the rat hippocampus.
The role of hippocampal noradrenergic inputs in the modulation of corticosteroid receptor expression has been investigated. Adult male rats were given central 6-hydroxydopamine (6-OHDA) and the expression of hippocampal mineralocorticoid (MR) and glucocorticoid (GR) receptor mRNA was examined after two weeks by in situ hybridization histochemistry. Expression of MR mRNA was significantly decreased in all subregions of the hippocampus except CA2, but 6-OHDA lesions had no effect on GR mRNA expression. These data reveal differential regulation of the two receptor types by noradrenergic inputs.


Embryonic appearance of rod opsin in the urodele amphibian eye.
Notophthalmus (Triturus) viridescens, a urodele amphibian (newt) common to the Eastern United States, is a promising subject for developmental and regeneration studies. We have available a monoclonal antibody shown to be specific in many vertebrates for rod opsin, the membrane apoprotein of the visual pigment rhodopsin. This antibody to an N-terminal epitope, by rigorous biochemical and immunological criteria, recognizes only rod photoreceptor cells of the retina in light-and electron-microscopic immunocytochemistry. To determine the ontogeny and localization of rhodopsin in developing rods as an indicator of function in the embryonic urodele retina, we have utilized this antibody in the immunofluorescence technique on sections of developing N. viridescens. It was applied to serial sections of the eye region of Harrison stage 28 (optic vesicle) through stage 43 (most adult retina histology complete) embryos, and subsequently visualized with biotinylated species antibody followed by extravidin fluorescein isothiocyanate. The first positive reaction to rhodopsin could be detected in two to four cells (total) of the stage 37 embryonic eye, in the region of the central retinal primordium where the photoreceptors will be found. Some indications of retinal outer nuclear and inner plexiform layers could be seen at this time. Later embryonic stages demonstrated increasing numbers of positive cells in the future photoreceptor outer nuclear layer and outer and inner segments, spreading even to the peripheral retina. Nevertheless, by stale 43, no positive cells could be found at the dorsal or ventral retinal margins. Thus, biochemical differentiation of a photoreceptor population in the urodele retina occurs at a stage before retinal histogenesis is complete. The total maturation of retinal rods occurs topographically over a long period until the adult distribution is achieved.


Mapping apolipoprotein B on the low density lipoprotein surface by immunoelectron microscopy.
Apolipoprotein B (apoB) was mapped using electron microscopy to visualize pairs of monoclonal antibodies binding to the low density lipoprotein (LDL) surface. The sites at which these monoclonals bind the apoB polypeptide sequence had already been established. The angular distances between all possible pairs of binding sites except one allowed the relative placement of six epitopes on the LDL sphere. We conclude that apoB extends over at least a hemisphere of the LDL surface since four epitopes are located in the Northern Hemisphere at sites arbitrarily designated as the North Pole, the Aleutian Islands, Bogotá, and in the Atlantic Ocean, while two are found in the Southern Hemisphere at Buenos Aires and at Madagascar. ApoB appears to possess a restricted flexibility, since these relative epitope locations show a substantial standard deviation in latitude and longitude. Mapping of additional epitopes may provide an answer to the question of whether apoB circumnavigates the LDL sphere.


Effects of environmental intervention in workplace cafeterias on vegetable consumption by male workers.
To assess the effects of an environmental intervention based on the transtheoretical model to increase access to nutritional information about vegetable consumption in workplace cafeterias. Nonrandomized controlled trial. Sixteen workplaces with cafeterias in Niigata, Japan, were assigned to intervention (n = 8) or comparison sites (n = 8). A total of 349 Japanese male workers aged 20-59 years, who visited the cafeterias ≥ 3 times/wk. For the intervention group, 12 types of table tents containing information on increasing vegetable consumption, based on the transtheoretical model stages and processes of change, were distributed to cafeterias for 24 weeks in 2009. Information was presented according to the sequence suggested by the stages of change. Vegetable consumption in the cafeteria and per day and stage of change were assessed using self-administered questionnaires. Differences between groups were tested using a generalized linear model adjusted for age, work environment, and position. The difference in the stage of change was not statistically significantly different (P = .05), but the intervention group (n = 181) had increased vegetable consumption in the cafeteria (+0.18 servings; P = .01) and per day (+0.32 servings; P = .01) vs the comparison group. The findings suggest a beneficial effect of providing access to nutrition information about vegetable consumption as an environmental intervention in workplace cafeterias.


Effect of splinting on abutment tooth movement.
The effect of splinting on abutment tooth movement was investigated in an in vitro study. An acrylic resin mandibular model with missing molars and a removable partial denture framework were constructed. The roots of the premolars and edentulous ridges were coated with silicone rubber. A modified Ney surveyor was used for load application, and abutment tooth movement measurements were made with a macroperiodontometer. Four conditions were tested by applying unilateral loadings: 1. Single abutments of both sides 2. Load side double abutment 3. Nonload side double abutment 4. Double abutments of both sides The results showed that a significant decrease in the magnitude of movement resulted when the abutment teeth were splinted.


Nanoscale repulsive forces between mica and silica surfaces in aqueous solutions.
Nanoscale repulsive forces between mineral surfaces in aqueous solutions were measured for the asymmetric mica-silica system. The force measured with an atomic force microscope (AFM) has universal character in the short range, less than ∼1 nm or about 3-4 water molecules, independent of solution conditions, that is, electrolyte ion (Na, Ca, Al), concentration (10(-6)-10(-2)M), and pH (3.9-8.2). Notably, the force is essentially the same as for the glass-silica system. Single force curves for a mica-silica system in a 10(-4)M aqueous NaCl solution at pH ∼ 5.1 show oscillations with a period of about 0.25 nm, roughly the diameter of a water molecule, a consequence of a layer-by-layer dehydration of the surfaces when pushed together. This result provides additional support to the idea that nanoscale repulsive forces between mineral surfaces in aqueous solutions arise from a surface-induced water effect; the water between two mineral plates that are pushed together becomes structured and increasingly anchored to the surface of the plates by the creation of a hydrogen-bonding network that prevents dehydration of the surfaces.


Facilitating access to consumer health information: a collaborative approach employing applied research.
Responsibility for the provision of consumer health information typically lies within the public library domain or the health sciences library arena. In many communities, both types of libraries provide support for consumer health information services, often with varying levels of expertise. Public library employees may or may not be trained in the use of health and biomedical information resources. Conversely, health sciences library staff may or may not be familiar with information needs of the lay public within their community. To offset these potential differences, a model was developed to assess the health information needs of community members and to provide training for public library staff regarding use of relevant electronic consumer health information resources.


Bidirectional association between irritable bowel syndrome and restless legs syndrome: a systematic review and meta-analysis.
Several observational studies have shown that patients with irritable bowel syndrome (IBS) may have a high risk of restless legs syndrome (RLS). This systematic review and meta-analysis aimed to comprehensively investigate the bidirectional association between IBS and RLS. All conservational studies on IBS and RLS were searched in MEDLINE (assessed by PubMed), Embase, Web of Science, CINAHL, the Cochrane Library database and Google Scholar from inception to June 14, 2020. The Newcastle-Ottawa Scale and Agency for Healthcare Research and Quality were used to assess the methodological quality of the cohort and cross-sectional studies, respectively. The pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using Reviewer Manager 5.3. A total of five cross-sectional studies of moderate methodological quality and one cohort study of high methodological quality were included in our review. Four cross-sectional studies and one cohort study involving 86 438 individuals met the criteria of IBS predicating the onset of RLS. Patients with IBS had a nearly three-fold increased odds of RLS compared with controls (OR = 2.60, 95%CI: 2.17-3.12, P < 0.00001; I2 = 48%, P = 0.11). Three sensitivity analyses confirmed the robustness of the pooled result. Two cross-sectional studies involving 3581 individuals met the criteria of RLS predicating the onset of IBS. RLS patients had a nearly four-fold increased odds of IBS compared with controls without RLS (OR = 3.87, 95%CI: 1.73-8.66, P = 0.0010; I2 = 77%, P = 0.04). In this systematic review and meta-analysis, we found a substantial bidirectional association between IBS and RLS. More prospective, high-quality, population-based studies are warranted in the future.


High-performance liquid chromatographic determination of penicillamine in whole blood, plasma, and urine.
A high-performance liquid chromatographic method for the determination of penicillamine in plasma, whole blood, and urine samples is described. The method uses a commercially available electrochemical detector at a potential of +0.1 V versus the Ag/AgCl reference electrode. This method is selective and sensitive for sulfhydryl compounds. The chromatography separates penicillamine from other endogenous sulfhydryl compounds with a limit of detection for penicillamine in biological samples of ca. 10(07) M.


Does running speed affect the response of joint level mechanics in non-rearfoot strike runners to footwear of varying longitudinal bending stiffness?
Modifying the longitudinal bending stiffness (LBS) of footwear has become a popular method to improve sport performance. It has been demonstrated to influence running economy by altering lower extremity joint level mechanics. Previous studies have only examined within-participant effects at one running speed. Do joint level mechanics differ in response to varying footwear LBS at a range of running speeds? This study utilized a cross-sectional repeated measure study design using a convenience sample. Ten well trained non-rearfoot strike male distance runners ran at 3.89, 4.70, and 5.56 m/s (14, 17, 20 km/hr) in footwear of three different LBS levels. Mechanics and energetics of the metatarsophalangeal joint (MTPJ), ankle, knee, and hip joints during stance phase were assessed using an 8-camera optical motion capture system (fs = 200 Hz), a force instrumented treadmill (fs = 1000 Hz) and standard inverse dynamics theory. Range of motion and negative work decreased and angular stiffness increased for the MTPJ with increasing LBS at all speeds (p < .001). Peak MTPJ moment did not change at any speed in response to increased LBS. Negative work at the ankle decreased in the stiff shoe at 17 km/hr (p = .036). Peak ankle plantar flexion velocity decreased with increasing LBS at all speeds (p < .05). While changes in MTPJ mechanics were consistent across speeds, decreased negative ankle work was only observed at 17 km/hr in the stiff shoe, suggesting that perhaps tuned footwear LBS may need to focus primarily on metabolically beneficial changes in ankle plantar flexor mechanical behavior to improve performance in distance runners. Tuning footwear stiffness may also be beneficial to clinical populations, as clinicians seek to optimize their patients' locomotion economy.


Validity of robotic simulation for high-stakes examination: a pilot study.
Simulation is increasingly being used to train surgeons and access technical competency in robotic skills. The construct validity of using simulation performance for high-stakes examinations such as credentialing has not been studied appropriately. There are data on how simulation exercises can differentiate between novice and expert surgeons, but there are limited data to support their use for distinguishing intermediate from competent surgeons. Senior cardiothoracic trainees with limited robotic but significant laparoscopic experience ("intermediate surgeons", IS) and practicing robotic thoracic surgeons ("competent surgeons", CS) participating in a thoracic cadaver robotic course were evaluated on three Da Vinci (Xi) simulations. Scores were separately recorded into components and analyzed by t-test for significant differences between groups. 21 competent and 17 intermediate surgeons participated. Overall scores did not have a statistically significant difference in any exercise between groups. Simulation exercises do not appear to distinguish intermediate from competent surgeon performance of robotic skills. Without better validity data, the use of simulation for credentialing should be thoughtfully considered.


Potent activation of RhoA by Galpha q and Gq-coupled receptors.
Heterotrimeric G proteins of the G(i), G(s), and G(q) family control a wide array of physiological functions primarily by regulating the activity of key intracellular second messenger-generating systems. alpha subunits of the G(12) family, Galpha(12) and Galpha(13), however, can promote cellular responses that are independent of conventional second messengers but that result from the activation of small GTP-binding proteins of the Rho family and their downstream targets. These findings led to the identification of a novel family of guanine-nucleotide exchange factors (GEFs) that provides a direct link between Galpha(12/13) and Rho stimulation. Recent observations suggest that many cellular responses elicited by Galpha(q) and its coupled receptors also require the functional activity of Rho. However, available evidence suggests that Galpha(q) may act on pathways downstream from Rho rather than by promoting Rho activation. These seemingly conflicting observations and the recent development of sensitive assays to assess the in vivo levels of active Rho prompted us to ask whether Galpha(q) and its coupled receptors can stimulate endogenous Rho. Here we show that the expression of activated forms of Galpha(q) and the stimulation of G(q)-coupled receptors or chimeric Galpha(q) molecules that respond to G(i)-linked receptors can promote a robust activation of endogenous Rho in HEK-293T cells. Interestingly, this response was not prevented by molecules interfering with the ability of Galpha(13) to stimulate its linked RhoGEFs, together suggesting the existence of a novel molecular mechanism by which Galpha(q) and the large family of G(q)-coupled receptors can regulate the activity of Rho and its downstream signaling pathways.


Comparing three mathematical models using different substrates for prediction of partial nitrification.
Modelling of partial nitrification process is affected by several factors such as selection of true substrates, FA and FNA inhibition, and pH effect on growth rate. Among these factors, the selection of true substrates is very critical as it affects the structure of the model. In the present work, a new model adopting free ammonia (FA) and free nitrous acids (FNA) as the true substrate for ammonia oxidizing bacteria (AOB) and nitrite oxidizing bacteria (NOB) was proposed. Then the proposed model was compared with two reported models which adopted ammonium and nitrite, and FA and nitrite as the true substrate for AOB and NOB, respectively. The three mathematical models were compared in terms of predicted minimum dissolved oxygen (DO) in response to varied solids retention time (SRT) (10-30 d), pH (7-8.5), and temperature (10-35 °C). The input kinetic values were justified and updated based on statistical analysis of literature data. Adopting FA as the true substrate increased the minimum DO for AOB. Further, experimental data from different literature studies were taken for model simulation and comparison. Inconsistency was observed between the model prediction and literature data for all three models. The model that adopted ammonium and nitrite as the true substrate for AOB and NOB had better consistency with literature data than other two models. The affecting factors for the model prediction was classified into three levels and discussed in detail. Future work was proposed. The results of this study provide valuable information for the design and modelling of partial nitrification process.


Unroofing site-specific α-synuclein-lipid interactions at the plasma membrane.
Parkinson's disease is associated with α-synuclein (α-syn), a cytosolic protein enriched in presynaptic terminals. The biological function of α-syn remains elusive; however, increasing evidence suggests that the protein is involved in the regulation of synaptic vesicle fusion, signifying the importance of α-syn-lipid interactions. We show that α-syn preferentially binds to GM1-rich, liquid-ordered lipid domains on cytoplasmic membranes by using unroofed cells, which encapsulates lipid complexity and cellular topology. Moreover, proteins (Rab3a, syntaxin-1A, and VAMP2) involved in exocytosis also localize with α-syn, supporting its proposed functional role in exocytosis. To investigate how these lipid/protein interactions influence α-syn at the residue level, α-syn was derivatized with an environmentally sensitive fluorophore (7-nitrobenz-2-oxa-1,3-diazol-4-yl [NBD]) at different N- and C-terminal sites. Measurements of NBD fluorescence lifetime distributions reveal that α-syn adopts a multitude of membrane-bound conformations, which were not recapitulated in simple micelle or vesicle models, indicating an exquisite sensitivity of the protein to the complex lipid environment. Interestingly, these data also suggest the participation of the C terminus in membrane localization, which is generally overlooked and thus emphasize the need to use cellularly derived and biologically relevant membranes for biophysical characterization. Collectively, our results demonstrate that α-syn is more conformationally dynamic at the membrane interface than previously appreciated, which may be important for both its physiological and pathological functions.


The novel KIR3DS1*078 allele identified in a southern Chinese Han individual.
KIR3DS1*078 allele differs from the closest allele KIR3DS1*01301 at nucleotide 775 G>C in exon 5.


The Delivery Challenge of Genome Editing in Human Epithelia.
Despite exciting advances in gene editing, their clinical translation is still hampered by the lack of delivery systems that can encapsulate and deliver gene editing tools like CRISPR-Cas9 or prime editors to the target side. This is particularly challenging in human epithelia, such as the skin and the lung; the latter of which being a mucosal surface that is covered by a mucus layer. In this perspective, the design and biological assessment of delivery systems for gene editing tools like CRISPR in skin and mucosal surfaces are discussed. The current state-of-the-art, current knowledge, and translational gaps, and guide toward improved translation are highlighted.


Benzyladenine and gibberellin treatment of developing "Pink Lady" apples results in mature fruits with a thicker cuticle comprising clusters of epidermal cells.
A mixture of 6-benzyladenine (BA) and gibberellins GA4 plus GA7 applied to "Pink Lady" apple at early phenological stages was previously shown to result in an immediate increase in epidermal cell density and associated reduction in calyx-end cracking disorder in the mature fruit, implying a long-term effect of the BA + GA4+7 mixture. Here, we analyzed the anatomical changes in the mature peel at the calyx end 210 days after full bloom (DAFB), following application of the plant growth regulators (PGRs) at the cell-division phase of fruit development, 21-50 DAFB. Experiments were conducted in northern Israel, and the PGRs were applied as the commercial formulation Superlon™ (Fine Agrochemicals Ltd.), composed of 19 g l(-1) BA and 19 g l(-1) GA4+7. Trees were sprayed with 0.025, 0.1, or 0.2 % (v/v) Superlon™. The most obvious phenomenon was the presence of epidermal cell clusters within the cuticular matrix that were detached from the native epidermal layer located at the bottom of the cuticle and which could not be detected in the untreated control fruits. Treatment with 20 mg l(-1) BA + GA4+7 (0.1 % Superlon™) resulted in a markedly thicker cuticle, a higher percentage of detached epidermal cells within the cuticular membrane and a significant reduction in calyx-end cracking at harvest. The presence of cuticle-embedded epidermal cell clusters may have contributed to strengthening the peel by adding more cell-wall components, thickening the cuticle layer and possibly enhancing crack repair.


Turpentine-induced acute inflammatory response in Gallus gallus: oedema, vascular permeability and effects of non-steroidal anti-inflammatory drugs.
Turpentine-induced acute inflammatory responses in chicks were studied experimentally. Foot pad oedema was measured using a plethysmograph. Skin vascular permeability was evaluated using the Evans blue technique. Turpentine injury induced a typical biphasic response when the two parameters of the inflammatory reaction were studied. Some unexpected alterations of the turpentine-induced inflammatory response were seen when chicks received non-steroidal anti-inflammatory drugs. Pretreatment with promethazine, phenylbutazone, methysergide and indomethacin resulted in a decrease in foot oedema. An inhibitory effect upon vascular permeability was found when promethazine, phenylbutazone and indomethacin were used. Methysergide did not inhibit the increase in vascular permeability of the skin. Possible mechanisms are discussed.


Patient-reported outcomes after robot-assisted radical prostatectomy and institutional learning curve for functional outcomes.
The study was performed to examine patient-reported outcomes (PROs) in the 1st year after surgery and the institutional learning curve after the introduction of robot-assisted radical prostatectomy (RARP). The subjects were 320 consecutive patients who underwent RARP from 2014 to 2018. These cases were divided into three groups treated in the early, middle, and late periods, with about 100 cases in each. PROs were recorded using the Expanded Prostate Cancer Index Composite (EPIC). There were no significant differences among the early, middle, and late periods based on EPIC scores. Urinary function and bother decreased in the 1st month after surgery, and gradually recovered thereafter. However, urinary function was significantly worse in the 1st year after surgery than at baseline. Urinary function and bother were better in patients treated with nerve-sparing surgery, and in nerve-sparing cases, urinary function and bother were best in the early period and worst in the late period. These cases also had the best score for sexual function in the early period, but sexual bother was worst in the early period. In contrast, in cases treated without nerve-sparing surgery, urinary function and bother were best in the late period and worst in the early period, although without significant differences. The functional results of this study based on PROs are useful for providing information for patients. Interestingly, the institutional learning curves for RARP differed in cases that did and did not undergo a nerve-sparing procedure.


Simulated home treatment of depression with nortriptyline.
1. Twenty-two patients hospitalized for treatment of depression were treated under conditions simulating those of home treatment. 2. Full doses of nortriptyline, from 100 to 150 mg/day, were started after baseline observations were made. 3. Two patients were dropped from the study, one for orthostatic hypotension, one for an aberrant response to nortriptyline. Two additional patients developed orthostasis which was easily managed. Otherwise no unusual side effects were noted. 4. After six days of treatment, 9 of 20 patients showed significant improvement with an overall reduction in scores on the Hamilton Depression Scale of 49% for the entire group. 5. Using the weight-adjusted dosage schedule, 18 of the 21 patients attained plasma concentrations of nortriptyline within the presumed therapeutic range; however, no clear relationship could be established between plasma concentrations and clinical response. 6. With proper selection of patients, it should be possible to treat at home some patients who currently are considered to require hospitalization.


Cross-Sectional Magnetic Resonance and Modeling Comparison From Just After Fontan to the Teen Years.
Little is known of baseline anatomic, hemodynamic, and fluid dynamic cardiac magnetic resonance data in single-ventricle patients immediately after Fontan. A comparison from that time point to the teen years can demonstrate clinical course, potentially predict future events, and may shed some light regarding how to optimize outcome. This cross-sectional study is meant to characterize these variables from just after Fontan to the teenage years. The anatomy, flows, and computational fluid dynamic modeling of 22 patients 3 to 9 months after Fontan (age 3 ± 1.1 years) and 25 teens (age 16 ± 1.8 years) were compared. Significance was defined as P less than .05. The percentage of Fontan pathway stenosis was greater with cardiac index and fenestration flow while caval return was lower in teens than in younger patients (for Fontan pathway stenosis, 43% vs 21%, P = .009); however, hepatic flow distribution was more evenly distributed in older patients. Pulmonary artery size kept up with somatic growth. In the teen group, indexed power loss (R = .39), percentage of Fontan pathway stenosis (R = .62), and particle resident time (R = .42) deteriorated as time from Fontan increased (P < .04 for all). There are mostly aspects of deterioration with a few bright spots of stability in anatomy, blood flow, and fluid dynamic variables in Fontan patients from the postoperative period to the teenage years. Most notably, Fontan pathway stenosis increases with decreasing flows while pulmonary artery size and hepatic flow distribution remain stable or improved. These data may be aid in designing improved Fontan reconstruction to optimize clinical outcome and to understand future complications.


Arteriovenous shunting in patients with colorectal liver metastases.
The outlook for patients with colorectal liver metastases is poor. Microspheres have been combined with cytotoxics and administered via the hepatic artery in an attempt to improve tumour drug exposure within the liver. However, it has been suggested that arteriovenous connections might occur in association with intrahepatic tumours causing loss of regional advantage, and that the administration of microspheres further exacerbates arteriovenous shunting. In seven patients with colorectal liver metastases, base-line shunting was measured using a tracer quantity of radio-labelled albumin microspheres. The shunted fraction of a 'therapeutic quantity' of microspheres was subsequently measured in the same group of patients using albumin microspheres carrying a different radio-label. Base-line shunt for 0.5 x 10(6) microspheres was found to be 2.2 +/- 1.8% (mean +/- s.d.); the percentage shunt of a therapeutic quantity (40-80 x 10(6)) of microspheres was 3.0 +/- 0.8%. We conclude that arteriovenous shunting in patients with colorectal liver metastases is minimal, and is not significantly increased by the administration of therapeutic quantity of microspheres during regional chemotherapy.


Cross-sectional study of blood biomarkers of patients with moderate to severe alopecia areata reveals systemic immune and cardiovascular biomarker dysregulation.
Although there is increased understanding of the alopecia areata (AA) pathogenesis based on studies in scalp tissues, little is known about its systemic profile. To evaluate the blood proteomic signature of AA and determine biomarkers associated with increased disease severity. In a cross-sectional study, we assessed 350 inflammatory and cardiovascular proteins using OLINK high-throughput proteomics in patients with moderate to severe AA (n = 35), as compared with healthy individuals (n = 36), patients with moderate to severe psoriasis (n = 19), and those with atopic dermatitis (n = 49). Seventy-four proteins were significantly differentially expressed between AA and control individuals (false discovery rate, <.05) including innate immunity (interleukin [IL] 6/IL-8), T helper (Th) type 1 (interferon [IFN] γ/CXCL9/CXCL10/CXCL11), Th2 (CCL13/CCL17/CCL7), Th17 (CCL20/PI3/S100A12), and cardiovascular-risk proteins (OLR1/OSM/MPO/PRTN3). Eighty-six biomarkers correlated with AA clinical severity (P < .05), including Th1/Th2, and cardiovascular/atherosclerosis-related proteins, including SELP/PGLYRP1/MPO/IL-18/OSM (P < .05). Patients with AA totalis/universalis showed the highest systemic inflammatory tone, including cardiovascular risk biomarkers, compared to control individuals and even to patients with atopic dermatitis and those with psoriasis. The AA profile showed some Th1/Th2 differences in the setting of concomitant atopy. Our analysis was limited to 350 proteins. This study defined the abnormalities of moderate to severe AA and associated circulatory biomarkers. It shows that AA has systemic immune, cardiovascular, and atherosclerosis biomarker dysregulation, suggesting the need for systemic treatment approaches.


Standardized uptake value in para-aortic lymph nodes is a significant prognostic factor in patients with primary advanced squamous cervical cancer.
We sought to identify prognostic factors-including positron emission tomography (PET) parameters-in patients with previously untreated squamous carcinoma of the uterine cervix and MRI- or CT-defined pelvic or para-aortic lymph node (PLN or PALN) metastasis. Patients with untreated squamous cell cervical cancer and PLN or PALN metastasis detected by CT/MRI were enrolled. FDG-PET scans were performed for primary staging. Prognostic variables were investigated by univariate and multivariate analyses. Five-year recurrence-free and 5-year overall survivals (RFS and OS) were evaluated using the Kaplan-Meier method. A total of 70 patients [54 patients with International Federation of Gynecology and Obstetrics (FIGO) stage I or II, and 16 patients with stage III or IV] were eligible. Follow-up ranged from 26.1 to 71.6 months. In multivariate analysis, FIGO stage > or =III (5-year RFS, p = 0.008; 5-year OS, p = 0.008) was a significant prognostic factor for both RFS and OS. In addition, SUV(max) for PALN (dichotomized by 3.3) was significantly associated with OS (p = 0.012) and marginally with RFS (p = 0.078). The presence of SUV(max) > or = 3.3 at PALN or FIGO stage > or =III were significantly associated with both recurrence [5-year RFS; HR = 4.52, 95% confidence interval (CI) = 1.73-11.80] and death (5-year OS; HR = 6.04, 95% CI = 1.97-18.57). SUV(max) > or = 3.3 for PALN and FIGO stage > or =III were significant adverse factors in patients with primary squamous cervical carcinoma and PLN or PALN metastasis detected by CT/MRI.


Arthroscopic suturing of TFCC lesions.
Different types of triangular fibrocartilage complex (TFCC) lesions have been described. We propose an arthroscopic repair of the peripheral tear, as it is a tear in the vascular portion of the TFCC. The technique is based on one used for meniscal repairs of the knee, and it is quite easy to perform.


Recognition of Kidney Donation by Living Kidney Donors That Accompanies Changes in the Recipients' Physical Condition: Focusing on Its Influences on Donors.
In 2013, a total of 1586 kidney transplants were performed in Japan, and 1431 (90.2%) of the organs were from living donors. The purpose of this study is to illuminate the awareness of living kidney donors toward kidney donation after the condition of the recipient changed, thus clarifying the influence of that recognition on the donor. This study design was qualitative descriptive research. Transplant coordinators at 4 hospitals were commissioned to screen subject candidates and hand-deliver printed research explanations to them. Candidates who responded were selected as subjects. I conducted semistructured interviews and analyzed them using the grounded theory approach. This research was approved by the Ethics Research Committee, Faculty of Nursing, Toho University. The survey period was from April to November 2014, and consent was obtained from 5 donors and 5 recipients. The outcome of recipients who received kidneys from the 5 donors was as follows: recovered after temporary worsening (n = 3), early graft loss (n = 1), and early death (n = 1). The core category was "to the donor, the meaning of kidney donation is continually redefined." The donors had a strong interest in the physical condition of the recipient. The 3 changes in the recipients' physical condition, defined as "recovery," "temporary worsening," and "complete deterioration," affected the donor's condition. Due to changes in the recipient's physical condition, donors' psychological and physical condition and their definition of the meaning of kidney donation also changed. Health care systems that guarantee lifelong follow-up of the physical and psychological condition of donors after donation are needed.


Targeting the glycans: A paradigm for host-targeted and COVID-19 drug design.
There is always a need for new approaches for the control of virus burdens caused by seasonal outbreaks, the emergence of novel viruses with pandemic potential and the development of resistance to current antiviral drugs. The outbreak of the 2019 novel coronavirus-disease COVID-19 represented a pandemic threat and declared a public health emergency of international concern. Herein, the role of glycans for the development of new drugs or vaccines, as a host-targeted approach, is discussed where may provide a front-line prophylactic or threats to protect against the current and any future respiratory-infecting virus and possibly against other respiratory pathogens. As a prototype, the role of glycans in the coronavirus infection, as well as, galectins (Gal) as the glycan-recognition agents (GRAs) in drug design are here summarized. Galectins, in particular, Gal-1 and Gal-3 are ubiquitous and important to biological systems, whose interactions with viral glycans modulate host immunity and homeostatic balance.


Addressing the MSICS learning curve: identification of instrument-holding techniques used by experienced surgeons.
To identify instrument holding archetypes used by experienced surgeons in order to develop a universal language and set of validated techniques that can be utilized in manual small incision cataract surgery (MSICS) curricula. Experienced cataract surgeons performed five MSICS steps (scleral incision, scleral tunnel, side port, corneal tunnel, and capsulorhexis) in a wet lab to record surgeon hand positions. Images and videos were taken during each step to identify validated hand position archetypes. For each MSICS step, one or two major archetypes and key modifying variables were observed, including tripod for scleral incision, tripod-thumb bottom for scleral tunnel, underhand-index to thumb grip for side port, index-contact tripod for corneal entry, and tripod-forceps for capsulorhexis. Key differences were noted in thumb placement and number of fingers supporting the instrument, and modifying variables included index finger curvature and amount of flexion. Identification of optimal hand positions and development of a formal nomenclature has the potential to help trainees adopt hand positions in an informed manner, influence instrument design, and improve surgical outcomes.


Are summer schools a way to improve recruitment in psychiatry?
Summer schools are traditionally used to encourage sixth form students to consider a career in medicine. Is it worth attracting students earlier in their school career, concentrating on psychiatry? Wyke et al describe an innovative project attempting to do just that.


Telemetry data of red king crab (Paralithodes camtschaticus) migrations in a north Norwegian fjord.
Acoustic telemetry allows for high-resolution, long-term tracking of moving animals. Here, we describe data on the movement patterns of 37 adult red king crab (RKC, Paralithodes camtschaticus) obtained by means of acoustic telemetry. Acoustically tagged RKC were released in Gamvikfjorden (Sørøya, northern Norway) the 24th of May 2016 and tracked until the 1st of November 2016. Individual crabs resided in the fjord for 1-162 days and were recorded 16 - 11,501 times (mean number of records per crab: 2,851). In total, the data set consist of 105,484 pairs of accurate spatio-temporal coordinates. The acoustic receivers (n = 38) deployed close to the seabed were integrated with temperature sensors that continuously recorded the ambient seawater temperature, resulting in 174,154 water temperature recordings. These novel tracking data can be used to investigate the species' migratory behaviour, spatio-temporal habitat selection, and the relative role of their environment and their possible food sources. Moreover, the high-resolution seawater temperature dataset may serve independently as input data in physical-oceanographic models of this sub-Arctic sill fjord.


Is another meta-analysis on the effects of intramural fibroids on reproductive outcomes needed?
Intramural fibroids when encountered in women undergoing fertility treatment present a clinical dilemma. Despite recent studies that have suggested a negative outcome for intramural fibroids on fertility outcomes, the evidence remains far from conclusive. The current study presents a systematic review and meta-analysis of the currently available evidence. Relevant articles were identified in MEDLINE and EMBASE. Ten studies reported the effects of intramural fibroids on assisted conception treatment including one study reporting the effect of myomectomy for these fibroids. Combined analysis of the included studies, after taking into account possible confounding factors, showed no evidence of a significant effect for intramural fibroids on clinical pregnancy rate (odds ratio (OR) 0.74, 95% confidence intervals (CI) 0.50-1.09), live birth rate (OR 1.17, 95% CI 0.62-2.22) or miscarriage rate (OR 1.61, 95% CI 0.61-4.20). There was also no evidence for a significant effect for myomectomy on the clinical pregnancy rate (OR 1.88, 95% CI 0.57-6.14) or the miscarriage rate (OR 0.89, 95% CI 0.14-5.48). These findings highlight the current deficiency in the literature and suggest that evidence is insufficient to draw any conclusions regarding the effect of intramural fibroids on reproductive outcomes.


Oral hygiene in patients with oral cancer undergoing chemotherapy and/or radiotherapy after prosthesis rehabilitation: protocol proposal.
This study was aimed at assessing the effectiveness and the importance of an oral hygiene (OH) protocol in patients undergoing radiation therapy and chemotherapy after prosthesis rehabilitation, in order to reduce or minimize oral complications. This study was carried out at the Department of Dental Science, at the University of Bari-Italy from December 2012 to December 2015 on 34 selected patients with primary oral cancer undergoing chemotherapy and radiotherapy after prosthesis rehabilitation. They were divided into 2 groups according to their age, sex and cancer therapy. Seventeen patients were assigned to the control group and seventeen in the experimental one. In the experimental group (Table 1), patients underwent an oral hygiene protocol whereas in the control group (Table 2) patients received the usual care provided within the clinical setting. All the patients gave written informed consent. It has been asked and obtained the authorisation from the Ethics Committee of the Dental Science and Surgery Department. Results show that in patients undergoing the oral hygiene protocol, the complications and the risks of infection and permanent dental problems have been minimized. Indeed, of the seventeen patients undergoing the OH protocol, 70% obtained positive results and were satisfied with the program outcome. The role of the health care providers is essential to educate patients to adhere to the prescribed treatments and reinforce their motivation in oral hygiene. The oral hygiene procedures prevent and ameliorate oral complications due to the radiation therapy and chemotherapy.


Developmental toxicity of 2-bromoacetamide on peri- and early post-implantation mouse embryos in vitro.
2-bromoacetamide (BAcAm), a new class of disinfection by-products (DBPs), is widely detected in drinking water across the world. Reports of the high cytogenetic toxicity of BAcAm have aroused public attention concerning its toxic effects on early embryonic development. In this study, we optimized an in vitro culture (IVC) system for peri- and early post-implantation mouse embryos and used this system to determine the developmental toxicity of BAcAm. We found that exposure to BAcAm caused a reduction in egg cylinder formation rate and abnormal lineage differentiation in a dose-dependent manner. Transcriptomic analysis further revealed that BAcAm exposure at early developmental stages altered the abundance of transcripts related to a variety of biological processes including gene expression, metabolism, cell proliferation, cell death and embryonic development, thus indicating its toxic effects on embryonic development. Thus, we developed a robust tool for studying the toxicology of chemicals at the early stages of embryonic development and demonstrated the developmental toxicity of BAcAm in the early embryonic development of mammals.


Hybridization: expressing yourself in a crowd.
What happens to the expression of homeologous gene copies during the formation of new allopolyploid hybrids and their subsequent evolution? Recent studies have shown that hybridisation may relax transcriptional regulation and enable subsequent allopolyploid generations to develop novel patterns of parental gene expression.


Synthesis and characterization of gold graphene composite with dyes as model substrates for decolorization: a surfactant free laser ablation approach.
A facile surfactant free laser ablation mediated synthesis (LAMS) of gold-graphene composite is reported here. The material was characterized using transmission electron microscopy, field emission scanning electron microscopy, energy dispersive X-ray spectroscopy, powdered X-ray diffraction, Raman spectroscopy, Zeta potential measurements and UV-Visible spectroscopic techniques. The as-synthesized gold-graphene composite was effectively utilized as catalyst for decolorization of 4 important textile and laser dyes. The integration of gold nanoparticles (AuNPs) with high surface area graphene has enhanced the catalytic activity of AuNPs. This enhanced activity is attributed to the synergistic interplay of pristine gold's electronic relay and π-π stacking of graphene with the dyes. This is evident when the Rhodamine B (RB) reduction rate of the composite is nearly twice faster than that of commercial citrate capped AuNPs of similar size. In case of Methylene blue (MB) the rate of reduction is 17,000 times faster than uncatalyzed reaction. This synthetic method opens door to laser ablation based fabrication of metal catalysts on graphene for improved performance without the aid of linkers and surfactants.


Lower antibody response to tetanus toxoid associated with higher auto-anti-idiotypic antibody in old compared with young humans.
The production of anti-tetanus toxoid (TT) antibody and anti-anti-TT (auto-anti-Id) antibody has been measured in three young and three old persons. Both antibodies were measured using ELISA. We found that: (i) the anti-TT response of old subjects was lower than that of young subjects, (ii) serum auto-anti-Id antibody concentration was higher in old compared with young humans before boosting with TT, and (iii) anti-TT antibodies from different humans shared Id cross-reactivity when tested with a rabbit anti-Id antibody. Thus, the serum anti-TT antibody response to boosting was inversely correlated with the serum level of auto-anti-Id. This conclusion is consistent with the view that the higher level of auto-anti-antibody in older subjects contributes to their impaired antibody response to TT.


A randomized controlled trial of a new treatment for labor dystocia.
Labor dystocia is an intransigent, high-profile issue in obstetric care. Amniotic fluid lactate (AFL) reflects the uterine metabolic status. High levels associate with subsequent need for operative intervention due to dystocia. In sports medicine, it is known that lactic acid can affect muscular performance and can be decreased by bicarbonate given orally before physical activity. Two hundred dystocic deliveries were included. At the confirmation of dystocia, the AFL-level was analyzed. Deliveries were randomized to an intake of bicarbonate or not. In the "non-bicarbonate-group", stimulation with oxytocin was started immediately. In the "bicarbonate-group", bicarbonate was given; and oxytocin was started 1 hour after the intake. New sampling of AF was performed after 1 hour in both groups. if an oral intake of bicarbonate changes the AFL levels and enhances delivery outcome in dystocic deliveries. Bicarbonate decreases the AFL levels (p < .001). The spontaneous vaginal delivery rate after treatment with bicarbonate was increased (p = .007), without affecting the fetal outcome. An increase of spontaneous vaginal deliveries resulted from bicarbonate ingestion by dystocic women. A decreased level of AFL-level was shown. This simple, low cost treatment has the potential to improve maternal morbidity and satisfaction worldwide.


The meaning of rapport for patients, families, and healthcare professionals: A scoping review.
Rapport is considered fundamental to clinical relationships but is a concept which is rarely defined. This review explores how rapport is defined, characterised, and operationalised in healthcare. A scoping review methodology was used. Data were synthesised using thematic analysis. The review process adhered to the Preferred Reporting System for Meta-Analysis for Scoping reviews (PRISMA-ScR). Medline, CINAHL, and psychINFO were searched with thirty-four studies meeting inclusion criteria. Results were presented in two themes: The meanings of rapport and the implications for building rapport. This scoping review found rapport has no commonly shared definition or conceptualisation in the reviewed research. At the same time rapport is operationalised and characterised. Factors that facilitate, and hinder rapport-building were identified. Having a consistently used definition and conceptualisation will benefit the research that is needed into patient and family experiences and outcomes of rapport. It is crucial for health professionals to incorporate simple kind gestures into practice to facilitate rapport. Equally it is necessary for health professionals to review their practice for dismissive, avoiding behaviours that impede rapport-building and consider how they spend their time with patients.


Acute pulmonary emboli following rebound phenomenon after Nirmatrelvir/Ritonavir treatment for COVID-19.
The return of COVID-19 symptoms after Nirmatrelvir/Ritonavir (Nm/R) treatment is being increasingly reported. Limited evidence suggests most cases of rebound symptoms are mild and do not require further intervention. Here we present a male veteran reporting rebound symptoms who was found to be hypoxic with pulmonary emboli. Our case highlights the need to evaluate known complications of SARS-CoV-2 including venous thromboembolism in patients reporting recurring symptoms. Further, cases of severe rebound phenomenon should continue to be reported by clinicians to better appreciate the use of the Nm/R during the Omicron wave and among vaccinated persons.


Investigating the Lowest Threshold of Vascular Benefits from LDL Cholesterol Lowering with a PCSK9 mAb Inhibitor (Alirocumab) in Patients with Stable Cardiovascular Disease (INTENSITY-HIGH): protocol and study rationale for a randomised, open label, parallel group, mechanistic study.
Elevated low-density lipoprotein cholesterol (LDL-C) is a strong independent risk predictor of cardiovascular (CV) events, while interventions to reduce it remain the only evidence-based approach to reduce CV morbidity and mortality. Secondary prevention statin trials in combination with ezetimibe and/or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors showed that there is no 'J shaped curve' in LDL-C levels with regard to CV outcomes. The lowest threshold beyond which reduction of LDL-C confers no further CV benefits has not been identified.The INTENSITY-HIGH study seeks to explore physiological mechanisms mediating CV benefits of LDL-C lowering by PCSK9 inhibition in patients with established cardiovascular disease (CVD). The study examines the changes in measures of endothelial function and vascular inflammation imaging following intervention with PCSK9 and against standard of care. This is a single-centre, randomised, open label, parallel group, mechanistic physiological study. It will include approximately 60 subjects with established CVD, with LDL-C of <4.1 mmol/L on high-intensity statins. All eligible participants will undergo 18-fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) scanning of the aorta and carotid arteries, as well as baseline endothelial function assessment. Subsequently, they will be randomised on a 1:1 basis to either alirocumab 150 mg or ezetimibe 10 mg/day. Repeat FDG-PET/CT scan and vascular assessments will be undertaken after 8 weeks of treatment. Any changes in these parameters will be correlated with changes in lipid levels and systemic inflammation biomarkers. The study received a favourable opinion from the Wales Research Ethics Committee 4, was registered on clinicaltrials.gov and conformed to International Conference for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice. The results of this study will be reported through peer-reviewed journals and conference presentations. NCT03355027.


Proof of Concept: Drug Selection? Or Dose Selection? Thoughts on Multiplicity Issues.
In new drug development process, one of the most important milestones for a drug candidate is to establish Proof of Concept (PoC) at early Phase II stage. Among many challenges in PoC clinical trial design and analysis, the application of multiplicity comparison procedures (MCP) is frequently discussed when multiple doses or drugs are included in one PoC study. In such discussion, one fundamental question of applying multiplicity adjustment is which error one should consider to control and at what level. Should it be the experiment-wise error or the compound-wise error? In this paper, the multiplicity issues in two cases of PoC studies are used as examples to discuss the concept of different types of error and the level of the error rate control. With a clear understanding of the type of error and error rate control, the debate of applications of the multiplicity adjustment procedures in the PoC studies can be reconciled.


Recent development of multi-target VEGFR-2 inhibitors for the cancer therapy.
Vascular epidermal growth factor receptor-2 (VEGFR-2), as an important tyrosine transmembrane protein, plays an important role in regulating endothelial cell proliferation and migration, regulating angiogenesis and other biological functions. VEGFR-2 is aberrantly expressed in many malignant tumors, and it is also related to the occurrence, development, and growth of tumors and drug resistance. Currently, there are nine VEGFR-2 targeted inhibitors approved by US.FDA for clinical use as anticancer drugs. Due to the limited clinical efficacy and potential toxicity of VEGFR inhibitors, it is necessary to develop new strategies to improve the clinical efficacy of VEGFR inhibitors. The development of multitarget therapy, especially dual-target therapy, has become a hot research field of cancer therapy, which may provide an effective strategy with higher therapeutic efficacy, pharmacokinetic advantages and low toxicity. Many groups have reported that the therapeutic effects could be improved by simultaneously inhibiting VEGFR-2 and other targets, such as EGFR, c-Met, BRAF, HDAC, etc. Therefore, VEGFR-2 inhibitors with multi-targeting capabilities have been considered to be promising and effective anticancer agents for cancer therapy. In this work, we reviewed the structure and biological functions of VEGFR-2, and summarized the drug discovery strategies, and inhibitory activities of VEGFR-2 inhibitors with multi-targeting capabilities reported in recent years. This work might provide the reference for the development of VEGFR-2 inhibitors with multi-targeting capabilities as novel anticancer agents.


Automated detection and localization system of myocardial infarction in single-beat ECG using Dual-Q TQWT and wavelet packet tensor decomposition.
It is challenging to conduct real-time identification of myocardial infarction (MI) due to artifact corruption and high dimensionality of multi-lead electrocardiogram (ECG). In the present study, we proposed an automated single-beat MI detection and localization system using dual-Q tunable Q-factor wavelet transformation (Dual-Q TQWT) denoising algorithm. After denoising and segmentation of ECG, a fourth-order wavelet tensor (leads × subbands × samples × beats) was constructed based on the discrete wavelet packet transform (DWPT), to represent the features considering the information of inter-beat, intra-beat, inter-frequency, and inter-lead. To reduce the tensor dimension and preserve the intrinsic information, the multilinear principal component analysis (MPCA) was employed. Afterward, 84 discriminate features were fed into a classifier of bootstrap-aggregated decision trees (Treebagger). A total of 78 healthy and 328 MI (6 types) records including 57557 beats were chosen from PTB diagnostic ECG database for evaluation. The validation results demonstrated that our proposed MI detection and localization system embedded with Dual-Q TQWT and wavelet packet tensor decomposition outperformed commonly used discrete wavelet transform (DWT), empirical mode decomposition (EMD) denoising methods and vector-based PCA method. With the Treebagger classifier, we obtained an accuracy of 99.98% in beat level and an accuracy of 97.46% in record level training/testing for MI detection. We also achieved an accuracy of 99.87% in beat level and an accuracy of 90.39% in record level for MI localization. Altogether, the automated system brings potential improvement in automated detection and localization of MI in clinical practice.


Same-day-stay head and neck surgery.
The purpose of this study was to determine if selective head and neck surgical procedures on a same-day basis are justifiable. Two hundred consecutive head and neck same-day procedures were reviewed, including 84 parotidectomies and 116 other procedures previously managed as inpatients. Of the 200 patients, 36 (18%) were admitted, 33 for overnight observation, and 164 (82%) were discharged the same day. There were no complications reported in the discharged patients and a later questionnaire showed that 97% of the patients were satisfied. The advantages of selective same-day procedures outweigh the disadvantages for otolaryngologist and patient. The study shows that same-day-stay head and neck surgery for selective procedures is safe, reasonable, and cost-effective, but the combined efforts of the otolaryngologists, nurses, and administrators are required. Because of rising healthcare costs, experts are predicting a significant increase in the next few years of outpatient surgery, including surgery of the head and neck.