Triplets with growth failure, microcephaly, mental retardation, nail hypoplasia and corpus callosum agenesis: is it a variant of Coffin-Siris or a new syndrome?
We report eight-year-old triplet girls whose clinical features included microcephaly, severe mental retardation, hypoplasia of distal phalanges of both fifth and second fingers and nail hypoplasia on second fingers, dysmorphic facial features, and partial corpus callosum agenesis. During infancy, a Pavlik harness was used for congenital hip dislocation, and they had difficulty in feeding. One had been operated for patent ductus arteriosus. To our knowledge, this rare combination has not been previously reported in triplets whose clinical features closely resemble those of Coffin-Siris syndrome. The other diagnostic possibilities are also reviewed.


Characteristics of the rash associated with West Nile virus fever.
We characterized rash in 15 patients with West Nile virus (WNV) fever. Generalized, maculopapular rash typically occurred on days 5-12 of illness. Dysesthesia was reported by 27% of patients, and pruritus by 33% of patients. Because the rash was nonspecific and serologic test results were often negative for WNV at presentation, convalescent-phase testing was frequently required to diagnose WNV fever.


Elevated alpha-fetoprotein: differential diagnosis - hepatocellular carcinoma and other disorders.
The incidence of cirrhosis-related hepatocellular carcinoma (HCC) is rising. Curative surgical options are available; outcomes are acceptable with early diagnosis. Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) and des-gamma-carboxy prothrombin (DCP) are HCC risk markers. A high or increasing serum biomarker level can be predictive of the eventual development of HCC, large tumor size, advanced stage, extrahepatic metastases, portal vein thrombosis, and postoperative HCC recurrence. Based on FDA guidelines for HCC risk assessment, clinicians can consider using either the combination of AFP-L3 with DCP, or the combination of AFP-L3 with AFP and DCP.


Covariance density estimation for autoregressive spectral modelling of point processes.
The use of autoregressive modelling has acquired great importance in time series analysis and in principle it may also be applicable in the spectral analysis of point processes with similar advantages over the nonparametric approach. Most of the methods used for autoregressive spectral analysis require positive semidefinite estimates for the covariance function, while current methods for the estimation of the covariance density function of a point process given a realization over the interval [0, T] do not guarantee a positive semidefinite estimate. This paper discusses methods for the estimation of the covariance density and conditional intensity function of point processes and present alternative computational efficient estimation algorithms leading always to positive semidefinite estimates, therefore adequate for autoregressive spectral analysis. Autoregressive spectral modelling of point processes from Yule-Walker type equations and Levinson recursion combined with the minimum AIC or CAT principle is illustrated with neurobiological data.


Transurethral ethanol ablation of the prostate (TEAP): an effective minimally invasive treatment alternative to traditional surgery for symptomatic benign prostatic hyperplasia (BPH) in high-risk comorbidity patients.
To evaluate the efficacy and safety of transurethral ethanol ablation of the prostate (TEAP) for patients with symptomatic benign prostatic hyperplasia (BPH) and high-risk comorbidities. Thirty-six patients (mean age 77.3 years) with symptomatic BPH or persistent urinary retention were assessed at baseline and at 3, 6, and 12 months after treatment. All patients were affected by comorbidities (cardiovascular, respiratory, hematologic, neoplastic, dysmetabolic diseases, or coagulation disorders). Baseline evaluation was achieved by the International Prostate Symptom Score (IPSS) and quality of life (QoL) score, prostate-specific antigen (PSA), prostate transrectal ultrasound (TRUS), and the maximum peak flow rate with evaluation of post-voiding residual urine volume (PVR). Treatment was performed by injecting dehydrated ethanol at a rate correlated to prostate volume into the prostate. The primary end-point for response was > or = 80% improvement of the maximum peak flow rate and significant reduction of the PVR; secondary end-points included symptom improvement (> or = 40% reduction in IPSS and QoL scores). Statistical analysis was carried out with Pearson's Chi-square test and the non-parametric Wilcoxon test with an assigned statistical significance at P < 0.05. During the active follow-up period, we observed a statistically significant decrease of the baseline at the end of the study in the total IPSS score and in the QoL score. The mean peak flow rate improved from 6.0 +/- 2.40 ml/min to 15.2 +/- 0.14 ml/min (P < 0.001), while the PVR decreased from a baseline value of 290.6 +/- 14.14 ml to 4.2 +/- 14.10 ml (P < 0.001). We found that TEAP is a safe minimally invasive treatment, which significantly improves voiding dysfunctions in patients with symptomatic BPH.


Respiratory syncytial virus (RSV) loads in premature infants with and without prophylactic RSV fusion protein monoclonal antibody.
It has not been determined whether respiratory syncytial virus (RSV) fusion protein monoclonal antibody (MAb) (palivizumab) reduces infection or simply ameliorates disease. In a prospective observational study, 27 hospitalized premature infants with RSV who were not receiving MAb were compared with 10 such patients who were receiving MAb. Mean (SEM) RSV loads in the MAb and non-MAb groups were 3.36 (0.59) versus 4.89 (0.27) logPFU/ml (P=.01). Prophylactic palivizumab reduces nasal RSV in premature hospitalized infants.


Pancreatic exocrine insufficiency is not common in HNF-1alpha MODY.
Exocrine pancreatic insufficiency has been described in Type 1 and Type 2 diabetes. The hepatocyte nuclear factor (HNF)-1alpha gene associated with maturity-onset diabetes of the young (MODY3) is expressed in several organs, including the exocrine pancreas. The aim of this study was to determine the prevalence of exocrine pancreas dysfunction in HNF-1alpha MODY patients. Thirty-one diabetic HNF-1alpha MODY patients (mean age 37.2 +/- 14.6 years) and 35 healthy control subjects (39.1 +/- 13.9 years) participated. In addition, 25 Type 1 diabetic (T1DM) subjects were also examined (mean age 30.6 +/- 10.1 years). Exocrine pancreas function was assessed by measurement of stool elastase 1 (E1) activity. All diabetic patients and control subjects completed a gastrointestinal (GI) symptoms questionnaire. In all but two individuals, stool E1 levels were normal (> 200 microg/g). The only case of severely impaired pancreas exocrine function (E1 = 47.5 microg/g) was observed in the MODY3 group. The mean stool E1 elastase level in the HNF-1alpha MODY group was significantly lower than in the control subjects (401.0 +/- 118.4 vs. 482.7 +/- 151.1 microg/g, P = 0.001). Similarly, E1 levels in T1DM were lower than in control subjects (344.8 +/- 132.1 microg/g, P = 0.001); one patient with a moderate enzyme decrease was identified in this group. In addition, more frequent GI complaints were reported by HNF-1alpha MODY patients when compared with control subjects and also with T1DM patients. Pancreatic exocrine insufficiency is not common in HNF-1alpha MODY diabetic patients, although their stool E1 levels are lower than in healthy control subjects.


A novel hydantoinase process using recombinant Escherichia coli cells with dihydropyrimidinase and L-N-carbamoylase activities as biocatalyst for the production of L-homophenylalanine.
A dihydropyrimidinase gene (pydB) was cloned from the moderate thermophilic Brevibacillus agri NCHU1002 and expressed in Escherichia coli. The purified dihydropyrimidinase exhibited strict d-enantioselectivity for D,L-p-hydroxyphenylhydantoin and D,L-5-[2-(methylthio)ethyl]hydantoin, and non-enantiospecificity for D,L-homophenylalanylhydantoin (D,L-HPAH). The hydrolytic activity of PydB was enhanced notably by Mn2+, with a maximal activity at 60 degrees C and pH 8.0. This enzyme was completely thermostable at 50 degrees C for 20 days. A whole cell biocatalyst for the production of L-homophenylalanine (L-HPA) from D,L-HPAH by coexpression of the pydB gene and a thermostable L-N-carbamoylase gene from Bacillus kaustophilus CCRC11223 in E. coli JM109 was developed. The expression levels of dihydropyrimidinase and L-N-carbamoylase in the recombinant E. coli cells were estimated to be about 20% of the respective total soluble proteins. When 1% (w/v) isopropyl-beta-D-thiogalactopyranoside-induced cells were used as biocatalysts, a conversion yield of 49% for L-HPA with more than 99% ee could be reached in 16 h at pH 7.0 from 10mM D,L-HPAH. The cells can be reused for at least eight cycles at a conversion yield of more than 43%. Our results revealed that coexpression of pydB and lnc in E. coli might be a potential biocatalyst for L-HPA production.


Micro-structural evolution and biomineralization behavior of carbon nanofiber/bioactive glass composites induced by precursor aging time.
Bioactive glass (BG)-containing carbon nanofibers (CNFs) are promising orthopaedic biomaterials. Herein, CNF composites were produced from electrospinning of polyacrylonitrile (PAN)/BG sol-gel precursor solution, followed by carbonization. Choosing 58S-type BG (mol%: 58.0% SiO2-26.3% CaO-15.7% P2O5) as the model, micro-structural evolution of CNF/BG composites was systematically evaluated in relating to aging times of BG precursor solution. With aging time prolonging, BG precursors underwent morphological changes from small sol clusters with loosely and randomly branched structure to highly crosslinked Si-network structure, showing continuous increase in solution viscosity. BG precursor solution with low viscosity could mix well with PAN solution, resulting in CNF composite with homogeneously distributed BG component. Whereas, BG precursor gel with densely crosslinked Si-network structure led to uneven distribution of BG component along final CNFs due to its significant phase separation from PAN component. Meanwhile, BG nanoparticles in CNFs demonstrated micro-structural evolution that they transited from weak to strong crystal state along with longer aging time. Biomineralization in simulated body fluid and in vitro osteoblasts proliferation were then applied to determine the bioactivity of CNF/BG composites. CNF/BG composites prepared from shorter aging time could induce both faster apatite deposition and cell proliferation rate. It was suggested weakly crystallized BG nanoparticles along CNFs dissolved fast and was able to provide numerous nucleation sites for apatite deposition, which also favored the proliferation of osteoblasts cells. Aging time could thus be a useful tool to regulate the biological features of CNF/BG composites.


Clinicogenomic Features and Targetable Mutations in NSCLCs Harboring BRAF Non-V600E Mutations: A Multi-Institutional Genomic Screening Study (LC-SCRUM-Asia).
BRAF non-V600E mutations occur in 1% to 2% of NSCLCs. Because of their rarity, the clinical backgrounds and outcomes of cytotoxic chemotherapy or immunotherapy remain unclear, and no targeted therapies are approved for BRAF non-V600E-mutant NSCLC. In this multi-institutional prospective lung cancer genomic screening project (LC-SCRUM-Asia), we evaluated the clinicogenomic characteristics and therapeutic outcomes of BRAF non-V600E-mutant NSCLC. From March 2015 to November 2021, a total of 11,929 patients with NSCLC were enrolled. BRAF mutations were detected in 380 (3.5%), including the V600E (class I) in 119 (31%) and non-V600E in 261; the non-V600E were functionally classified into class II (122, 32%), class III (86, 23%), and non-classes I to III. Smokers and having concurrent RAS gene family or TP53 mutations were more frequently associated with class II or III than with class I. In patients with class III as compared with class I, the progression-free survival in response to platinum-containing chemotherapies (median, 5.3 versus 11.5 mo, p < 0.01) and the overall survival (median, 14.5 versus 34.8 mo, p < 0.02) were significantly shorter. Furthermore, class IIa mutations were significantly more frequent in our Asian cohort than in previously reported cohorts. The clinicogenomic features associated with class IIa were similar to those associated with class I, and one patient with NSCLC with K601E had a good response to dabrafenib plus trametinib. Patients with NSCLCs with BRAF non-V600E, especially class III, were associated with poorer therapeutic outcomes than those with V600E. Furthermore, patients with NSCLC with class IIa had distinct clinicogenomic features, and further preclinical and clinical studies are needed to evaluate class IIa mutations as a therapeutic target.


Effect of helium-oxygen mixture on myocardiac mitochondria of the rat.
Ultrastructural and stereological analysis of mitochondria of myocardiac cells from rats was performed after 2-hour breathing of helium-oxygen mixture. The following changes were observed in the cells of experimental animals as compared with the control ones: swelling of mitochondria, increase of the mean volume fraction of these structures and decrease of axial ratio of mitochondria.


Effect of hydrogenation of glucosyl- and galactosylceramide on their enzymatic hydrolysis.
Our earlier observation that N-stearoyl- and N-lignoceroyl-glucosyl-dihydro-sphingosines have much lower affinity to the hydrolytic enzyme, glucosylceramidase, than the natural mixture of glucosylceramide [11] has been further pursued with catalytically hydrogenated natural substrate. Similar experiments were also carried out for hydrolysis of galactosylceramide of different structures by galactosylceramidase. The hydrogenation procedure completely saturated both fatty acid and long chain base moieties. For either enzyme, the hydrogenated natural substrate had affinity approximately half of the untreated natural substrate mixture. However, the synthetic glucosylceramides which contained a single saturated fatty acid and dihydrosphingosine had generally still lower affinity than the hydrogenated natural mixture. When two synthetic substrates of different fatty acids were mixed together, the affinity to the enzyme increased to a level much higher than that of either of the synthetic substrates alone and reached that of the hydrogenated natural substrate mixture. The findings were similar for galactosylceramide hydrolysis except that the synthetic substrate with palmitic of stearic acid had affinity to the enzyme not much lower than that of the hydrogenated natural substrate mixture. These effects of different structures on their enzymatic hydrolysis remained similar when other constituents of the assay mixture, such as the buffer and detergents, were varied.


Development of a dual energy CT based model to assess response to treatment in patients with high grade serous ovarian cancer: a pilot cohort study.
In patients with cancer, the current gold standard for assessing response to treatment involves measuring cancer lesions on computed tomography (CT) imaging. The percentage change in size of specific lesions determines whether patients have had a complete/partial response or progressive disease, according to RECIST criteria. Dual Energy CT (DECT) permits additional measurements of iodine concentration, a surrogate marker of vascularity. Here we explore the role of changes in iodine concentration within cancer tissue on CT scans to assess its suitability for determining treatment response in patients with high grade serous ovarian cancer (HGSOC). Suitable RECIST measurable lesions were identified from the CT images of HGSOC patients, taken at 2 different time points (pre and post treatment). Changes in size and iodine concentration were measured for each lesion. PR/SD were classified as responders, PD was classified as non-responder. Radiological responses were correlated with clinical and CA125 outcomes. 62 patients had appropriate imaging for assessment. 22 were excluded as they only had one DECT scan. 32/40 patients assessed (113 lesions) had received treatment for relapsed HGSOC. RECIST and GCIG (Gynaecologic Cancer Inter Group) CA125 criteria / clinical assessment of response for patients was correlated with changes in iodine concentration, before and after treatment. The prediction of median progression free survival was significantly better associated with changes in iodine concentration (p = 0.0001) and GCIG Ca125 / clinical assessment (p = 0.0028) in comparison to RECIST criteria (p = 0.43). Changes in iodine concentration from dual energy CT imaging may be more suitable than RECIST in assessing response to treatment in patients with HGSOC. CICATRIx IRAS number 198179, 14 Dec 2015, https://www.myresearchproject.org.uk/ .


Structure of fructose bisphosphate aldolase from Bartonella henselae bound to fructose 1,6-bisphosphate.
Fructose bisphosphate aldolase (FBPA) enzymes have been found in a broad range of eukaryotic and prokaryotic organisms. FBPA catalyses the cleavage of fructose 1,6-bisphosphate into glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. The SSGCID has reported several FBPA structures from pathogenic sources, including the bacterium Brucella melitensis and the protozoan Babesia bovis. Bioinformatic analysis of the Bartonella henselae genome revealed an FBPA homolog. The B. henselae FBPA enzyme was recombinantly expressed and purified for X-ray crystallographic studies. The purified enzyme crystallized in the apo form but failed to diffract; however, well diffracting crystals could be obtained by cocrystallization in the presence of the native substrate fructose 1,6-bisphosphate. A data set to 2.35 Å resolution was collected from a single crystal at 100 K. The crystal belonged to the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a=72.39, b=127.71, c=157.63 Å. The structure was refined to a final free R factor of 22.2%. The structure shares the typical barrel tertiary structure and tetrameric quaternary structure reported for previous FBPA structures and exhibits the same Schiff base in the active site.


Absorption and metabolism of (all-trans-) retinol acetate, retinol, and retinoic acid in the single-pass, albumin-perfused rabbit ear.
Retinoic acid, a metabolite of retinol, is formed in the skin of various species. Formation rates have not been determined in a dynamic skin perfusion model which may show the dehydrogenation of retinol to be rate limited. (all-trans-) Retinol acetate, retinol, or retinoic acid was applied dermally with isopropyl myristate. The ears were single-pass perfused with 6% hetastarch or 5% bovine serum albumin in the buffer solution. The effluent was analyzed by HPLC for these substances. No ester hydrolysis of retinol acetate was observed, nor did this substrate appear in the effluent. Retinol or retinoic acid were detected in the effluent. The absorption rate was linearly related to the dermally applied concentration density. The absorption rate of retinoic acid was 70 times larger than that for retinol. The formation rate of retinoic acid from retinol was rate limited (apparent Vmax: 0.08 pmol/min/cm2 skin). Since retinoic acid is a recognized pharmacologically active ingredient in the skin, the dehydrogenation of retinol or retinal was also observed in the effluent of this skin perfusion model. The percutaneous retinol adds to the endogenous pool of retinoic acid by cytosolic dehydrogenation or microsomal oxidation elsewhere. The steady-state absorption rate of 0.1% retinoic acid in isopropyl myristate, referred to 500 cm2 of the human skin, would contribute about 20% of the daily requirement of vitamin A, without increase in endogenous retinoic acid plasma concentration.


[Contemporary methods of imaging injuries of the spine and spinal cord].
A review of current methods of visualization of injuries of the axial organ on the basis of the literature from the last decade, including also the author's own experience, has been done. The techniques of visualization accessible in Poland have been discussed more widely.


Pertussis toxin inhibits EGF-, phorbol ester- and insulin-stimulated DNA synthesis in BALB/c3T3 cells: evidence for post-receptor activation of Gi alpha.
The contribution of the GTP-binding protein, Gi, to EGF, phorbol dibutyrate (PdBu)-, and insulin-stimulated DNA synthesis was examined in BALB/c3T3 cells. Pertussis toxin inhibited DNA synthesis by each agonist, particularly at suboptimal agonist concentrations, but the inhibition could be partially overcome with higher agonist concentrations and combinations of these agonists. This suggested that (1) some, but not all, of the mitogenic signals for all three agonists were transduced by Gi (2) Gi may be activated by post-receptor mechanisms involving protein kinase C. Gi alpha-specific antibodies and ADP-ribosylation by pertussis toxin using 32P-NAD each labelled a single protein band, representing one or more species of Gi alpha. Pertussis toxin treatment increased the synthesis of Gi alpha. These results are discussed in relation to possible direct effects of Gi alpha on nuclear control during division.


Efficacy, safety and cost-effectiveness comparison between U-100 human regular insulin and rapid acting insulin when delivered by V-Go wearable insulin delivery device in type 2 diabetes.
We compared the efficacy and safety of human regular insulin (HRI) versus rapid-acting insulin (RAI) in a type 2 diabetes population already using the V-Go insulin delivery device. This was a 14-week, multicenter, randomized, open-label, parallel-group, phase IV, non-inferiority study. Patients ≥21years of age, with inadequately controlled type 2 diabetes who were currently using the V-Go insulin delivery system with RAI, with glycated hemoglobin (HbA1c) ≥6.5% (≥48 mmol/L) to ≤12.5% (≤108 mmol/L) were randomized 1:1 to RAI continuation or switch to HRI. The primary outcome was estimated treatment difference (ETD) in HbA1c least-squares mean change from baseline at 14 weeks (prespecified non-inferiority hypothesis with 95% CI upper limit <0.4%). Primary analysis was by per protocol (PP); safety analysis was by intention to treat. We randomized 136 patients to continued RAI treatment (n=67) or HRI (n=69); 113 patients were included in the PP analysis (RAI, n=54; HRI, n=59). Mean change in HbA1c from baseline to study end was -0.60±1.1% (95% CI -0.90 to -0.29); -6.6±12.0 mmol/mol (95% CI -9.8 to -3.2) with HRI treatment and -0.38±1.3% (95% CI -0.70 to -0.05); -4.2±14.2 mmol/mol (95% CI -7.7 to -0.5) with RAI treatment, with ETD of -0.22% (95% CI -0.67 to 0.22); -2.4 mmol/mol (95% CI -7.3 to 2.4), p=0.007, confirming non-inferiority of HRI to RAI. No between-group differences in changes in total daily insulin doses, number of hypoglycemic values (≤70 mg/dL (≤39 mmol/L) or body weight were observed. No severe hypoglycemic events were reported. Direct pharmacy cost savings (-US$265.85; 95% CI -US$288.60 to -US$243.11; p<0.0001) were observed with HRI treatment. Individuals with type 2 diabetes requiring insulin can be treated with V-Go wearable insulin delivery device using HRI, safely and effectively, and potentially at a much lower cost compared with RAI, which can lead to improved access to insulin therapy for these individuals. NCT03495908.


Integrated microarray analysis provided a new insight of the pathogenesis of Parkinson's disease.
Parkinson's disease (PD) is the second most common neurodegenerative disease and the exact pathogenic mechanism remains mostly elusive. Our study aims to identify the key differentially expressed genes (DEGs) and up regulators in PD. An integrated analysis of microarray studies of PD was performed to identify the DEGs in PD compared to normal control (NC). Based on these DEGs, we performed the functional annotation and transcriptional regulatory network constructions. Q-RT-PCR was performed to verify the expression of DEGs. Seven datasets were obtained from GEO. A total of 276 DEGs (262 up-regulated and 14 down-regulated DEGs) in PD compared to normal control were identified with selecting criteria of p-value<0.05. GO terms of respiratory electron transport chain, protein binding and cytoplasm were significantly enriched in PD. Pathways of oxidative phosphorylation, Parkinson's disease, Alzheimer's disease and Huntington's disease were significantly enriched in PD. SNCA was the hub protein in PD according to the protein-protein interaction (PPI) network. The top 3 transcription factor (TFs) covering the most downstream DEGs were Oct-1, Pax-4 and Evi-1. A total of 19 DEGs were firstly identified in our integrated analysis, not from the other individual datasets enrolled in this study. Several DEGs including SNCA, COX17, COX4I1, COX7B, COX6A1 and ATP5J targeted by Pax-4, Oct-1 and Evi-1 may involve in the neurodegeneration and pathogenesis of PD by regulating oxidative phosphorylation, ATP production and oxidative stress, which was benefit for uncovering the mechanism of PD and developing new diagnostic and therapeutic strategies.


Variability of Liver Shear Wave Measurements Using a New Ultrasound Elastographic Technique.
A new 2-dimensional (2D) shear wave elastographic (SWE) device has been developed for the noninvasive assessment of liver fibrosis. Guidelines on measurement acquisition parameters are not yet well established for this technique. Our study aimed to assess 2D SWE measurement variability and to determine the number of measurements required per patient to reliably assess liver stiffness. Two-dimensional SWE was assessed in 55 patients with mixed-etiology chronic liver disease on an Aplio 500 ultrasound system (Toshiba Medical Systems Corporation, Tochigi, Japan). Ten measurements were obtained per patient by an operator blinded to all preceding readings. Results were analyzed with clinical information obtained from medical records. The median interquartile range/median ratio for 2D SWE was 0.131 (quartiles 1-3, 0.089-0.174). Five readings provided an approximation within 0.11 m/s, or 4.2% of the median velocity of 10 measurements. Factors associated with increased measurement variability included body mass index (ρ = 0.388; P = .01), increased skin-to-liver capsule distance (ρ = 0.426; P = .002), and measurements taken within 1.5 cm of the liver capsule (P < .001). Measurements with heterogeneous shear wave profiles (indicated by a region of interest [ROI] SD/speed ratio > 0.15) showed greater deviation from the set's median velocity than those with an ROI SD/speed ratio of 0.15 or lower (0.42 versus 0.22 m/s; P = .001). Two-dimensional SWE showed low overall measurement variability, with a minimum of 5 readings providing equivalent precision to the existing method using 10 samples. Obesity, increasing abdominal wall thickness, subcapsular measurements and an ROI SD/speed ratio of greater than 0.15 were all associated with increased measurement variability. The ROI SD/speed ratio warrants further evaluation as a quality assessment metric, to allow objective operator assessment of individual 2D SWE measurement reliability in real time.


Distinguishing between endocrine disruption and non-specific effects on endocrine systems.
The endocrine system is responsible for growth, development, maintaining homeostasis and for the control of many physiological processes. Due to the integral nature of its signaling pathways, it can be difficult to distinguish endocrine-mediated adverse effects from transient fluctuations, adaptive/compensatory responses, or adverse effects on the endocrine system that are caused by mechanisms outside the endocrine system. This is particularly true in toxicological studies that require generation of effects through the use of Maximum Tolerated Doses (or Concentrations). Endocrine-mediated adverse effects are those that occur as a consequence of the interaction of a chemical with a specific molecular component of the endocrine system, for example, a hormone receptor. Non-endocrine-mediated adverse effects on the endocrine system are those that occur by other mechanisms. For example, systemic toxicity, which perturbs homeostasis and affects the general well-being of an organism, can affect endocrine signaling. Some organs/tissues can be affected by both endocrine and non-endocrine signals, which must be distinguished. This paper examines in vitro and in vivo endocrine endpoints that can be altered by non-endocrine processes. It recommends an evaluation of these issues in the assessment of effects for the determination of endocrine disrupting properties of chemicals. This underscores the importance of using a formal weight of evidence (WoE) process to evaluate potential endocrine activity.


Ultrasound Doppler flow studies of the ovarian and uterine arteries.
The feasibility of studying ovarian arterial blood flow has been demonstrated, using an ultrasonic method combining real-time imaging and pulsed Doppler (the 'duplex' method). Results using a percutaneous full-bladder technique were validated by comparison with use of an ultrasound probe applied directly to the arteries at laparotomy. The ovarian arteries demonstrated qualitatively and quantitatively distinct flow patterns compared with the internal and external iliac arteries. From recorded waveforms a pulsatility index (PI) reflecting vascular impedance was calculated. The PI was found to be lower, indicating increased blood flow, in the artery supplying the ovary carrying the dominant follicle or corpus luteum. Serial studies suggest that this change occurs at an early stage of the menstrual cycle, possibly before the dominant follicle can be recognized by its size or increased hormone production. Uterine arterial flow was also detectable, more accurately abdominally than vaginally, and the changes typical of late pregnancy were already found to be present, though to a lesser degree, in the first trimester.


Absolute thickness metrology with submicrometer accuracy using a low-coherence distance measuring interferometer.
Absolute physical thickness across the sample aperture is critical in determining the index of a refraction profile from the optical path length profile for gradient index (GRIN) materials, which have a designed inhomogeneous refractive index. Motivated by this application, instrumentation was established to measure the absolute thickness of samples with nominally plane-parallel surfaces up to 50 mm thick. The current system is capable of measuring absolute thickness with 120 nm (1σ) repeatability and submicrometer expanded measurement uncertainty. Beside GRIN materials, this method is also capable of measuring other inhomogeneous and opaque materials.


Generalizing routes of plant exposure to pesticides by plant uptake models to assess pesticide application efficiency.
Pesticide application techniques are critical not only for integrated pest management (IPM) but also for food and environmental safety. Assessing pesticide application efficiency on plants can help optimize IPM and reduce pesticide environmental impacts. With hundreds of pesticides registered for use in agriculture, this study proposed a modeling approach based on plant uptake models for generalizing routes of plant chemical exposures that can correspond to different types of pesticide application methods and evaluating their respective efficiency on plants. Three representative pesticide application methods (i.e., drip irrigation, foliar spray, and broadcast application) were selected for modeling simulations. The simulation results for three representative pesticides (i.e., halofenozide, pymetrozine, and paraquat) revealed that the soil-based transpiration exposure route facilitated the bioaccumulation of moderately lipophilic compounds in leaves and fruits. While the plant surface-based exposure route (i.e., leaf cuticle penetration) made it easier for highly lipophilic compounds to enter plants, moderately lipophilic pesticides (i.e., log KOW ∼ 2) were more soluble in phloem sap, which enhanced their subsequent transport within plant tissues. In general, moderately lipophilic pesticides had the highest simulated residue concentrations in plant tissues for the three specific application methods, indicating they had the highest application efficiency due to their enhanced uptake routes (via transpiration and surface penetration) and increased solubility in xylem and phloem saps. Compared to foliar spray and broadcast application, drip irrigation produced higher residue concentrations for a wide variety of pesticides, exhibiting the highest application efficiency for many pesticides, especially for moderately lipophilic compounds. Future research should incorporate plant growth stages, crop safety, pesticide formulations, and multiple application events into the modeling approach for understanding pesticide application efficiency evaluation.


Postural preinspiratory cortical activity, genioglossus activity and fluid shift in awake obstructive sleep apnoea patients.
What is the central question of this study? Transition to supine posture induces an inspiratory load associated with cortical activation in awake healthy subjects. Some obstructive sleep apnoea patients exhibit this cortical activity in the sitting position contributing to the arousal-dependent compensation of their upper airway abnormalities. Does a transition to the supine posture in awake obstructive sleep apnoea patients increase this cortical activity? What is the main finding and its importance? The transition to supine posture induces a reduction in the cortical activity despite evidence of an increase in genioglossus activity, suggesting that genioglossus activation is not driven by cortical activity. The anatomy and mechanical properties of the upper airway (UA) depend on posture. Lying in a supine position causes cephalad fluid shift to the neck, thus narrowing the UA and predisposing the individual to obstructive sleep apnoea (OSA). Increased UA dilator muscle activity during wakefulness prevents the UA collapse but the underlying mechanism has not yet been elucidated. In the sitting position during wakefulness, some OSA patients exhibit preinspiratory cortical activity (preinspiratory potential, PIP) probably related to UA abnormalities. The aim of this study was to investigate changes in the preinspiratory cortical activity and UA dilator muscle in OSA patients during postural challenge. An electroencephalogram was used to detect PIP, and the genioglossus electromyographic activity and ventilation were analysed in 17 awake, male OSA patients while they were sitting, just after lying down, and then in response to leg positive pressure to enhance cephalad fluid shift. The prevalence of PIP decreased from 53% (sitting) to 12% (supine) (P = 0.002) in association with increased genioglossus activity (tonic from median (25th, 75th centiles) 2.3 (1.8, 2.8)% to 3.6 (1.7, 5.0)% of voluntary deglutition, P = 0.019; phasic from 2.3 (1.9, 2.8)% to 3.7 (2.0, 6.1)%, P = 0.024), and with increased transcutaneous carbon dioxide pressure (from 43.0 (42.4, 44.2) to 44.6 (43.5, 45.2) mmHg). No change was observed during leg-positive-pressure application. Moving from the sitting position to the supine position reduces respiratory-related premotor cortical activity in awake OSA patients. The concomitant increase in genioglossus activity, therefore, is not driven by cortical respiratory activity.


Developmental and diel profiles of plasma corticosteroids in the bullfrog, Rana catesbeiana.
Corticosteroids synergize with the thyroid hormone (TH) at late metamorphic stages and might have a role in the hormonal regulation of amphibian metamorphosis. This role could be influenced by diel fluctuations, particularly if the peak of the plasma corticoids changed in relation to the TH peaks. Diel variation in plasma corticosteroids was studied in Rana catesbeiana prometamorphic and climax tadpoles on 18:6, 12:12 and 6:18 light:dark (LD) cycles. Cortisol (hydrocortisone; HC) and aldosterone (ALDO) exhibited different, but LD cycle-specific, circadian fluctuations at prometamorphosis, whereas corticosterone (CORT) was undetectable (less than 1.18 ng/ml). HC, ALDO and CORT rhythms became synchronous at early metamorphic climax on all LD cycles, although the cosinor-derived acrophases, which occurred around the time of the dark:light transition, shifted approximately 6 h earlier from 18L:6D to 6L:18D. On both 18L:6D and 12L:12D, the acrophase of HC changed little from prometamorphosis to climax, whereas that of ALDO underwent a major phase shift. On 6L:18D, both the ALDO and the HC acrophases shifted at climax. These LD cycle-specific phase shifts of the diel rhythms placed the acrophases of the corticoids in different phase relationships to that of the previously determined thyroxine (T(4)) acrophase at climax, and may partially explain the influence of the light regimen on metamorphic timing. The pronounced diel variations in the corticoid concentrations from the troughs to the peaks show that hormone levels are a function of the time of day and the environmental lighting regimen, which need to be taken into account in measuring the level of plasma hormones in amphibians. The 24-h means calculated from the data of all the sampling times showed that only plasma ALDO and CORT, but not HC, rose markedly at climax, although there were significant LD cycle-related differences in the mean levels of both HC and ALDO at prometamorphosis, and in HC at climax. Additional work sampling at mid-light showed that plasma CORT peaked at Stage XXIII, decreased at the end of climax, and remained low in the postmetamorphic froglet at 2.1 ng/ml. In the adult bullfrog, CORT was clearly the predominant corticosteroid at 34.3 ng/ml, whereas HC and ALDO levels were only approximately 1.3 ng/ml.


Neurotrophins as a reliable biomarker for brain function, structure and cognition: A systematic review and meta-analysis.
Neurotrophins are signalling molecules involved in the formation and maintenance of synapses in the brain. They can cross the blood-brain barrier and be detected in peripheral blood, suggesting they may be a potential biomarker for brain health and function. In this review, the available literature was systematically searched for studies comparing peripheral neurotrophins levels with MRI and cognitive measures in healthy adults. Twenty-four studies were identified, six of which included a neuroimaging outcome. Fifteen studies measuring cognition were eligible for meta-analysis. The majority of studies measured levels of brain-derived neurotrophic factor (BDNF), with few assessing other neurotrophins. Results revealed BDNF is related to some neuroimaging outcomes, with some studies suggesting older age may be an important factor. A higher proportion of studies who had older samples observed significant effects between cognition and neurotrophin levels. When cognitive studies were pooled together in a meta-analysis, there was a weak non-significant effect between BDNF and cognitive outcomes. There was also a high level of heterogeneity between cognitive studies. Results indicated that gender was a notable source of the heterogeneity, but additional studies employing relevant covariates are necessary to better characterise the inter-relationship between circulating neurotrophins and cognition.


From thrombasthenia to next generation thrombocytopenia: Neonatal alloimmune thrombocytopenia induced by maternal Glanzmann thrombasthenia.
Glanzmann thrombasthenia (GT) is a rare autosomal recessive disorder of platelet function caused by mutations in the genes coding for integrin αIIbβ3. The aim of this study was to examine the outcome of newborns of GT mothers, with emphasis on thrombocytopenia and bleeding manifestations and their relation to maternal antiplatelet antibodies. Medical files of all female patients with GT treated in a single tertiary center from 1999 to 2017 were searched for details on pregnancy and birth. The medical files of their newborns were retrieved, and data on the postnatal course were collected. Nine babies were born to five patients with GT at our center during the study period. Three of the nine newborns had severe thrombocytopenia, and all three were offspring of GT mothers who were positive for antiplatelet antibodies. Pregnant GT patients should be examined for platelet antibodies. Assessment and management protocols (including treatment with intravenous immunoglobulins) for fetal and neonatal alloimmune thrombocytopenia should be considered.


Dietary fatty acids affect learning and memory ability via regulating inflammatory factors in obese mice.
High-fat diets are linked to obesity, contributing to the alterations in inflammatory signaling pathways, which is associated with cognitive function. We aim to investigate the mechanisms by which various different types of dietary fatty acids affecting cognitive function in obese mice through the gut/brain axis-inflammatory signaling pathway. 8-week-old male C57BL/6 mice were fed with basal diet (control group), lard high-fat diet (containing long-chain saturated fatty acid (LCSFA group)), coconut oil high-fat diet (containing medium-chain saturated fatty acid (MCSFA group)), linseed oil high-fat diet (containing n-3 polyunsaturated fatty acid (n-3 PUFA group)), soybean oil high-fat diet (containing n-6 polyunsaturated fatty acid (n-6 PUFA group)), olive oil high-fat diet (containing monounsaturated fatty acid (MUFA group)) and 8% hydrogenated soybean oil high-fat diet (containing trans fatty acid (TFA group)) respectively for 16 weeks. Our results revealed that the mean escape latency was significantly prolonged in LCSFA group, and the latency to cross the platform location of n-6 PUFA and TFA groups were increased significantly. The differences of inflammatory markers and toll-like receptor-myeloid differentiation factor-88-nuclear factor kappa-B (TLR-MyD88-NF-κB) inflammatory signaling pathway expressions among all groups reached statistical significances. Compared to basal diet, high-fat diets enriched in LCSFA, MCSFA, n-6 PUFA, MUFA, and TFA might exert detrimental effects on cognitive function in obese mice via regulating the inflammatory markers and inflammatory signaling pathway in brain and intestine. High-fat diet enriched in n-3 PUFA might exhibit different effect on modulating inflammatory responses in different tissues and might benefit to cognitive function.


Engineering Escherichia coli Nissle 1917 as a microbial chassis for therapeutic and industrial applications.
Genetically engineered microbes, especially Escherichia coli, have been widely used in the biosynthesis of proteins and metabolites for medical and industrial applications. As a traditional probiotic with a well-established safety record, E. coli Nissle 1917 (EcN) has recently emerged as a microbial chassis for generating living therapeutics, drug delivery vehicles, and microbial platforms for industrial production. Despite the availability of genetic tools for engineering laboratory E. coli K-12 and B strains, new genetic engineering systems are still greatly needed to expand the application range of EcN. In this review, we have summarized the latest progress in the development of genetic engineering systems in EcN, as well as their applications in the biosynthesis and delivery of valuable small molecules and biomacromolecules of medical and/or industrial interest, followed by a glimpse of how this rapidly growing field will evolve in the future.


Recurrent gastrointestinal bleeding diagnosed by delayed scintigraphy with Tc-99m-labeled red blood cells.
A 56-year-old woman presented with bright-red blood from the rectum. Esophagogastroduodenoscopy revealed mild gastritis. Colonoscopy demonstrated diverticulosis without active bleeding, and in vitro tagged red blood cell scintigraphy was unremarkable. There was no further evidence of bleeding and the patient was discharged home. The patient returned with recurrent bright-red blood from the rectum. Although delayed scintigraphic images seldom demonstrate the site of bleeding, delayed images at 12 hours demonstrated active bleeding near the hepatic flexure in this patient. This was confirmed with selective mesenteric angiography, and was treated with coil embolization of the tertiary branches of the right middle colic artery.


Synthetic algocyanobacterial consortium as an alternative to chemical fertilizers.
The use of unregulated pesticides and chemical fertilizers can have detrimental effects on biodiversity and human health. This problem is exacerbated by the growing demand for agricultural products. To address these global challenges and promote food and biological security, a new form of agriculture is needed that aligns with the principles of sustainable development and the circular economy. This entails developing the biotechnology market and maximizing the use of renewable and eco-friendly resources, including organic fertilizers and biofertilizers. Phototrophic microorganisms capable of oxygenic photosynthesis and assimilation of molecular nitrogen play a crucial role in soil microbiota, interacting with diverse microflora. This suggests the potential for creating artificial consortia based on them. Microbial consortia offer advantages over individual organisms as they can perform complex functions and adapt to variable conditions, making them a frontier in synthetic biology. Multifunctional consortia overcome the limitations of monocultures and produce biological products with a wide range of enzymatic activities. Biofertilizers based on such consortia present a viable alternative to chemical fertilizers, addressing the issues associated with their usage. The described capabilities of phototrophic and heterotrophic microbial consortia enable effective and environmentally safe restoration and preservation of soil properties, fertility of disturbed lands, and promotion of plant growth. Hence, the utilization of algo-cyano-bacterial consortia biomass can serve as a sustainable and practical substitute for chemical fertilizers, pesticides, and growth promoters. Furthermore, employing these bio-based organisms is a significant stride towards enhancing agricultural productivity, which is an essential requirement to meet the escalating food demands of the growing global population. Utilizing domestic and livestock wastewater, as well as CO2 flue gases, for cultivating this consortium not only helps reduce agricultural waste but also enables the creation of a novel bioproduct within a closed production cycle.


Comorbid diseases among bullous pemphigoid patients in Germany: new insights from a case-control study.
Bullous pemphigoid (BP) is associated with neuropsychiatric disorders. Other comorbid diseases are discussed controversially. We evaluated the prevalence of comorbidity in BP patients in a representative area of Germany. Medical files of all BP patients treated at the Department of Dermatology, University Hospital Würzburg, Germany, between June 2002 and May 2013 were retrospectively reviewed. Bullous pemphigoid was diagnosed based on established criteria. For each patient, two controls were individually matched. Records were evaluated for age, sex, laboratory values, concomitant medication and comorbidity. Conditional logistic regression, multivariable regression analysis and complex regression models were performed to compare results. 300 BP patients were identified and compared to 583 controls. Bullous pemphigoid was associated with neuropsychiatric disorders as well as laboratory abnormalities including leukocytosis and eosinophilia. Importantly, a highly significant association of BP with anemia (OR 2.127; 95 % CI 1.532-2.953) and renal impairment (OR 2.218; 95 % CI 1.643-2.993) was identified. No association was found with malignancy and arterial hypertension. Our data revealed an increased frequency of anemia and renal impairment in BP patients. In accordance with previous studies the strong association for neuropsychiatric disorders was confirmed (p < 0.0005).


Polymeric microfluidic system for DNA analysis.
The application of micro total analysis system (microTAS) has grown exponentially in the past decade. DNA analysis is one of the primary applications of microTAS technology. This review mainly focuses on the recent development of the polymeric microfluidic devices for DNA analysis. After a brief introduction of material characteristics of polymers, the various microfabrication methods are presented. The most recent developments and trends in the area of DNA analysis are then explored. We focus on the rapidly developing fields of cell sorting, cell lysis, DNA extraction and purification, polymerase chain reaction (PCR), DNA separation and detection. Lastly, commercially available polymer-based microdevices are included.


Willingness to COVID-19 vaccination: Empirical evidence from EU.
The unforgettable COVID-19 shock is most likely to be reversed by a viable vaccination strategy. In this paper, we investigate willingness to be vaccinated (WTV) against the COVID-19. Current trends suggest that only around 73% of EU inhabitants (15 and +) were immunized, with more than 104 million people still warranted to be immunized. Vaccine reluctance is a key impediment to conducting immunization programs in the setting of a pandemic. We provide first of its kind empirical evidence on the citizens (N = 11,932) of the EU-27 by employing the recent data from the European Commission. Based on the survey responses, controlling for the correlations in the error terms, we utilize a simulated multivariate probit regression model. Our results show that amongst all the statistically significant drivers of the WTV, the positive perception (vaccination works and has no side effects); R&D information (clarity on how vaccination is developed, tested, authorized) has the largest impact on the WTV. We find that the group of variables on social feedback (Positive perception; social adoption and pressure), and on trustworthy sources of information (R&D info; medical advice) are to be considered for WTV policy. The counteracting policy gaps that act against WTV include vaccination governance dissatisfaction, perception of long-term side effects, growing mistrust in information sources, uncertainty between safety and efficacy, education level, and risky age group. Strategies based on the outcomes of this study are needed to address public acceptance and willingness to vaccinate during a pandemic. This research is novel and offers authorities in-depth insights into the challenges and solutions regarding the COVID-19 pandemic and thus to its end via stimulation of the WTV.


Preclinical analysis of human mesenchymal stem cells: tumor tropism and therapeutic efficiency of local HSV-TK suicide gene therapy in glioblastoma.
Glioblastoma are highly invasive and associated with limited therapeutic options and a grim prognosis. Using stem cells to extend current therapeutic strategies by targeted drug delivery to infiltrated tumors cells is highly attractive. This study analyzes the tumor homing and therapeutic abilities of clinical grade human mesenchymal stem cells (MSCs) in an orthotopic glioblastoma mouse model. Our time course analysis demonstrated that MSCs display a rapid targeted migration to intracerebral U87 glioma xenografts growing in the contralateral hemisphere within the first 48h hours after application as assessed by histology and 7T magnetic resonance imaging. MSCs accumulated predominantly peritumorally but also infiltrated the main tumor mass and targeted distant tumor satellites while no MSCs were found in other regions of the brain. Intratumoral application of MSCs expressing herpes simplex virus thymidine kinase followed by systemic prodrug application of ganciclovir led to a significant tumor growth inhibition of 86% versus the control groups (p<0.05), which translated in a significant prolonged survival time (p<0.05). This study demonstrates that human MSCs generated according to apceth's GMP process from healthy donors are able to target and provide a significant growth inhibition in a glioblastoma model supporting a potential clinical translation.


Esophagogastroduodenoscopy in a public referral hospital in Lilongwe, Malawi: spectrum of disease and associated risk factors.
Esophagogastroduodenoscopy (EGD) is a valuable tool for diagnosing and treating upper gastrointestinal disease. Prioritizing the use of EGD in resource-limited settings must be customized to local populations to maximize population benefit from the examination. Cross-sectional, retrospective review of EGD reports was conducted at Kamuzu Central Hospital (KCH), Lilongwe, Malawi. Esophageal tumors were defined as obstructive or nonobstructive and esophageal varices were graded on a scale of I to IV. Descriptive statistics were calculated and logistic regression performed for each disease state compared with all other reports. A total of 1,034 cases were reviewed (56% male; mean age (standard deviation), 44 (17) years). The most common indications were dysphagia (37%), hematemesis (21%), and epigastric pain (16%). The most common diagnoses were normal (36%), esophageal cancer (27%), and esophageal varices (17%). Eighty-six percent of esophageal tumors were obstructive and 45% of esophageal varices were grade III or IV. Normal examinations were more likely to be female, younger, and present with dyspepsia. Esophageal cancers were more likely to be male, older, present with dysphagia, and present from districts outside Lilongwe. Esophageal varices were more likely to present with hematemesis. EGD is a limited resource at KCH; patient selection should be guided by patient age and indication. The high burden of esophageal cancer and varices in Malawi suggests that therapeutic endoscopy would be beneficial.


Effects of critical medium components on the production of antifungal lipopeptides from Bacillus amyloliquefaciens Q-426 exhibiting excellent biosurfactant properties.
In this study, influence of three critical parameters nitrogen sources, initial pH and metal ions was discussed in the production of antifungal lipopeptides from Bacillus amyloliquefaciens Q-426. The results revealed that lipopeptide biosynthesis might have relations with the population density of strain Q-426 and some special amino acids. Also, the alkali-resistant strain Q-426 could grow well in the presence of Fe(2+) ions below 0.8 M l(-1) and still maintain the competitive advantage below 0.2 M l(-1). Moreover, lipopeptides exhibited significant inhibitory activities against Curvularia lunata (Walk) Boed even at the extreme conditions of temperature, pH and salinity. Finally, biosurfactant properties of lipopeptides mixture were evaluated by use with totally six different methods including bacterial adhesion to hydrocarbons assay, lipase activity, hemolytic activity, emulsification activity, oil displacement test and surface tension measurement. The research suggested that B. amyloliquefaciens Q-426 may have great potential in agricultural and environmental fields.


Detection of sympathomimetic central nervous stimulants with special reference to doping. II. Comparative study of two adsorption chromatography methods using different XAD resins.
Recoveries of a series of sympathomimetic central nervous stimulants in human urine are measured using either adsorption chromatography on self-filled columns (method A) or with a special resin method suitable for racehorse urine (method B). The Amberlite resins used are XAD-2, XAD-4, XAD-7 and XAD-8 and elution is performed using chloroform. The reported comparative drug extractabilities indicate that in most instances the recoveries follow the sequence XAD-4 greater than XAD-2 approximately XAD-8 greater than XAD-7 using method A. Based on the recovery and purity of the extracts obtained, XAD-8 is preferred for gas chromatographic analysis while XAD-4 is very suitable for thin-layer chromatographic screening work. Comparing the two methods, equally good or better results were obtained with method A for all of the resins studied except XAD-7. Finally, it was found that the effect of refrigerated storage of the resins on the drug extractabilities for central nervous stimulants could be neglected.


Re-vitrectomy for recurrent retinal detachment in post-vitrectomy eyes of rhegmatogenous retinal detachment.
Recurrent retinal detachment (Re-RD) usually affects the prognosis of surgery for rhegmatogenous retinal detachment (RRD). Previous clinical studies of Re-RD were not specific. This study aimed to analyze the clinical characteristics of Re-RD in post-vitrectomy eyes with RRD and surgical outcomes after revitrectomy without combining it with retinectomy or scleral buckling. This is a retrospective case series analyzed the ocular characteristics of 20 recurrent and contralateral eyes, evaluated the significance of the associations between variables before reoperation and the final best-corrected visual acuity (BCVA), and calculated the outcome of revitrectomy. Patients with phakic eyes, those undergoing only one surgery, and those with more than one break had better final BCVA. The final BCVA was negatively correlated with the axial length and positively correlated with the preoperative BCVA. Among the 12 eyes with no break detected before surgery, 11 (92%) were found to have a small crevice-like break beside the pigment scar of a large number of original laser spots. The single-operation complete retinal reattachment rate was 75%, the complete retinal reattachment rate was 80%, and the final incomplete retinal reattachment rate was 90%. The BCVA improved from 1.2 ± 0.6LogMAR (0.06 ± 0.25) before surgery to 0.8 ± 0.7LogMAR (0.15 ± 0.2) at the last follow-up. The BCVA of 16 patients with complete retinal reattachment improved from 1.0 ± 0.5LogMAR (0.1 ± 0.3) to 0.6 ± 0.4LogMAR (0.25 ± 0.4). In the contralateral eyes, 15% already had vision-damaging disease, and the incidence of eyesight-threating lesions was 5.9% during follow-up. Revitrectomy without retinectomy or scleral buckling can effectively treat Re-RD in post-vitrectomy eyes. In Re-RD patients with no definite retinal break detected preoperatively, the retinal hole usually shows small crevice-like changes alongside a large number of original laser pigment scars.


Detection of colorectal adenomas with texture and color enhancement imaging: Multicenter observational study.
We aimed to evaluate the efficacy of texture and color enhancement imaging (TXI), which allows the acquisition of brighter images with enhanced color and surface structure in colorectal polyp detection compared to white light imaging. Patients who underwent colonoscopy with repeated ascending colon observation using TXI and white light imaging between August 2020 and January 2021 were identified in three institutions. The outcomes included the mean number of adenomas detected per procedure (MAP), adenoma detection rate (ADR), and ascending colonic adenoma miss rate (Ac-AMR). Logistic regression was used to determine the effects of the variables on the outcomes. We included 1043 lesions from 470 patients in the analysis. The MAP, ADR, flat polyp detection rate, and Ac-AMR in TXI and white light imaging were 1.5% (95% confidence interval 1.3-1.6%) vs. 1.0% (0.9-1.1%), 58.2% (51.7-64.6%) vs. 46.8% (40.2-53.4%), 66.2% (59.8-72.2%) vs. 49.8% (43.2-56.4%), and 17.9% (12.1-25.2%) vs. 28.2% (20.0-37.6%), respectively. TXI, age, withdrawal time, and endoscopy type were identified as significant factors affecting the MAP and the ADR using multivariate regression analysis. Our study indicates that TXI improve the detection of colorectal neoplastic lesions. However, prospective randomized trials are required to confirm these findings.


Low serum concentration of free triiodothyronine (FT3) is associated with increased risk of Alzheimer's disease.
In epidemiological studies, thyroid hormones (THs) have been associated with the risk of dementia. However, little is known of the relation between THs and risk of Alzheimer's disease (AD) or vascular dementia (VaD) in a memory clinic population. In a mono-center study, serum concentrations of thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) were assessed in 302 patients. All patients had subjective or objective mild cognitive impairment and none received treatment with THs. Cox proportional hazards regression analyses was used to determine whether THs at baseline were associated with the risk of conversion to all-cause dementia, AD or VaD. During the follow-up (mean 2.8 years), 82 (28%) of the patients progressed to dementia [AD, n = 55 (18%) and VaD, n = 17 (6%)]. Serum concentrations of TSH, FT4, and FT3 did not associate with all-cause dementia or VaD. Higher serum FT3 was associated with lower risk of conversion to AD [hazard ratio (HR) = 054; 95% confidence interval (CI): 0.32-0.92 per 1 pmol/L increase]. Furthermore, patients in the lowest serum FT3 quartile had a twofold increased risk of AD compared to those in the highest quartile (HR = 2.63; 95% CI: 1.06-6.47). These associations remained after adjustment for multiple covariates. In a memory clinic population, there was an inverse, linear association between serum FT3 and risk of AD whereas THs did not associate with all-cause dementia or VaD. Further studies are needed to determine the underlying mechanisms as well as the clinical significance of these findings.


Sulfate-reducing ammonium oxidation: A promising novel process for nitrogen and sulfur removal.
Sulfate-reducing ammonium oxidation (sulfammox), a novel and promising process that has emerged in recent years, is essential to nitrogen and sulfur cycles and offers significant potential for the elimination of ammonium and sulfate. This review discussed the development of sulfammox process, the mechanism, characteristics of microbes, potential influencing factors, applicable bioreactors, and proposed the research needs and future perspective. The sulfammox process could be affected by many factors, such as the NH4+/SO42- ratio, carbon source, pH, and temperature. However, these potential influencing factors were only obtained based on what has been seen in papers studying related processes such as denitrification, sulfate-reduction, etc., and have to be further tested in bioreactors carrying out the sulfammox process in the future. Currently, sulfammox is predominantly used in granular activated carbon anaerobic fluidized beds, up-flow anaerobic sludge blanket reactors, anaerobic expanded granular bed reactors, rotating biological contact reactors, and moving bed biofilm reactors. In the future, the operating parameters of sulfammox should be further optimized to improve the processing performance, and the system can be further scaled up for actual wastewater treatment. In addition, the isolation, identification, and characterization of key functional microbes and the analysis of microbial interrelationships will also be focused on in future studies to enable an in-depth analysis of the sulfammox mechanism.


A basic needs assessment of Kenyan health care practitioners' training and ability in providing resuscitation management for patients in Mbagathi Hospital, Nairobi.
To determine if health care providers at one district hospital in Nairobi, Kenya, possess the training and confidence necessary to attend to basic needs for patient resuscitation. Prospective cohort study. Mbagathi District Hospital, Nairobi, Kenya, a 300-bed, government district-level health care facility serving over one million Kenyans. 21 medical officers, clinical officers, medical officer and clinical officer interns, and nurses. An investigator-designed survey, the Self Assessment of Clinical Skills, designed to assess training and level of confidence in addressing basic resuscitation, was administered. 80% of respondents have been taught how to maintain a patent airway, but 22% felt less than confident in their ability. Nearly two thirds (62%) of respondents had not been trained to use a pulse oximeter. 100% of respondents felt they would benefit from additional training in airway and pulse oximetry assessment. While 90% reported that they had been taught to treat hypotension and 76% had experience treating hypotension, only 62% felt confident in their ability to treat hypotension. 95% desired additional training in hypotension management. 85% wanted additional training in measuring blood pressure, and every respondent desired additional training in the other circulatory monitoring skills listed on the survey. Providers of the Mbagathi District Hospital, Nairobi, report a lack of confidence in recognizing basic resuscitation needs, and they desire additional training.


Changes in the concentration of insulin-like growth factor I and transforming growth factor beta1 in rat femoral bone during growth.
Our knowledge of the concentration of growth factors in growing bone is limited. In the present study, we examined the developmental changes in the concentrations of insulin-like growth factor I (IGF-I) and transforming growth factor beta (TGF-beta) in the rat femur between weanling and maturity. We show that during the rapid growth phase there is a continuous rise in bone matrix IGF-I and TGF-beta in all compartments of the femoral bone. The association between IGF-I and TGF-beta is not only temporal, but with few exceptions is also observed within the animals of each age class. These data support the hypothesis that IGF-I and TGF-beta play an important role in the growth-associated accumulation of bone mass.


Niche metrics and diversity components.
Pielou's (1972) measures of niche width and overlap are related to ecological components of diversity. This relation is exploited to derive modified niche metrics with improved characteristics.


Point-of-care multiplex molecular diagnosis coupled with procalcitonin-guided algorithm for antibiotic stewardship in lower respiratory tract infection: a randomized controlled trial.
We aimed to show that coupling molecular syndromic respiratory panel (RP) testing with procalcitonin (PCT) measurement in the emergency department improves antibiotic (ATB) stewardship in lower respiratory tract infection. Open-label, prospective, randomized interventional trial, conducted from 2019 to 2022 in an adult emergency department. Patients with a suspicion of lower respiratory tract infection were randomized into an intervention arm (PCT measurement and point-of-care BIOFIRE RP2.1 plus testing, accompanied by a recommended ATB algorithm) or a standard of care (SOC) arm (PCT allowed as current practice). The primary endpoint was the duration of antibiotic exposure. Four hundred fifty-one patients were randomized, median age 65 years (Q1-Q3: 49-77), the hospitalization rate was 59.9% (270/451), the median length of stay 5 days (Q1-Q3: 3 - 12), and the 28-day mortality rate 5.3% (23/451). The median duration of ATB exposure was 6 days (Q1-Q3: 0-9) and 5 days (Q1-Q3: 0-9) in the SOC and interventional arm respectively (p = 0.71). ATB was started in 29.6 % (67/226) and 33.8% (76/225) respectively (p = 0.54). The BIOFIRE RP2.1 plus identified at least one viral species in 112/225 patients (49.8%) of intervention arm. Two hundred twelve out of two hundred twenty-six (93.8%) SOC patients had PCT measurement. The adherence rate to algorithm in the intervention arm was 93.3 % (210/225). Displaying PCT and real-time RP results to emergency physicians failed to significantly reduce ATB exposure in lower respiratory tract infection suspicions. However, the median ATB duration and rate of initiation were already low in the SOC arm using PCT measurement routinely.


A pilot study examining the frequency and quantity of gas embolization during operative hysteroscopy using a monopolar resectoscope.
To assess baseline frequency of gas embolization during standard monopolar resectoscopic surgery. Prospective, nonrandomized, observational study (Canadian Task Force classification II-2). Tertiary care medical center. Eleven women and three controls. Operative hysteroscopy. Echocardiography and serum studies were performed to detect bubble formation in the inferior vena cava, hepatic veins, and right heart. Gas bubbles were present in the hepatic veins or right heart in 10 patients and no controls. No patients had changes in coagulation profile and only one had clinical changes during surgery. Gas bubbles can been detected by echocardiography in most patients undergoing resectoscopic surgery in the uterus. Clinical significance may relate to anatomic variations as well as to gas bubble content and volume.


1,3,5-Triaza-7-phosphaadamantane (PTA) Derived Caged Phosphines for Palladium-Catalyzed Selective Functionalization of Nucleosides and Heteroarenes.
Phosphines have, in combination with transition metals, played a pivotal role in the rapid development of efficient catalytic processes. Caged phosphines constitute a class of three-dimensional scaffolds providing unique control over steric and electronic properties. The versatility of the caged phosphine ligands has been demonstrated elegantly by the groups of Verkade, Gonzalvi as well as Stradiotto. Our research group has also been working extensively for the past several years in the development of 1,3,5-triaza-7-phosphaadamantane-based caged ligands and in this personal note we have summarized these applications pertaining to the modification of biologically useful nucleosides and heteroarenes.


Comparison of Aripiprazole and Risperidone effectiveness in treating obsessive-compulsive disorder in patients with bipolar disorder: Double-blind, randomized clinical trial.
Obsessive-compulsive disorder (OCD) is a mental illness with a chronic coarse and waxing and waning of symptoms. Treatment of OCD in patients with bipolar disorder (BD) remains challenging. The present study aims to compare the safety and effectiveness of Risperidone and Aripiprazole as adjunctive therapy with valproate sodium, in treating mania, depression, and OCD in patients with comorbidity of OCD-BD. This research is 3 phase, double-blind, randomized clinical trial, with a total number of 64 patients. The diagnostic psychiatrist clinical interview was based on diagnostic and statistical manual of mental disorders, 5th edition (DSM-5) criteria. For assessing severity of OCD, mania, and depression, Yale-Brown obsessive-compulsive scale (Y-BOCS), young mania rating scale (YMRS), and Hamilton depression rating scale (HAM-D) scores were used. Patients were randomly assigned to the two parallel groups. All patients in both group were received valproate sodium, one group was treated with Aripiprazole and the other group was treated with Risperidon as adjective therapy with valproate sodium.The SPSS software (version 22), χ 2 test, t-test, and analysis of variance with repeated measures were used to analyze the data. The dosage and time of both drugs were statistically significant in reducing the mean score of all three mentioned scales, but the effect of group was not statistically significant in HAM-D and YMRS scores, only in terms of OCD, the mean of the Y-BOCS score was significantly lower in the Aripiprazole group (p < 0.001). In relation to side effects, Risperidone induced statistically significant weight gain (p < 0.001) and Aripiprazole induced statistically significant sleep disturbance (p < 0.05). Both Aripiprazole and Risperidone can be used effectively as adjunctive therapy with valproate sodium in treating OCD in patients with BD without any serious and life threatening adverse effect. Aripiprazole is more effective than Risperidone in treating OCD in BD.


Effect and formulation of ecolabel policy: A perspective of green supply chain decision and coordination.
Ecolabel policy has become an important strategy to encourage the consumption of green products throughout the world, contributing to sustainable development which is an inevitable choice for human society. Considering the manufacturer's reputation, consumer's environmental awareness, and effects of ecolabel certification on product demand, this study proposes several Stankelberg game models containing one manufacturer and one retailer to compare the optimal decisions and the impacts on the green supply chain with/without ecolabel certification, where four different scenarios are investigated in the centralized and decentralized situations. The results indicate that the ecolabel policy only functions below a threshold associated with the consumer's environmental awareness, which is higher in the decentralized situation. On the contrary, the optimal ecolabel standard in the centralized decision-making situation is higher than that in the decentralized ones if maximizing the environmental benefit. For the manufacturer, only when producing products as the ecolabel standard can it get the optimal profit. Finally, a wholesale price contract with the manufacturer's reputation is proposed, which improves the product's green degree and the environmental benefit to the optimal level in a decentralized supply chain.


Decentralizing conservation and diversifying livelihoods within Kanchenjunga Conservation Area, Nepal.
To alleviate poverty and enhance conservation in resource dependent communities, managers must identify existing livelihood strategies and the associated factors that impede household access to livelihood assets. Researchers increasingly advocate reallocating management power from exclusionary central institutions to a decentralized system of management based on local and inclusive participation. However, it is yet to be shown if decentralizing conservation leads to diversified livelihoods within a protected area. The purpose of this study was to identify and assess factors affecting household livelihood diversification within Nepal's Kanchenjunga Conservation Area Project, the first protected area in Asia to decentralize conservation. We randomly surveyed 25% of Kanchenjunga households to assess household socioeconomic and demographic characteristics and access to livelihood assets. We used a cluster analysis with the ten most common income generating activities (both on- and off-farm) to group the strategies households use to diversify livelihoods, and a multinomial logistic regression to identify predictors of livelihood diversification. We found four distinct groups of household livelihood strategies with a range of diversification that directly corresponded to household income. The predictors of livelihood diversification were more related to pre-existing socioeconomic and demographic factors (e.g., more landholdings and livestock, fewer dependents, receiving remittances) than activities sponsored by decentralizing conservation (e.g., microcredit, training, education, interaction with project staff). Taken together, our findings indicate that without direct policies to target marginalized groups, decentralized conservation in Kanchenjunga will continue to exclude marginalized groups, limiting a household's ability to diversify their livelihood and perpetuating their dependence on natural resources.


Concerns with the health check-up system for chronic obstructive pulmonary disease on two Japanese islands.
Early diagnosis is a key factor in the management of chronic obstructive pulmonary disease (COPD). Although mass screening is widely used, little is known about its accuracy and efficacy. This study investigated whether using spirometry during mass screening to detect COPD among community residents might be ineffective because of variability in the training and experience of examiners. Both spirometry and a self-written questionnaire-based survey, including questions designed to detect respiratory symptoms, were conducted on community residents. Two separate studies were conducted on islanders living in similar environments. Study I was performed from 2004 to 2007 on Hachijyo Island residents, while study II, with a similar study design, was performed in 2003 on Inno Island residents. In study I, 3,592 subjects underwent examination over the 4-year study period; of these, 378 subjects underwent repeated examinations. Approximately 25% of the subjects had respiratory symptoms. Acceptable spirometry recordings were obtained for 62.0% (2004) to 84.1% (2006) of the subjects. In study II, 167 of the 254 subjects (65.7%) had respiratory symptoms. Acceptable assessment recordings were achieved in 254 subjects (95.5%). The suitability of the recordings was influenced by the extent/level of training of the examiners and the accompanying thoracic specialists. We concluded that the effectiveness of health check-ups for COPD evaluation using spirometry was greatly influenced by the quality of the examiners, even when the subjects had respiratory symptoms. Thus, we recommend caution when screening for early signs of COPD during health check-ups.


Pediatric round pneumonia.
"Round pneumonia" or "spherical pneumonia" is a well-characterized clinical entity that seems to be less addressed by pediatricians in Taiwan. We herein report the case of a 7-year-old boy who presented with prolonged fever, cough, and chest X-rays showing a well-demarcated round mass measuring 5.9 × 5.6 × 4.3 cm in the left lower lung field, findings which were typical for round pneumonia. The urinary pneumococcal antigen test was positive, and serum anti-Mycoplasma pneumoniae antibody titer measurement using a microparticle agglutination method was 1:160 (+). After oral administration of antibiotics including azithromycin and amoxicillin/clavulanate, which was subsequently replaced by ceftibuten due to moderate diarrhea, the fever subsided 2 days later and the round patch had completely resolved on the 18th day after the diagnosis. Recent evidence suggests treating classical round pneumonia with antibiotics first and waiving unwarranted advanced imaging studies, while alternative etiologies such as abscesses, tuberculosis, nonbacterial infections, congenital malformations, or neoplasms should still be considered in patients with atypical features or poor treatment response.


Flumazenil responsive ornithine transcarbamylase deficiency encephalopathy: clinical and radiographic features.
A 22-year-old woman with a negative urine drug screen and somnolence rapidly reversed by intravenous flumazenil was found to have elevated ammonia levels and punctate calcifications of the subcortical frontal white matter. Abnormally high levels of orotic acid were found in serum and urine, confirming the diagnosis of ornithine transcarbamylase deficiency. Although computed tomography findings are non-specific, young patients with unexplained hyperammonemic states of somnolence reversed by flumazenil should be screened for this X-linked recessive metabolic disorder.


Quantification of foveal avascular zone area and macular vascular density changes in papilledema by swept-source optical coherence tomography angiography.
This work provide objective measures of foveal avascular zone area and macular vascular density by swept-source optical coherence tomography angiography during the follow-up of a patient with papilledema due to secondary intracranial hypertension.


Occupational health properties of organic pigments.
Certain terms and statements made by the author of Ref. [1] are criticized. Published evidence dose not support the term "probable carcinogen". "Possible carcinogen" is preferred. Extrapolation of conclusions of carcinogenicity to pigments not yet tested is unwarranted.


Inner myometrial laceration - an unusual presentation of antepartum and postpartum hemorrhage: case reports and review of the literature.
The aim of this study is to evaluate the diagnostic criteria, treatment options and progression of cases who have antenatal or postpartum hemorrhage due to internal myometrial laceration (IML) and to review the literature. The files of eight patients who were diagnosed to have IML between August 2012 and July 2015 were evaluated retrospectively. The patient group consisted of four patients who had an emergency c-section due to massive bleeding during labor and four patients who had an emergency laparotomy due to uncontrolled bleeding after vaginal delivery after evaluation of the patient for signs of 4Ts (trauma, tissue retention, uterine tonus, and trombin). Primary suturation was the first-line treatment in all patients. In two of the patients, hysterectomy was performed after the defined surgical procedures were not successful in controling the bleeding. The presented case series is a pioneering study that describes IM which is a poorly defined reason of postpartum hemorrhage, as the cause of bleeding during labor. Primary suturation is the first-step, further surgery might be required in order to treat this life-threathening condition and the decision should be based on the age and the fertility status of the patient.


Comparison of the orthodontic load systems created with elastomeric power chain to close extraction spaces on different rectangular archwires.
The 3-dimensional load system (forces and moments) was quantified at the canine bracket during space closure with sliding mechanics with elastomeric chain on dry and wet stainless steel and beta-titanium 0.019 × 0.025-in archwires. A custom-made maxillary dentoform simulating first premolar extractions was attached to an orthodontic force tester. The canine was attached to a load cell through an adaptor with silicone simulating the periodontal ligament. The orthodontic force tester simultaneously measured the entire load system produced at the canine bracket by an elastomeric chain. The effects of archwire material, time (activation and 1 hour), and lubrication were analyzed by using 3-way repeated measures analysis of variance (ANOVA, α = 0.05). Stainless steel provided a greater (P = 0.001) load system than did beta-titanium. The force was greatest on the canine in the lingual axis. The greatest moment was about the y-axis. The moment-to-force ratio, the most critical ratio, was greater for beta-titanium than stainless steel; however, both were close to the ideal 10:1. With a stainless steel archwire for retraction sliding mechanics, a canine will experience a greater load system in all 3 dimensions than with a beta-titanium wire. Both archwires produced a moment-to-force ratio adequate for translation.


Radioprotective effect of vitamins C and E.
Albino rats were treated with aqueous vitamin C solution and vitamin E solution dissolved in olive oil at two concentrations, 100 and 300 mg/kg/day, for 6 months. Some of the animals were then subjected to whole-body irradiation. Chromosomal aberrations and mitotic activity in non-irradiated and irradiated groups were recorded. Both vitamins were found to be non-mutagenic. Vitamin C exerted a radioprotective effect but vitamin E was not radioprotective and it suppressed the radioprotection otherwise produced by olive oil.


Changes in serum concentrations of beta-carotene and changes in the dietary intake frequency of green-yellow vegetables among healthy male inhabitants of Japan.
Serum levels of beta-carotene among 147 healthy male inhabitants were measured twice with an interval of one year in order to determine the relationship between changes in serum beta-carotene levels and changes in the dietary intake of green-yellow vegetables. A positive association was found to exist between changes in the intake frequency of green-yellow vegetables and changes in serum beta-carotene levels, whereas changes in alcohol intake and smoking were discovered to be negatively associated with changes in serum beta-carotene levels. The positive association between changes in the intake frequency of green-yellow vegetables and changes in serum beta-carotene levels was preserved after adjustment for these negative factors.


RNA sequencing as an alternative tool for detecting measurable residual disease in core-binding factor acute myeloid leukemia.
DNA sequencing-based measurable residual disease (MRD) detection has shown to be clinically relevant in AML. However, the same methodology cannot be applied to fusion gene-driven subtypes of AML such as core-binding factor AML (CBF-AML). Here in this study, we evaluated the effectiveness of using DNA and RNA sequencing in MRD detection and in tracking clonal dynamics in CBF-AML. Using RNA-seq, we were able to quantify expression levels of RUNX1-RUNX1T1 and CBFB-MYH11 at diagnosis and their levels of reduction during remission (P < 6.3e-05 and P < 2.2e-13). The level of reduction of RUNX1-RUNX1T1 as measured by RNA-seq and qPCR were highly correlated (R2 = 0.74, P < 5.4e-05). A decision tree analysis, based on 3-log reduction of RUNX1-RUNX1T1 and cKIT-D816mut at diagnosis, stratified RUNX1-RUNX1T1 AML patients into three subgroups. These three subgroups had 2-year overall survival rates at 87%, 74%, and 33% (P < 0.08) and 2-year relapse incidence rates at 13%, 42%, and 67% (P < 0.05). On the other hand, although low residual allelic burden was common, it was not associated with long-term outcome, indicating that mutation clearance alone cannot be interpreted as MRD-negative. Overall, our study demonstrates that the clinical utility of RNA sequencing as a potential tool for MRD monitoring in fusion gene-driven AML such as RUNX1-RUNX1T1 AML.


Inflammatory response and biomechanical properties of coaxial scaffolds for engineered skin in vitro and post-grafting.
Engineered skin (ES) offers many advantages over split-thickness skin autografts for the treatment of burn wounds. However, ES, both in vitro and after grafting, is often significantly weaker, less elastic and more compliant than normal human skin. Biomechanical properties of ES can be tuned in vitro using electrospun co-axial (CoA) scaffolds. To explore the potential for coaxial scaffold-based ES use in vivo, two CoA scaffolds were fabricated with bioactive gelatin shells and biodegradable synthetic cores of polylactic acid (PLA) and polycaprolactone (PCL), and compared with gelatin monofilament scaffolds. Fibroblast and macrophage production of inflammatory cytokines interleukin 6 (IL-6) and transforming growth factor β-1 was significantly higher when cultured on PLA and PCL monofilament scaffolds compared to gelatin monofilament scaffolds. The core-shell fiber configuration significantly reduced production of pro-inflammatory cytokines to levels similar to those of gelatin monofilament scaffolds. In vitro, ES mechanical properties were significantly enhanced using CoA scaffolds; however, after grafting CoA- and gelatin-based ES to full-thickness excisional wounds on athymic mice, the in vitro mechanical advantage of CoA grafts was lost. A substantially increased inflammatory response to CoA-based ES was observed, with upregulation of IL-6 expression and a significant M2 macrophage presence. Additionally, expression of matrix metalloproteinase I was upregulated and collagen type I alpha 1 was downregulated in CoA ES two weeks after grafting. These results suggest that while coaxial scaffolds provide the ability to regulate biomechanics in vitro, further investigation of the inflammatory response to core materials is required to optimize this strategy for clinical use. STATEMENT OF SIGNIFICANCE: Engineered skin has been used to treat very large burn injuries. Despite its ability to heal these wounds, engineered skin exhibits reduced biomechanical properties making it challenging to manufacture and surgically apply. Coaxial fiber scaffolds have been utilized to tune the mechanical properties of engineered skin while maintaining optimal biological properties but it is not known how these perform on a patient especially with regards to their inflammatory response. The current study examines the biomechanical and inflammatory properties of coaxial scaffolds and uniaxial scaffolds in vitro and in vivo. The results show that the biological response to the scaffold materials is a critical determinant of tissue properties after grafting with reduced inflammation and rapid scaffold remodeling leading to stronger skin.


Clinical features of biliary tract cancer in Japanese individuals with Lynch syndrome.
Biliary tract cancer (BTC) is a Lynch syndrome (LS)-associated cancer with a high mortality rate. This study aimed to clarify the clinical features of BTC in individuals with LS and to discuss its management. We obtained data from genetically verified Japanese individuals with LS who were diagnosed at a single institution, between January 2003 and April 2021. Moreover, 21 individuals with sporadic BTC (n=15) and LS associated BTC (n=6) underwent microsatellite instability (MSI) testing. Among 92 individuals with LS, 6 individuals with MLH1 variants developed BTCs (10 lesions, male/female, 2:1). The median age at diagnosis of initial BTC was 69 years (range, 34-78 years). Histological examination revealed a predominance of differentiated adenocarcinoma (89%). Then, 2 individuals had multiple BTCs. All available 7 BTC lesions showed high-frequency of microsatellite instability (MSI-H). MLH1 carriers showed a 7.2% cumulative risk of BTC development at an age of 70 years. Five of the six individuals died of BTC. MSI analysis could facilitate LS identification in individuals with BTC. Surveillance for BTC should be considered for MLH1 carriers in Japan.


Vein patch grafting for repair of short ureteric strictures.
The generally accepted treatment for short and medium-length strictures of the ureter has been to split the stricture and splint the ureter for a month or more. A new method is here described in which the ureteric stricture is split and the opening is covered with a vein patch-graft. The length of hospital stay is considerably reduced by this operation. Four successfully treated cases with follow-up periods of six months to ten years are presented.


Development of innovative methodology for determination of 6-thioguanine in whole blood erythrocytes by HPLC-PDA-based technique for medical diagnostics purposes.
6-Thioguanine is an immunosuppressive drug, an analogue of guanine, applied to treat acute leukemia and inflammatory bowel disease. Excessive use of 6-thioguanine during clinical treatment may cause side effects. Moreover, providing a dose too low will be ineffective. Therefore, there is a critical need for a rapid, selective and routine approach to quantifying 6-thioguanine in body fluids to support a clinical application. A fully validated HPLC method has been developed to determine 6-thioguanine in whole blood samples using 5-bromouracil as an internal standard. 6-Thioguanine nucleotides were released from erythrocytes by perchloric acid, and then hydrolysed at 100 °C to the parent thiopurine, 6-thioguanine. The following validation parameters of the method were determined: specificity/selectivity, linearity range (479-17,118 ng/mL, R > 0.992), limits of detection (150 ng/mL) and quantification (479 ng/mL), accuracy (- 5.6 < Bias < 14.7), repeatability (CV 1.30-3.24%), intermediate precision (CV 4.19-5.78%), extraction recovery (79.1-103.6%) and carryover. Furthermore, the stability of the drug in whole blood samples under various storage conditions was investigated. The suggested method is suitable for determining 6-thioguanine in whole blood erythrocyte samples for drug level monitoring, thus correct dosing.


Impact of payer status and hospital volume on outcomes after head and neck oncologic reconstruction.
High-volume centers improve outcomes in head and neck cancer (HNCA) reconstruction, yet it is unknown whether patients of all payer status benefit equally. We identified patients undergoing HNCA surgery between 2002 and 2015 using the National Inpatient Sample. Outcomes included receipt of care at high-volume centers, receipt of reconstruction, and post-operative complications. Multivariate regression analysis was stratified by payer status. 37,442 patients received reconstruction out of 101,204 patients who underwent HNCA surgery (37.0%). Privately-insured and Medicaid patients had similar odds of receiving high-volume care (OR = 0.99, 95% CI = 0.87-1.11) and undergoing reconstruction (OR = 0.96, 95% CI = 0.86-1.05). Medicaid beneficiaries had higher odds of complication (OR = 1.36, 95% CI = 1.22-1.51). The discrepancy in complication odds was significant at low-volume (OR = 1.44, 95% CI = 1.12-1.84) and high-volume centers (OR = 1.30, 95% CI = 1.15-1.47). Medicaid beneficiaries are as likely to receive care at high-volume centers and undergo reconstruction as privately-insured individuals. However, they have poorer outcomes than privately-insured individuals at both low- and high-volume centers.


[Evaluation of treatment with hemineurine in delirium tremens].
The authors make a sum-up of all cases of delirium tremens admitted to the Lausanne University Psychiatric Clinic during the period 1970-1974. All were treated by intravenous and oral chlormethiazole (hemineurine), its technique being described. The need to restablish the fluid and electrolitic balance is stressed. Side effects are not important and there is a shortening of the acute phase, as compared to other techniques. Mortality is nil. The authors suggest that chlormethiazole is an indication of choice in the treatment of delirium tremens and are surprised that this substance has not yet taken its place in the U.S.A.


Association between Carotid Intima-media Thickness and Early-onset Coronary Artery Disease: Does the site of Sonographic Evaluation Matter?
Intima-media thickness (IMT) is frequently used for risk stratification (RS) due to the association with coronary artery disease (CAD). Nonetheless, the best carotid site to scan is uncertain, especially in the young. The aim of this study was to evaluate the diagnostic performance of IMT measurements performed at different carotid sites. Eighty-nine subjects ≤45 years were studied (55 with known CAD and 34 controls). IMT measurements were performed at the common carotid (CC), bulb and internal branch (IB) of both carotid arteries, (2112 measures). The diagnostic performance of IMT measurements performed at different sites, regarding the presence of CAD, was evaluated with ROC curves. Carotid plaques were found in 20.0% of the patients and 6.0% of the controls. The diagnostic performance of carotid IMT measures obtained at the CC, bulb or IB was not significantly different, with the CC and IB being slightly better (AUC ROC =0.82 and 0.80 respectively). IMT measures obtained at different carotid sites are associated with CAD in young (≤45 years) individuals. The diagnostic performance of IMT measured at the CC and IB is the more accurate measure, and this may be the most adequate for the measurement of IMT in this population.


Perceived naturalness of facial expression after hyaluronic acid filler injection in nasolabial folds and lower face.
In addition to having a younger and more attractive appearance after facial aesthetic treatment, patients desire natural-looking and long-lasting results. To evaluate perceived naturalness of dynamic facial expressions after treatment with hyaluronic acid fillers in nasolabial folds (NLFs) and lower face wrinkles and folds. Subjects requiring treatment of moderate-to-severe NLFs and at least one other lower face indication were treated with hyaluronic acid fillers. Assessments included perceived naturalness, attractiveness and age, NLF severity, aesthetic improvement, satisfaction, and safety. Sixty-three subjects were enrolled. Six months after treatment, naturalness of facial expression was maintained or enhanced for ≥98% of subjects, attractiveness was enhanced for ≥61% of subjects, and ≥34% of subjects looked younger, as assessed by investigators and an independent evaluator. Wrinkle severity had improved at least 1 grade for ≥54% of subjects at Month 12. Aesthetic improvement was reported for ≥92% of subjects 12 months after treatment. Satisfaction with treatment outcome was high. Local tolerability events and adverse events were mainly mild or moderate and resolved spontaneously. Hyaluronic acid treatment in NLFs and lower face was well tolerated and achieved natural-looking results, long-lasting aesthetic improvement, and high satisfaction with treatment outcome.


Prognosis and chemosensitivity of non-colorectal alimentary tract cancers with microsatellite instability.
Data on outcomes of microsatellite instable and/or mismatch repair deficient (dMMR/MSI) digestive non-colorectal tumors are limited. To evaluate overall survival (OS) of patients with dMMR/MSI digestive non-colorectal tumor. All consecutive patients with a dMMR/MSI digestive non-colorectal tumor were included in this French retrospective multicenter study. One hundred and sixteen patients were included with a mean age of 63.6 years and 32.6% with a Lynch syndrome. Most tumors were oesophago-gastric (54.3%) or small bowel (32.8%) adenocarcinomas and at a localized stage at diagnosis (86.7%). In patients with localized tumors and R0 resection, median OS was 134.0 ± 64.2 months. Median disease-free survival (DFS) was 100.3 ± 65.7 months. Considering oesophago-gastric tumors, median DFS was improved when chemotherapy was added to surgery (not reached versus 22.8 ± 10.0 months, p = 0.03). In patients with advanced tumors treated by chemotherapy, median OS was 14.2 ± 1.9 months and median progression-free survival was 7.4 ± 1.6 months. dMMR/MSI digestive non-colorectal tumors are mostly diagnosed at a non-metastatic stage with a good prognosis. Advanced dMMR/MSI digestive non-colorectal tumors have a poor prognosis with standard chemotherapy.