Search

Although infection with the methicillin-resistant Staphylococcus aureus (MRSA) clone USA300 is extremely rare in Japan, the uniquely evolved clone ΨUSA300 has been reported in Japan. An outbreak of a distinct USA300 clone was recently reported in an HIV/AIDS referral hospital in Tokyo. The present study investigated the evolutionary origin and genetic diversity of USA300-related clones causing regional outbreaks among people living with HIV (PLWHIV) in Tokyo. MRSA isolates collected from PLWHIV in an HIV/AIDS referral center in Tokyo were subjected to whole-genome sequencing and their genetic features were compared with those of previously described USA300 MRSA genomes. Of the 28 MRSAs isolated in 2016–2019, 23 (82.1%) were identified as USA300, with 22 (95.6%) of the latter identified as ΨUSA300. Although the genomic structure of ΨUSA300 was identical to the structures of reference USA300 strains, one clade (cluster A) was found to have acquired 29 previously identified lineage-specific mutations in a stepwise manner. The estimated divergence dates of ΨUSA300 and Cluster A were 2009 and 2012, respectively. These findings suggested that the ΨUSA300 clone had spread among PLWHIVs in Tokyo in the early 2010s, with stepwise acquisition of lineage-specific nonsynonymous mutations.

Utilizing the red mud sustainably is now a challenging issue. Red mud due to its wide production, presence of some radioactive elements, high alkalinity, and salinity, has a dramatic potential to contaminate soil and groundwater. Notwithstanding its drawbacks, Red mud consists several elements, including Ca, Al, Ti, Si, and Fe, in various mineral forms. In this study, stepwise leaching was applied as a proper method to separate and purify the main valuable elements using available and affordable HCl. The pre-leaching step under optimized conditions using HCl (0.2 M) at room temperature for 2 h removed 89% of the calcium content from red mud. To selectively remove the solid silica, the residue was treated with concentrated HCl (3.0 M, L/S of 20 mL/g) at 95 °C, resulting in the dissolution of iron and aluminum content with up to 90% efficiency. After precipitation of the Fe3+ and Al3+, they were characterized using FT-IR, BET, EDS, XRD, SEM and TEM monographs, confirming the formation of nanosized hematite (α-Fe2O3) and mesoporous gamma alumina (γ-Al2O3). Consequently, inexpensive red mud was converted into highly valuable nano-sized metal oxides using simple, sustainable techniques and cheap reagents. Moreover, this technique generates the lowest amounts of waste during the leaching process and all reagents can be recycled for further uses, making this method a sustainable utilization.

To investigate the outcomes of the modified radial tongue-shaped flap following stepwise surgery release for treating Benson type I camptodactyly of the 5th digit. A retrospective analysis involving patients with Benson type I camptodactyly of the 5th digit was performed. A total of 8 patients with 12 affected digits were included. Extent of surgical release depended on the degree of soft tissue contracture. Skin release, subcutaneous fascial release, and flexor digitorum superficialis tenotomy were performed in all 12 digits, sliding volar plate release in 2 digits, and intrinsic tendon transfer in 1 digit. The mean total passive motion of proximal interphalangeal joint significantly increased from 32.5° ± 16° to 86.3° ± 20.4°, while mean total active motion significantly increased from 22° ± 10.5° to 73.8° ± 27.5° (P

In this paper, six types of air pollutant concentrations are taken as the research object, and the data monitored by the micro air quality detector are calibrated by the national control point measurement data. We use correlation analysis to find out the main factors affecting air quality, and then build a stepwise regression model for six types of pollutants based on 8 months of data. Taking the stepwise regression fitting value and the data monitored by the miniature air quality detector as input variables, combined with the multilayer perceptron neural network, the SRA-MLP model was obtained to correct the pollutant data. We compared the stepwise regression model, the standard multilayer perceptron neural network and the SRA-MLP model by three indicators. Whether it is root mean square error, average absolute error or average relative error, SRA-MLP model is the best model. Using the SRA-MLP model to correct the data can increase the accuracy of the self-built point data by 42.5% to 86.5%. The SRA-MLP model has excellent prediction effects on both the training set and the test set, indicating that it has good generalization ability. This model plays a positive role in scientific arrangement and promotion of miniature air quality detectors. It can be applied not only to air quality monitoring, but also to the monitoring of other environmental indicators.

Neural regeneration is extremely difficult to achieve. In traumatic brain injuries, the loss of brain parenchyma volume hinders neural regeneration. In this study, neuronal tissue engineering was performed by using electrically charged hydrogels composed of cationic and anionic monomers in a 1:1 ratio (C1A1 hydrogel), which served as an effective scaffold for the attachment of neural stem cells (NSCs). In the 3D environment of porous C1A1 hydrogels engineered by the cryogelation technique, NSCs differentiated into neuroglial cells. The C1A1 porous hydrogel was implanted into brain defects in a mouse traumatic damage model. The VEGF-immersed C1A1 porous hydrogel promoted host-derived vascular network formation together with the infiltration of macrophages/microglia and astrocytes into the gel. Furthermore, the stepwise transplantation of GFP-labeled NSCs supported differentiation towards glial and neuronal cells. Therefore, this two-step method for neural regeneration may become a new approach for therapeutic brain tissue reconstruction after brain damage in the future.

BackgroundHearing loss is one of the most common birth disorders in humans with an estimated prevalence of 1-3 in every 1000 newborns. This study has investigated the molecular etiology of a deaf cohort using a stepwise strategy to effectively diagnose patients and the challenges faced to verify genetic heterogenicity and the variable mutation spectrums of hearing loss.MethodsIn order to target known pathogenic variants, multiplex PCR plus next-generation sequencing was applied in the first tier, while undiagnosed cases were further referred to exome sequencing. A total of 92 unrelated patients with nonsyndromic hearing loss were enrolled.ResultsIn total, 64% (59/92) of patients were molecularly diagnosed, 44 of which were identified in the first tier by multiplex PCR plus sequencing. Of 48 undiagnosed patients from the first tier, exome sequencing identified eleven diagnoses (23%, 11/48) and four probably diagnoses (8%, 4/48). The rate of secondary findings of exome sequencing in our cohort is 3.4%.ConclusionThe research presented a molecular diagnosis spectrum of 92 non-syndromic hearing loss patients and demonstrated the benefits of using the stepwise diagnostic approach in the genetic test of the non-syndromic hearing loss patient cohort.

We present a theoretical model describing photoelectron transport dynamics in stepwise-doped GaAs photocathodes. Built-in electric field caused by the doping structure is analyzed, and the time-evolution of electron concentration in the active layer induced by a femtosecond laser pulse is solved. The predictions of the model show excellent agreement with the experimental data measured with pump-probe transient reflectometry, demonstrating the capability of the theoretical model in predicting photoelectron behaviors in real devices. Comparisons are also made between this stepwise doping model and the conventional gradient doping model with a continuous doping profile, thereby providing the first quantitative evaluation of the effectiveness and the limitation of the gradient doping model in describing actual stepwise-doped devices.

Conventional neuronal network pattern formation techniques cannot control the arrangement of axons and dendrites because network structures must be fixed before neurite differentiation. To overcome this limitation, we developed a non-destructive stepwise microfabrication technique that can be used to alter microchannels within agarose to guide neurites during elongation. Micropatterns were formed in thin agarose layer coating of a cultivation dish using the tip of a 0.7 [Formula: see text]-diameter platinum-coated glass microneedle heated by a focused 1064-nm wavelength infrared laser, which has no absorbance of water. As the size of the heat source was 0.7 [Formula: see text], which is smaller than the laser wavelength, the temperature fell to 45 [Formula: see text] within a distance of 7.0 [Formula: see text] from the edge of the etched agarose microchannel. We exploited the fast temperature decay property to guide cell-to-cell connection during neuronal network cultivation. The first neurite of a hippocampal cell from a microchamber was guided to a microchannel leading to the target neuron with stepwise etching of the micrometer resolution microchannel in the agarose layer, and the elongated neurites were not damaged by the heat of etching. The results indicate the potential of this new technique for fully direction-controlled on-chip neuronal network studies.

The aim of this study was to analyze changes in refraction and evaluate the variables in school children who received atropine as myopic control for 10 years. Low-concentration atropine (0.05%) was prescribed initially, and the dose was increased in a stepwise manner if rapid myopic progression (≥ 0.5D per half year) was noted during the regular follow-up visit. 23 children with a mean age of 6.96 ± 1.07 years were included. The initial spherical equivalent was − 1.25 ± 0.84 D. The overall mean myopic progression was − 0.30 ± 0.27 D/year. Younger initial age, female, higher initial spherical equivalent and the need of higher concentration of atropine were found to be risk factors for myopic progression in multivariate mixed-effect analysis (p = 0.013, 0.017, 0.024 and 0.014). Children who kept using a lower concentration of atropine (≤ 0.1%) tended to have slower myopic progression throughout the 10-year course than those who shifted to higher concentrations (> 0.1%) (p ≤ 0.001). Stepwise low concentration of atropine might be effective for long-term myopic control in school students. Those who had poor response to lower concentration of atropine may have the risk of faster progression, even with high concentration of atropine. Additional or alternative treatment might be considered.

Next-generation sequencing (NGS) has greatly advanced the studies of causative genes and variants of inherited diseases. While it is sometimes challenging to determine the pathogenicity of identified variants in NGS, the American College of Medical Genetics and Genomics established the guidelines to help the interpretation. However, as to the genetic screenings for patients with retinitis pigmentosa (RP) in Japan, none of the previous studies utilized the guidelines. Considering that EYS is the major causative gene of RP in Japan, we conducted stepwise genetic screening of 220 Japanese patients with RP utilizing the guidelines. Step 1–4 comprised the following, in order: Sanger sequencing for two major EYS founder mutations; targeted sequencing of all coding regions of EYS; whole genome sequencing; Sanger sequencing for Alu element insertion in RP1, a recently determined founder mutation for RP. Among the detected variants, 2, 19, 173, and 1 variant(s) were considered pathogenic and 8, 41, 44, and 5 patients were genetically solved in step 1, 2, 3, and 4, respectively. Totally, 44.5% (98/220) of the patients were genetically solved, and 50 (51.0%) were EYS-associated and 5 (5.1%) were Alu element-associated. Among the unsolved 122 patients, 22 had at least one possible pathogenic variant.

Trypanosoma brucei is a protozoan parasite that causes important human and livestock diseases in sub-Saharan Africa. By overexpressing a single RNA-binding protein, RBP6, in non-infectious procyclics trypanosomes, we previously recapitulated in vitro the events occurring in the tsetse fly vector, namely the development of epimastigotes and infectious, quiescent metacyclic parasites. To identify genes involved in this developmental progression, we individually targeted 86 transcripts by RNAi in the RBP6 overexpression cell line and assessed the loss-of-function phenotypes on repositioning the kinetoplast, an organelle that contains the mitochondrial genome, the expression of BARP or brucei alanine rich protein, a marker for epimastigotes, and metacyclic variant surface glycoprotein. This screen identified 22 genes that positively or negatively regulate the stepwise progression towards infectivity at different stages. Two previously uncharacterized putative nucleic acid binding proteins emerged as potent regulators, namely the cold shock domain-containing proteins CSD1 and CSD2. RNA-Seq data from a selected group of cell lines further revealed that the components of gene expression regulatory networks identified in this study affected the abundance of a subset of transcripts in very similar fashion. Finally, our data suggest a considerable overlap between the genes that regulate the formation of stumpy bloodstream form trypanosomes and the genes that govern the development of metacyclic form parasites.

During chronic cerebral hypoperfusion (CCH), the cerebral blood flow gradually decreases, leading to cognitive impairments and neurodegenerative disorders, such as vascular dementia. The reduced oxygenation, energy supply induced metabolic changes, and insufficient neuroplasticity could be reflected in the synaptic proteome. We performed stepwise bilateral common carotid occlusions on rats and studied the synaptic proteome changes of the hippocampus, occipital and frontal cortices. Samples were prepared and separated by 2-D DIGE and significantly altered protein spots were identified by HPLC–MS/MS. We revealed an outstanding amount of protein changes in the occipital cortex compared to the frontal cortex and the hippocampus with 94, 33, and 17 proteins, respectively. The high alterations in the occipital cortex are probably due to the hypoxia-induced retrograde degeneration of the primary visual cortex, which was demonstrated by electrophysiological experiments. Altered proteins have functions related to cytoskeletal organization and energy metabolism. As CCH could also be an important risk factor for Alzheimer’s disease (AD), we investigated whether our altered proteins overlap with AD protein databases. We revealed a significant amount of altered proteins associated with AD in the two neocortical areas, suggesting a prominent overlap with the AD pathomechanism.

Recent progress in regenerative medicine has enabled the utilization of pluripotent stem cells (PSCs) as the resource of therapeutic cells/tissue. However, immune suppression is still needed when the donor–recipient combination is allogeneic. We have reported previously that mouse PSCs-derived immunosuppressive cells contribute to prolonged survival of grafts derived from the same mouse PSCs in allogeneic recipients. For its clinical application, a preclinical study using non-human primates such as common marmoset must be performed. In this study, we established the induction protocol of immunosuppressive cells from common marmoset ES cells. Although similar immunosuppressive macrophages could not be induced by same protocol as that for mouse PSCs, we employed an inhibitor for histone methyltransferase, DZNep, and succeeded to induce them. The DZNep-treated macrophage-like cells expressed several immunosuppressive molecules and significantly inhibited allogeneic mixed lymphocyte reaction. The immunosuppressive cells from non-human primate ESCs will help to establish an immunoregulating strategy in regenerative medicine using PSCs.

Nowadays, early oral feeding after gastrectomy has been gradually accepted and applied in the clinical practice, but there is still no specific uniform feeding regimen available which works best for patients in different regions with different races and eating habits. Aiming to establish an early oral feeding schedule suitable for local Chinese patients after gastric surgery, from May 2014 to May 2018, 87 gastric cancer patients undergoing various types of gastric resections were enrolled in an early feeding protocol and their clinical course was reviewed retrospectively. A stepwise, local patient-specific, early oral feeding schedule was proposed, implemented within an early recovery after surgery (ERAS) protocol and accessed in terms of its safety and tolerability. The primary surgical outcomes included: a median (interquartile range; IQR) postoperative hospital stay of 6 (3) days; 67 (77%) patients were well tolerant of this schedule from postoperative day (POD) 1 to POD 4; 20 (23%) patients had mild I/II grade complications (Clavien-Dindo classification); 3 (3%) patients had IIIB complications, zero cases of hospital mortality. Compared to similar studies in the past, our early oral feeding program is also safe and beneficial, and it can shorten the postoperative hospital stay without causing any increase in postoperative complications. In summary, our work herein reported the establishment of a detailed early oral feeding schedule embedded within an ERAS protocol which was found to be suitable for local Chinese patients after gastric surgery. Accordingly, this early oral feeding schedule is worth further research and promotion.

Controllable conversion of biomass to value-added carbon materials is attractive towards a wide variety of potential applications. Herein, hydrothermal treatment and KOH activation are successively employed to treat the cheap and abundant camellia oleifera shell as a new carbon raw material. It is shown that this stepwise activation process allows the production of porous nitrogen-doped carbon with optimized surface chemistry and porous structure compared to the counterparts prepared by a single activation procedure. Benefiting from the modulated porous structure, the as-produced porous nitrogen-doped carbon electrode delivered a high reversible capacity of 1080 mAh g−1 at a current density of 100 mA g−1, which is 3.3 and 5.8 times as high as that of the carbon materials prepared by bare hydrothermal treatment or KOH activation, respectively. Moreover, the optimized surface composition of the porous nitrogen-doped carbon endows it with a highest initial Coulombic efficiency among the three samples, showing great potentials for practical applications. This work is expected to pave a new avenue to upgrade biomass to carbon materials with tunable surface properties and microstructures for target applications.

Graphene Oxides (GO) typically contains different oxygen containing groups such as hydroxyl, carboxyl and epoxy, and reduced GO (r-GO) represents a family of material with diverse chemical properties. In an effort to understand how properties of r-GO change as GO is reduced, a stepwise reduction of the same GO to r-GO containing different levels of oxygen was carried out, and their corresponding chemical and colloidal properties are reported. Starting with GO containing 49 percent oxygen, r-GOs containing 31, 19 and 9 percent oxygen were synthesized. The aqueous behavior in terms of solubility gradually decreased from 7.4 µg/ml for GO to nearly zero for r-GO with 9% oxygen, while dispersibility under sonication decreased from 8 to 2.5 µg/ml for the same samples. Hydrophobicity index as measured as the octanol water partition coefficient decreased from −3.89 to 5.2% as oxygen content dropped from 49 to 9%. Colloidal behavior was also dramatically affected by reduction, and critical coagulation concentration (CCC) dropped from 28 to 15 in presence of 0.5 mmole/l NaCl and from 6 to 2 in presence of 0.5 mmole/l MgCl2 as the oxygen in the original GO was reduced to 9%.

Condensation and remodeling of nuclear genomes play an essential role in the regulation of gene expression and replication. Yet, our understanding of these processes and their regulatory role in other DNA-containing organelles, has been limited. This study focuses on the packaging of kinetoplast DNA (kDNA), the mitochondrial genome of kinetoplastids. Severe tropical diseases, affecting large human populations and livestock, are caused by pathogenic species of this group of protists. kDNA consists of several thousand DNA minicircles and several dozen DNA maxicircles that are linked topologically into a remarkable DNA network, which is condensed into a mitochondrial nucleoid. In vitro analyses implicated the replication protein UMSBP in the decondensation of kDNA, which enables the initiation of kDNA replication. Here, we monitored the condensation of kDNA, using fluorescence and atomic force microscopy. Analysis of condensation intermediates revealed that kDNA condensation proceeds via sequential hierarchical steps, where multiple interconnected local condensation foci are generated and further assemble into higher order condensation centers, leading to complete condensation of the network. This process is also affected by the maxicircles component of kDNA. The structure of condensing kDNA intermediates sheds light on the structural organization of the condensed kDNA network within the mitochondrial nucleoid.

Considerable efforts have been made to develop technologies for selection of peptidic molecules that act as substrates or binders to a protein of interest. Here we demonstrate the combination of rational peptide array library design, parallel screening and stepwise evolution, to discover novel peptide hotspots. These hotspots can be systematically evolved to create high-affinity, high-specificity binding peptides to a protein target in a reproducible and digitally controlled process. The method can be applied to synthesize both linear and cyclic peptides, as well as peptides composed of natural and non-natural amino acid analogs, thereby enabling screens in a much diverse chemical space. We apply this method to stepwise evolve peptide binders to streptavidin, a protein studied for over two decades and report novel peptides that mimic key interactions of biotin to streptavidin.

The triethylamine promoted stepwise 1,3-dipolar cycloaddition reaction of N-phenacylbenzothiazolium bromides with nitroalkenes in ethanol resulted in a mixture of two isomeric tetrahydrobenzo[d]pyrrolo[2,1-b]thiazoles with cis/trans/cis- and all-trans-configurations. More importantly, the corresponding dihydrobenzo[d]pyrrolo[2,1-b]thiazoles can be selectively prepared in refluxing ethanol and the benzo[d]pyrrolo[2,1-b]thiazoles can be obtained in satisfactory yields by sequential dehydrogenation with DDQ as oxidizer. On the other hand, the similar cycloaddition reaction of N-phenacylbenzothiazolium bromides with 1-methy-1-nitroalkenes in refluxing ethanol afforded benzo[d]pyrrolo[2,1-b]thiazoles with splitting out of nitro group. The stereochemistry of the spiro compounds was clearly elucidated on the basis of NMR spectra and sixteen single crystal structures.

XAD-8 adsorption technique coupled with stepwise elution using pyrophosphate buffers with initial pH values of 3, 5, 7, 9 and 13 was developed to isolate Chinese standard fulvic acid (FA) and then separated the FA into five sub-fractions: FApH3, FApH5, FApH7, FApH9 and FApH13, respectively. Mass percentages of FApH3-FApH13 decreased from 42% to 2.5% and the recovery ratios ranged from 99.0% to 99.5%. Earlier eluting sub-fractions contained greater proportions of carboxylic groups with greater polarity and molecular mass and later eluting sub-fractions had greater phenolic and aliphatic content. Protein-like components, as well as amorphous and crystalline poly(methylene)-containing components were enriched using neutral and basic buffers. Three main mechanisms likely affect stepwise elution of humic components from XAD-8 resin with pyrophosphate buffers including: 1) the carboxylic-rich sub-fractions are deprotonated at lower pH values and eluted earlier, while phenolic-rich sub-fractions are deprotonated at greater pH values and eluted later. 2) protein or protein-like components can be desorbed and eluted by use of stepwise elution as progressively greater pH values exceed their isoelectric points. 3) size exclusion affects elution of FA sub-fractions. Successful isolation of FA sub-fractions will benefit exploration of the origin, structure, evolution and the investigation of interactions with environmental contaminants.

Tetrahydropapaveroline (THP), a benzylisoquinoline alkaloid (BIA) found in diverse pharmaceutical compounds, is used as a starting material for the production of BIA. THP also has various neurobiological properties but is difficult to synthesize. Therefore, a simple method for THP production is desired. Recent studies have shown that microbes, especially bacteria, can serve as platforms for synthesizing these complex compounds; however, because bacteria lack organelles, the designed synthetic pathway cannot be compartmentalized. Thus, the metabolic flow is frequently inhibited or disrupted by undesirable reactions. Indeed, in the first attempt to synthesize THP using a single strain of engineered Escherichia coli, the yield was quite low (R,S)-THP production system, in which the dopamine-producing step and the subsequent THP-producing step were separated. The yield of (R,S)-THP reached 1.0 mM (287 mg/L), the highest yielding BIA production method using a microbe reported to date. Furthermore, we demonstrated that (R,S)-THP produced by stepwise fermentation is useful for the production of reticuline, an important BIAs intermediate. Based on these observations, applying the stepwise fermentation method is discussed.

Carbapenem resistant Enterobacteriaceae (CRE) pose an urgent risk to global human health. CRE that are non-susceptible to all commercially available antibiotics threaten to return us to the pre-antibiotic era. Using Single Molecule Real Time (SMRT) sequencing we determined the complete genome of a pandrug-resistant Klebsiella pneumoniae isolate, representing the first complete genome sequence of CRE resistant to all commercially available antibiotics. The precise location of acquired antibiotic resistance elements, including mobile elements carrying genes for the OXA-181 carbapenemase, were defined. Intriguingly, we identified three chromosomal copies of an ISEcp1-blaOXA-181 mobile element, one of which has disrupted the mgrB regulatory gene, accounting for resistance to colistin. Our findings provide the first description of pandrug-resistant CRE at the genomic level and reveal the critical role of mobile resistance elements in accelerating the emergence of resistance to other last resort antibiotics.

We used 344 mitochondrial control region (717 bp) sequences from the finless porpoise (genus Neophocaena) from the northwestern Pacific to investigate the extent and manner in which past climatic oscillations may have shaped patterns of genetic diversity for this marine mammal. Both SplitsTree and Analysis of Molecular Variance (AMOVA) revealed the presence of a deep divergence among N. phocaenoides in subtropical waters compared with N. asiaeorientalis in temperate waters. Results from Migrate-n indicated that migration increased along the continent during the early Pleistocene period. Migration increased, although to a lesser extent than that during the Pleistocene, along the marginal shelf in the Yellow/Bohai Sea during the Last Glacial Maximum (LGM) due to a shortening coastline. Our results suggest that the current patterns of genetic diversity of Neophocaena vary at a hierarchy on a temporal and spatial scale, and phylogeographic history should be taken into account when examining species population structure and taxonomy.

Small-cell lung cancer (SCLC) easily recurs with a multidrug resistant phenotype. However, standard therapeutic strategies for relapsed SCLC remain unestablished. We found that human epidermal growth factor receptor 2 (HER2) is not only expressed in pretreated human SCLC specimens, but is also upregulated when HER2-positive SCLC cells acquire chemoresistance. Trastuzumab induced differential levels of antibody-dependent cell-mediated cytotoxicity (ADCC) to HER2-positive SCLC cells. Furthermore, as a mechanism of the differential levels of ADCC, we have revealed that coexpression of intracellular adhesion molecule (ICAM)-1 on SCLC cells is essential to facilitate and accelerate the trastuzumab-mediated ADCC. Although SN-38–resistant SCLC cells lacking ICAM-1 expression were still refractory to trastuzumab, their in vivo growth was significantly suppressed by bevacizumab treatment due to dependence on their distinctive and abundant production of vascular endothelial growth factor. Collectively, stepwise treatment with trastuzumab and bevacizumab is promising for the treatment of chemoresistant SCLC.

While chromatin modifications can offer a useful readout for enhancer activities, it is less clear whether these modification marks are a cause or consequence of transcription factor occupancy and enhancer activation. We have examined in details the temporal events of acetyltransferase associations and histone acetylations at different regulatory regions of the Myod1 locus. Our studies demonstrate that the histone acetyltransferase (HAT) p300 is stepwise enriched at distinct Myod1 regulatory regions during myogenic differentiation. This enrichment of p300 is associated with increased histone acetylation in a discrete pattern. Inhibition of p300 HAT activity impedes myogenic differentiation, which is coupled with decreased histone acetylation at specific Myod1 regulatory regions. We show for the first time that p300 is directly involved in the early regulation of Myod1 enhancer, and provide molecular insights into how p300 HAT activity and histone acetylation are related to enhancer activation and, consequently, gene transcription.

Hypertension is the leading single contributor to all-cause death and disability worldwide. However, there is scarce evidence on the prevalence and risk factors of hypertension for Chinese youth. This study aimed to investigate the prevalence of hypertension among Chinese college freshmen and to identify the influencing factors. We conducted a cross-sectional study of all freshmen from 2015 to 2017 at a university in Wuhan, China by physical examination and standard-structured questionnaire. The Pearson chi-square test was used to compare categorical variables. Forward stepwise logistic regression method was used in the multivariate analysis to identify independent predictors of hypertension in youth. A total of 12,849 participants were included, and the prevalence of hypertension of Chinese college freshmen was 4.3% (7.9% in men and 1.6% in women). Men had a higher risk of hypertension than women (odds ratio [OR]: 5.358, 95% confidence interval [CI]: 4.345–6.607, P P P P P P P

Hospitalized cancer patients are at increased risk for Thromboembolic Events (TEs). As untailored thromboprophylaxis is associated with hemorrhagic complications, the definition of a risk-assessment model (RAM) in this population is needed. INDICATE was a prospective observational study enrolling hospitalized cancer patients, with the primary objective of assessing the Negative Predictive Value (NPV) for TEs during hospitalization and within 45 days from discharge of low-grade Khorana Score (KS = 0). Secondary objectives were to assess KS Positive Predictive Value (PPV), the impact of TEs on survival and the development of a new RAM. Assuming 7% of TEs in KS = 0 patients as unsatisfactory percentage and 3% of as satisfactory, 149 patients were needed to detect the favorable NPV with one-sided α = 0.10 and power = 0.80. Stepwise logistic regression was adopted to identify variables included in a new RAM. Among 535 enrolled patients, 153 (28.6%) had a KS = 0. The primary study objective was met: 29 (5.4%) TEs were diagnosed, with 7 (4.6%) cases in the KS = 0 group (NPV = 95.4%, 95% CI 90.8–98.1%; one-sided p = 0.084). However, the PPV was low (5.7%, 95% CI 1.9–12.8%); a new RAM based on albumin (OR 0.34, p = 0.003), log(LDH) (OR 1.89, p = 0.023) and presence of vascular compression (OR 5.32, p

The present study examined whether differences in the heart rate recovery following flywheel exercise cessation were associated with differences in maximal oxygen uptake ($${\dot{\text{V}}}$$ V ˙ O2 max.), age and sex in trained adults. Eleven men (age range 22–49 years, $${\dot{\text{V}}}$$ V ˙ O2 max. = 43.6 ± 7.6 mL kg min−1) and ten women (age range 20—53 years, $${\dot{\text{V}}}$$ V ˙ O2 max. = 38.0 ± 5.7 mL kg min−1) were randomly assigned to complete a squat-exercise on the flywheel ergometer set at three different moments of inertia, while their cardiovascular responses were continuously monitored. During the flywheel exercise the mean arterial pressure rose by ~ 35 to 40% (p = .001), and the increment was more robust in men than women. The cardiac index was two-fold greater across both sexes compared to the baseline (p = .001), while the rise in heart rate (~ 144 bpm) was more pronounced in women to compensate for their load-dependent stroke index decline (p = .001). The load-independent time-course changes in heart rate recovery markers were comparable between the sexes. When these indicators were pooled, a stepwise regression revealed age as the only relevant predictor of both fast and slow components of the heart rate recovery (~ 30% of the shared variance explained, p = .014). The present data suggest that the heart rate recovery declines with age, irrespective of sex, or well-preserved cardiorespiratory fitness in moderately-trained adults.

This retrospective study explored the effect of the ratio of axial length (AL) to average keratometry (K) on intraocular lens power calculation in long eyes. The clinical records of eyes that had an AL of 26.0 mm or longer, and underwent cataract surgery with intraocular lens implantations, were reviewed. This study was approved by the institutional review board of Miyata Eye Hospital. Preoperative biometry data were obtained using optical low-coherence reflectometry. Prediction errors in the use of the SRK/T formulas were obtained from manifest refraction spherical equivalents one month postoperatively. Significant factors inducing prediction errors were examined using stepwise multiple regression analysis with descriptive factors of AL, K value, and their ratio (AL/K). Clinical records related to 49 long eyes of 49 patients, and 93 eyes of 93 patients with normal AL, were evaluated. Stepwise multiple regression analysis revealed that the AL/K was a significant factor increasing the prediction errors (P = 0.0003). With the regression equation, 98% of prediction errors with the use of the SRK/T formula were within ±1.00 D of differences. For our sample of 49 long eyes, the ratio of AL to K was a significant factor inducing hyperopic prediction errors with the use of SRK/T for long eyes.

Chinese fir is one of the most important commercial timber species in China, with many geographic sources. However, little is known of the variation in wood physical properties among them. To explore the differences in wood physical properties and their influencing factors, five geographic sources of Chinese fir were selected. The variance inflation factor, stepwise regression, and principle component analysis were used to reduce multicollinearity and dimensions of the 19 wood physical properties (including density, shrinkage, and mechanical properties). The results showed that the wood density differed significantly among five geographic sources. The tangential shrinkage rate and radial shrinkage rate reached maximum values in black-heart Chinese fir (HNYX-T) but accompanied by the lowest value for difference dry shrinkage. The wood density and mechanical properties of HNYX-T was exceeded to that of others geographic sources. Fast-growth Chinese fir (FJYK-P) had the lowest value for all mechanical properties. The precipitation and temperature had significant correlations with the wood physical properties of this five geographic sources. The temperature in summer was mainly positive correlated with physical properties, while precipitation was negatively correlated with them. HNYX-T had the highest comprehensive score of PCA, followed by JXCS-R, emerged as higher-quality geographic source, which is important for selecting and utilizing geographic sources in forest management.

We begin by arguing that the often used algorithm for the discovery and use of disease risk factors, stepwise logistic regression, is unstable. We then argue that there are other algorithms available that are much more stable and reliable (e.g. the lasso and gradient boosting). We then propose a protocol for the discovery and use of risk factors using lasso or boosting variable selection. We then illustrate the use of the protocol with a set of prostate cancer data and show that it recovers known risk factors. Finally, we use the protocol to identify new and important SNP based risk factors for prostate cancer and further seek evidence for or against the hypothesis of an anticancer function for Selenium in prostate cancer. We find that the anticancer effect may depend on the SNP-SNP interaction and, in particular, which alleles are present.

Our aim was to develop practical models built with simple clinical and radiological features to help diagnosing Coronavirus disease 2019 [COVID-19] in a real-life emergency cohort. To do so, 513 consecutive adult patients suspected of having COVID-19 from 15 emergency departments from 2020-03-13 to 2020-04-14 were included as long as chest CT-scans and real-time polymerase chain reaction (RT-PCR) results were available (244 [47.6%] with a positive RT-PCR). Immediately after their acquisition, the chest CTs were prospectively interpreted by on-call teleradiologists (OCTRs) and systematically reviewed within one week by another senior teleradiologist. Each OCTR reading was concluded using a 5-point scale: normal, non-infectious, infectious non-COVID-19, indeterminate and highly suspicious of COVID-19. The senior reading reported the lesions’ semiology, distribution, extent and differential diagnoses. After pre-filtering clinical and radiological features through univariate Chi-2, Fisher or Student t-tests (as appropriate), multivariate stepwise logistic regression (Step-LR) and classification tree (CART) models to predict a positive RT-PCR were trained on 412 patients, validated on an independent cohort of 101 patients and compared with the OCTR performances (295 and 71 with available clinical data, respectively) through area under the receiver operating characteristics curves (AUC). Regarding models elaborated on radiological variables alone, best performances were reached with the CART model (i.e., AUC = 0.92 [versus 0.88 for OCTR], sensitivity = 0.77, specificity = 0.94) while step-LR provided the highest AUC with clinical-radiological variables (AUC = 0.93 [versus 0.86 for OCTR], sensitivity = 0.82, specificity = 0.91). Hence, these two simple models, depending on the availability of clinical data, provided high performances to diagnose positive RT-PCR and could be used by any radiologist to support, modulate and communicate their conclusion in case of COVID-19 suspicion. Practically, using clinical and radiological variables (GGO, fever, presence of fibrotic bands, presence of diffuse lesions, predominant peripheral distribution) can accurately predict RT-PCR status.

Tobacco- or human papillomavirus- driven oropharyngeal squamous cell carcinomas (OpSCC) represent distinct clinical, biological and epidemiological entities. The aim of this study was to identify genetic variants based on somatic alterations in OpSCC samples from an admixed population, and to test for association with clinical features. The entire coding region of 15 OpSCC driver genes was sequenced by next-generation sequencing in 51 OpSCC FFPE samples. Thirty-five percent of the patients (18/51) were HPV-positive and current or past tobacco consumption was reported in 86.3% (44/51). The mutation profile identified an average of 2.67 variants per sample. Sixty-three percent of patients (32/51; 62.7%) were mutated for at least one of the genes tested and TP53 was the most frequently mutated gene. The presence of mutation in NOTCH1 and PTEN, significantly decreased patient’s recurrence-free survival, but only NOTCH1 mutation remained significant after stepwise selection, with a risk of recurrence of 4.5 (HR 95% CI = 1.11–14.57; Cox Regression p = 0.034). These results show that Brazilian OpSCC patients exhibit a similar clinical and genetic profile in comparison to other populations. Molecular characterization is a promising tool for the definition of clinical subgroups, aiding in a more precise tailoring of treatment and prognostication.

We developed a diet and lifestyle score based on high sensitivity C-reactive protein (hsCRP), and investigated its association with odds of adenoma. We performed stepwise linear regression to develop the predicted hsCRP score among 23,330 participants in the Health Examinee Study and examined its association with colorectal adenoma among 1,711 participants in a cross-sectional study of colorectal adenoma. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) of colorectal adenoma using logistic regression models. Variances in hsCRP explained by body mass index were 61.1% in men and 64.5% in women in the prediction model. The increasing predicted hsCRP score was positively associated with colorectal adenoma (ORquartile 4 VS quartile 1 1.71, 95% CI: 1.12–2.62; Ptrend = 0.011 in men; ORquartile 4 VS quartile 1 2.86, 95% CI: 1.26–6.49; Ptrend = 0.019 in women). In subgroups, the associations differed by age and menopausal status among women, with stronger associations among women aged less than 50 years (OR≥median VS 3.74, 95% CI: 1.77–7.90, p for interaction 0.014) or premenopausal women (OR≥median vs 4.21, 95% CI: 2.12–8.36, p for interaction

This study determined relationships between age, BMI and cranio-vertebral angle (CVA) (independent variables) and stiffness and elasticity of sternocleidomasteoid [SCM] and upper trapezius [UT] (dependent variables) muscles in sitting posture in 95 women across adult life. Moreover, a stepwise regression was performed to determine to what extent the dependent variables are explained by age, BMI and CVA. Age was moderately correlated with BMI (r = 0.41), and both age and BMI were moderately negatively correlated with CVA (r = −0.54 and −0.55, respectively). High (r = 0.73) and moderate (r = 0.53) linear relationships were present between age and logarithmic decrement (inversely related to elasticity) and stiffness of SCM muscle, respectively. Low (r = 0.36) and moderate (r = 0.47) relationships were present between age and logarithmic decrement and stiffness of UT muscle, respectively. Age accounted for 53% variance in elasticity and 28.5% variance in stiffness of SCM, and for 13% variance in elasticity and 22% variance in stiffness of UT muscle. Introduction of BMI but not CVA to the model explained the variance of these parameters by additional 0–8%. Among the studied factors age is the major correlate of stiffness and elasticity of neck muscles across the adult life.

Favorable effects of sauna bathing on cardiovascular disease have been demonstrated. Hot water bathing is an alternative, and could also have similar effects. Information pertaining to hot water bathing frequency and water temperature was obtained from 873 subjects. Carotid mean and max intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV) were measured as indices of atherosclerosis. Central haemodynamics were evaluated using radial pulse waveform analyses. Plasma levels of B-type natriuretic peptide (BNP) were measured as an index for cardiac loading. The mean duration of a single hot bath was 12.4 ± 9.9 min. Subject bathing in hot water ≥5 times per week had significantly lower baPWV, central pulse pressure (PP), and BNP after correcting for possible confounding parameters. Stepwise regression analyses revealed that hot water temperature was negatively associated with baPWV, while bathing frequency was negatively related to central PP and BNP. A longitudinal follow-up in 164 subjects showed that hot water bathing ≥5 times per week was associated with significantly lower increase in BNP over time, while the temperature of the water tended to be related to lower increases in carotid max IMT and baPWV. Hot water bathing showed a favorable effect on atherosclerotic and central haemodynamic parameters.

Understanding the epidemiology and risk factors of adverse drug events (ADEs) in pediatric inpatient is essential if we are to prevent, reduce or ameliorate the harm experienced. The Global Trigger Tool (GTT) is a method of retrospective medical record review that measures harm in hospitalized children. We employed a three-stage retrospective chart review of random samples of 1800 pediatric inpatients discharged from January 2013 to December 2015. 31 kinds of pediatric-specific triggers were made based on the previous trigger tool studies developed for use in adult or pediatric. Positive predictive value (PPV) of individual triggers, as well as ADEs detection rates were calculated. Stepwise logistic regression was performed to investigate risk factors associated with ADEs. Of 1746 patients, detected in 221 patients (12.7%) with 247 ADEs. The PPV of the trigger tool was 13.3%. Of the 247 ADEs, 82.6% were identified as category E, 11.7% category F and 5.7% category H. The pediatric-focused trigger tool is a feasible and useful tool for detecting pediatric ADEs. Especially for patients who have had more drugs, more doses or more admissions which needs to be closely monitored as triggers to improve the safety.

The aims of this study were to investigate the outcomes of patients requiring prolonged mechanical ventilation (PMV) and to identify risk factors associated with its mortality rate. All patients admitted to the respiratory care centre (RCC) who required PMV (the use of MV ≥21 days) between January 2006 and December 2014 were enrolled. A total of 1,821 patients were identified; their mean age was 69.8 ± 14.2 years and 521 patients (28.6%) were aged >80 years. Upon RCC admission, the APACHE II scores were 16.5 ± 6.3 and 1,311 (72.0%) patients had at least one comorbidity. Pulmonary infection was the most common diagnosis (n = 770, 42.3%). A total of 320 patients died during hospitalization and the in-hospital mortality rate was 17.6%. A multivariate stepwise logistic regression analysis indicated that patients were more likely to die if they who were >80 years of age, had lower albumin levels (

The purpose of this study was to investigate the relationship between bilateral differences of upper airway and mandibular morphologic patterns in subjects with skeletal Class III mandibular deviation. 47 skeletal Class III (ANB

Apolipoprotein CIII (apoCIII) has been reported to be tightly associated with triglyceride metabolism and the susceptibility to coronary artery disease (CAD). Besides, apoCIII has also been found to affect the anti-apoptotic effects of HDL. However, the effect of apoCIII on HDL-mediated cholesterol efflux, the crucial function of HDL, has not been reported. A hospital-based case-control study was conducted to compare the apoCIII distribution in lipoproteins between CAD patients and nonCAD controls and to explore the relationship between HDL-associated apoCIII (apoCIIIHDL) and HDL-mediated cholesterol efflux. One hundred forty CAD patients and nighty nine nonCAD controls were included. Plasma apoCIII, apoCIIIHDL and cholesterol efflux capacity was measured. The apoCIIIHDL ratio (apoCIIIHDL over plasma apoCIII) was significantly higher in CAD patients than that in control group (0.52 ± 0.24 vs. 0.43 ± 0.22, P = 0.004). Both apoCIIIHDL and apoCIIIHDL ratio were inversely correlated with cholesterol efflux capacity (r = −0.241, P = 0.0002; r = −0.318, P HDL ratio was an independent contributor to HDL-mediated cholesterol efflux capacity (standardized β = −0.325, P

The aim of this study was to find an accurate method for the detection of extracapsular extension (ECE) in papillary thyroid carcinoma (PTC). A total of 102 patients with 109 PTC nodules were retrospectively enrolled. Contrast-enhanced ultrasound (CEUS) characteristics were evaluated. The diagnostic efficacy of quantitative CEUS and tumor size was analyzed. The qualitative CEUS features did not differ significantly between the ECE and non-ECE groups (P > 0.05). All of the quantitative CEUS parameters with the exception of peak intensity and tumor size were found to differ significantly between the ECE and non-ECE groups (P P = 0.000, P = 0.005 and P = 0.030, respectively).The sensitivity and specificity in the diagnosis of ECE were: TPH, 75.4% (43/57) and 78.9% (41/52), respectively; WIS, 87.7% (50/57) and 42.3% (22/52), respectively; and tumor size, 71.9% (41/57) and 65.4% (34/52), respectively. Quantitative CEUS analysis and tumor size are essential for the prediction of ECE in PTC; in particular TPH has good diagnostic value in detecting ECE. Our study provides important insights into the prediction of ECE in PTC.

Clinical investigations have indicated women have higher levels of adipocyte fatty acid binding protein (A-FABP) than men. The present study aimed to identify factors related to gender difference in serum A-FABP levels. A total of 507 participants (194 men, 132 premenopausal women, and 181 postmenopausal women) were enrolled in the present study. Serum A-FABP levels increased in the order from men to premenopausal women to postmenopausal women in both body mass index categories (2; all P

Prognostic models play an important role in the clinical management of cervical radiculopathy (CR). No study has compared the performance of modern machine learning techniques, against more traditional stepwise regression techniques, when developing prognostic models in individuals with CR. We analysed a prospective cohort dataset of 201 individuals with CR. Four modelling techniques (stepwise regression, least absolute shrinkage and selection operator [LASSO], boosting, and multivariate adaptive regression splines [MuARS]) were each used to form a prognostic model for each of four outcomes obtained at a 12 month follow-up (disability—neck disability index [NDI]), quality of life (EQ5D), present neck pain intensity, and present arm pain intensity). For all four outcomes, the differences in mean performance between all four models were small (difference of NDI

The study determines how burden and patterns of somatic symptom reporting developed over almost four decades in the general German population. Additionally, we studied how socio-demographic factors affected the degree of somatic symptoms. Population-based samples representative for West Germany between 18 and 60 years of age were analyzed comparing three cross-sectional samples of 1975 (N = 1601), 1994 (N = 1416), and 2013 (N = 1290) by conducting a three-way analysis of variance (sex, age, survey). The prevalence rates for somatic symptoms in men and women were lower in the more recent surveys; this affected women most strongly. Exhaustion and musculoskeletal complaints remained leading symptoms (affecting 25%, resp. 11% of the men and 30%, resp. 19% of the women). There was a slight increase in women’s prevalence of exhaustion from 1994 (15%) to 2013 (19%). As determined by stepwise multiple regression, somatic symptoms were consistently associated with female sex and higher age. In the 2013 survey, education became an additional negative predictor of somatic symptom load, while the impact of age and sex on somatic symptoms reporting decreased. Somatic symptoms remain a major burden in the general population. Findings are interpreted with regard to improved living and health care conditions, different cohort experiences, and more public health information.

The early detection of cognitive impairment or dementia is in the focus of current research as the amount of cognitively impaired individuals will rise intensely in the next decades due to aging population worldwide. Currently available diagnostic tools to detect mild cognitive impairment (MCI) or dementia are time-consuming, invasive or expensive and not suitable for wide application as required by the high number of people at risk. Thus, a fast, simple and sensitive test is urgently needed to enable an accurate detection of people with cognitive dysfunction and dementia in the earlier stages to initiate specific diagnostic and therapeutic interventions. We examined digital Clock Drawing Test (dCDT) kinematics for their clinical utility in differentiating patients with amnestic MCI (aMCI) or mild Alzheimer’s dementia (mAD) from healthy controls (HCs) and compared it with the diagnostic value of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropsychological battery total score. Data of 381 participants (138 patients with aMCI, 106 patients with mAD and 137 HCs) was analyzed in the present study. All participants performed the clock drawing test (CDT) on a tablet computer and underwent the CERAD test battery and depression screening. CERAD total scores were calculated by subtest summation, excluding MMSE scores. All tablet variables (i.e. time in air, time on surface, total time, velocity, pressure, pressure/velocity relation, strokes per minute, time not painting, pen-up stroke length, pen-up/pen-down relation, and CDT score) during dCDT performance were entered in a forward stepwise logistic regression model to assess, which parameters best discriminated between aMCI or mAD and HC. Receiver operating characteristics (ROC) curves were constructed to visualize the specificity in relation to the sensitivity of dCDT variables against CERAD total scores in categorizing the diagnostic groups. dCDT variables provided a slightly better diagnostic accuracy of 81.5% for discrimination of aMCI from HCs than using CERAD total score (accuracy 77.5%). In aMCI patients with normal CDT scores, both dCDT (accuracy 78.0%) and CERAD total scores (accuracy 76.0%) were equally accurate in discriminating against HCs. Finally, in differentiating patients with mAD from healthy individuals, accuracy of both dCDT (93.0%) and CERAD total scores (92.3%) was excellent. Our findings suggest that dCDT is a suitable screening tool to identify early cognitive dysfunction. Its performance is comparable with the time-consuming established psychometric measure (CERAD test battery).

The rising incidence rate of prostate cancer (PCa) worldwide has become a public health concern. PCa has a multifactorial etiology, and the link between human papillomavirus (HPV) and PCa has been widely investigated by numerous case–control studies. This age-matched, case–control study included 143 PCa patients and 135 benign prostatic hyperplasia (BPH) patients, with prostatic specimens testing negative for malignancy, as control. Study participants were recruited from four major hospitals in Taoyuan City, Taiwan, period 2018–2020, looking into HPV infection and other PCa risk factors, including dietary habits, family history, personal lifestyle, and sexual behavior. Multiple logistic regression analysis and forward stepwise selection analysis were conducted to identify potential risk factors for PCa. HPV DNA was found in 10 of the 143 PCa cases (7%) and 2 of the 135 BPH controls (1.5%) (OR = 6.02, 95% CI = 1.03–30.3, p = 0.046). This association was slightly significant, and furthermore, high risk HPV was not found to be associated with PCa. Higher body mass index (BMI) (OR = 1.15, 95% CI = 1.05–1.27, p = 0.003), more total meat consumption (OR = 2.74, 95% CI = 1.26–5.94, p = 0.011), exhibited association to PCa. However, PCa family history only presented a statistically significant difference by forward stepwise analysis (OR = 3.91, 95% CI = 1.17–13.12, p = 0.027). While much focus has been on the association between HPV and PCa, the results of this study indicate that more efforts should be directed towards investigating dietary habits, personal lifestyle and family history as factors for PCa. These results could serve as a basis for designing PCa prevention strategies.

Species that are geographically widespread may exist across environmentally heterogeneous landscapes that could influence patterns of occupation and phylogeographic structure. Previous studies have suggested that geographic range size should be positively correlated with niche breadth, allowing widespread species to sustain viable populations over diverse environmental gradients. We examined the congruence of phenotypic and phylogenetic divergence with the environmental factors that help maintain species level diversity in the geographically widespread hoary bats (Lasiurus cinereusand relatives) across their distribution. Genetic data were analyzed using multiple phylogenetic and species delimitation methods, and phenotypic data were analyzed using supervised and unsupervised machine learning approaches. Spatial data from environmental, geographic, and topographic features were analyzed in a stepwise multiple regression analysis to determine their role in maintaining phenotypic diversity. Ecological niches of each hoary bat species were examined in environmental space to quantify niche overlap, equivalency, and the magnitude of niche differentiation. Phylogenetic and species delimitation analyses support existence of three geographically structured species of hoary bat, each of which is phenotypically distinct; however, the Hawaiian hoary bat is morphologically more similar to the South American species than to the North American species despite a closer phylogenetic relationship to the latter. Stepwise multiple regression and niche analyses revealed higher environmental similarities between the South American and Hawaiian species. Hoary bats thus exhibit a pattern of phenotypic variation that disagrees with well-supported genetic divergences, instead indicating phenotypic convergence driven by similar environmental features and relatively conserved niches occupied in tropical latitudes.

This study aimed to compare the predictive performance of different modeling methods in developing normal tissue complication probability (NTCP) models for predicting radiation-induced esophagitis (RE) in non–small cell lung cancer (NSCLC) patients receiving proton radiotherapy. The dataset was composed of 328 NSCLC patients receiving passive-scattering proton therapy and 41.6% of the patients experienced ≥ grade 2 RE. Five modeling methods were used to build NTCP models: standard Lyman–Kutcher–Burman (sLKB), generalized LKB (gLKB), multivariable logistic regression using two variable selection procedures-stepwise forward selection (Stepwise-MLR), and least absolute shrinkage and selection operator (LASSO-MLR), and support vector machines (SVM). Predictive performance was internally validated by a bootstrap approach for each modeling method. The overall performance, discriminative ability, and calibration were assessed using the Negelkerke R2, area under the receiver operator curve (AUC), and Hosmer–Lemeshow test, respectively. The LASSO-MLR model showed the best discriminative ability with an AUC value of 0.799 (95% confidence interval (CI): 0.763–0.854), and the best overall performance with a Negelkerke R2 value of 0.332 (95% CI: 0.266–0.486). Both of the optimism-corrected Negelkerke R2 values of the SVM and sLKB models were 0.301. The optimism-corrected AUC of the gLKB model (0.796) was higher than that of the SVM model (0.784). The sLKB model had the smallest optimism in the model variation and discriminative ability. In the context of classification and probability estimation for predicting the NTCP for radiation-induced esophagitis, the MLR model developed with LASSO provided the best predictive results. The simplest LKB modeling had similar or even better predictive performance than the most complex SVM modeling, and it was least likely to overfit the training data. The advanced machine learning approach might have limited applicability in clinical settings with a relatively small amount of data.

Canine mesenchymal stem cells (cMSCs) have potential applications for regenerative therapy, including the generation of insulin-producing cells (IPCs) for studying and treating diabetes. In this study, we established a useful protocol for generating IPCs from canine adipose mesenchymal stem cells (cAD-MSCs). Subsequently, in vitro preservation of pluronic F127-coated alginate (ALGPA)-encapsulated cAD-MSC-derived IPCs was performed to verify ready-to-use IPCs. IPCs were induced from cAD-MSCs with the modulated three-stepwise protocol. The first step of definitive endoderm (DE) induction showed that the cooperation of Chir99021 and Activin A created the effective production of Sox17-expressed DE cells. The second step for pancreatic endocrine (PE) progenitor induction from DE indicated that the treatment with taurine, retinoic acid, FGF2, EGF, TGFβ inhibitor, dorsomorphin, nicotinamide, and DAPT showed the significant upregulation of the pancreatic endocrine precursor markers Pdx1 and Ngn3. The last step of IPC production, the combination of taurine, nicotinamide, Glp-1, forskolin, PI3K inhibitor, and TGFβ inhibitor, yielded efficiently functional IPCs from PE precursors. Afterward, the maintenance of ALGPA-encapsulated cAD-MSC-derived IPCs with VSCBIC-1, a specialized medium, enhanced IPC properties. Conclusion, the modulated three-stepwise protocol generates the functional IPCs. Together, the encapsulation of cAD-MSC-derived IPCs and the cultivation with VSCBIC-1 enrich the maturation of generated IPCs.

Socioeconomic status has been associated with obesity prevalence increase in both males and females worldwide. We examined the magnitude of the difference between the two relationships and explored the independence of both relationships. Country specific data on gross domestic product (GDP) per capita, sex-specific obesity prevalence rates, urbanisation, total calories availability and level of obesity, genetic background accumulation (measured by the Biological State Index, Ibs) were obtained for 191 countries. Curvilinear regressions, bivariate and partial correlations, linear mixed models and multivariate linear regression analyses were used to examine the relationship between GDP and obesity prevalence rates in males and females respectively. Fisher’s r-to-z transformation, F-test and R2increment in multivariate regression were used to compare results for males and females. GDP significantly correlated with sex-specific obesity prevalence rates, but significantly more strongly with male obesity prevalence in bivariate correlation analyses. These relationships remained independent of calories availability, Ibsand urbanization in partial correlation model. Stepwise multiple regression identified that GDP was a significant predictor of obesity prevalence in both sexes. Multivariate stepwise regression showed that, when adding GDP as an obesity prevalence predictor, the absolute increment of R2in male fit model (0.046) was almost four (4) times greater than the absolute increment in female model fit (0.012). The Stepwise analyses also revealed that 68.0% of male but only 37.4% of female obesity prevalence rates were explained by the total contributing effects of GDP, Ibs, urbanization and calories availability. In both Pearson’s r and nonparametric analyses, GDP contributes significantly more to male obesity than to female obesity in both developed and developing countries. GDP also determined the significant regional variation in male, but not female obesity prevalence. GDP may contribute to obesity prevalence significantly more in males than in females regardless of the confounding effects of Ibs, urbanization and calories. This may suggest that aetiologies for female obesity are much more complex than for males and more confounders should be included in the future studies when data are available.