First-year nursing students' attitudes towards artificial intelligence: Cross-sectional multi-center study.
To assess the attitudes of nursing students toward artificial intelligence. Possible applications of artificial intelligence-powered systems in nursing cover all aspects of nursing care, from patient care to risk management. Although the final acceptance of artificial intelligence in practice will depend on positive 'nurses' attitudes toward artificial intelligence, those attitudes have gained little attention so far. A cross-sectional multicenter study. The study was performed at nursing schools of four Croatian universities, surveying a total of 336 first-year nursing students (response rate 69.7%) enrolled in 2021. A validated instrument, the General Attitudes towards Artificial Intelligence Scale, consisting of 20 Likert-type items, was chosen for the study. Where applicable, the items were contextualized for nursing. Four sub-scales were identified based on the outcomes of the factor analysis. The average attitude score was (mean ± standard deviation) 64.5 ± 11.7, out of a maximum of 100, which was significantly higher than the neutral score of 60.0 (p < 0.001). The attitude towards AI did not differ across the universities and was not associated with students' age. Male students scored slightly higher than their female colleagues. Scores on subscales "Benefits of artificial intelligence in nursing", "Willingness to use artificial intelligence in nursing practice", and "Dangers of artificial intelligence" were favorable of artificial intelligence-based solutions. However, scores on the subscale "Practical advantages of artificial intelligence" were somewhat unfavorable. First-year nursing students had slightly positive attitudes towards artificial intelligence in nursing, which should make it easier for the new generations of nurses to embrace and implement artificial intelligence systems. Reservations about artificial intelligence in daily nursing practice indicate that nursing students might benefit from education focused specifically on applications of artificial intelligence in nursing.


Anti-p53 autoantibody in colorectal cancer: prognostic significance in long-term follow-up.
The prognostic significance of anti-53 autoantibody in colorectal cancer (CRC) patients is unclear due to measurement of overall rather than disease-specific survival and generally short follow-up periods in many studies. We aim to investigate prognostic significance of anti-p53 auto-antibodies in a study with long-term follow-up (minimum 5 years). ELISA for anti-p53 autoantibody was assayed in serum from 92 patients with CRC and 28 controls. Anti-p53 autoantibody was found in 20 patients (21.7%) and none of the controls. No difference in Dukes' (A/B vs. C/D), Stage (I/II vs. III/IV), T1/2 vs. T3/4, N0 vs. N1/2, M0 vs. M1, poor vs. well/moderate differentiation and proximal vs. distal CRC was observed. Median overall survival was 62 months and median disease-specific survival was 73 months. Dukes' C/D, Stage III/IV, N1/2 and M1 were associated with poor disease-specific survival in univariate analysis. Stage III/IV was an independent prognostic factor in overall and disease-free survival in multivariate analysis. Anti-p53 autoantibody sero-positivity did not influence overall (p = 0.980) or disease-specific survival (p = 0.874). Median overall survival in anti-p53 autoantibody positive patients was 62 months vs. 60 months in anti-53 autoantibody negative patients. Median disease-specific survival in anti-p53 autoantibody positive patients was 73 months vs. 82 months. Anti-p53 autoantibody is not related to clinical parameters of CRC and has no prognostic significance in long-term follow-up.


Estimating vaccination coverage: validity of household-retained vaccination cards and parental recall.
Public health programs rely on household-survey estimates of vaccination coverage as a basis of programmatic and policy decisions; however, the validity of estimates derived from household-retained vaccination cards and parental recall has not been thoroughly evaluated. Using data from a vaccination coverage survey conducted in the Western Pacific's Northern Mariana Islands, we compared results from household data sources to medical record sources for the same children. We calculated the percentage of children aged 1, 2, and 6 years who received all vaccines recommended by age 12 months, 24 months, and for school entry, respectively. Coverage estimates based on vaccination cards ranged from 14% to 30% in the three age groups compared to 78-91% for the same children based on medical records. When cards were supplemented by parental recall, estimates were 51-53%. Concordance, sensitivity, specificity, positive and negative predictive values, and kappa statistics generally indicated poor agreement between household and medical record sources. Household-retained vaccination cards and parental recall were insufficient sources of information for estimating vaccination coverage in this population. This study emphasizes the importance of identifying reliable sources of vaccination history information and reinforces the need for awareness of the potential limitations of vaccination coverage estimated from surveys that rely on household-retained cards and/or parental recall.


Non-fusion expression in Escherichia coli: Single-step purification of recombinant human annexin A5 for detection of apoptosis.
Recombinant human annexin A5 (rh-annexin A5) was originally used to detect early stages of apoptosis in vitro. With the development of radioactive labeling and imaging techniques, annexin A5 labeled with radioactive markers can play a more important role in monitoring apoptotic cells in vivo. To obtain highly pure rh-annexin A5 with an easy and inexpensive purification approach, we constructed a pJLA503-annexin A5 expression plasmid, which could overexpress human annexin A5 in a soluble form in Escherichia coli. Then a novel purification method based on Ca2+-dependent phosphatidylserine (PS)-binding activity was established, whereby the purity of rh-annexin A5 was increased to 98%. To confirm the PS affinity of rh-annexin A5 produced by this purification protocol, a simple and reliable lipid membrane model was prepared and used in the binding test. As a probe to detect apoptosis, the fluorescein isothiocyanate-labeled rh-annexin A5 was incubated with apoptotic cells. The results showed that the labeled rh-annexin A5 possessed high affinity for PS molecule and was able to indicate different apoptotic states.


Multiple myeloma as a major cause of false-positive galactomannan tests in adult patients with cancer.
The galactomannan (GM) test is a useful method for early diagnosis of invasive aspergillosis. Recently, multiple myeloma has newly been suggested to be related to false-positive results of GM. We performed a case-control study to validate this finding. Electronic medical records were reviewed for patients admitted March through June 2014. Patients with false-positive GM results were selected as cases and those with negatives as controls. To verify the results of the four-month analysis, additional analysis was performed in multiple myeloma patients over a three-year period. There were 30 false-positive and 316 negative cases during the four-month period. Among the factors evaluated, multiple myeloma was the only significant factor in the adjusted analysis (OR = 3.59, CI 1.28-10.04). In the three-year analysis of 145 multiple myeloma patients, 25.5% showed false-positive results, which was 3 times higher than overall. GM false-positivity was not related to serum monoclonal protein level or type of immunoglobulin. GM optical density indexes (ODIs) in all false positives were lower than 3.0. Multiple myeloma was a major cause of GM false-positivity in adult cancer patients. GM was false-positive in 25.5% of multiple myeloma patients with GM ODIs lower than 3.0.


Synthesis of porous iron hydroxy phosphate from phosphate residue and its application as a Fenton-like catalyst for dye degradation.
Phosphate residue is a kind of hazardous solid waste and if not properly disposed of, could cause serious environmental contaminations. The abundant iron salt available in phosphate residue can be used to prepare photo-Fenton catalytic reagent for wastewater treatment. In this study, the phosphate residue was effectively purified by a hydrothermal recrystallization method, reaching an iron phosphate purity of 94.2%. The particles of iron phosphate were further processed with ball milling with their average size reduced from 19.4 to 1.6 μm. By hydrothermal crystallization of iron phosphate and thermal decomposition of oxalate precursor, porous iron hydroxy phosphate was prepared. The modified porous iron hydroxy phosphate (m-PIHP) of higher surface area with iron oxalate on its surface can degrade 98.87% of Rhodamine B in 15 min. Cyclic experiment showed that the catalyst still had a good catalytic activity after six cycles (>40%). The X-ray photoelectron spectroscopy results showed that the iron oxalate complex on the catalyst surface decomposed to produce ferrous ions and accelerated the rate of •OH production. The current work demonstrated that the m-PIHP synthesized from phosphate residue and modified with iron oxalate can be used as an effective dye wastewater treatment agent.


Prenatal diagnosis of Morquio disease type A using a simple fluorometric enzyme assay.
A new fluorogenic substrate, 4 methylumbelliferyl beta-D-6-sulphogalactoside, was used for the assay of galactose-6-sulphate sulphatase activity in chorionic villi, cultured villus cells, and amniocytes. The fluorometric assay is much more convenient than the conventional assay using radiolabelled, sulphated oligosaccharides. Both types of substrate were used in the prenatal diagnosis of three pregnancies at risk for Morquio type A disease using amniocytes. These enzyme tests, as well as electrophoresis of glycosaminoglycans in the amniotic fluid, indicated affected fetuses in two pregnancies and a non-affected fetus in one.


A Population-Based Cohort Study on the Drug-Specific Effect of Statins on Sepsis Outcome.
Whether statin treatment, proved by recent experimental studies to have an antimicrobial activity, exerts a drug- or a class-specific effect in sepsis remains unknown. Short-term mortality in patients with sepsis was analyzed using data from the National Health Insurance Research Database. Use of statins was defined as the cumulative use of a specific statin (atorvastatin, simvastatin, or rosuvastatin) for > 30 days prior to the index sepsis admission. We determined the association between statin and sepsis outcome by multivariate-adjusted Cox models and propensity score (PS)-matched analysis, using a 1:1:1 PS matching technique. A total of 52,737 patients with sepsis fulfilled the inclusion criteria, of which 1,855 were prescribed atorvastatin, 916 were prescribed simvastatin, and 732 were prescribed rosuvastatin. Compared with nonusers, simvastatin (hazard ratio [HR], 0.72; 95% CI, 0.58-0.90) and atorvastatin (HR, 0.78; 95% CI, 0.68-0.90) were associated with an improved 30-day survival, whereas rosuvastatin was not (HR, 0.87; 95% CI, 0.73-1.04). Using rosuvastatin as the reference, atorvastatin (HR, 0.79; 95% CI, 0.64-0.99) and simvastatin (HR, 0.77; 95% CI, 0.59-0.99) had superior effectiveness in preventing mortality. Compatible with in vitro experimental findings, our results suggest that the drug-specific effect of statins on sepsis is not correlated to their lipid-lowering potency.


A Phase II Study of the Efficacy and Safety of Oral Selinexor in Recurrent Glioblastoma.
Selinexor is an oral selective inhibitor of exportin-1 (XPO1) with efficacy in various solid and hematologic tumors. We assessed intratumoral penetration, safety, and efficacy of selinexor monotherapy for recurrent glioblastoma. Seventy-six adults with Karnofsky Performance Status ≥ 60 were enrolled. Patients undergoing cytoreductive surgery received up to three selinexor doses (twice weekly) preoperatively (Arm A; n = 8 patients). Patients not undergoing surgery received 50 mg/m2 (Arm B, n = 24), or 60 mg (Arm C, n = 14) twice weekly, or 80 mg once weekly (Arm D; n = 30). Primary endpoint was 6-month progression-free survival rate (PFS6). Median selinexor concentrations in resected tumors from patients receiving presurgical selinexor was 105.4 nmol/L (range 39.7-291 nmol/L). In Arms B, C, and D, respectively, the PFS6 was 10% [95% confidence interval (CI), 2.79-35.9], 7.7% (95% CI, 1.17-50.6), and 17% (95% CI, 7.78-38.3). Measurable reduction in tumor size was observed in 19 (28%) and RANO-response rate overall was 8.8% [Arm B, 8.3% (95% CI, 1.0-27.0); C: 7.7% (95% CI, 0.2-36.0); D: 10% (95% CI, 2.1-26.5)], with one complete and two durable partial responses in Arm D. Serious adverse events (AEs) occurred in 26 (34%) patients; 1 (1.3%) was fatal. The most common treatment-related AEs were fatigue (61%), nausea (59%), decreased appetite (43%), and thrombocytopenia (43%), and were manageable by supportive care and dose modification. Molecular studies identified a signature predictive of response (AUC = 0.88). At 80 mg weekly, single-agent selinexor induced responses and clinically relevant PFS6 with manageable side effects requiring dose reductions. Ongoing trials are evaluating safety and efficacy of selinexor in combination with other therapies for newly diagnosed or recurrent glioblastoma.


Human neural stem cells over-expressing choline acetyltransferase restore cognition in rat model of cognitive dysfunction.
A human neural stem cell (NSC) line over-expressing human choline acetyltransferase (ChAT) gene was generated and these F3.ChAT NSCs were transplanted into the brain of rat Alzheimer disease (AD) model which was induced by application of ethylcholine mustard aziridinium ion (AF64A) that specifically denatures cholinergic nerves and thereby leads to memory deficit as a salient feature of AD. Transplantation of F3.ChAT human NSCs fully recovered the learning and memory function of AF64A animals, and induced elevated levels of acetylcholine (ACh) in cerebrospinal fluid (CSF). Transplanted F3.ChAT human NSCs were found to migrate to various brain regions including cerebral cortex, hippocampus, striatum and septum, and differentiated into neurons and astrocytes. The present study demonstrates that brain transplantation of human NSCs over-expressing ChAT ameliorates complex learning and memory deficits in AF64A-cholinotoxin-induced AD rat model.


Imidazoline versus alpha₂-adrenoceptors in the control of gastric motility in mice.
Several lines of evidence suggest that imidazoline receptors mediate various physiological processes. It is rather difficult, however, to distinguish the imidazoline receptor-mediated effects from the alpha₂-adrenoceptor-mediated ones due to the reasonable affinity of most imidazoline ligands for the alpha₂-adrenoceptors. In the present study the effects of different imidazoline ligands were tested on the electrical field stimulation (EFS)-induced gastric contractions in wild-type (WT), alpha₂A-, alpha₂B- and alpha₂C-adrenoceptor knockout (KO) mice in order to analyze, whether imidazoline I₁ and I₂ receptors take part in the regulation of gastric motor activity. Clonidine, moxonidine and rilmenidine inhibited the EFS-induced gastric contractions in a concentration dependent manner in WT, alpha₂B- and alpha₂C-adrenoceptor KO mice, whereas they had no or only weak effect in alpha₂A-adrenoceptor KO mice. Their effects in WT mice were inhibited by idazoxan and BRL 44408, but not by ARC 239, AGN 192403 and BU 224. The endogenous imidazoline receptor ligand agmatine failed to affect the EFS-induced contractions, while harmane (an other endogenous imidazoline receptor ligand) and 2-BFI (a selective imidazoline I2 receptor agonist) exerted a slight effect in both WT and alpha2A-adrenoceptor KO mice, but this was not reversible by idazoxan, AGN 192403 and BU 224. It can be concluded, that the inhibitory effect of the tested imidazoline compounds on cholinergic gastric contractions is mediated mainly by alpha₂A-adrenoceptors. Although at higher concentrations other receptors may also contribute to their effects, the lack of inhibition by AGN 192403 and BU 224 suggests that these are not imidazoline I₁ and I₂ receptors.


In vivo Targeting of DNA Vaccines to Dendritic Cells via the Mannose Receptor Induces Long-Lasting Immunity against Melanoma.
Herein, we report effective, C-type lectin mannose receptor (MR)-selective, in vivo dendritic cell (DC)-targeting lipid nanoparticles (LNPs) of a novel lipid-containing mannose-mimicking di-shikimoyl- and guanidine head group and two n-hexadecyl hydrophobic tails (DSG). Subcutaneous administration of LNPs of the DSG/p-CMV-GFP complex showed a significant expression of green fluorescence protein in the CD11c+ DCs of the neighboring lymph nodes compared to the control LNPs of the BBG/p-CMV-GFP complex. Mannose receptor-facilitated in vivo DC-targeted vaccination (s.c.) with the electrostatic complex of LNPs of DSG/pCMV-MART1 stimulated long-lasting (270 days post B16F10 tumor challenge) antimelanoma immunity under prophylactic conditions. Remarkably, under therapeutic settings, vaccination (s.c.) with LNPs of the DSG/pCMV-MART1 complex significantly delayed melanoma growth and improved the survival of mice with melanoma. These findings demonstrate that this nonviral delivery system offers a resilient and potential approach to deliver DNA vaccines encoding tumor antigens to DCs in vivo with high efficacy.


Role of antiparasitic therapy for seizures and resolution of lesions in neurocysticercosis patients: an 8 year randomised study.
Neurocysticercosis is a common cause of acquired seizure disorder in developing countries, including India. The role of antiparasitic (albendazole) therapy for seizure control and resolution of lesions is still controversial due to a lack of adequately controlled studies. The objective of the present study was to evaluate the role of albendazole therapy for neurocysticercosis patients with two or more lesions to achieve seizure-free status and resolution of lesions. This was a randomised controlled study in which patients suffering from neurocysticercosis were prospectively followed up for more than 5 years (from January 1997 to January 2005). Patients were divided into two groups: patients in group A (n=150) were treated with a combination of tapered doses of dexamethasone and albendazole, plus antiepileptic drugs; patients in group B (n=150) were treated with antiepileptic drugs plus a placebo control. Patients were followed up every month for the first 6 months and then at 3-month intervals thereafter up to 5 years. Variables of interest were (i) recurrence of seizures; (ii) encephalopathy (headache/vomiting/altered sensorium); (iii) need for subsequent hospital admission; (iv) death; (v) resolution of lesions on follow-up CT. During the first 6 months and at intervals thereafter, increased seizure frequency and hospital readmissions, and increased incidence of encephalopathy were observed in group A (p=0.01), and two patients in this group died with intractable seizures and encephalopathy. A greater proportion of lesions completely resolved in group B (p=0.05), whereas a greater proportion of lesions calcified in group A (p=0.05). Albendazole plus antiepileptic drugs did not have greater beneficial effects than antiepileptic drugs alone, but may have an adverse effect with respect to seizure control, encephalopathy, recurrent hospital admissions, calcification of lesions and cost of treatment.


Airway responses to salbutamol after exposure to chemical warfare.
Increased airway responsiveness to beta-agonists is noted in asthmatics and smokers. The lung may be exposed to chemical warfare agents such as mustard gas and pulmonary complications of exposure range from no effect to severe bronchial stenosis. There is little understanding of airway hyperresponsiveness to beta-agonist drugs in chemical war victims and this study examined airway responsiveness to salbutamol in victims of chemical warfare. The threshold concentrations of inhaled salbutamol required for a 20% change in FEV(1) as PC(20), or a 35% change in specific airway conductance (sGaw) as PC(35) were measured in 22 persons exposed to chemical warfare and 15 normal control subjects. In 11 of the 22 subjects PC(20) salbutamol could be measured and in 15 of the 22 subjects PC(35) salbutamol could be measured. This group of patients was the responder group (PC(20) = 10.79 and PC(35) = 8.55 mg/L) and in them the concentration of salbutamol needed for a response was significantly lower than that required in normal controls (PC(20) = 237.68 and PC(35) = 88.72 mg/L, P < 0.001). There was a significant correlation between FEV(1) and PC(20) salbutamol (r = 0.815, P < 0.001). These results showed increased airway responsiveness to salbutamol in most subjects exposed to chemical warfare; this was correlated with airway calibre.


Patient safety in cancer rehabilitation.
Cancer patients receive rehabilitation services in acute hospitalizations, rehabilitation wards, outpatient rehabilitation facilities, and home settings. Given the complexity and acuity of their medical care coupled with the long-term effects of the cancer and its treatments, patient safety is a significant concern in the delivery of rehabilitation services for this population. Cancer survivorship is growing in importance as a significant number of adults and children diagnosed with cancer are surviving beyond the 5-year mark. The goal of this article is to provide an overview to rehabilitation clinicians on the topic of patient safety in the rehabilitation of cancer patients.


Evaluation of low back pain frequency and related factors among people over 18 years of age.
The present study aimed to evaluate the incidence of LBP and related factors in over 18-year-olds. This research was a cross-sectional study involving individuals over 18 years of age with any complaints in the period from May 2015-June 2016 at different hospitals. The research data were evaluated by the SPSS 15.0 statistical package program. Descriptive statistics were presented as mean (±) standard deviation, median (min, max), frequency distribution, and percentage. Pearson's Chi-square test, Yates corrected Chi-square test, and Fisher's test were used as statistical methods. Statistical significance was accepted as P < 0.05. A total of 5,989 people admitted during that period and 50% unknown frequency were taken to reach 1715 subject persons with 2% deviation and 95% confidence interval which reached 1720. The sociodemographic status, occupational conditions, the frequency of low back pain, and risk factors have been evaluated. Around 92.9% of individuals of 65 years of age and older have lifelong LPB while 57.1% have present LBP. The difference was statistically significant for "the satisfaction of working people" and "individuals working more than 41 h a week." (P < 0.001). Low back pain is still a serious problem that can be avoided by ensuring optimal working conditions and a healthier life.


Minor axial tooth movement in preparation for fixed prostheses.
In this first of two articles the theory and practice of creating occlusal clearance for restorative procedures without the removal of tooth tissue is discussed. Earlier techniques for producing minor axial tooth movement are reviewed, together with the relevant literature on continuous eruption and occlusal stability. The indications for axial tooth movement and alternative treatment options are also considered.


Changes in the intestinal microbiota of Pacific white shrimp (Litopenaeus vannamei) with different severities of Enterocytozoon hepatopenaei infection.
The intestinal microbiota of the Pacific white shrimp Litopenaeus vannamei during Enterocytozoon hepatopenaei (EHP) infection was investigated by 16S rRNA gene-based analysis. The results showed that bacterial diversity in the intestine of L. vannamei was high, but it decreased with increasing severity of EHP infection. The relative abundances of the phyla Planctomycetes, Actinobacteria and Acidobacteria decreased significantly with a decrease in body size or EHP infection severity (P < 0.05). The most abundant genera were Pseudomonas, Methylobacterium, Bradyrhizobium, Bacteroides, Vibrio, Prevotella and so on. In addition, the relative abundances of some bacteria, such as Pseudomonas, Bradyrhizobium, Bacteroides and Vibrio, increased significantly with a decrease in body size or EHP infection severity (P < 0.05). These findings suggest that changes in the intestinal microbiota occur depending on the severity of EHP infection.


Erratum regarding previously published articles.
[This corrects the article DOI: 10.1016/j.hest.2020.01.002.][This corrects the article DOI: 10.1016/j.hest.2020.01.004.][This corrects the article DOI: 10.1016/j.hest.2020.01.001.][This corrects the article DOI: 10.1016/j.hest.2020.06.002.][This corrects the article DOI: 10.1016/j.hest.2020.10.004.][This corrects the article DOI: 10.1016/j.hest.2020.12.001.][This corrects the article DOI: 10.1016/j.hest.2020.12.003.][This corrects the article DOI: 10.1016/j.hest.2021.04.002.][This corrects the article DOI: 10.1016/j.hest.2021.07.002.][This corrects the article DOI: 10.1016/j.hest.2021.02.002.][This corrects the article DOI: 10.1016/j.hest.2021.06.005.][This corrects the article DOI: 10.1016/j.hest.2021.07.003.][This corrects the article DOI: 10.1016/j.hest.2021.09.005.].


Parental DNA strands segregate randomly during embryonic development of Caenorhabditis elegans.
The fate of gamete DNA was followed in the next generation embryos of the nematode C. elegans. Either male worms or spermless hermaphrodites were grown on bromodeoxyuridine-containing E. coli in order to label germ-line DNA. Matings then produced embryos in which only the DNA strands provided by the gametes contained label. This original gamete DNA could be detected during embryonic development by using a fluorescently labeled monoclonal antibody specific to bromodeoxyuridine. Both the number and position of fluorescent spots in the embryo indicate that gamete DNA strands segregate randomly during development. Random segregation of parental DNA strands rules out models of development that invoke chromosome imprinting or immortal DNA strands.


Stability of sample extracts of vitamin D3 metabolites after chemical derivatization for LC-MS/MS analysis.
Liquid chromatography/tandem mass spectrometry (LC-MS/MS) is widely used to determine vitamin D3 metabolites in biological samples. The ionization efficiencies of these metabolites, however, are poor under electrospray ionization conditions. Moreover, the chromatographic separation of multiple vitamin D metabolites and their epimers can be challenging. For these reasons, chemical derivatization reagents are often used to improve sensitivity and selectivity of analysis. While the derivatization schemes have been proven to be very effective, one missing aspect is the investigation of the stability of the chemical derivatization products in stored sample extracts. In this study, we investigated the long-term stability of several vitamin D3 metabolites after 1 and 3 months of storage at - 20 °C. Five vitamin D3 metabolites were examined after derivatization with seven different derivatization reagents. Generally, Amplifex products were the most stable in the long term in our study with 11-20% degraded after 1 month of storage and 14-35% after 3 months. The stabilities for some of the metabolites' 4-[2-(6,7-dimethoxy-4-methyl-3-oxo-3,4-dihydroquinoxalyl)ethyl]-1,2,4-triazoline-3,5-dione (DMEQ-TAD), 2-fluoro-1-methylpyridinium p-toluenesulfonate (FMP-TS), isonicotinoyl chloride (INC) and 4-phenyl-1,2,4-triazoline-3,5-dione acetylated (PTAD-Ac) products were also acceptable after 1 month of storage. Other derivatized metabolites, however, degraded extensively already after 1 month of storage, such as 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) (54-72% degradation) and 2-nitrosopyridine (PyrNO) (32-100% degradation). Importantly, for every metabolite, there was an optimum derivatization reagent that met the criteria of stability proposed by international regulatory bodies after 1 month of storage. Some derivatives were stable for even up to 3 months of storage, with degradation of less than 15%.


Perfusion MR imaging: evolution from initial development to functional studies.
A critical indicator of tissue viability and function is blood delivery to the capillary bed (referred to as perfusion or tissue/capillary blood flow), so the measurement of this process has been pursued by many MR scientists. Perfusion MRI is currently an effective tool to non-invasively quantify cerebral blood flow (CBF) and to easily obtain its relative change due to neural activity or other stimulus. This article describes the author's experiences in perfusion MRI over the past quarter-century, including initial development of the field, development of a flow-sensitive alternating inversion recovery (FAIR) MRI technique, development of a functional oxygen consumption MRI measurement approach, validation of the FAIR technique, characterization of perfusion changes induced by neural activity, and determination of arterial blood volume.


Fish collagen-based scaffold containing PLGA microspheres for controlled growth factor delivery in skin tissue engineering.
To design a scaffold controlled release system for skin tissue engineering, fish collagen/chitosan/chondroitin sulfate scaffolds were fabricated by freeze-drying and incorporated with bFGF-loaded PLGA microspheres (MPs). SEM showed that the scaffolds exhibited an interconnected porous structure, and the spherical MPs were uniformly distributed into the scaffolds. The higher swelling and degradation rate of scaffolds/MPs could lead to a higher diffusion rate of MPs from the scaffolds, causing an increase in the protein release. The release rate of proteins could be adjusted by the size of MPs and the ratio of collagen to chitosan of scaffolds. Circular dichroism spectroscopy and MTT of bFGF after release indicated that the released bFGF retained its structural integrity and bioactivity during preparation. Cell proliferation and in vivo evaluation results suggested that the scaffolds/MPs had a good biocompatibility and an ability to promote fibroblast cell proliferation and skin tissue regeneration. These results demonstrated that this scaffold/MP controlled release system has the potential for skin tissue engineering.


Non-warfarin oral anticoagulant copayments and adherence in atrial fibrillation: A population-based cohort study.
In patients with atrial fibrillation, incomplete adherence to anticoagulants increases risk of stroke. Non-warfarin oral anticoagulants (NOACs) are expensive; we evaluated whether higher copayments are associated with lower NOAC adherence. Using a national claims database of commercially-insured patients, we performed a cohort study of patients with atrial fibrillation who newly initiated a NOAC from 2012 to 2018. Patients were stratified into low (<$35), medium ($35-$59), or high (≥$60) copayments and propensity-score weighted based on demographics, insurance characteristics, comorbidities, prior health care utilization, calendar year, and the NOAC received. Follow-up was 1 year, with censoring for switching to a different anticoagulant, undergoing an ablation procedure, disenrolling from the insurance plan, or death. The primary outcome was adherence, measured by proportion of days covered (PDC). Secondary outcomes included NOAC discontinuation (no refill for 30 days after the end of NOAC supply) and switching anticoagulants. We compared PDC using a Kruskal-Wallis test and rates of discontinuation and switching using Cox proportional hazards models. After weighting patients across the 3 copayment groups, the effective sample size was 17,558 patients, with balance across 50 clinical and demographic covariates (standardized differences <0.1). Mean age was 62 years, 29% of patients were female, and apixaban (43%), and rivaroxaban (38%) were the most common NOACs. Higher copayments were associated with lower adherence (P < .001), with a PDC of 0.82 (Interquartile range [IQR] 0.36-0.98) among those with high copayments, 0.85 (IQR 0.41-0.98) among those with medium copayments, and 0.88 (IQR 0.41-0.99) among those with low copayments. Compared to patients with low copayments, patients with high copayments had higher rates of discontinuation (hazard ratio [HR] 1.13, 95% confidence interval [CI] 1.08-1.19; P < .001). Among atrial fibrillation patients newly initiating NOACs, higher copayments in commercial insurance were associated with lower adherence and higher rates of discontinuation in the first year. Policies to lower or limit cost-sharing of important medications may lead to improved adherence and better outcomes among patients receiving NOACs.


Simvastatin protects osteoblast against H2O2-induced oxidative damage via inhibiting the upregulation of Nox4.
Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, have been used clinically as a cholesterol-lowering drug to treat hyperlipidemia. In recent years, accumulating evidence indicates the possible beneficial effect of statins on osteoporosis. However, the underlying molecular mechanism remains to be elucidated. In the present study, we investigated the therapeutic effects of simvastatin on cell viability, apoptosis, and alkaline phosphatase activity in murine osteoblastic MC3T3-E1 cells treated by hydrogen peroxide (H(2)O(2), 100 μM). It was shown that simvastatin suppressed H(2)O(2)-induced oxidative stress and attenuated H(2)O(2)-induced cell injury including increasing osteoblastic viability, inhibiting apoptosis, and promoting differentiation. Then, we examined the effects of simvastatin (10(-7) M) on Nox1, Nox2, and Nox4 expressions in osteoblastic cells treated by H(2)O(2) (100 μM). We found that in MC3T3-E1 cells, H(2)O(2)-induced upregulation of Nox4 expression was inhibited by simvastatin, which was restored by farnesyl pyrophosphate (5 μM) as well as geranylgeranyl pyrophosphate (5 μM). RNAi approach was used to reduce Nox4 protein levels in osteoblastic cells to explore its biological effects against H(2)O(2)-induced oxidative damage. When Nox4 expression was reduced in osteoblastic cells, H(2)O(2)-induced cell injury was attenuated markedly. We concluded that simvastatin protected osteoblast against H(2)O(2)-induced oxidative damage, at least in part, via inhibiting the upregulation of Nox4.


Retrograde popliteal access as bail-out strategy for challenging occlusions of the superficial femoral artery: a multicenter registry.
The concomitant use of femoral and popliteal accesses has been recommended for challenging superficial femoral artery (SFA) occlusions, but no comprehensive comparison of this approach to a strategy of femoral access only is available. We thus aimed to appraise the risk-benefit balance of retrograde popliteal access as bail-out strategy for SFA occlusions. Consecutive patients with symptomatic SFA occlusion and undergoing percutaneous revascularization were enrolled. We distinguished patients in whom retrograde popliteal access was required as bail-out strategy versus those not requiring such access. The primary end-point was procedural success. A total of 130 patients (152 limbs) were included, with 23 patients (25 limbs) requiring retrograde popliteal access. Occlusion length was 20.6 ± 8.8 cm in those requiring popliteal access versus 18.5 ± 8.5 cm in those without popliteal access, with TASC C/D lesions in 23 (92%) versus 106 (83%). Procedural success was achieved in 92 out of 107 patients (86.0%) treated with a standard approach and 22 out of 23 patients (95.7%) treated with retrograde popliteal access (total 114 out of 130 [87.7%]) and 112 out of 127 limbs (88.2%) and 24 out of 25 limbs (96.0%), respectively (total 136 out of 152 [89.5%]). No significant increase in early or long-term adverse events was associated with retrograde popliteal access. Whenever standard access sites do not enable successful recanalization of SFA occlusions, retrograde popliteal access can be safely and effectively envisioned as bail-out strategy.


The scientist center stage.
While rehearsing for a performance for London's Science Museum, I ask how scientists and theater artists might collaborate to produce theater that serves the science as much as the art.


Evidence that additional mechanisms to cyclic GMP mediate the decrease in intracellular calcium and relaxation of rabbit aortic smooth muscle to nitric oxide.
1. The role of cyclic GMP in the ability of nitric oxide (NO) to decrease intracellular free calcium concentration [Ca2+]i and divalent cation influx was studied in rabbit aortic smooth muscle cells in primary culture. In cells stimulated with angiotensin II (AII, 10(-1) M), NO (10(-10) - 10(-6) M) increased cyclic GMP levels measured by radioimmunoassay and decreased [Ca2+]i and cation influx as indicated by fura-2 fluorimetry. 2. Zaprinast (10(-4) M), increased NO-stimulated levels of cyclic GMP by 3-20 fold. Although the phosphodiesterase inhibitor lowered the level of [Ca2+]i reached after administration of NO, the initial decreases in [Ca2+]i initiated by NO were not significantly different in magnitude or duration from those that occurred in the absence of zaprinast. 3. The guanylyl cyclase inhibitor, H-(1,2,4) oxadiazolo(4,3-a) quinoxallin-1-one (ODQ, 10(-5) M), blocked cyclic GMP accumulation and activation of protein kinase G, as measured by back phosphorylation of the inositol trisphosphate receptor. ODQ and Rp-8-Br-cyclic GMPS, a protein kinase G inhibitor, decreased the effects of NO, 10(-10) - 10(-8) M, but the decrease in [Ca2+]i or cation influx caused by higher concentrations of NO (10(-7) - 10(-6) M) were unaffected. Relaxation of intact rabbit aorta rings to NO (10(-7) - 10(-5) M) also persisted in the presence of ODQ without a significant increase in cyclic GMP. Rp-8-Br-cyclic GMPS blocked the decreases in cation influx caused by a cell permeable cyclic GMP analog, but ODQ and/or the protein kinase G inhibitor had no significant effect on the decrease caused by NO. 4. Although inhibitors of cyclic GMP, protein kinase G and phosphodiesterase can be shown to affect the decrease in [Ca2+]i and cation influx via protein kinase G, these studies indicate that when these mechanisms are blocked, cyclic GMP-independent mechanisms also contribute significantly to the decrease in [Ca2+]i and smooth muscle relaxation to NO.


Discrepancy between superior vena cava oxygen saturation and mixed venous oxygen saturation can predict postoperative complications in cardiac surgery patients.
To determine if increases in discrepancy between ScvO2 and SvO2 (ScvO2 - SvO2 = ΔSO2) during surgery in cardiac surgery patients can predict postoperative complications. Prospective, observational study. University hospital. One hundred two patients undergoing cardiac surgery were enrolled. None. Central venous oxygen saturation (ScvO2) and mixed venous oxygen saturation (SvO2) values during surgery automatically were collected. The average value of ΔSO2 for every minute was calculated. The area under the receiver operating characteristic curve for prolonged postoperative ICU stay (≥3 days) was 0.745 for ΔSO2, which was significantly different from those of ScvO2 and SvO2 (p<0.05) (ScvO2; 0.584, SvO2; 0.598). The optimal threshold value of ΔSO2 to predict prolonged ICU stay (≥3 days) was 12% (sensitivity: 72.0%, specificity: 76.9%). Postoperative ICU duration, ventilation time, and hospital stay were significantly longer in Group D patients (intraoperative maximum ΔSO2 ≥12%) than those in Group N patients (intraoperative maximum ΔSO2<12%). As for postoperative complications, the number of patients with postoperative use of intra-aortic balloon pumping, delirium, respiratory failure requiring tracheotomy, and severe complications was significantly higher in Group D patients. Multivariate logistic regression models were used to evaluate the independent effects of perioperative variables on the risk of developing prolonged ventilation (>24 hours) and prolonged ICU stay (≥3 days). A discrepancy in intraoperative ΔSO2 was an independent risk factor for prolonged postoperative ventilation and ICU stay. The discrepancy between ScvO2 and SvO2 during cardiac surgery is an independent risk factor of postoperative complications such as prolonged ICU stay and ventilation time.


Chagas disease: an impediment in achieving the Millennium Development Goals in Latin America.
Achieving sustainable economic and social growth through advances in health is crucial in Latin America within the framework of the United Nations Millennium Development Goals. Health-related Millennium Development Goals need to incorporate a multidimensional approach addressing the specific epidemiologic profile for each region of the globe. In this regard, addressing the cycle of destitution and suffering associated with infection with Trypanosoma cruzi, the causal agent of Chagas disease of American trypanosomiasis, will play a key role to enable the most impoverished populations in Latin America the opportunity to achieve their full potential. Most cases of Chagas disease occur among forgotten populations because these diseases persist exclusively in the poorest and the most marginalized communities in Latin America. Addressing the cycle of destitution and suffering associated with T. cruzi infection will contribute to improve the health of the most impoverished populations in Latin America and will ultimately grant them with the opportunity to achieve their full economic potential.


Laryngeal mask ventilation with chest compression during neonatal resuscitation: randomized, non-inferiority trial in lambs.
Effective positive-pressure ventilation is a critical factor in newborn resuscitation. Neonatal endotracheal intubation (ETT) needs considerable training and experience, which poses a human factor challenge. Laryngeal mask airway (LMA) ventilation can be a secure and viable alternative during the initial stages of newborn resuscitation. However, there is limited evidence for its use during chest compression (CC). Seventeen lambs were randomized into LMA or ETT ventilation post cord occlusion induced cardiac arrest. After 5 min of cardiac arrest, resuscitation was initiated as per NRP recommendations. Ventilation, oxygenation, systemic and pulmonary hemodynamic parameters were recorded till the return of spontaneous circulation (ROSC) or 20 min. Baseline characteristics were similar between the groups. The incidence of ROSC was 75% (6/8) in the LMA group and 56% (5/9) in the ETT group (p = 0.74). The median (IQR) time to achieve ROSC was 6.85 min (6 min-9.1 min) in the LMA group and 7.50 min (5.33 min-18 min) in the ETT group (p = 0.65). LMA ventilation during CC is feasible and non-inferior to ETT in this model. Laryngeal mask airway (LMA) ventilation with chest compression is feasible and non-inferior to endotracheal tube ventilation in this experimental near-term lamb model of asphyxial cardiac arrest. First translational study to evaluate the use of LMA as an airway device with chest compression. Evidence primer for clinical studies to evaluate and confirm the feasibility and efficacy of LMA ventilation with chest compression are necessary before randomized clinical trials in neonates. LMA use in neonatal cardiopulmonary resusciation (CPR) could have the potential to optimize advanced resuscitation, especially in resource-limited healthcare settings.


MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling.
Mitsugumin 53 (MG53) negatively regulates skeletal myogenesis by targeting insulin receptor substrate 1 (IRS-1). Here, we show that MG53 is an ubiquitin E3 ligase that induces IRS-1 ubiquitination with the help of an E2-conjugating enzyme, UBE2H. Molecular manipulations that disrupt the E3-ligase function of MG53 abolish IRS-1 ubiquitination and enhance skeletal myogenesis. Skeletal muscles derived from the MG53-/- mice show an elevated IRS-1 level with enhanced insulin signalling, which protects the MG53-/- mice from developing insulin resistance when challenged with a high-fat/high-sucrose diet. Muscle samples derived from human diabetic patients and mice with insulin resistance show normal expression of MG53, indicating that altered MG53 expression does not serve as a causative factor for the development of metabolic disorders. Thus, therapeutic interventions that target the interaction between MG53 and IRS-1 may be a novel approach for the treatment of metabolic diseases that are associated with insulin resistance.


Hepatotoxicity during legacy cancer chemotherapy in patients infected with hepatitis C virus: A retrospective cohort study.
The rates and causes of significant hepatotoxicity with cancer chemotherapy (CCT) in patients infected with hepatitis C virus (HCV) are incompletely characterized. We compared rates of grade 3 or 4 hepatotoxicity, defined as elevated transaminases, during CCT in patients who are mono-infected with HCV compared with rates in controls matched on demographics, diagnosis, and rituximab use. We excluded patients with hepatobiliary cancers, hepatitis B virus or human immunodeficiency virus infection. Hepatotoxicity was attributed to a medical cause, cancer progression, or CCT, including HCV flare. Patients with HCV (n = 196) had a higher rate of cirrhosis than the 1,130 matched controls (21.9% versus 4%; P <0.001). Their higher rate of overall hepatotoxicity (8.7% versus 4.5% of controls, P = 0.01) was due to higher rate of CCT-related hepatotoxicity (4.1% versus 1.2%, P = 0.01). On multivariable analysis, the largest risk factor for overall hepatotoxicity was cirrhosis, and the only risk factor for CCT-related hepatotoxicity was HCV infection. Among those with HCV, the only significant risk factor for hepatotoxicity was rituximab use. Hepatotoxicity caused by CCT delayed or altered treatment in only 3 HCV patients and 1 control (1.5% versus 0.1%, P = 0.01). Most patients with HCV can safely be treated with cancer chemotherapy. Cirrhosis and HCV infection contributed to increased hepatotoxicity in subjects on CCT. Among HCV patients, rituximab use was the major risk factor for increased hepatotoxicity. Hepatotoxicity due to CCT itself rarely altered or delayed CCT. Nonetheless, HCV-positive patients should be monitored carefully during CCT.


Options and strategies for hearing restoration in pediatric neurofibromatosis type 2.
In this article, we will review the mechanisms and natural history of hearing loss in neurofibromatosis type 2 (NF2) and discuss the hearing outcomes with different rehabilitation options. Review of the published literature. NF2 is a rare autosomal dominant syndrome characterized by vestibular schwannomas and other intracranial and spinal tumors. Bilateral vestibular schwannomas are the hallmark of the disease which occur in 90 to 95% of the patients. As a result, hearing loss will eventually occur in almost all NF2 patients. Deafness can occur from tumor progression or from treatment of vestibular schwannomas and is among the most debilitating aspects of NF2. A number of surgical and non-surgical rehabilitation options are available for these patients including cochlear and auditory brainstem implants. The audiologic outcomes with surgical rehabilitation options have been variable but most patients are able to achieve sound awareness and benefit from auditory cues in lip reading. Early identification and treatment of NF2 patients can help in achieving better hearing outcomes in the pediatric population. An increasing number of NF2 patients are receiving open set word understanding with refinement in surgical techniques.


Design of nanocrystalline mixed oxides with improved oxygen mobility: a simple non-aqueous route to nano-LaFeO3 and the consequences on the catalytic oxidation performances.
LaFeO3 nanoparticles, with improved oxygen mobility, leading to enhanced catalytic oxidation activities, are obtained through a simple nonaqueous route.


Transit-Time Flow Measurement and Outcomes in Coronary Artery Bypass Graft Patients.
Transit-time flowmetry (TTFM) is commonly used during coronary artery bypass grafting for intraoperative graft assessment. This study aimed to investigate whether TTFM values were predictive of graft failure and major adverse cardiac and cerebrovascular events (MACCEs). Between 2011 and 2018, 1933 patients with 3-vessel coronary artery disease who underwent off-pump coronary artery bypass were retrospectively analyzed. Among them, 1288 sequential venous grafts in 538 consecutive patients were measured using TTFM's 2 parameters, pulsatility index (PI) and flow (mL/min). The anastomoses were divided in the 3 groups depending on the anastomotic site: group A, first side-to-side anastomoses (n = 538), group B; second side-to-side (n = 212), group C; end-to-side (n = 538). MACCEs were related to TTFM. The mean clinical follow-up time was 64.8 ± 21.2 months. Postoperative graft patency was confirmed with multi-slice computed tomography or coronary angiography (follow-up interval: 64.8 ± 50.4 and 27.8 ± 20.5 months based on the date of examination). The 5-year survival rate was 93.7%. The mean graft flow was 59.1 ± 31.3, 41.0 ± 25.2, and 38.9 ± 22.8 mL/minute, and the PI was 2.2 ± 1.3, 2.5 ± 3.4, and 2.4 ± 2.5, in groups A, B, and C, respectively. Graft failure occurred in 23/1055 (2.2%) anastomoses. The 5-year MACCE rate was 6.9% (37/538 patients). Kaplan-Meier analysis revealed that graft patency was significantly lower in low MGF (p = 0.044) and high PI (p < 0.001). Multivariable logistic analysis showed that high PI (>5; HR 2.276; 95%CI 2.188-2.406, p < 0.001) was an independent risk factor for MACCEs. The cutoff values for PI of sequential grafts were 3.65, 3.55, and 3.17 in groups A, B, and C, respectively for the prediction of MACCE. A high PI predicts more predictive poor outcomes of sequential venous grafts after surgery than the low mean graft blood flow.


Impact of Navier's slip and MHD on laminar boundary layer flow with heat transfer for non-Newtonian nanofluid over a porous media.
The current studies analytically summarize the impact of magnetohydrodynamic and thermal radiation on the non-Newtonian continuous uniform motion of viscid non-compressible nanofluid across a penetrable stretching/shrinking sheet, even though accomplish Navier's first and second order slips along mass transpiration. Blood-bearing silver and copper nanomaterials have distinct flow and heat transfer properties when exposed to heat. Silver (Ag) as well as copper (Cu) nanoparticles are assumed to be present in blood as the non-Newtonian liquid; this fluid serves as the base. We anticipate that the current study will be useful in fields including food, petrochemical products, and medicines, as well as blood circulation, and highly beneficial for patients who are dealing with blood clotting in the uterus, which may result in infertility or cancer, to evaluate the blood flow in the tube. Employing the similarity conversion technique, the ruling partial differential equations are modified into a couple of non-linear ordinary differential equations. Then the transformed ordinary differential equations are analytically solved with the Laplace transformation and expressed in terms of an incomplete gamma function. The current analytical results are compared to previous studies. It is addressed how several physical features such as magnetic field M, Navier's first and second order slip, permeability, Prandtl number Pr, and radiation parameter affect non-dimensional velocity as well as temperature patterns through graphs. The results obtained reveal that there is an enhancement in the rate of heat transfer with the rise in nanoparticle volume fraction and radiation. The temperature distribution is also influenced by the presence of Prandtl numbers, radiation, solid volume fraction, permeability, and slip conditions. This shows that the solid volume fraction of nanoparticles can be used to control the behaviour of heat transfer and nanofluid flows.


alpha-substituted quisqualic acid analogs: new metabotropic glutamate receptor group II selective antagonists.
Syntheses of both the alpha-methyl and benzyl analogs of quisqualic acid are described. Testing of these compounds for their activity at excitatory amino acid receptors revealed a striking change in activity in comparison to quisqualic acid. This structural modification results in the loss of quisqualate's potent agonist action at both non-NMDA ionotropic glutamate receptors as well as at group I mGluRs, while allowing these analogs to acquire antagonist properties with relative selectivity for group II metabotropic glutamate receptors.


Population interactions among free-living bluefish and prey fish in an ocean environment.
We used sonar to measure relative abundance, location, and depth of prey fish schools (primarily Anchoa and Ammodytes) in the ocean near Fire Island Inlet, New York from May to August for 4 years to examine predatorprey interactions. Prey fish numbers built through May, peaked in June, and thereafter declined coincident with the arrival of predatory bluefish. Bluefish abundance and feeding behavior correlated inversely with prey fish abundance and depth. Bluefish may drive seasonal patterns of prey abundance and distribution in this area through direct predation and by causing prey to flee.


Acute effects of physical activity patterns on plasma cortisol and brain-derived neurotrophic factor in relation to corticospinal excitability.
Brain-derived neurotrophic factor (BDNF) and cortisol are both capable of modulating synaptic plasticity, but it is unknown how physical activity-induced changes in their plasma levels relate to corticospinal plasticity in humans. Sixteen inactive middle-aged men and women participated in three separate interventions consisting of 3 h prolonged sitting (SIT); 3 h sitting interrupted every 30 min with frequent short physical activity breaks (FPA); and 2.5 h prolonged sitting followed by 25 min of moderate intensity exercise (EXE). These 3 h sessions were each followed by a 30 min period of paired associative stimulation over the primary motor cortex (PAS). Blood samples were taken and corticospinal excitability measured at baseline, pre PAS, 5 min and 30 min post PAS. Here we report levels of plasma BDNF and cortisol over three activity conditions and relate these levels to previously published changes in corticospinal excitability of a non-activated thumb muscle. There was no interaction between time and condition in BDNF, but cortisol levels were significantly higher after EXE compared to after SIT and FPA. Higher cortisol levels at pre PAS predicted larger increases in corticospinal excitability from baseline to all subsequent time points in the FPA condition only, while levels of BDNF at pre PAS did not predict such changes in any of the conditions. Neither BDNF nor cortisol modified changes from pre PAS to the subsequent time points, suggesting that the increased corticospinal excitability was not mediated though an augmented effect of the PAS protocol. The relationship between cortisol and plasticity has been suggested to be inverted U-shaped. This is possibly why the moderately high levels of cortisol seen in the FPA condition were positively associated with changes AURC, while the higher cortisol levels seen after EXE were not. A better understanding of the mechanisms for how feasible physical activity breaks affect neuroplasticity can inform the theoretical framework for how work environments and schedules should be designed.


RPS6KA5 methylation predict response to 6-week treatment for adolescent MDD patients.
We aimed to investigate the effect of differentially methylated genes and chronic childhood stress on the development of depressive symptoms in Chinese adolescents, as well as to test whether methylation at baseline can be used as a predictor of remission at follow-up after six weeks of treatment. After recruiting 87 MDD patients and 53 healthy controls, we compared demographic and baseline clinical characteristics. The Childhood Chronic Stress Questionnaire was used to assess stress caused by early-life events. MDD patients underwent six weeks of treatment, and response to treatment was assessed using the Beck Depression Inventory-II. In addition, four MDD patients and five controls were randomly chosen for genome-wide methylation analysis. The gene RPS6KA5 showed significant methylation differences between the two groups. Severity of chronic childhood stress was significantly associated with increased risk of depression in adolescents, but not with treatment response. Baseline RPS6KA5 methylation can predict remission after six weeks of treatment. We did not observe any interaction between RPS6KA5 methylation and chronic childhood stress. Our results suggest that RPS6KA5 methylation can be used as a predictor of response to treatment in adolescent MDD patients. Here we offer new evidence for the role of epigenetics in early response to treatment of depression. ChiCTR, ChiCTR2000033402, 31/05/2020, http://www.chictr.org.cn/index.aspx.


Quantitation of differential renal blood flow and renal function using dynamic contrast-enhanced MRI in rats.
A first-pass upslope approach was used to estimate differential renal blood flow (DRBF) and a Patlak-Rutland approach was used to estimate differential renal function (DRF) using Gd-DTPA-BMA-enhanced MRI. DRBF and DRF were estimated in rat kidneys under three different experimental conditions: 1) transient renal artery occlusion (TRAO); 2) partial unilateral ureteric obstruction (PUO); and 3) sham-operated control rats (SHAM). A bolus of Gd-DTPA-BMA was given intravenously during a dynamic single slice T1-weighted gradient echo sequence, which allowed calculation of concentration from signal intensity values. Calculations based on the raw signal intensity showed that DRBF was decreased in both PUO (44 +/- 1%; P < 0.05) and in TRAO (38 +/- 1%; P < 0.05) compared with SHAM (52 +/- 1%). Converting the signal intensity into a measure of Gd-DTPA-BMA concentration did not substantially alter these findings (PUO: 40 +/- 3%, P < 0.05; TRAO: 35 +/- 2%, P < 0.05; SHAM 49 +/- 1%). Likewise, DRF decreased in both PUO (43 +/- 4%; P < 0.05) and TRAO (39 +/- 3%; P < 0.05) compared with SHAM (48 +/- 2%). Converting the signal intensity into measurements of Gd-DTPA-BMA concentration revealed similar findings (PUO: 41 +/- 5%, P < 0.05; TRAO: 34 +/- 5%, P < 0.05; SHAM: 49 +/- 2%). Our results suggest that renal damage in rats may be demonstrated by an observed reduction of DRBF and DRF as estimated from single-slice Gd-DTPA-BMA enhanced signal intensity using time-activity curves with and without quantitation of Gd-concentration.


Real-time monitoring of vitamin C levels in trauma patients by electron-spin resonance spectrometry.
In critically ill patients, healthy vitamin C levels are important to avoid an imbalance in reactive oxygen species. To achieve this, oxidative stress levels in emergency patients need to be accurately measured in real-time. However, normally, reactive oxygen/nitrogen species are short-lived, rendering measurement difficult; moreover, measurement of relatively stable antioxidants and other oxidative stress markers in real-time is challenging. Therefore, we used electron-spin resonance spectrometry (ESR) to assess vitamin C levels, clarify their relationship with patients' severity, and establish more effective vitamin C therapy in critically ill patients. We studied 103 severely ill emergency patients and 15 healthy volunteers. Vitamin C radical (VCR/dimethyl sulfoxide [DMSO]) values were analyzed in arterial blood samples by ESR at admission and once daily thereafter during the acute recovery phase. Severity scores were calculated. The relationship between these scores and VCR/DMSO values and chronological changes in VCR/DMSO values were analyzed. Serum VCR/DMSO values were significantly lower in critically ill patients than in healthy volunteers (0.264 ± 0.014 vs. 0.935 ± 0.052, p < 0.05), particularly in the severe trauma group and the cardiopulmonary arrest/post-cardiac arrest syndrome group. VCR/DMSO values and various severity scores did not correlate at admission; however, they correlated with SOFA scores from days 2-6. VCR/DMSO values remained low from the first measurement day through Day 6 of illness. Vitamin C levels were low at admission, remained low with conventional nutritional support, and did not correlate with the initial patient's severity; however, they correlated with patients' severity after admission. Some patients had normal vitamin C levels. Therefore, vitamin C levels should be measured in real-time and supplemented if they are below normal levels. Retrospectively registered.


The relationship of patient characteristics to physician delivery of advice to stop smoking.
To investigate the frequency of physician delivery of advice to stop smoking and patient characteristics affecting whether physicians deliver such advice, the authors surveyed 97 current cigarette smokers seen in two specialty and one general medicine clinic at a university medical center. Approximately two thirds of the smokers reported ever having been advised to stop smoking by their current physicians. In univariate and multivariate analyses, the presence of a smoking-related illness, the number of prior attempts to quit, and the duration of cigarette smoking were significantly related to delivery of smoking cessation advice by physicians. Knowledge of factors that affect the provision of advice to stop smoking can be used to enhance the physician's role in smoking intervention.


Design, development and evaluation of rK28-based point-of-care tests for improving rapid diagnosis of visceral leishmaniasis.
Visceral leishmaniasis (VL) is diagnosed by microscopic confirmation of the parasite in bone marrow, spleen or lymph node aspirates. These procedures are unsuitable for rapid diagnosis of VL in field settings. The development of rK39-based rapid diagnostic tests (RDT) revolutionized diagnosis of VL by offering high sensitivity and specificity in detecting disease in the Indian subcontinent; however, these tests have been less reliable in the African subcontinent (sensitivity range of 75-85%, specificity of 70-92%). We have addressed limitations of the rK39 with a new synthetic polyprotein, rK28, followed by development and evaluation of two new rK28-based RDT prototype platforms. Evaluation of 62 VL-confirmed sera from Sudan provided sensitivities of 96.8% and 93.6% (95% CI = K28: 88.83-99.61%; K39: 84.30-98.21%) and specificities of 96.2% and 92.4% (95% CI = K28: 90.53-98.95%; K39: 85.54-96.65%) for rK28 and rK39, respectively. Of greater interest was the observation that individual VL sera with low rK39 reactivity often had much higher rK28 reactivity. This characteristic of the fusion protein was exploited in the development of rK28 rapid tests, which may prove to be crucial in detecting VL among patients with low rK39 antibody levels. Evaluation of two prototype lateral flow-based rK28 rapid tests on 53 VL patients in Sudan and 73 VL patients in Bangladesh provided promisingly high sensitivities (95.9% [95% CI = 88.46-99.1 in Sudan and 98.1% [95% CI = 89.93-99.95%] in Bangladesh) compared to the rK39 RDT (sensitivities of 86.3% [95% CI = 76.25-93.23%] in Sudan and 88.7% [95% CI = 76.97-95.73%] in Bangladesh). Our study compares the diagnostic accuracy of rK39 and rK28 in detecting active VL cases and our findings indicate that rK28 polyprotein has great potential as a serodiagnostic tool. A new rK28-based RDT will prove to be a valuable asset in simplifying VL disease confirmation at the point-of-care.


Does Cervical Sagittal Balance Affect the Preoperative Neck Disability Index in Patients With Cervical Myelopathy?
This was a retrospective study. This study aimed to ascertain the relationship between preoperative Neck Disability Index (NDI) scores and cervical sagittal alignment in patients with cervical spondylotic myelopathy (CSM). Cervical alignment may influence postoperative clinical outcomes. However, the effect of preoperative sagittal balance on the preoperative status in CSM patients remains uncertain. From 2010 to 2016, 90 patients who underwent cervical surgery for CSM were enrolled. The inclusion criteria for this study included preoperative standing cervical radiographs and a preoperative NDI score. The following radiographic parameters were measured: (1) C0-C2 lordosis, (2) C2-C7 lordosis, (3) C2-C7 sagittal vertical axis (SVA), (4) neck tilt, (5) thoracic inlet angle, (6) T1 slope, and (7) T1 slope minus cervical lordosis (T1S-CL). The Pearson product-moment correlation coefficients were calculated between all radiographic variables and the NDI scores, and multiple regression analysis was performed to determine the independent predictors of high preoperative NDI scores. Both C2-C7 SVA and T1S-CL were positively correlated with NDI scores (r=0.732, P<0.001 and r=0.333, P=0.001). Cervical lordosis was negatively correlated with NDI scores (r=-0.267, P=0.011). Significant correlations were found between C2-C7 SVA and the C0-C2 Cobb angle (r=0.244, P=0.020), C2-C7 SVA and the C2-C7 Cobb angle (r=-0.359, P=0.001), the C2-C7 Cobb angle and the C0-C2 Cobb angle (r=-0.457, P<0.001), and the C2-C7 Cobb angle and T1 slope (r=-0.385, P<0.001). The disability of the neck increased with increasing C2-C7 SVA and T1S-CL and decreasing cervical lordosis before surgical reconstruction. High C2-C7 SVA, low thoracic inlet angle, and high neck tilt values are independent predictors of high preoperative NDI scores.


Ferritin on the surface of lymphocytes in Hodgkin's disease patients. A possible blocking substance removed by levamisole.
Enzymatic radioiodination of surface proteins of Hodgkin's disease peripheral blood mononuclear cells revealed the presence of a blocking protein on their surface. This protein shed into the medium after incubation with levamisole, which resulted in the unmasking of surface proteins similar to those on normal monunuclear cells. The blocking substance was identified. It reacted with anti-human spleen ferritin. It had no detectable iron and dissociated into monomeric subunits of 18,000 mol. wt. by reduction and alkylation, and therefore it is most probably apoferritin rather than ferritin.


Dextran sulfate sodium-induced colitis-associated neoplasia: a promising model for the development of chemopreventive interventions.
Individuals diagnosed with ulcerative colitis face a significantly increased risk of developing colorectal dysplasia and cancer during their lifetime. To date, little attention has been given to the development of a chemopreventive intervention for this high-risk population. The mouse model of dextran sulfate sodium (DSS) - induced colitis represents an excellent preclinical system in which to both characterize the molecular events required for tumor formation in the presence of inflammation and assess the ability of select agents to inhibit this process. Cyclic administration of DSS in drinking water results in the establishment of chronic colitis and the development of colorectal dysplasias and cancers with pathological features that resemble those of human colitis-associated neoplasia. The incidence and multiplicity of lesions observed varies depending on the mouse strain used (ie, Swiss Webster, C57BL/6J, CBA, ICR) and the dose (0.7%-5.0%) and schedule (1-15 cycles with or without a subsequent recovery period) of DSS. The incidence of neoplasia can be increased and its progression to invasive cancer accelerated significantly by administering DSS in combination with a known colon carcinogen (azoxymethane (AOM), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-1- methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)) or iron. More recent induction of colitis-associated neoplasia in genetically defined mouse strains has provided new insight into the role of specific genes (ie, adenomatous polyposis coli (Apc), p53, inducible nitric oxide synthase (iNOS), Msh2) in the development of colitis-associated neoplasias. Emerging data from chemopreventive intervention studies document the efficacy of several agents in inhibiting DSS-induced neoplasia and provide great promise that colitis-associated colorectal neoplasia is a preventable disease.


Travel distance, frequency of return, and the spread of disease.
Human mobility is a key driver of infectious disease spread. Recent literature has uncovered a clear pattern underlying the complexity of human mobility in cities: [Formula: see text], the product of distance traveled r and frequency of return f per user to a given location, is invariant across space. This paper asks whether the invariant [Formula: see text] also serves as a driver for epidemic spread, so that the risk associated with human movement can be modeled by a unifying variable [Formula: see text]. We use two large-scale datasets of individual human mobility to show that there is in fact a simple relation between r and f and both speed and spatial dispersion of disease spread. This discovery could assist in modeling spread of disease and inform travel policies in future epidemics-based not only on travel distance r but also on frequency of return f.


Modified Cupar's method for immediate diastema closure.
Anterior maxillary osteotomy or ostectomy (AMO) is a safe, reliable, and easily adaptable procedure routinely performed in orthognathic surgery for the management of the dentoalveolar segment of the anterior maxilla. The anterior segmental maxillary osteotomy was first performed in 1921 by Cohn-Stock. Several modifications were done regarding approaches for AMO; however, Cupar's method is the most preferred approach by the surgeons and in practice since several decades. A novel midline split osteotomy is performed in combination with Cupar's method for superior and posterior repositioning of anterior maxillary segment in combination with immediate closure of diastema in this case report.


Quantitative assessment of vascular features in port wine stains through optical coherence tomography angiography.
Vascular lesions such as port wine stains (PWS) lead to facial and psychological problems, which require careful and precise treatments. The key point of treating PWS is to selectively destroy the abnormal blood vessels. Hence, the in vivo monitoring of targeted vessels is crucial. Optical coherence tomography angiography (OCTA), an emerging label-free imaging tool, facilitates the evaluation of skin structure and vasculature at a high resolution. In this study, we utilised OCTA to capture the structural and vascular morphology in patients with PWS. Moreover, we quantitatively characterised the morphological features of different types of PWS. This observational clinical study was conducted on 3 patients with flat PWS and 3 patients with thickened PWS. The age range was 4-27 years, and all of them had not received any treatment before this study. The OCTA images of the PWS lesions and contralateral skin were compared. Vascular morphology was characterized, and ectatic vessel depth was quantified according to the OCTA images. The blood vessels of the PWS lesions tend to had larger diameters and higher densities than those in the contralateral normal skin. The vessel diameters of PWS lesions were 73 ± 14 μm, with high heterogeneity ranging from 10 to >150 μm, however, the vessel diameters of normal skin were 28 ± 2 μm, ranging from 10 μm to 60 μm. In terms of different PWS lesions, the thickened type showed a trend of larger vessel diameter and higher density than those of the purplish red type. The ectatic vessels were located at the depth of 216 ± 13 μm in the PWS skin. OCTA can facilitate the in vivo three-dimensional visualization of structure and vasculature for PWS lesions. Various quantitative analysis parameters, such as vessel diameter, density, and depth, are typically measured using OCTA. This fact demonstrates the superior capability of OCTA for the precise and comprehensive assessment of PWS lesions.


Enhanced secretion of hydrophobic peptide fused lysozyme by the introduction of N-glycosylation signal and the disruption of calnexin gene in Saccharomyces cerevisiae.
The insertion of a hydrophobic pentapeptide (Phe-Phe-Val-Ala-Pro) into the C-terminus in hen egg white lysozyme by genetic modification resulted in an unstable structure which caused little secretion in a yeast expression system, although this modification is useful to enhance bactericidal action to gram-negative bacteria [Ibrahim et al. (1994) J. Biol. Chem. 269, 5059-5063]. To enhance the secretion of the unstable hydrophobic pentapeptide fused lysozymes (H5-Lz), we attempted to introduce the signal sequence (Asn-X-Ser/Thr) of N-linked glycosylation into lysozyme and to suppress the quality control of the unstable mutant in the yeast expression system. The polymannosyl hydrophobic fused lysozyme (H5/G49N-Lz) having the N-glycosylation signal sequence was expressed in the medium at 3.4 times that of unglycosylated lysozyme. Further, the secretion of the unstable mutant lysozyme was done in the Saccharomyces cerevisiae disrupted calnexin gene to avoid the degradation of the unstable mutant by the quality control. Although disruption of the calnexin gene did not lead to gross effects on the levels of growth of S. cerevisiae (W303-1b), the secretion amount of H5/G49N-Lz in calnexin disrupted S. cerevisiae was 2.5 times larger than that in wild type S. cerevisiae. These results suggest that the secretion of unstable glycosylated lysozyme (H5/G49N) was suppressed by the quality control function of calnexin and that the disruption of calnexin is effective to increase the secretion of unstable glycosylated protein.


The Scianna blood group lies distal to uridine monophosphate kinase on chromosome 1p.
Linkage between the Scianna blood group and the Rhesus blood group has been confirmed. Families demonstrating recombinants between U M P K and Sc suggest that U M P K lies between Sc and PGM1.


Image quality of the CAIPIRINHA-Dixon-TWIST-VIBE technique for ultra-fast breast DCE-MRI: Comparison with the conventional GRE technique.
The aim of this study was to evaluate image quality of the CAIPIRINHA-Dixon-TWIST-Volume-Interpolated Breath-hold Examination (CDT-VIBE) technique for ultra-fast breast dynamic contrast enhanced (DCE) MRI with respect to conventional Gradient-Recalled Echo (GRE) technique. A total of 58 patients underwent a DCE-MRI based on CDT-VIBE sequence (temporal resolution: 11.9 s), immediately followed by 1 phase of a conventional T1 weighted GRE sequence (acquisition time: 68 s). The Signal-to-Noise Ratio (SNR) on phantom images, lesion/parenchyma signal ratio (LPSR), image quality, and morphological characterization were compared between the last phase of CDT-VIBE and conventional GRE images. The image quality was assessed by visual grading analysis (VGA). Reader agreement was assessed using Kappa analysis. There was no significant difference in SNR (phantom) or LPSR (patient) between CDT-VIBE and conventional GRE images (P > 0.05). Significant parallel acquisition technique (PAT) noise and mild blurriness was observed on CDT-VIBE images. Visual grading analysis (VGA) confirmed significantly worse ratings for CDT-VIBE compared to the conventional GRE sequence in terms of PAT noise, lesion's internal feature clarity, and therefore overall image quality (area under contrast curve [AUC] values: 0.578 ‒ 0.764, P < 0.05), but edge sharpness and lesion conspicuity were equivalent (P > 0.05). Kappa analysis revealed good agreement on image quality scores (к = 0.725 ‒ 0.908) and on morphologic terms (к = 0.745-1.000). The CDT-VIBE sequence provides excellent spatial resolution and adequate image quality in ultra-fast breast DCE-MRI. Further improvement in PAT noise and internal structure blurriness may be necessary.


Dummy run quality assurance study in the Korean Radiation Oncology Group 19 - 09 multi-institutional prospective cohort study of breast cancer.
The Korean Radiation Oncology Group (KROG) 19 - 09 prospective cohort study aims to determine the effect of regional nodal irradiation on regional recurrence rates in ypN0 breast cancer patients. Dosimetric variations between radiotherapy (RT) plans of participating institutions may affect the clinical outcome of the study. We performed this study to assess inter-institutional dosimetric variations by dummy run. Twelve participating institutions created RT plans for four clinical scenarios using computed tomography images of two dummy cases. Based on a reference structure set, we analyzed dose-volume histograms after collecting the RT plans. We found variations in dose distribution between institutions, especially in the regional nodal areas. Whole breast and regional nodal irradiation (WBI + RNI) plans had lower inter-institutional agreement and similarity for 95% isodose lines than WBI plans. Fleiss's kappa values, which were used to measure inter-institutional agreement for the 95% isodose lines, were 0.830 and 0.767 for the large and medium breast WBI plans, respectively, and 0.731 and 0.679 for the large and medium breast WBI + RNI plans, respectively. There were outliers in minimum dose delivered to 95% of the structure (D95%) of axillary level 1 among WBI plans and in D95% of the interpectoral region and axillary level 4 among WBI + RNI plans. We found inter-institutional and inter-case variations in radiation dose delivered to target volumes and organs at risk. As KROG 19 - 09 is a prospective cohort study, we accepted the dosimetric variation among the different institutions. Actual patient RT plan data should be collected to achieve reliable KROG 19 - 09 study results.


Three-element model for total systemic circulation: emphasis on the accuracy of parameter estimates.
In this study, the accuracy achievable in the parameter estimates of a three-element linear model for the systemic vascular bed is considered. The model neglects inertial effects and includes only three elements representing arterial compliance, peripheral resistance and venous compliance, in agreement with recent sensitivity investigations. Parameter estimation starts from arterial and right atrial pressure signals generated by a closed-loop simulator of the cardiovascular circulation and corrupted with normal noise to account for measurement errors. In this way, the influences of a wide variety of circulatory conditions were investigated. The results achieved give evidence that arterial compliance is generally well estimated, while venous compliance is more variable, particularly at high peripheral resistance when measured signals appear to be less sensitive to this parameter. However, presence of cardiac disease, such as heart failure and valvular stenosis has minimal influence on compliance estimates. These results suggest that this simple model can be conveniently applied even under noisy conditions.


Serial studies of virus multiplication and intestinal damage in gnotobiotic piglets infected with rotavirus.
A serial study of rotavirus infection in gnotobiotic piglets is described. They were infected when 7 days old and the course of infection was followed for 21 days, by immunofluorescence and histological examinations of the intestinal epithelium and by titration of the virus content of the gut lumen. There appeared to be two stages of recovery of the intestinal wall, the earlier stage involving non-immune mechanisms and the later invloving antibody.


Differences in early, intermediate, and long-term mortality among elderly patients admitted to the ICU: results of a retrospective observational study.
Few studies have investigated both short- and long-term prognostic factors, and the differences between chronic and acute conditions in the very old critically ill patient. Our study aims to shed light in this field and to provide useful prognostic factors that may support clinical decisions in the management of the elderly. Six ICUs collected data concerning 80-year-old (or more) patients admitted in 2015 and 2016 and followed-up until May 2018. Three prognostic models were developed: an in-hospital mortality model, a model for patients discharged from the hospital and entering follow-up, and an intermediate model for those alive after three days from ICU admission. Our centers admitted 1189 patients, 1071 (90.1%) had survived after three days from admission, 889 (74.8%) were discharged from the hospital, 701 (59.0%) survived six months after hospital discharge, 539 (45.3%) survived at the end of follow-up. Among survivors the median follow-up time was 810 days. Acute organ failures were the main causes of death in the hospital mortality multivariable model. These factors are modifiable and potentially a target for intervention to improve outcome. The model focused on mortality six months after hospital in patients that survived a three-day time-limited trial, showed a clear shift toward chronic diseases, unmodifiable factors crucial for prognostic assessment. This trend was even more evident at the end of follow-up. Among very old ICU patients, prognostic factors shift from acute to chronic conditions in passing from in-hospital to posthospital outcomes.


A rapid and simple cannulation technique for repeated sampling of cerebrospinal fluid in freely moving rats.
A cannulation technique for frequent sampling of cerebrospinal fluid (CSF) in unanaesthetized freely moving rats is described. A permanent stainless steel cannula, constructed in such a way that no loss of CSF occurs, is placed into the rat's cisterna magna and fixed to the skull by anchoring screws and dental cement. A special CSF outflow opening of the cannula is connected to polyethylene tubing for CSF sampling. Amounts of 50-150 microliters CSF can be collected repeatedly without any sign of disturbing the animal. The technique lends itself not only to pilot studies in which within a short period of time a large amount of CSF is wanted, but also to experiments in which physiological conditions are required.


Management challenges with brown tumor of primary hyperparathyroidism masked by severe vitamin D deficiency: a case report.
Hyperparathyroidism is a disease characterized by excessive secretion of parathyroid hormone, the hormone responsible for calcium and phosphate homeostasis in the body. It can be of three types: primary, secondary, or tertiary. It is essential to bear in mind that in any one patient more than one type of hyperparathyroidism may be found, which may create perplexity regarding the etiology of the case. Hyperparathyroidism can become apparent early in its course when a patient presents with symptoms of abdominal pain, recurrent renal calculi, repeated fractures, or behavior changes. It is generally accepted that bone involvement is a late manifestation of primary hyperparathyroidism. It is imperative to consider that some patients, such as our patient described in this report, may be previously asymptomatic clinically and on the basis of laboratory findings and present with only late skeletal manifestations. Brown tumors are one of the mimickers of lytic lesions of the jaw and need to be ruled out early in the course of management. Researchers in several studies published in high-impact journals have recommended the use of high-dose vitamin D as safe in patients with primary hyperparathyroidism without the risk of raising calcium levels significantly. In our patient, we observed considerable hypercalcemia after high-dose vitamin D therapy, and we propose exercising discretion with the use of high-dose therapies. We report a case of a 21-year-old Arab woman with a brown tumor who presented with hypocalcaemia. She presented with a mixed picture of primary hyperparathyroidism and severe vitamin D deficiency. Brown tumors, although thought to be a forgotten entity with the advent of early screening for hypercalcemia, is still prevalent, as a handful of patients may present late in the disease course with no early markers, such as in our patient. We emphasize using a holistic approach for early diagnosis and adopting a restricted attitude to treating these benign entities, especially in the context of cosmesis for sensitive locations such as the face. In addition, we express caution in using daily supplementation with a high vitamin D dose to improve vitamin D status and decrease parathyroid hormone.


If we build it, will they come? And will they stay? Commentary on Holmes et al. "Examining patterns of dose response for clients who do and do not complete Cognitive Processing Therapy".
Although evidence-based practice is becoming more widely accepted, the issue of patient preference has been relatively ignored. As noted by Holmes and colleagues (2019), when delivered in a community setting, Cognitive Processing Therapy (CPT) can have a relatively high dropout rate (42 % in the Holmes et al., 2019). In this commentary, issues about the conceptualization of treatment dropout as one index of patient preference are discussed. Dropout can be conceptualized as a potential reflection of poor fit between the patient and a specific empirically-supported treatment. Consideration of ways in which an empirically-supported treatment can be personalized, while remaining true to its underlying principles, are discussed using CPT as an example.


Irradiation of rats abolishes susceptibility of PGI2 synthesis in blood vessels to peroxidative agents.
Thoracic and abdominal aortas were obtained from rats after irradiation and used for the estimation of the synthesis of prostacyclin (PGI2) determined as 6-keto PGF1 alpha. Twenty four h after exposure to 7.0 Gy an increase was noted in the amount of PGI2 released, and 4 weeks later its level significantly decreased. The 24 h value did not increase with the further radiation dose increment (9, 12.5, 15 Gy). Cysteine or H2O2 intensified prostacyclin synthesis in control vessels but decreased it in vessels from the animals irradiated 24 h earlier. Later after the exposure cysteine or H2O2 were no longer effective.


Simulation of Pediatric Anterior Skull Base Anatomy Using a 3D Printed Model.
The pediatric skull base may present anatomic challenges to the skull base surgeon, including limited sphenoid pneumatization and a narrow nasal corridor. The rare nature of pediatric skull base pathology makes it difficult to gain experience with these anatomic challenges. The objective of this study was to create a 3-dimensionally (3D) printed model of the pediatric skull base and assess its potential as a training tool. Twenty-eight participants at various stages of training and practice were included in our study. They completed a pre- and postdissection questionnaire assessing challenges with endoscopic endonasal skeletonization of the carotid arteries and sella face using the 3D printed model. The majority of participants had completed a skull base surgery fellowship (60.7%), were <5 years into practice (60.7%), and had <10 cases of pediatric skull base experience (82.1%). Anticipated challenges included limitation of maneuverability of instruments (71.4%), narrow nasal corridor and nonpneumatized bone (57.1%). On a scale of 0-10, 10 being very difficult, the average participant expected level of difficulty with visualization was 6.89 and expected level of difficulty with instrumentation was 7.3. On postdissection assessment, there was a nonstatistically significant change to 6.93 and 7.5, respectively. Participants endorsed on a scale of 0-10, 10 being very realistic, an overall model realism of 7.0 and haptic realism of 7.1. A 3D printed model of the pediatric skull base may provide a realistic model to help participants gain experience with anatomic limitations characteristic of the pediatric anterior skull base.


Pollution characteristics and microbial community succession of a rural informal landfill in an arid climate.
Informal landfills pose potential threats to the environment and human health due to the lack of anti-seepage measures. However, little research has been conducted on the distribution of pollutants in informal landfill sites situated in arid climates, as well as the underlying interaction mechanisms between environmental factors and microbial structure. In this study, we sought to investigate the pollution characteristics and microbial community succession of the landfill in northern China. The results revealed that heavy metals in the landfill showed poor mobility and migration. The lower layers of the garbage samples had higher water-soluble contents of heavy metals compared to the upper layers. The landfill-derived dissolved organic matter (DOM) was found to originate from microbial production, and four fluorescent components were identified, including fulvic acid-like substances, humus-like substances, and protein-like components. Fluorescence intensity and humification degree increased with increasing depth. The microbial diversity and richness decreased with sampling depth. The most abundant phyla in the samples were Proteobacteria, unidentified_Bacteria, Bacteroidota, Firmicutes, Myxococcota, Gemmatimonadota, Actinobacteria, and Deinococcota. As the sampling depth increased, Proteobacteria decreased, while Bacteroidota and Firmicutes showed a remarkable increase, with little variation observed in the other phyla. The partial least-squares path model (PLS-PM) results indicated that pH had the most significant effect on microbial abundance and diversity (direct effect value = -5.560), while DOM and heavy metals had the opposite effect, with direct effects of 1.838 and 3.231, respectively. DOM was identified as the driving factor for the variation in other environmental factors. The redundancy analysis (RDA) showed that the dominant genera were greatly influenced by Cu, humic-like substances, and protein-like substances. Among them, Bacillus, Alcanivorax, Devosia, and Chryseolinea may play important roles in the remediation of landfills. Our study not only gains a deeper understanding of the pollution risk of informal landfills in arid climates, but also provides a scientific basis for the future treatment and restoration of contaminated sites associated with landfills.


A critical analysis of three quantitative methods of assessment of hepatic steatosis in liver biopsies.
The issue of adequately quantitatively evaluating hepatic steatosis is still unresolved. Therefore, we compared three methods of quantitative assessment. Two groups of mice (n = 10 each) were fed standard chow (10% fat, SC group) or a high-fat diet (60% fat, HF group) for 16 weeks, and hepatic triglyceride (HT) and liver tissue were then studied. Paraplast-embedded tissues stained by hematoxylin and eosin (H-E) were compared to frozen sections stained by Oil Red-O (ORO). In addition, the volume density of steatosis (Vv[steatosis, liver]) was measured by point counting (P-C, sections H-E or ORO) or by image analysis (I-A, sections ORO). HT was significantly higher in the HF group (104% greater, P = 0.0004) than in the SC group. With P-C and H-E, Vv[steatosis, liver] was 4.80 ± 0.90% in the SC group and 33.50 ± 3.17% in the HF group (600% greater, P < 0.0001). With P-C and ORO, Vv[steatosis, liver] was 4.86 ± 0.89% in the SC group and 25.21 ± 1.27% in the HF group (420% greater, P < 0.0001). With I-A and ORO, Vv[steatosis, liver] was 4.17 ± 0.85% in the SC group and 23.35 ± 1.58% in the HF group (460% greater, P < 0.0001). Correlations between Vv[steatosis, liver] and HT were strong and significant in all methods. In conclusion, all methods were appropriate and reproducible. In P-C and H-E, there is a slight overestimation of steatosis in the HF animals in comparison to frozen sections and ORO; in frozen sections, differences between P-C and I-A are insignificant.


Auricular therapy for chronic pain management in adults: A synthesis of evidence.
To evaluate the efficacy and safety of auricular therapy (AT) on chronic pain. A systematic review. Randomized controlled trials investigating AT for chronic pain were retrieved and RevMan 5.3 was used for meta-analysis. Fifteen trials were included. The overall assessment indicated that AT could be a promising intervention for chronic pain relief. Meta-analyses showed that AT decreased pain intensity, especially for chronic low back pain and chronic tension headache. The lasting effect of AT was not obvious, and it began to diminish 3 months after the completion of treatment. AT may positively control pain intensity for patients with chronic pain. However, due to the significant heterogeneity and methodological flaws identified in the analyzed trials, the current evidence on AT for chronic pain management is still uncertain. More rigorously designed large-scale randomized controlled trials are required to evaluate the efficacy of AT for patients with chronic pain.


The effects of length and sequence of gRNA on Cas13b and Cas13d activity in vitro and in vivo.
Cas13 are the only CRISPR/Cas systems found so far, which target RNA strand while preserving chromosomal integrity. Cas13b or Cas13d cleaves RNA by the crRNA guidance. However, the effect of the characteristics of the spacer sequences, such as the length and sequence preference, on the activity of Cas13b and Cas13d remains unclear. Our study shows that neither Cas13b nor Cas13d has a particular preference for the sequence composition of gRNA, including the sequence of crRNA and its flanking sites on target RNA. However, the crRNA, complementary to the middle part of the target RNA, seems to show higher cleavage efficiency for both Cas13b and Cas13d. As for the length of crRNAs, the most appropriate crRNA length for Cas13b is 22-25 nt and crRNA as short as 15 nt is still functional. Whereas, Cas13d requires longer crRNA, and 22-30 nt crRNA can achieve good effect. Both Cas13b and Cas13d show the ability to process precursor crRNAs. Our study suggests that Cas13b may have a stronger precursor processing ability than Cas13d. There are few in vivo studies on the application of Cas13b or Cas13d in mammals. With the methods of transgenic mice and hydrodynamic injection via tail vein, our study showed that both of them had high knock-down efficiency against target RNA in vivo. These results indicate that Cas13b and Cas13d have great potential for in vivo RNA operation and disease treatment without damaging genomic DNA.


Critical role of HIF-1alpha in keratinocyte defense against bacterial infection.
Skin, the first barrier against invading microorganisms, is hypoxic, even under baseline conditions. The transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha, the principal regulator of cellular adaptation to low oxygen, is strongly expressed in skin epithelium. HIF-1alpha is now understood to play a key role in the bactericidal capacity of phagocytic cells such as macrophages and neutrophils. In the skin, keratinocytes provide a direct antibacterial activity through production of antimicrobial peptides, including cathelicidin. Here, we generate mice with a keratinocyte-specific deletion of HIF-1alpha and examine effects on intrinsic skin immunity. Keratinocyte HIF-1alpha is seen to provide protection against necrotic skin lesions produced by the pathogen group A Streptococcus. RNA interference studies reveal that HIF-1alpha regulation of keratinocyte cathelicidin production is critical to their antibacterial function.


A novel serine/threonine protein kinase homologue of Pseudomonas aeruginosa is specifically inducible within the host infection site and is required for full virulence in neutropenic mice.
A genetic locus of Pseudomonas aeruginosa was identified that is highly and specifically inducible during infection of neutropenic mice. This locus, ppkA, encodes a protein that is highly homologous to eukaryote-type serine/threonine protein kinases. A ppkA null mutant strain shows reduced virulence in neutropenic mice compared to the wild type. Overexpression of the PpkA protein greatly inhibited the growth of Escherichia coli or P. aeruginosa. However, a single amino acid change at the catalytic site of the kinase domain eliminated the toxic effect of PpkA on bacterial cells, suggesting that the kinase domain of PpkA is functional within bacterial cells.


Mechanisms of fatigue-induced activation of group IV muscle afferents: the roles played by lactic acid and inflammatory mediators.
We already showed that group IV muscle afferents are activated during electrically-induced fatigue. The purpose of this study is to identify the mechanisms of stimulation of these muscle afferents by electrically-induced fatigue at a high (100 Hz; high frequency fatigue, HFF) or a low rate (10 Hz; low frequency fatigue, LFF) of stimulation. In 23 paralyzed and anaesthetized rabbits, group IV afferent activity from the tibialis anterior muscle was recorded before and after 3-min HFF or 5-min LFF runs eliciting the same force failure. Plasma lactic acid concentration (LA) was also measured in leg venous blood. We tested the effects of dichloroacetate (DCA), which reduces lactic acid production, and of acetylsalicylic acid (ASA), a blocker of cyclooxygenase, on fatigue-induced activation of group IV muscle afferents after HFF and LFF trials. Pretreatment by ASA or DCA did not modify HFF-induced activation of muscle afferents. On the other hand, LFF-induced response was markedly depressed by each pharmacological agent (-44% after ASA and -75% after DCA). We verified that DCA markedly lowered LA production after LFF. The present results show that the activation of group IV muscle afferents by LFF or HFF results from different mechanisms and also demonstrate the major role played by lactic acid production and, to a lesser extent, the release of inflammatory mediators in LFF-induced activation of group IV muscle afferents.